Harmonizer Tablet by Classical Remedia Ltd

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there has been interest in using oral Baikal skullcap for allergic rhinitis, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Anxiety. Although there has been interest in using oral Baikal skullcap for anxiety, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Atherosclerosis. Although there has been interest in using oral Baikal skullcap for atherosclerosis, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Attention deficit-hyperactivity disorder (ADHD). Although there has been interest in using oral Baikal skullcap for ADHD, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Bronchiolitis. Intravenous Baikal skullcap has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that a combination of Baikal skullcap, forsythia, and honeysuckle, known as Shuang Huang Lian in traditional Chinese medicine, given intravenously, with or without antibiotics, decreases the duration of cough by about 1.5-2 days, the duration of wheezing by about 2 days, and the duration of hospitalization by about 2-3 days when compared with antibiotics alone in children with respiratory syncytial virus (RSV) infection. Baikal skullcap injection was administered as a 20 mL dose for patients under 6 months, a 40 mL dose for patients 7-36 months, or a 60 mL dose for patients older than 36 months (12613).
• Cancer. Although there has been interest in using oral Baikal skullcap for cancer, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Diabetes. It is unclear if oral Baikal skullcap is beneficial in patients with diabetes. Details: A very small clinical trial in patients with uncontrolled diabetes taking metformin 500 mg daily shows that taking Baikal skullcap extract 3.52 grams in three divided doses daily for 8 weeks does not decrease levels of fasting glucose or insulin or improve levels of glycated hemoglobin (HbA1c) when compared with placebo. However, taking Baikal skullcap reduces blood glucose levels during an oral glucose tolerance test (OGTT) at 60 minutes, but not 120 minutes, when compared with placebo (101738). This study may have been inadequately powered to detect a difference between groups.
• Epilepsy. Although there has been interest in using oral Baikal skullcap for epilepsy, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Hand, foot, and mouth disease. It is unclear if intravenous Baikal skullcap is beneficial in patients with hand, foot, and mouth disease. Details: Low-quality observational research in children hospitalized with severe hand, foot, and mouth disease has found that children who are given Baikal skullcap intravenously as a Tanreqing injection 0.3-0.5 mL/kg once daily have a shorter duration of fever, oral ulcers, and rash, as well as reduced viral load, when compared with those given ribavirin 10 mg/kg once daily (96281). The validity of these findings is limited by the retrospective nature of the study.
• Headache. Although there has been interest in using oral Baikal skullcap for headache, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Hemorrhoids. Although there has been interest in using oral Baikal skullcap for hemorrhoids, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Hepatitis. Although there has been interest in using oral Baikal skullcap for hepatitis, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• HIV/AIDS. Although there has been interest in using oral Baikal skullcap for HIV/AIDS, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Insomnia. Although there has been interest in using oral Baikal skullcap for insomnia, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Osteoarthritis. Oral Baikal skullcap has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific product (Limbrel, Primus Pharmaceuticals) that contains flavocoxid, a blend of Baikal skullcap extract and catechu flavonoid extract, 500 mg once or twice daily for up to 12 weeks reduces symptoms of osteoarthritis of the knee when compared with baseline. These studies found no significant difference between this combination product and naproxen 440 mg once daily to 500 mg twice daily for reducing symptoms (17030,18012,92776). However, in 2017, the US Food and Drug Administration (FDA) formally requested the recall of all non-expired lots of this product due to the risk for liver and lung injury (106042). See the Adverse Effects section for more information.
• Peyronie disease. It is unclear if oral Baikal skullcap is beneficial in patients with Peyronie disease. Details: Observational research has found that taking oral Baikal skullcap root extract 150 mL twice daily for 6 months is associated with reduced time to disease stabilization, with an average reduction of 5 months, when compared with no treatment. In addition, 17% of patients taking Baikal skullcap had pain resolution and only 33% required surgical correction, compared with 0% and 58%, respectively, of control patients. In patients requiring surgery, taking Baikal skullcap did not appear to affect resolution; however, the study may have been inadequately powered to detect a difference between groups (105867).
• Prostate cancer. Although there has been interest in using oral Baikal skullcap for prostate cancer, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Psoriasis. Although there has been interest in using oral Baikal skullcap for psoriasis, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Seizures. Although there has been interest in using oral Baikal skullcap for seizures, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose.
• Upper respiratory tract infection (URTI). Although there has been interest in using oral and intravenous Baikal skullcap for upper respiratory tract infections, there is insufficient reliable information about the clinical effects of Baikal skullcap for this purpose. More evidence is needed to rate Baikal skullcap for these uses.

