Dr. Shen's Rhubarb by Shen Herbal Products

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there has been interest in using oral bitter orange for allergic rhinitis, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Androgenic alopecia. Although there has been interest in using topical bitter orange for androgenic alopecia, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Anxiety. It is unclear if oral bitter orange or aromatherapy with bitter orange is beneficial in patients with anxiety. Details: Aromatherapy with bitter orange has been evaluated for anxiety in hospitalized or recently hospitalized patients. A clinical study in conscious patients admitted to the intensive care unit shows that inhaling bitter orange as aromatherapy for 30 minutes is associated with lower anxiety scores immediately and 3 hours after the intervention, but not at 1 hour after, when compared with placebo. It is unclear if the improvement from baseline differed between groups; baseline anxiety scores were significantly higher in the placebo group (108752). Another clinical study in adults with acute coronary syndrome shows that aromatherapy with bitter orange essential oil 30% for the 2 days immediately after hospitalization improves anxiety scores by 19%, compared with a 6% improvement in those inhaling placebo (101710). Oral bitter orange has also been evaluated in patients with anxiety. A small clinical study in postmenopausal adults with moderate anxiety shows that taking dried bitter orange flower powder 500 mg orally twice daily for 8 weeks reduces anxiety symptoms by about 4% when compared with placebo, as measured on the State-Trait Anxiety Inventory Scale (97256). However, this improvement is not likely to be considered clinically significant.
• Athletic performance. Several small, short-term clinical studies suggest that oral bitter orange does not improve athletic performance, although some conflicting findings exist. Details: One small clinical study in young males who were former athletes shows that taking 100 mg of p-synephrine from bitter orange extract (Advantra Z, Nutratech Inc.), with or without caffeine 100 mg, daily for 4 days increases the number of total repetitions and volume load by 11% during resistance squat exercise performance when compared with placebo. However, there was no difference in ratings of perceived exertion, and only the p-synephrine plus caffeine group showed an increase in mean power and velocity measures (95683). Other small studies have failed to show a benefit, with or without caffeine. One small study of physically active males with habitual caffeine use shows that taking caffeine 100 mg and bitter orange 100 mg once before exercise does not affect peak power, mean power, total work, or perceived effort or fatigue when compared with placebo (101709). Another small clinical study shows that taking p-synephrine (Synephrine HCL 99%, Nutrition Power) 3 mg/kg orally 60 minutes before exercise does not improve jump tests, 60-meter sprints, or 100-meter sprints in healthy sprint athletes (95655). A small clinical study shows that taking a specific caffeine-containing pre-workout supplement (Cellucor C4 Pre-Workout, Nutrabolt) along with bitter orange extract (Nutratech Inc.) as a single dose 30 minutes before exercise does not improve athletic performance during anaerobic cycling or leg and bench press exercises (95657). Also, taking this combination daily for 8 weeks does not improve strength or body composition when compared with placebo (95656).
• Cancer. Although there has been interest in using oral bitter orange to prevent cancer, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Chronic kidney disease (CKD). Although there has been interest in using oral bitter orange for CKD and other kidney and bladder conditions, there is insufficient reliable information about the clinical effects of bitter orange for these conditions.
• Conjunctivitis. Although there has been interest in using topical bitter orange for conjunctivitis, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Constipation. Although there has been interest in using oral bitter orange for constipation, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Diabetes. Oral bitter orange has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in patients with type 2 diabetes shows that drinking a tea made from the leaves of Indian snakeroot and the fruit of bitter orange for 4 months decreases fasting and postprandial glucose levels and glycated hemoglobin (HbA1c) levels when compared with placebo (35751). However, it is unclear if these effects are due to bitter orange, Indian snakeroot, or the combination.
• Diarrhea. Although there has been interest in using oral bitter orange for diarrhea, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Dyspepsia. It is unclear if oral bitter orange is beneficial in patients with dyspepsia. Details: One small clinical trial in patients with functional dyspepsia shows that taking a specific product containing bitter orange in combination with other ingredients (Zhizhu) three times daily for 4 weeks improves symptoms of functional dyspepsia in 67% of patients, compared with 45% of patients taking a similar product containing sweet orange instead of bitter orange (35757).
• Fatigue. Although there has been interest in using oral bitter orange for fatigue, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Flatulence. Although there has been interest in using oral bitter orange for flatulence, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Frostbite. Although there has been interest in using oral bitter orange to prevent frostbite, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Gallbladder disease. Although there has been interest in using oral bitter orange for gallbladder disease, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Headache. Although there has been interest in using topical bitter orange for headache, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Hyperlipidemia. Although there has been interest in using oral bitter orange for hyperlipidemia, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Insomnia. It is unclear if using bitter orange aromatherapy for sleep disturbances is beneficial in postmenopausal or pregnant adults. Details: A small clinical study in postmenopausal adults with sleep disturbances shows that inhaling essential oil of bitter orange 10% as aromatherapy for 5 minutes twice daily for 4 consecutive days each week for 4 weeks does not improve sleep quality when compared with odorless sweet almond oil (108642). Other clinical research in pregnant adults with sleep disturbances shows that inhaling bitter orange essential oil as aromatherapy for 20 minutes twice daily for 1 month improves sleep scores, including sleep duration, latency, and efficiency, when compared with sweet almond oil (110043).
• Obesity. It is unclear if oral bitter orange, or its constituent p-synephrine, is beneficial for obesity. Details: A meta-analysis of clinical trials in adults with or without obesity shows that taking p-synephrine, a constituent of bitter orange, 6-214 mg orally daily for up to 8 weeks does not reduce body weight or fat mass, or alter blood glucose levels, when compared with placebo (109950). Bitter orange has also been studied in combination with other ingredients. One small clinical trial in overweight adults shows that taking a combination of bitter orange 975 mg, caffeine 528 mg, and St. John's wort 900 mg daily along with calorie restriction and exercise reduces body weight when compared with caloric restriction and exercise alone (11268). Another small clinical study in overweight adults shows that taking a specific combination product (Prograde Metabolism, Prograde Nutrition) containing bitter orange, raspberry ketone, caffeine, capsaicin, garlic, ginger, black pepper, cayenne pepper, and chromium along with diet and exercise for 8 weeks reduces body weight, fat mass, and hip and waist girth and increases lean body mass and energy levels when compared with placebo (91291). However, a small clinical trial in overweight and obese adults shows that taking a different combination product (Charge, Labrada), containing bitter orange 150 mg, providing 9 mg synephrine, plus caffeine and several other ingredients twice daily for 8 weeks does not reduce body weight (15381). The effects of bitter orange alone on body weight are unclear.
• Pain (acute). It is unclear if aromatherapy with bitter orange essential oil is beneficial in hospitalized patients with pain. Details: One small clinical trial in conscious patients in intensive care units shows that aromatherapy with bitter orange essential oil for 30 minutes does not reduce pain when compared with placebo (104187).
• Peptic ulcers. Although there has been interest in using oral bitter orange for peptic ulcers, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Premenstrual syndrome (PMS). It is unclear if aromatherapy with bitter orange essential oil is beneficial in patients with PMS. Details: One small clinical trial in healthy female students with PMS shows that inhaling bitter orange blossom 0.5% essential oil as aromatherapy for 5 minutes twice daily for 5 days, starting about one week before menstruation and repeating for two menstrual cycles, improves psychological but not physical symptoms of PMS when compared with aromatherapy with odorless sweet almond oil (98331).
• Pre-procedural anxiety. It is unclear if oral bitter orange or aromatherapy with bitter orange is beneficial for reducing anxiety before surgery. Details: One small clinical study in patients undergoing minor operations shows that taking bitter orange blossom distillate 1 mL/kg two hours prior to surgery reduces preoperative anxiety when compared to baseline. No significant improvements in anxiety were reported in patients taking placebo before surgery (35759). Another small clinical study in patients undergoing coronary angiography shows that inhaling bitter orange essential oil for 15-20 minutes about one hour prior to the procedure reduces anxiety when compared with placebo (104186).
• Pressure ulcers. Although there has been interest in using topical bitter orange for pressure ulcers, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Rheumatoid arthritis (RA). Although there has been interest in using topical bitter orange for RA, there is insufficient reliable information about the clinical effects of bitter orange for this condition.
• Rhinosinusitis. Although there has been interest in using oral bitter orange for rhinosinusitis, there is insufficient reliable information about the clinical effects of bitter orange for this purpose.
• Sexual dysfunction. It is unclear if topical bitter orange oil is beneficial in postmenopausal adults with sexual dysfunction. Details: Preliminary clinical research in postmenopausal adults with sexual dysfunction shows that inhaling bitter orange essential oil 10% as aromatherapy for 5 minutes twice daily, 4 days per week for 4 weeks, improves sexual dysfunction scores by 58% when compared with almond oil. Patients reported improvements in the domains of desire, arousal, lubrication, orgasm, pain, and satisfaction (110042).
• Tinea corporis. It is unclear if topical bitter orange oil is beneficial in patients with tinea corporis. Details: In one small clinical study of patients with either tinea corporis, tina cruris, or tinea pedis, 80% of patients applying a bitter orange oil 25% emulsion three times daily experienced a cure within 1-2 weeks, and 20% experienced a cure within 2-3 weeks. For those applying a solution of bitter orange oil 20% in alcohol, 50% experienced a cure in 1-2 weeks, 30% in 2-3 weeks, and 20% in 3-4 weeks (6972). The validity of these findings is limited by the lack of a comparator group.
• Tinea cruris. It is unclear if topical bitter orange oil is beneficial in patients with tinea cruris. Details: In one small clinical study of patients with either tinea corporis, tina cruris, or tinea pedis, 80% of patients applying a bitter orange oil 25% emulsion three times daily experienced cure within 1-2 weeks, and 20% experienced a cure within 2-3 weeks. For those applying a solution of bitter orange oil 20% in alcohol, 50% experienced a cure in 1-2 weeks, 30% in 2-3 weeks, and 20% in 3-4 weeks (6972). The validity of these findings is limited by the lack of a comparator group.
• Tinea pedis. It is unclear if topical bitter orange oil is beneficial in patients with tinea pedis. Details: In one small clinical study of patients with either tinea corporis, tina cruris, or tinea pedis, 80% of patients applying a bitter orange oil 25% emulsion three times daily experienced cure within 1-2 weeks, and 20% experienced a cure within 2-3 weeks. For those applying a solution of bitter orange oil 20% in alcohol, 50% experienced a cure in 1-2 weeks, 30% in 2-3 weeks, and 20% in 3-4 weeks (6972). The validity of these findings is limited by the lack of a comparator group. More evidence is needed to rate bitter orange for these uses.