(Read more about BAIKAL SKULLCAP)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there is interest in using oral danshen for acne, there is insufficient reliable information about the clinical effects of danshen for this condition.
• Angina. Preliminary clinical research suggests that compound danshen dripping pill, containing danshen extract, Panax notoginseng, and borneol, reduces symptoms and improves electrocardiogram (ECG) parameters in adults with angina. The effect of danshen alone is unclear. Details: Analyses of preliminary clinical research, as well as individual lower-quality clinical studies, have shown that danshen dripping pill is effective in reducing symptoms of angina, although the extent of this effect and place in therapy is unclear (47021,47025,96442,96443,96445). Analyses of the available clinical research, involving up to 109 studies with 11,973 patients, show that compound danshen dripping pill, 216-270 mg, taken as 8-10 pills, three times daily for 1-6 months, is more effective than isosorbide dinitrate taken as 5-20 mg three times daily in improving the symptoms and ECG parameters associated with angina (96442,96445). Another analysis involving 17 studies with 1,433 patients found that danshen injection as an adjunct to standard treatment options was more effective in improving symptoms of angina and ECG parameters when compared with standard treatment alone. However, details on the dose of danshen injection and the standard treatments used in the reviewed studies were not provided (96443). The low quality and high heterogeneity of the reviewed studies limit the validity of these findings. Also, the optimal dose and optimal form of danshen for treating angina has not been identified. Additionally, the effects of danshen alone are unclear. Salvianolate, a component of danshen, has been evaluated for the treatment of angina. A review of the available research shows that giving salvianolate as an intravenous infusion 250 mg in 250 mL dextrose daily for 10-14 days reduces angina severity and nitroglycerin tablet use in about 28% of people with stable angina. The patients most likely to respond are overweight, hypertensive, or experience at least 3 angina episodes per week (99069).
• Atopic dermatitis (eczema). Although there is interest in using oral danshen for eczema, there is insufficient reliable information about the clinical effects of danshen for this condition.
• Cancer. It is unclear if oral danshen is beneficial for cancer treatment. Details: A meta-analysis of 13 small, heterogenous clinical trials shows that taking various formulas containing danshen in combination with chemotherapy increases the odds of response and survival over 1-5 years when compared with chemotherapy alone. In patients with various types of cancer, including leukemia, and lung, liver, breast, colon, and gastric cancer, the odds of survival were increased by at least 1.7-fold (101976). It is unclear what other treatments these patients were receiving.
• Cirrhosis. It is unclear if oral or intravenous danshen are beneficial for cirrhosis. Details: A meta-analysis of results from low-quality clinical research, including 11 studies involving 1,086 patients, suggests that compound danshen injection or danshen injection 16-30 mL in conjunction with astragalus injection 10-30 mL daily for up to 90 days is superior to control in reducing liver function enzyme levels, increasing albumin levels, and reducing markers of fibrosis in adults with cirrhosis. However, the variability of treatments used as control, the wide range of outcomes assessed, and the significant heterogeneity between trials limits the validity of these findings (90662). Additionally, the effect of danshen injection alone is unclear.
• Coronary heart disease (CHD). Preliminary clinical research suggests that taking compound danshen dripping pills containing danshen extract, Panax notoginseng, and borneol may improve some cardiac symptoms, surrogate markers of cardiac function, and metabolic indices in patients with CHD. The effect of danshen alone is unclear. Details: A meta-analysis of the results of low-quality clinical research, including 10 studies involving 1,367 patients, shows that taking compound danshen dripping pills 240-270 mg as 10 tablets three times daily in combination with aspirin 25-100 mg daily for 4 weeks to 2 years reduces symptoms of CHD and pain when compared with aspirin alone in adults with CHD (96439). Also, meta-analyses of low-quality clinical research, including up to 19 studies, show that taking compound danshen dripping pills in combination with aspirin reduces total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels, as well as plasma viscosity and platelet aggregation, and increases high-density lipoprotein (HDL) cholesterol levels, when compared with aspirin alone in adults with CHD (96439,109369). The low quality and high heterogeneity of the reviewed studies limit the validity of these findings. A meta-analysis of randomized clinical trials in adults with CHD that require percutaneous coronary intervention (PCI) shows that taking compound danshen dripping pills three times daily for 1-6 months reduces the risk of recurrent angina by 80%, coronary restenosis by 71%, heart failure by 55%, and malignant arrhythmia by 47% when compared with usual treatment, although there was no reduction in the risk for acute myocardial infarction or sudden cardiac death. Taking compound danshen dripping pills also improved LDL cholesterol levels, but not HDL cholesterol or triglyceride levels (105516). The validity of this study is limited by an unreported dose of compound danshen dripping pills, unclear use of antiplatelet and other adjunctive therapies in the control group, and possible publication bias. A more recent large clinical trial in adults with CHD complicated with anxiety and depression who recently underwent PCI shows that taking compound danshen dripping pills 400 mg three times daily for three months improves quality of life, anxiety, angina symptoms, and surrogate biomarkers such as endothelin and high-sensitivity C-reactive protein compared with placebo (112398).
• Diabetes. Although there is interest in using oral danshen for diabetes, there is insufficient reliable information about the clinical effects of danshen for this condition.
• Diabetic foot ulcers. Although there is interest in using oral danshen for diabetic foot ulcers, there is insufficient reliable information about the clinical effects of danshen for this condition.
• Diabetic nephropathy. It is unclear if oral or intravenous danshen are beneficial for diabetic nephropathy. Details: A meta-analysis of up to 13 preliminary clinical trials in patients with early diabetic kidney disease shows that intravenous administration of danshen and Ligusticum striatum extract for 2-4 weeks, in combination with conventional medications such as angiotensin receptor blockers, alprostadil, benazepril, and others, modestly reduces urinary albumin and serum creatinine levels when compared with conventional medications alone (109380). The effects of oral danshen or intravenous danshen alone in patients with diabetic nephropathy are unclear.
• Diabetic retinopathy. Preliminary clinical research suggests that taking compound danshen dripping pills, containing danshen extract, Panax notoginseng, and borneol, may improve visual acuity and the severity of diabetic retinopathy. The effect of danshen alone is unclear. Details: Meta-analyses of available preliminary clinical research in adults with diabetic retinopathy, including up to 13 studies, show that taking compound danshen dripping pill at doses of 270-540 mg or ten pills three times daily improves retinal and choroid circulation, visual field, and visual acuity, and reduces the occurrence of microaneurysm and retinal hemorrhage when compared with placebo, control, or conventional treatment alone. However, the low quality and high heterogeneity of the reviewed studies limit the validity of these findings (96437,109376). Some clinical research shows that taking compound danshen dripping pill 5 mg three times daily for 6 months may be more effective than taking captopril 12.5 mg two or three times daily for reducing macular edema and the severity of retinopathy and improving vision (109372). Additional clinical research shows that higher doses of compound danshen dripping pill of 540-810 mg three times daily may be most effective in improving symptoms of diabetic retinopathy when compared with placebo (96444).
• Endometriosis. Preliminary clinical research suggests that taking danshen-containing herbal products with gonadotropin-releasing hormone agonist (GnRH-a) may improve postoperative management of endometriosis. The effect of danshen alone is unclear. Details: A meta-analysis of eight preliminary clinical trials shows that taking danshen-containing herbal products along with GnRH-a following surgery for endometriosis reduces the recurrence of endometriosis by 74% when compared with GnRH-a alone. Some research also suggests that danshen-containing products reduce symptoms such as abnormal vaginal bleeding and hot flashes and increase the pregnancy rate (109381).
• Heart failure. Oral danshen has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of small clinical trials in adults with heart failure shows taking a danshen decoction 400 to 1600 mL daily for 2 to 8 weeks in combination with conventional therapy improves some markers of cardiac function such as left ventricular ejection fraction, left ventricular end-diastolic dimension, left ventricular end-systolic diameter, and serological indicators such as brain natriuretic peptide, N-terminal pro-B type natriuretic peptide, and C-reactive protein when compared with conventional therapy alone (112397). Danshen comprised 75% of the herbs in the decoction and Tanxiang and Sha ren equally comprised the other 25%. It is unclear if these findings are due to danshen, other ingredients, or the combination. The moderate to low quality of the evidence limits the validity of these findings. All studies in this analysis were conducted in China which may limit generalizability to other geographic regions.