(Read more about BITTER ORANGE)

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)

POSSIBLY EFFECTIVE

• Chronic kidney disease (CKD). Oral rehmannia acteosides might reduce proteinuria when used in conjunction with angiotensin II receptor blockers in patients with CKD. Details: A large clinical trial in adults with chronic glomerulonephritis shows that taking rehmannia acteosides extract 400 mg twice daily, in conjunction with irbesartan 150 mg daily, for 8 weeks decreases proteinuria by 36%, compared with a reduction of 28% with irbesartan alone (93662).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aplastic anemia. It is unclear if oral rehmannia is beneficial in patients with aplastic anemia. Details: A small clinical study in adults with aplastic anemia shows that taking rehmannia polysaccharide (dose unknown), in conjunction with stanozolol, increases the incidence of symptom remission by 45% when compared with stanozolol alone (70704).
• Atopic disease. Although there has been interest in using oral rehmannia for atopic disease, there is insufficient reliable information about the clinical effects of rehmannia for this purpose.
• Diabetes. Although there has been interest in using oral rehmannia for diabetes, there is insufficient reliable information about the clinical effects of rehmannia for this purpose.
• Diabetic nephropathy. Oral rehmannia has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large clinical study in adults with chronic kidney disease due to type 2 diabetes receiving standard care with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker shows that taking a specific combination product (Rehmannia-6, PuraPharm) containing rehmannia, Japanese cornel dogwood, wild yam, poria mushroom, Asian water plantain, and peony root bark twice daily for 48 weeks modestly slows the decline in kidney function when compared with standard care alone (112821). It is unclear if this effect is due to rehmannia, other ingredients, or the combination.
• Metabolic syndrome. Although there has been interest in using oral rehmannia for metabolic syndrome, there is insufficient reliable information about the clinical effects of rehmannia for this purpose.
• Obesity. It is unclear if oral rehmannia root extract is beneficial in patients with obesity. Details: A very small clinical study in females with obesity shows that taking steamed rehmannia root extract 4 grams twice daily for 8 weeks decreases waist circumference by 2.6%, but does not affect body weight or body fat percentage, when compared to baseline (93660). The validity of these findings is limited by the lack of a control group.
• Osteoporosis. Although there has been interest in using oral rehmannia for osteoporosis, there is insufficient reliable information about the clinical effects of rehmannia for this purpose.
• Rheumatoid arthritis (RA). Although there has been interest in using oral rehmannia for RA, there is insufficient reliable information about the clinical effects of rehmannia for this purpose. More evidence is needed to rate rehmannia for these uses.

(Read more about REHMANNIA)