• Hepatitis. Although there is interest in using oral danshen for chronic hepatitis, there is insufficient reliable information about the clinical effects of danshen for this condition.
• Hyperlipidemia. It is unclear if oral or intravenous danshen are beneficial for hyperlipidemia. Details: Preliminary clinical research in adults with hyperlipidemia shows that taking lipid-lowering medication and injecting 1 mL of danshen into two of four possible acupuncture points daily for 30 days decreases total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides, and increases high-density lipoprotein (HDL) cholesterol. Improvements appear to occur in 90% of patients using danshen plus lipid-lowering medication, compared with only 44% of patients using lipid-lowering medication alone (47072). However, other preliminary clinical research shows that taking danshen extract 3 grams three times daily for 28 days leads to increases in total cholesterol and LDL cholesterol levels, with no change in HDL cholesterol levels, when compared with placebo in adults with hyperlipidemia and hypertension (96441).
• Hypertension. It is unclear if oral danshen is beneficial for hypertension. Details: Clinical research in adults with uncontrolled hypertension shows that taking a mixture of extracts of danshen 450 mg, rhodiola 40 mg, chrysanthemum 200 mg, and kudzu 200 mg twice daily for 12 weeks along with antihypertensive drugs does not increase response to treatment, defined as a sitting systolic blood pressure (SBP) less than 140 mmHg and/or sitting diastolic blood pressure (DBP) less than 90 mmHg OR achieving a reduction of more than 10 mmHg in SBP or more than 5 mmHg in DBP. However, taking this combination along with antihypertensive drugs increases the percentage of patients with a sitting SBP less than 140 mmHg and/or sitting DBP less than 90 mmHg by about 3.5-fold when compared with antihypertensive drugs alone (94396). However, other preliminary clinical research shows that taking danshen extract 3 grams three times daily for 28 days does not lower SBP or DBP when compared with placebo in adults with hyperlipidemia and hypertension (96441).
• Hypoparathyroidism. Intravenous danshen has only been evaluated in combination with other ingredients; its effect when used alone is unclear. The effect of oral danshen is unclear. Details: Preliminary clinical research in patients with postoperative hypoparathyroidism after a total thyroidectomy shows that intravenous danshen and the rhizome of Ligusticum chuanxiong 10 mL daily for one week reduces the time to recovery of parathyroid function by about 2 weeks, and results in increased serum parathyroid hormone and calcium levels over 6 months, when compared with conventional treatment including calcitriol and calcium gluconate. Also, there was a reduction in the number of patients with permanent hypoparathyroidism (109379).
• Intrauterine Adhesions. Intrauterine danshen has only been evaluated in combination with various oral ingredients; its effect when used alone is unclear. The effect of oral danshen is unclear. Details: Preliminary clinical research in patients with moderate to severe intrauterine adhesions shows that use of intrauterine danshen (Harbin Pharm Group Sanjing Pharmaceutical Co, Ltd.) 5 mL, along with oral Chinese medications for 6 months after adhesion resection and balloon uterine stent placement, may improve clinical efficacy when compared with a control group receiving hyaluronic acid and an intrauterine device (IUD). Clinical efficacy, defined as normal menstruation with at least a near normal intrauterine lining and normal or slightly reduced blood volume, was 89% after treatment with danshen, compared with 69% in the control group. Uterine re-adhesion after 3 months was also reduced. However, there was no difference in the 6-month follow-up pregnancy rate (109374).
• Kidney transplant. It is unclear if oral or intravenous danshen are beneficial following kidney transplantation. Details: Preliminary clinical research shows that injection with danshen 60 mL daily for 10 days in addition to conventional treatment improves urinary volume and creatinine clearance and reduces the incidence of renal function recovery after kidney transplantation when compared with conventional treatment alone. However, the risk of acute rejection does not seem to be affected (47019).
• Obesity. Although there is interest in using oral danshen for obesity, there is insufficient reliable information about the clinical effects of danshen for this condition.
• Oral submucous fibrosis. It is unclear if oral or intravenous danshen are beneficial for oral submucous fibroids. Details: A meta-analysis of 13 generally low-quality randomized controlled trials shows that danshen injection with corticosteroids, usually triamcinolone acetonide, improves symptoms of oral submucous fibrosis better than conventional corticosteroid treatment alone. Danshen modestly improved maximal mouth opening and moderately improved the oral mucosal lesion area and sensation of burning (101975). The effect of oral danshen is unclear.
• Pancreatitis. Although there is interest in using oral danshen for pancreatitis, there is insufficient reliable information about the clinical effects of danshen for this condition.
• Polycystic ovary syndrome (PCOS). It is unclear if oral danshen is beneficial for PCOS. Details: A meta-analysis of two preliminary clinical trials in patients with PCOS shows that taking danshen along with medication does not increase the pregnancy rate when compared with medication alone. However, these studies differed in their findings, with a 2.6-fold increase in pregnancy rate when compared with letrozole alone in one study and no increase when compared with cyproterone acetate in the other. Taking danshen may decrease fasting levels of glucose and insulin and improve levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and reproductive hormones when compared with placebo or medications alone (109378). However, the number of clinical trials in each meta-analysis was small.
• Pre-eclampsia. It is unclear if intravenous or oral danshen is beneficial for pre-eclampsia. Details: Preliminary clinical research in patients with severe pre-eclampsia on bed rest shows that intravenous danshen 16 mL in combination with magnesium sulfate up to 30 grams daily for 7 days results in clinical improvements when compared with magnesium sulfate alone. Blood pressure reductions to below 150/100 mmHg and improvement in clinical symptoms occurred in 93% of patients, compared with 77% of those in the control group. There were also modest improvements in liver and kidney function indices (109382). The effect of oral danshen is unclear.
• Pregnancy-induced hypertension. It is unclear if intravenous or oral danshen is beneficial for pregnancy-induced hypertension. Details: Preliminary clinical research in patients with pregnancy-induced hypertension shows that intravenous danshen 10-20 mL in combination with magnesium sulfate 4-10 mL once daily for 10 days modestly reduces systolic and diastolic blood pressure, as well as 24-hour urinary protein levels, when compared with magnesium sulfate alone. Also, the number of patients with a reduction or elimination of clinical symptoms was increased (109373).
• Psoriasis. Although there is interest in using oral danshen for psoriasis, there is insufficient reliable information about the clinical effects of danshen for this condition.
• Stroke. Preliminary clinical research suggests that oral or intravenous danshen may be beneficial for reducing symptoms following a stroke. Details: Preliminary clinical research shows that taking danshen orally or intravenously, usually as composite products, or administering the constituent salvianolic acid intravenously, might produce some improvement in neurological deficits, sleep quality, and blood flow indices after acute ischemic stroke (15538,47002,47017,101978,109371,109377). In one study, compound danshen dripping pills prepared with Panax notoginseng, borneol, and extracts of danshen, 270 mg (10 pills) three times daily for 28 days was used (15538). Compound danshen 16 mL or 20 mL and danshen 30 mL injection have been used for up to 28 days, occasionally in combination with snake venom (15538,96436). Other research shows that danshen injection is not as effective as danhong injection, an extract of danshen and safflower, in improving neurological deficits after acute ischemic stroke; however, the clinical relevance of this finding in the context of standard treatments is unclear (96436).
• Unstable angina. Oral danshen has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with unstable angina shows that taking danshen dripping pill 0.4 grams three times daily, alone or in combination with andrographis 0.2 grams three times daily, for 4 weeks modestly improves symptoms, although the combination of andrographis with danshen dripping pill was more effective than danshen dripping pill alone (109370).
• Venous Thromboembolism (VTE). Oral danshen has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with multiple myeloma receiving treatment with thalidomide shows that taking compound danshen dripping pill, containing danshen extract, Panax notoginseng, and borneol, 108 mg (4 tablets) three times daily for 8 months is as effective as warfarin for preventing VTE. Compound danshen dripping pills and warfarin demonstrate equal efficacy in preventing thalidomide-induced elevations in D-dimer and fibrinogen levels after 3 months of prophylaxis (96440). The effects of danshen alone are unclear.
• Wound healing. Although there is interest in using oral danshen for wound healing, there is insufficient reliable information about the clinical effects of danshen for this purpose. More evidence is needed to rate danshen for these uses.