POSSIBLY EFFECTIVE

• Menopausal symptoms. Oral rhubarb root extract seems to help improve symptoms of menopause. Details: Clinical research in perimenopausal and postmenopausal patients shows that taking a specific dry extract of rhubarb root (ERr 731, Estroease, Lupin Pharmaceuticals) 4 mg orally daily for 3-27 months improves symptoms of menopause by 46% to 83% compared to an improvement of less than 20% with placebo. About 83% of females taking the rhubarb extract report overall clinical improvement, with specific improvements in anxiety, hot flushes, sweating, sleep, mood, quality of life, fatigue, sexual problems, urinary tract problems, vaginal dryness, and joint and muscle issues (92294,92295,92296,92297,92298,108960).
• Pancreatitis. Oral or rectal rhubarb might improve symptoms and duration of hospital stay in individuals with acute pancreatitis. It is unclear if oral rhubarb helps to prevent pancreatitis in individuals undergoing endoscopic retrograde cholangiopancreatography (ERCP). Details: Meta-analyses of clinical research in adults with acute pancreatitis in China shows that administering rhubarb 10-90 grams daily via gastric tube or rectal enema for 3-14 days, in combination with somatostatin, octreotide, or ulinastatin, reduces the risk for complications such as sepsis or kidney failure by 45%, duration of abdominal pain by 1.3-2 days, and duration of hospital stay by 6.7-6.9 days when compared with taking these medications alone (97922,100964). However, the included studies were of low methodological quality. Additionally, somatostatin and octreotide are not recommended for the treatment of acute pancreatitis by the American College of Gastroenterology or the American Gastroenterological Association (101001,100965). A separate meta-analysis and individual clinical studies show that administering rhubarb 6-20 grams 1-3 times daily for 5-14 days, usually via nasojejunal tube with early enteral nutrition, reduces the duration of hospital stay and improves abdominal symptoms when compared with enteral nutrition alone (92301,103475). The meta-analysis shows that administering rhubarb reduces hospital stay by 4.5 days and intensive care unit stay by 2.8 days. The use of rhubarb also reduced the duration of severe abdominal pain, abdominal distention, and abnormal bowel sounds by 1-2 days. However, there was no effect on mortality rate, infection rate, or the incidence of multiple organ dysfunction (103475). Rhubarb has also been studied for the prevention of pancreatitis in patients undergoing a specific procedure called endoscopic retrograde cholangiopancreatography (ERCP). Preliminary clinical research in patients at high risk for post-ERCP complications shows that drinking a raw rhubarb solution after the procedure reduces the incidence of post-ERCP pancreatitis by 74% and post-ERCP hyperamylasemia by 81% when compared to standard care. However, this study was of low methodological quality, and the rhubarb solution preparation and dose were not reported (97920).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acute respiratory distress syndrome (ARDS). It is unclear if oral rhubarb reduces ARDS. Details: A small clinical study in patients with ARDS shows that administering rhubarb leachate 10 grams in 30 mL water via nasogastric tube three times daily for 7 days, in addition to standard treatment, modestly improves oxygenation and reduces indices of pulmonary vascular permeability when compared with standard treatment (97921).
• Appendicitis. Oral rhubarb has only been evaluated in combination with other ingredients for use in pediatric appendiceal abscess; its effect when used alone is unclear. Details: A large observational study in children 3-14 years old with appendiceal abscess also receiving intravenous antibiotics suggests that taking a rhubarb peony decoction twice daily for 7-14 days is associated with a higher clinical cure rate of 93% when compared with 81% in the control group, but does not improve length of stay, post-operative complications, or recurrence rate (112380). However, it is unclear if the effects are from rhubarb, other ingredients, or the combination.
• Canker sores. Topical rhubarb has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small open-label clinical study in adults with mild canker sores shows that topical application of a specific combination product (Pyralvex Soluté, Laboratoires Norgine Pharma) containing rhubarb extract 5% and salicylic acid reduces the time to symptom resolution by about 3 days when compared to using a water control (97919).
• Chronic kidney disease (CKD). It is unclear if oral rhubarb prevents the progression of CKD or improves markers of kidney function. Details: A meta-analysis of results from two low-quality clinical studies shows that taking rhubarb 1-7.7 grams daily for up to 48 months as part of traditional Chinese medicine does not delay the onset of kidney failure when compared with standard treatment (92302). However, these results were calculated using regression analysis rather than long-term follow-up, which limits the validity of these findings. Another meta-analysis of clinical research shows that rhubarb may improve serum creatinine and blood urea nitrogen in patients with CKD when compared with no treatment (92302). However, rhubarb does not appear to improve blood urea nitrogen when compared with captopril (71329). The validity of the research to date is limited by the low to very low methodological quality of the studies and the high risk of bias. Additionally, all of the studies were conducted in China; it is unclear if these findings are applicable to other populations.
• Constipation. It is unclear if rhubarb is beneficial for constipation. Details: A small clinical study in middle-aged adults with constipation shows that taking rhubarb extract 12.5 mg or 25 mg based on rhein content (Gutisrheum, Laboratories Ortis) at bedtime for 1 month improves stool frequency and consistency when compared with placebo (112381). The validity of these findings is limited by patient-reported outcomes. A clinical study in patients with chronic constipation, defined as having a bowel movement no more than twice per week, shows that a specific combination product (Nucarb; Wilshire Laboratories Ltd) containing rhubarb extract 250 mg, activated charcoal 180 mg, calcium sennosides 50 mg, peppermint oil 0.5 mg, fennel oil 0.5 mg, and sulfur 50 mg, taken as two tablets at bedtime for one week, followed by 1 tablet at bedtime for 1 week, reduces passing gas, abdominal pain, and sensation of bloating by 81%, 73%, and 72% respectively, when compared with baseline. Sensation of straining, severity of constipation, and feeling of incomplete evacuation were reduced by 69%, 67%, and 54% respectively, when compared with baseline (108853). The validity of these findings is limited by the lack of a comparator group, and it is unclear whether the effects are due to rhubarb, the combination, or other ingredients.
• Dysmenorrhea. It is unclear if oral rhubarb reduces dysmenorrhea. Details: Preliminary clinical research in young adults with dysmenorrhea shows that taking rhubarb root and rhizome powder 2520 mg daily, beginning 2 days before menstruation and continuing for 5 days, repeated for three consecutive cycles, has similar efficacy to mefenamic acid 500 mg three times daily in reducing pain and improving quality of life. Those receiving either treatment experienced an overall improvement of greater than 80%, which is attributed to a reduction in pain, fatigue, headache, and gastrointestinal symptoms (92300).
• Gastrointestinal bleeding. It is unclear if spraying rhubarb powder with a gastroscope reduces gastrointestinal bleeding. Details: In patients with acute gastrointestinal bleeding, a meta-analysis of mainly preliminary clinical research shows that spraying rhubarb powder under a gastroscope has a small to moderate hemostatic effect over 24-72 hours when compared with norepinephrine. The risk of re-bleeding over 48 hours was also reduced by about 58% (103474).
• Herpes labialis (cold sores). Topical rhubarb has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that applying a cream containing rhubarb and sage to cold sores is similarly effective to acyclovir (Zovirax) cream. Acyclovir cream heals lesions in about 6.3 days; the rhubarb and sage cream heals lesions in about 7.2 days (10437). It is not clear if these improvements are due to the treatments used or to the natural resolution of the cold sores. Additionally, it is unclear if the benefit is due to rhubarb, other ingredients, or the combination.
• Hypercholesterolemia. It is unclear if oral rhubarb helps to lower cholesterol levels. Details: A very small clinical study including 10 males with hypercholesterolemia shows that eating ground rhubarb stalk fiber 27 grams daily for 4 weeks reduces total cholesterol by 8% and low-density lipoprotein (LDL) cholesterol by 9%, but does not affect high-density lipoprotein (HDL) cholesterol levels, when compared to baseline (71363). The validity of these findings is limited by the very small study size and the lack of a comparator group.
• Malignant pleural effusions. Topical rhubarb powder has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients living in China with advanced malignant cancer and malignant pleural effusions shows that applying a combination product (Hehuang Company) containing rhubarb powder 100 grams and mirabilite 400 grams to the chest wall for 8 hours daily for 28 days as an adjunct to standard therapy leads to partial or complete reduction of effusion in 67% of participants, compared with 55% of those receiving placebo and standard therapy (105961).
• Nasopharyngeal cancer. Oral rhubarb has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with nasopharyngeal carcinoma shows that taking a specific combination product (Shenlong) containing rhubarb and other herbs along with radiation therapy does not improve tumor remission or survival when compared to radiation therapy alone (71380).
• Nonalcoholic fatty liver disease (NAFLD). Oral rhubarb has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with NAFLD shows that taking 3-5 tablets of a specific Chinese herbal medicine (Danning Pian) containing rhubarb, giant knotweed, dried green orange peel, and dried ripe orange peel three times daily for 3 month improves lipids, liver function, and clinical symptoms (71315). It is not clear if this effect is due to rhubarb, the other ingredients, or the combination.
• Obesity. It is unclear if oral rhubarb is beneficial for weight loss. Details: A small clinical study in overweight and obese females shows that taking rhubarb with ginger, astragalus, red sage, and turmeric does not reduce body weight when compared with placebo (20346).
• Organophosphorus pesticide poisoning. It is unclear if giving rhubarb by gastric tube, nasal feeding, or enema is beneficial for organophosphorus pesticide poisoning. Details: A meta-analysis of low-quality clinical research in patients with acute organophosphorus pesticide poisoning shows that taking crude rhubarb 9-120 grams daily via gastric tube, nasal feeding, or retention enema, in conjunction with standard treatment, decreases the incidence of intermediate syndrome by 78% and organ dysfunction syndrome by 66% when compared to standard treatment alone. Rhubarb also reduces the duration of hospital stay by 2.8 days, but with no change in mortality rate, when compared to standard treatment alone. Standard treatment in these studies included atropine, pralidoxime, ventilation, diuresis, other supportive measures, and/or mannitol (92303).
• Sepsis. It is unclear if oral rhubarb is beneficial for sepsis. Details: A meta-analysis of low-quality clinical research in patients with sepsis or systemic inflammatory response syndrome (SIRS) shows that taking rhubarb powder in conjunction with conventional therapy reduces the incidence of gastrointestinal dysfunction, but does not reduce mortality rate, when compared to conventional therapy alone (92305).
• Stroke. Oral rhubarb has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of clinical research in patients with acute ischemic stroke shows that taking traditional Chinese medicine containing rhubarb root and rhizome in conjunction with traditional Western medicine for up to 30 days enhances overall clinical improvement by 27% when compared with traditional Western medicine alone. However, the validity of this outcome is limited by small sample size, the variability in the Chinese medicine formulas used, and the high risk for bias of the included studies (92299). More evidence is needed to rate rhubarb for these uses.