(Read more about DANSHEN)

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

• Hemorrhoids. Oral pagoda tree flower has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in adults with active hemorrhoids shows that taking a sophora flower formula, containing pagoda tree, oriental arborvitae, schizonepeta, and bitter orange, 2 grams daily for 2 weeks, does not improve symptoms of hemorrhoids when compared with placebo (99963).
• Menopausal symptoms. It is unclear if oral pagoda tree fruit is beneficial for patients with menopausal symptoms. Details: Preliminary clinical research in adults with mild to moderate menopausal symptoms shows that taking a specific pagoda tree fruit extract (Rexflavone, Rexgene Biotech Co. Ltd.) 175 mg twice daily for 12 weeks reduces overall menopausal symptom scores by an additional 30% when compared with placebo. However, there was no effect on hot flashes, insomnia, nervousness, headache, or vaginal dryness (99966). More evidence is needed to rate pagoda tree for these uses.

(Read more about PAGODA TREE)

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)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Rheumatoid arthritis (RA). Clinical research shows that taking a combination of self-heal, Clematis mandshurica, and Chinese cucumber 200 mg three times daily for 6 weeks is as effective as celecoxib 200 mg twice daily for reducing pain and disease activity associated with RA. There was no difference between groups in the use of rescue medication or the response rate (101041). It is unclear whether these effects are due to self-heal, the other ingredients, or the combination. More evidence is needed to rate self-heal for this use.

(Read more about SELF-HEAL)

POSSIBLY SAFE ...when used orally and appropriately, short-term. Oral Baikal skullcap 0.5-3.52 grams daily has been used with apparent safety for up to 8 weeks (92776,101738,101739,110023). However, a high quality assessment of safety has not been conducted. A specific product (Limbrel, Primus Pharmaceuticals) containing flavocoxid, a mixture of Baikal skullcap flavonoid extract and catechu extract, has been associated with an increased risk for liver and lung injury. In 2017, the US Food and Drug Administration (FDA) formally requested the recall of all non-expired lots of this product (106042). It is unclear if these effects were due to Baikal skullcap, catechu, or the combination. There is insufficient reliable information available about the safety of Baikal skullcap when used intravenously or topically.

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

(Read more about BAIKAL SKULLCAP)

POSSIBLY SAFE ...when used orally and appropriately (12,94396,96441,96444). There is insufficient reliable information available about the safety of danshen when used by intravenous injection.

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

(Read more about DANSHEN)

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 the fruit is used orally and appropriately. A specific brand of pagoda tree fruit extract (Rexflavone, Rexgene Biotech Co. Ltd.) has been used safely in doses of up to 350 mg daily for up to 12 weeks (99966).

POSSIBLY UNSAFE ...when the seeds are used orally (18). Regular use of seed meal can cause facial edema or even death (18).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when the seed is used orally (18); avoid using. There is insufficient reliable information available about the safety of the fruit when used orally during pregnancy or lactation.

(Read more about PAGODA TREE)

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)

There is insufficient reliable information available about the safety of self-heal.

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

(Read more about SELF-HEAL)

ALCOHOL (Ethanol) Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, Baikal skullcap might potentiate the sedative effects of alcohol.  Details In vitro and animal research suggests that Baikal skullcap binds to GABA-A receptors and causes sedation. Theoretically, Baikal skullcap might potentiate the sedative effects of alcohol (6290,6291,33477). Preliminary clinical research has not identified clinically relevant sedation after use of Baikal skullcap; however, a thorough evaluation of safety outcomes has not been conducted.

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, Baikal skullcap might increase the risk of bleeding when used concomitantly with anticoagulant and antiplatelet drugs.  Details Preliminary clinical research suggests that taking capsules containing a combination of astragalus, goldthread, and Baikal skullcap daily for 4 weeks inhibits platelet aggregation; the effect seems to be similar to that of aspirin 50 mg daily (33075). It is unclear if this effect is due to Baikal skullcap, other ingredients, or the combination.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use of Baikal skullcap with antidiabetes drugs might enhance blood glucose lowering effects.  Details Baicalein, a constituent of Baikal skullcap, has alpha-glucosidase inhibitory activity in vitro (6292). Animal research also suggests that Baikal skullcap enhances the antidiabetic effects of metformin (33408). However, in a small human study, taking Baikal skullcap extract did not enhance the antidiabetic effects of metformin, although it did modestly lower glucose levels during an oral glucose tolerance test (OGTT) (101738). Until more is known, use cautiously.

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of Baikal skullcap with antihypertensive drugs might have additive effects and increase the risk of hypotension.  Details Animal research suggests that baicalein, a constituent of Baikal skullcap, might lower blood pressure (33374).

ANTITHYROID DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of Baikal skullcap and antithyroid drugs may result in additive activity and increase the risk of hypothyroidism.  Details In an animal hyperthyroid model, Baikal skullcap improved levels of triiodothyronine (T3), thyroxine (T4), and thyroid stimulating hormone (TSH) (101736). The clinical significance of this effect is unclear.

CNS DEPRESSANTS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, Baikal skullcap might cause additive therapeutic and adverse effects when used concomitantly with drugs with sedative properties.  Details In vitro and animal research suggests that Baikal skullcap binds to GABA-A receptors and causes sedation. Theoretically, Baikal skullcap might cause additive therapeutic and adverse effects when used concomitantly with drugs with sedative properties (6290,6291,33477). Preliminary clinical research has not identified clinically relevant sedation after use of Baikal skullcap; however, a thorough evaluation of safety outcomes has not been conducted.

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, Baikal skullcap may increase levels of drugs metabolized by CYP1A2 enzymes.  Details In vitro evidence suggests that constituents of Baikal skullcap inhibit the activity of CYP1A2 (33346,33484). This effect has not been reported in humans.

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, Baikal skullcap might increase levels of drugs metabolized by CYP2C19 enzymes.  Details In vitro evidence suggest that wogonin, a constituent of Baikal skullcap, modestly inhibits the activity of CYP2C19 enzymes (33484). This effect has not been reported in humans.

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of large amounts of Baikal skullcap might interfere with hormone replacement therapy, due to competition for estrogen receptors.  Details In vitro evidence suggests that Baikal skullcap has estrogenic activity (16061).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, Baikal skullcap might reduce lithium excretion and increase serum levels of lithium.  Details Baikal skullcap is thought to have diuretic properties, which may reduce lithium excretion (5541). The dose of lithium might need to be decreased.

ORGANIC ANION-TRANSPORTING POLYPEPTIDE SUBSTRATES (OATP) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, Baikal skullcap might alter the levels and clinical effects of OATP substrates.  Details Some pharmacokinetic research shows that baicalin, a constituent of Baikal skullcap, can decrease plasma levels of rosuvastatin. The mechanism is thought to involve stimulation of the activity of the organic anion-transporting polypeptide 1B1 (OATP1B1), which transports rosuvastatin into the liver. This decreases plasma levels of the drug, but increases levels at the site of action in the liver. The degree to which rosuvastatin levels are affected depends on the OATP1B1 haplotype of the individual (16395). Baikal skullcap might also affect other OATP1B1 substrates (16396,16397,16398).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, Baikal skullcap might increase levels of drugs transported by P-glycoprotein.  Details In vitro and animal research suggests that baicalein, oroxylin A, and wogonin, constituents of Baikal skullcap, can inhibit P-glycoprotein (33372,33395,33440,33462). This effect has not been reported in humans.

(Read more about BAIKAL SKULLCAP)

AMLODIPINE (Norvasc) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking danshen in combination with amlodipine may decrease the clinical effects of amlodipine.  Details In animal research, taking danshen orally in combination with amlodipine reduced blood levels of amlodipine by about 52%. This may have been due to induction of cytochrome P450 3A4 (CYP3A4) by danshen, which has been demonstrated in vitro (101977). So far, this interaction has not been reported in humans.