(Read more about RHUBARB)

LIKELY SAFE ...when used orally in amounts commonly found in foods. Bitter orange has Generally Recognized as Safe (GRAS) status in the US (4912,35751).

POSSIBLY SAFE ...when bitter orange essential oil is used topically or by inhalation as aromatherapy (6972,7107,98331,104186,104187,108642).

POSSIBLY UNSAFE ...when used orally for medicinal purposes. Although single doses of synephrine, or low daily doses used short-term, may be safe in healthy adults (2040,11269,15381,35757,35759,91681,97256,98332), laboratory analyses raise concerns that many marketed bitter orange products contain higher amounts of synephrine and other natural and synthetic amines than on the label, increasing the risk for serious stimulant-related adverse effects (104185). Additionally, there is a lack of agreement regarding a safe daily dose of synephrine. Health Canada has approved 50 mg of p-synephrine daily when used alone, or 40 mg of p-synephrine in combination with up to 320 mg of caffeine daily in healthy adults (91684). The Federal Institute for Risk Assessment in Germany recommends that supplements should provide no more than 6.7 mg of synephrine daily. This recommendation is meant to ensure that patients who frequently consume synephrine in conventional foods will receive no more than 25.7 mg daily (91290). These limits are intended to reduce the risk for serious adverse effects. There have been several case reports of ischemic stroke and cardiotoxicity including tachyarrhythmia, cardiac arrest, syncope, angina, myocardial infarction, ventricular arrhythmia, and death in otherwise healthy patients who have taken bitter orange extract alone or in combination with other stimulants such as caffeine (2040,6979,12030,13039,13067,14326,14342,91680).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in the amounts found in foods. Bitter orange has Generally Recognized as Safe (GRAS) status in the US (4912).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally for medicinal purposes. There are case reports of cardiotoxicity including tachyarrhythmia, syncope, and myocardial infarction in otherwise healthy adults who have taken bitter orange extract alone or in combination with other stimulants such as caffeine (2040,6979,12030,13039,13067,14326,14342,91680). The effects of bitter orange during lactation are unknown; avoid use.

(Read more about BITTER ORANGE)

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.

(Read more about DONG QUAI)

POSSIBLY SAFE ...when used orally and appropriately, short term. Rehmannia root extract 4 grams daily or rehmannia leaf extract 800 mg daily has been used with apparent safety for 8 weeks in clinical studies (93660,93662).

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

(Read more about REHMANNIA)

LIKELY SAFE ...when the stalk is used in amounts commonly found in foods and when the root is used as a food flavoring. Rhubarb has Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when the root or rhizome is used orally and appropriately in medicinal amounts for up to 2 years (92294,92295,92297). ...when the stalk is used orally and appropriately in medicinal amounts for up to 4 weeks (71351,71363,97920). ...when used topically and appropriately (10437,97919).

POSSIBLY UNSAFE ...when the leaf is used orally. Rhubarb leaf contains oxalic acid and soluble oxalate, which can cause abdominal pain, burning of the mouth and throat, diarrhea, nausea, vomiting, seizures, and death (17).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used in medicinal amounts, rhubarb root is a stimulant laxative; avoid using (12).

(Read more about RHUBARB)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, bitter orange might increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Some clinical research shows that drinking a tea containing bitter orange and Indian snakeroot reduces fasting and postprandial glucose levels in patients with type 2 diabetes who are using antidiabetes drugs (35751). However, it is unclear if these effects are due to bitter orange, Indian snakeroot, or the combination. An animal study also shows that p-synephrine in combination with gliclazide , a sulfonylurea, causes an additional 20% to 44% decrease in glucose levels when compared with gliclazide alone (95658).

CAFFEINE Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Bitter orange might increase blood pressure and heart rate when taken with caffeine.  Details Small clinical studies show that taking bitter orange in combination with caffeine can increase blood pressure and heart rate in otherwise healthy normotensive adults (13657,95659). Theoretically, this might increase the risk of serious cardiovascular adverse effects.

COLCHICINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Bitter orange might affect colchicine levels.  Details Colchicine is a substrate of P-glycoprotein and cytochrome P450 3A4 (CYP3A4). Bitter orange has been reported to inhibit CYP3A4 and increase levels of CYP3A4 substrates (7029,11362,93470). However, one small clinical study in healthy adults shows that drinking bitter orange juice 240 mL twice daily for 4 days and taking a single dose of colchicine 0.6 mg on the 4th day decreases colchicine peak serum levels by 24%, time to peak serum level by 1 hour, and overall exposure to colchicine by 20% (35762). The clinical significance of this finding is unclear.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, bitter orange might increase levels of drug metabolized by CYP2D6.  Details In vitro research shows that octopamine, a constituent of bitter orange, weakly inhibits CYP2D6 enzymes (91878). This effect has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Bitter orange might increase levels of drugs metabolized by CYP3A4.  Details Small clinical studies suggest that single or multiple doses of freshly squeezed bitter orange juice 200-240 mL can inhibit CYP3A4 metabolism of drugs (7029,11362,93470), causing increased drug levels and potentially increasing the risk of adverse effects. However, the extent of the effect of bitter orange on CYP3A4-mediated drug interactions is unknown. Some evidence suggests that bitter orange selectively inhibits intestinal CYP3A4, but not hepatic CYP3A4. Its effect on P-glycoprotein, which strongly overlaps with CYP3A4 interactions, is unclear (7029,11269,11270,11362). One small clinical study shows that drinking 8 ounces of freshly squeezed bitter orange juice has no effect on cyclosporine, which seems to be more dependent on hepatic CYP3A4 and P-glycoprotein than intestinal CYP3A4 (11270).

DEXTROMETHORPHAN (Robitussin DM, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Bitter orange might increase blood levels of dextromethorphan.  Details One small clinical study shows that bitter orange juice increases dextromethorphan levels, likely through cytochrome P450 3A4 (CYP3A4) inhibition (11362). Theoretically, bitter orange might increase the risk for dextromethorphan-related adverse effects.

FELODIPINE (Plendil) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Bitter orange might increase blood levels of felodipine.  Details One small clinical study shows that bitter orange juice increases felodipine levels, likely through cytochrome P450 3A4 (CYP3A4) inhibition (7029). Theoretically, bitter orange might increase the risk for felodipine-related adverse effects.

INDINAVIR (Crixivan) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Bitter orange might increase blood levels of indinavir.  Details One small clinical study shows that bitter orange juice slightly increases indinavir levels, but this effect is likely to be clinically insignificant. Bitter orange selectively inhibits intestinal cytochrome P450 3A4 (CYP3A4); however, the metabolism of indinavir seems to be more dependent on hepatic CYP3A4 (11269). The effect of bitter orange on other protease inhibitors has not been studied.

MIDAZOLAM (Versed) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Bitter orange might increase blood levels of midazolam.  Details One small clinical study shows that bitter orange juice can increase midazolam levels, likely through inhibition of cytochrome P450 3A4 (CYP3A4) (7029). Theoretically, bitter orange might increase the risk of midazolam-related adverse effects.

MONOAMINE OXIDASE INHIBITORS (MAOIs) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, taking MAOIs with synephrine-containing bitter orange preparations might increase the hypertensive effects of synephrine, potentially leading to hypertensive crisis.  Details Bitter orange contains tyramine, octopamine, and synephrine, which are MAO substrates (11267,11995,12378).

QT INTERVAL-PROLONGING DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, bitter orange might have an additive effect when combined with drugs that prolong the QT interval, potentially increasing the risk of ventricular arrhythmias.  Details One case report suggests that taking bitter orange in combination with other stimulants such as caffeine might prolong the QT interval in some patients (13039).

SILDENAFIL (Viagra) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Bitter orange juice might increase blood levels of sildenafil.  Details A small clinical study in healthy adult males shows that drinking freshly squeezed bitter orange juice 250 mL daily for 3 days and taking a single dose of sildenafil 50 mg on the 3rd day increases the peak plasma concentration of sildenafil by 18% and the overall exposure to sildenafil by 44%. Theoretically, this may be due to inhibition of cytochrome P450 3A4 by bitter orange (93470).

STIMULANT DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, bitter orange might increase the risk of hypertension and adverse cardiovascular effects when taken with stimulant drugs.  Details Bitter orange appears to have stimulant effects (2040,6979).

(Read more about BITTER ORANGE)

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)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, rehmannia might increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Animal research shows that rehmannia may have hypoglycemic effects (15061,93668).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, rehmannia might increase the risk of hypotension when taken with antihypertensive drugs.  Details Animal research shows that rehmannia may have hypotensive effects. Laboratory research shows that formulations of dried and processed rehmannia root inhibit angiotensin-converting enzyme (ACE) (104272).

(Read more about REHMANNIA)

CORTICOSTEROIDS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, frequent and high doses of rhubarb might increase the risk of hypokalemia when taken with corticosteroids.  Details Rhubarb has stimulant laxative effects. Overuse of rhubarb might compound corticosteroid-induced potassium loss (2,12).

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking rhubarb with cyclosporine might reduce cyclosporine levels.  Details Animal research shows that co-administration of rhubarb decoction 0.25 or 1 gram/kg with cyclosporine 2.5 mg/kg, decreases cyclosporine maximum plasma concentration and overall exposure levels when compared with taking cyclosporine alone. The authors theorize that rhubarb might reduce cyclosporine bioavailability by inducing of P-glycoprotein and/or cytochrome P450 3A4 (92304). However, since rhubarb was administered as a single oral dose and enzyme induction usually occurs after multiple doses, it is possible that cyclosporine absorption was actually reduced via rhubarb's stimulant laxative effects (12). Also, the composition of the rhubarb decoction was not described.

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, overuse of rhubarb might increase the risk of adverse effects when taken with digoxin.  Details Rhubarb has stimulant laxative effects. Overuse of rhubarb might cause potassium depletion, increasing the risk of digoxin toxicity (12,19).

DIURETIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, frequent and high doses of rhubarb might increase the risk of hypokalemia.  Details Rhubarb has stimulant laxative effects. Overuse of rhubarb might cause potassium depletion and compound diuretic-induced potassium loss (12,19).

HEPATOTOXIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of rhubarb with potentially hepatotoxic drugs might increase the risk of developing liver damage.  Details Some animal research suggests that anthraquinones in rhubarb might have hepatotoxic effects (105960). Also, rhubarb use has been linked to at least 24 cases of liver injury, although details on the dose of rhubarb and duration of use in these cases is unclear (100963).

NEPHROTOXIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, long-term use of anthraquinones from rhubarb might increase the risk of nephrotoxicity when used with nephrotoxic drugs.  Details The anthraquinone constituents of rhubarb have been shown to induce nephrotoxicity in animal research (71322). Additionally, in a case report, a 23-year old female presented with kidney failure after taking 6 tablets of a proprietary slimming agent (found to contain the anthraquinones emodin and aloe-emodin from rhubarb) daily for 6 weeks and then adding diclofenac 25 mg 4 times daily for 2 days. The authors postulate that the anthraquinone constituents of rhubarb contributed to the renal dysfunction, and the addition of diclofenac, a nephrotoxic drug, led to renal failure (15257). Until more is known, advise patients to avoid taking rhubarb if they are taking other potentially nephrotoxic drugs.

STIMULANT LAXATIVES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, rhubarb might increase the risk for fluid and electrolyte loss when taken with other stimulant laxatives.  Details Rhubarb has stimulant laxative effects (12). Concomitant use with stimulant laxatives might compound fluid and electrolyte loss (24427).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, excessive use of rhubarb might increase the risk of bleeding when taken with warfarin.  Details Rhubarb has stimulant laxative effects and can cause diarrhea (12,19). Diarrhea can increase the effects of warfarin, increase international normalized ratio (INR), and increase the risk of bleeding. Advise patients who take warfarin not to take excessive amounts of rhubarb.

(Read more about RHUBARB)

General ...Orally, bitter orange might be unsafe when used in medicinal amounts. Topically and when inhaled as aromatherapy, bitter orange seems to be well tolerated.
Most Common Adverse Effects:
Orally: Hypertension and tachycardia, particularly when used in combination with caffeine and/or other stimulant ingredients.
Topically: Skin irritation.
Serious Adverse Effects (Rare):
Orally: Myocardial infarction, QT prolongation, seizures, stroke, syncope, tachyarrhythmia, and ventricular fibrillation have been reported in patients taking bitter orange in combination with other ingredients. It is unclear if these effects are due to bitter orange, other ingredients, or the combination.

Cardiovascular ...Bitter orange, which contains adrenergic agonists synephrine and octopamine, may cause hypertension and cardiovascular toxicity when taken orally (2040,6969,6979). Studies evaluating the effect of bitter orange on cardiovascular parameters have been mixed. Several studies show that taking bitter orange alone or in combination with caffeine increases blood pressure and heart rate. In one clinical study, bitter orange in combination with caffeine increased systolic and diastolic blood pressure and heart rate in otherwise healthy normotensive adults (13657). In another study, a single dose of bitter orange 900 mg, standardized to 6% synephrine (54 mg), also increased systolic and diastolic blood pressure and heart rate for up to 5 hours in young, healthy adults (13774). Using half that dose of bitter orange and providing half as much synephrine, did not seem to significantly increase blood pressure or QT interval in healthy adults (14311). Increased diastolic, but not systolic, blood pressure or heart rate also occurred in a clinical trial involving a specific supplement containing synephrine 21 mg and caffeine 304 mg (Ripped Fuel Extreme Cut, Twinlab) (35743). Synephrine given intravenously to males increased systolic blood pressure, but lacked an effect on diastolic blood pressure or heart rate (12193).
In clinical research and case reports, tachycardia, tachyarrhythmia, QT prolongation, ischemic stroke, variant angina, and myocardial infarction have occurred with use of bitter orange or synephrine-containing multi-ingredient products (12030,13039,13067,13091,13657,14326,35749,91680). In one case report, a combination product containing bitter orange may have masked bradycardia and hypotension while exacerbating weight loss in a 16 year-old female with an eating disorder taking the product for weight loss (35740). From 1998 to 2004, Health Canada received 16 reports of serious adverse cardiovascular reactions such as tachycardia, cardiac arrest, ventricular fibrillation, blackout, and collapse. In two of these cases, the patient died. In almost all of these cases, bitter orange was combined with another stimulant such as caffeine, ephedrine, or both (14342).
Other research has found no significant effect of bitter orange on blood pressure or heart rate. Several clinical studies have reported that, when taken as a single dose or in divided doses ranging from 20-100 mg for one day, p-synephrine had no significant effect on blood pressure, heart rate, electrocardiogram results or adverse cardiovascular events in healthy adults (35772,91681,91681,95659,101708) Similarly, no difference in blood pressure, heart rate or electrocardiogram results were reported when p-synephrine from bitter orange (Advantra Z/Kinetic; Nutratech/Novel Ingredients Inc.) was taken for 6 weeks in healthy patients (11268). Another clinical study showed no significant effect of bitter orange (Nutratech Inc.), standardized to synephrine 20 mg, on blood pressure or heart rate when taken daily for 8 weeks in healthy males (95656). In other research, changes in blood pressure, heart rate, or QTc interval were lacking when bitter orange was given alone or in combination with caffeine and green tea (14311,35753,35755,35764,35769,35770). In one study of healthy adults, taking a single dose of p-synephrine 103 mg actually reduced mean diastolic blood pressure by 0.4-4 mmHg at 1 and 2 hours after administration when compared with placebo (95659).
A meta-analysis of clinical trials in adults with or without obesity suggests that taking p-synephrine 6-214 mg orally daily does not affect blood pressure or heart rate when used short-term, but modestly increases blood pressure and heart rate when taken for 56-60 days (109950).
The effect of bitter orange on blood pressure, heart rate, and electrocardiogram results in patients with underlying conditions, particularly cardiovascular disease, is unknown and requires further study.

Dermatologic ...Photosensitivity may occur, particularly in fair-skinned people (11909). In a clinical trial, topical application with bitter orange essential oil resulted in irritation (6972).

Endocrine ...Some clinical research shows that taking a specific supplement containing 21 mg of synephrine and 304 mg of caffeine (Ripped Fuel Extreme Cut, Twinlab) increases levels of postprandial glucose (35743). Other preliminary clinical research shows that taking a specific pre-workout supplement (Cellucor C4 Pre-Workout, Nutrabolt) along with a bitter orange extract standardized for synephrine 20 mg (Nutratech Inc.) 30 minutes once before exercise causes a significant 12% increase in glucose (95657); however, there is no difference in blood glucose when compared with placebo when this combination is taken daily for 8 weeks (95656). The effect of bitter orange itself is unclear.

Gastrointestinal ...Bitter orange has been linked to a report of ischemic colitis. In one case, a 52-year-old female developed ischemic colitis after taking a bitter orange-containing supplement (NaturalMax Skinny Fast, Nutraceutical Corporation) for a week. Symptoms resolved within 48 hours after discontinuing the supplement (15186). As this product contains various ingredients, the effect of bitter orange itself is unclear.

Musculoskeletal ...Unsteady gait has been noted in one case report of a patient taking bitter orange (13091). In another case, an otherwise healthy, Black male with sickle cell trait, developed severe rhabdomyolysis following ingestion of a specific weight loss product (Lipo 6, Nutrex Research Inc.), which contained synephrine and caffeine (16054). However, other preliminary clinical research shows that taking a specific pre-workout supplement (Cellucor C4 Pre-Workout, Nutrabolt) along with a bitter orange extract standardized for synephrine 20 mg (Nutratech Inc.), taken 30 minutes once before exercise (95657) or daily for 8 weeks, does not affect creatine kinase or serum creatinine levels when compared with placebo (95656). As these products contain various ingredients, the effect of bitter orange itself is unclear.

Neurologic/CNS ...Dizziness, difficulty in concentrating, memory loss, syncope, seizure, and stroke have been noted in case reports following bitter orange administration (13091,13039). Theoretically, bitter orange may trigger a migraine or cluster headache due to its synephrine and octopamine content (35768). When used as aromatherapy, bitter orange essential oil has also been reported to cause headache in some patients (104187). Sprint athletes taking the bitter orange constituent p-synephrine 3 mg/kg (Synephrine HCL 99%, Nutrition Power) 60 minutes before exercises and sprinting reported more nervousness (mean difference 0.9) when compared with placebo on a Likert scale. Although statistically significant, this difference is not considered clinically significant (95655).

(Read more about BITTER ORANGE)

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).

(Read more about DONG QUAI)

General ...Orally, rehmannia seems to be well tolerated.

(Read more about REHMANNIA)

General ...Orally, rhubarb root and stalk are well tolerated when used in food amounts and seem to be well tolerated when used in medicinal amounts. Rhubarb leaf contains oxalic acid and can be toxic. Topically, rhubarb seems to be well tolerated.
Most Common Adverse Effects:
Orally: Cramps, diarrhea, gastrointestinal discomfort, nausea, vomiting.
Topically: Rash.
Serious Adverse Effects (Rare):
Orally: Anaphylaxis.

Cardiovascular ...Orally, chronic use or abuse of rhubarb can cause arrhythmias (12).

Dermatologic ...Orally, rhubarb taken alone or in combination with other ingredients has been reported to cause rash (71315,71342). Topically, short term application of a specific product (Pyralvex) containing rhubarb, salicylic acid, and ethanol to the gums has been reported to cause slight burning and dark discoloration of the gums in approximately 1% of patients (71369). It is unclear if this effect is due to rhubarb, other ingredients, or the combination.

Endocrine ...Orally, chronic use or abuse of rhubarb can cause electrolyte loss (especially potassium), hyperaldosteronism, albuminuria, and edema (12).

Gastrointestinal ...Orally, rhubarb can cause cramp-like or spasmodic gastrointestinal discomfort, watery diarrhea, and uterine contractions (18). Rhubarb, alone or in combination with other ingredients, has also been reported to cause bloating, nausea, diarrhea, vomiting, and stomach upset or pain in clinical studies. Diarrhea is more common with a starting dose of at least 3 grams of extract (71315,71329,71339,71340,71341,71342,71373,92300). Chronic use or abuse of rhubarb can cause inhibition of gastric motility and pseudomelanosis coli (pigment spots in the intestinal mucosa) (12,6138).
Although some research suggests that rhubarb and other anthranoid laxatives might increase the risk of colorectal cancer due to pseudomelanosis coli (30743), more recent research suggests that this condition is harmless, typically reversed with rhubarb discontinuation, and not associated with an increased risk for colorectal adenoma or carcinoma (6138).

Hematologic ...Orally, chronic use or abuse of rhubarb can cause hematuria (12).

Hepatic ...Orally, chronic use of anthraquinone-containing products, such as rhubarb, has been associated with hepatotoxicity (15257). Use of rhubarb specifically has been linked to at least 24 reports of liver injury, although details on the dose of rhubarb and duration of use in these cases are not clear (100963). In one clinical study, rhubarb, taken in combination with other ingredients, has been reported to cause mild to moderate elevations of serum alanine aminotransferase (71315).

Immunologic ...Orally, rhubarb has rarely been reported to cause anaphylaxis (18).

Musculoskeletal ...Orally, chronic use or abuse of rhubarb can cause accelerated bone deterioration and muscular weakness (12).

Renal ...Orally, chronic use or abuse of rhubarb can cause electrolyte loss (especially potassium), albuminuria, hematuria, dehydration, and nephropathies (12). There is one case report of renal failure in a patient who took a product containing rhubarb for six weeks. The patient presented with renal failure two days after starting diclofenac, which is known to have nephrotoxic effects. It is hypothesized that the combination of diclofenac with the anthraquinone constituents of rhubarb precipitated renal dysfunction (15257).

(Read more about RHUBARB)