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, danshen may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Danshen has been reported to have antithrombotic effects (6048,96440). Animal research also suggests that taking a danshen combination formula with clopidogrel exhibits a synergistic increase in antiplatelet aggregation and prolongation of coagulation time when compared with either taken alone (112399).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking danshen with antihypertensive drugs might increase the risk of hypotension.  Details Animal research suggests that danshen can produce dose-dependent hypotensive effects. Furthermore, concomitant use with captopril appears to potentiate this effect (47071).

ASPIRIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, danshen may increase the levels of aspirin and the risk of bleeding.  Details Research in healthy adult males shows that taking a combination of danshen and kudzu with aspirin increases plasma aspirin area under the curve by approximately 3.4-fold (105517). Animal research also shows that taking a combination of danshen and kudzu (danshen-gegen formula) with aspirin increases maximal blood levels of aspirin and salicylic acid by approximately 4-fold and 3.7-fold, respectively, without impacting blood loss (94399). Taking danshen increases the antiplatelet activity of aspirin and might increase the side effects of aspirin (105517).

CLOPIDOGREL (Plavix) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, danshen may increase the risk of bleeding if taken with clopidogrel.  Details Clopidogrel is an antiplatelet prodrug that is metabolized by carboxyl esterase 1 (CES1) to an inactive metabolite. Animal research shows that a danshen combination formula decreases the activity of CES1, decreasing levels of the inactive metabolite in the blood and possibly increasing levels of the active metabolite (94389). Animal research also suggests that taking a danshen combination formula with clopidogrel exhibits a synergistic increase in antiplatelet aggregation and prolongation of coagulation time when compared with either taken alone (112399).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, danshen may increase the levels and clinical effects of drugs metabolized by CYP1A2.  Details In vitro research shows that danshen tincture and various constituents of danshen inhibit the activity of CYP1A2 (94393,94394). However, this activity has not been shown in humans when theophylline, a CYP1A2 substrate, was used as a target drug (94398).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, danshen may increase the levels and clinical effects of drugs metabolized by CYP2C9.  Details In vitro research shows that various constituents of danshen inhibit the activity of CYP2C9 (94393). So far, this interaction has not been reported in humans.

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, danshen may increase the levels and clinical effects of drugs metabolized by CYP2E1.  Details In vitro research shows that various constituents of danshen inhibit the activity of CYP2E1 (94393). So far, this interaction 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 Danshen might alter the levels and clinical effects of drugs metabolized by CYP3A4.  Details Preliminary clinical research in healthy males shows that the administration of danshen for 10-14 days induces intestinal CYP3A4 and increases the clearance of midazolam, a CYP3A4 substrate. The maximum concentration of midazolam was decreased by 31% to 67%, and drug levels were decreased by 27% to 80% (17404,94390). However, a single dose of danshen has the opposite effect, increasing maximum concentrations of midazolam by 87% (94390).

DIGOXIN (Lanoxin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, using danshen with digoxin might increase the risk of adverse effects.  Details Danshen has structural and pharmacological similarities to cardiac glycosides (5884,6048,7311).

FEXOFENADINE (Allegra) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Danshen might increase the levels and clinical effects of fexofenadine.  Details Pharmacokinetic research in healthy volunteers shows that taking danshen extract 1 gram three times daily for 10 days prior to receiving fexofenadine 60 mg increases peak levels of fexofenadine, a p-glycoprotein substrate, by 27.4% and area under the curve (AUC) by 37.2% (94391).

GLUCURONIDATED DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, danshen might affect the levels and clinical effects of drugs requiring glucuronidation.  Details In vitro research shows that danshen induces the expression of glucuronosyltransferases. However, it also inhibits the activity of glucuronosyltransferases, including various members of the 1A and 2B families. The extent of inhibition of a specific glucuronosyltransferase seems to be dependent on whether or not the danshen is processed via 'sweating'. This type of processing may affect the levels of constituents in danshen that alter glucuronosyltransferase activity (109375). So far, this interaction has not been reported in humans.

MIDAZOLAM (Versed) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Danshen might alter the levels and clinical effects of midazolam.  Details Preliminary clinical research in healthy males shows that the administration of danshen for 10-14 days induces intestinal CYP3A4 and increases midazolam clearance. The maximum concentration was decreased by 31% to 67%, and drug levels were decreased by 27% to 80% (17404,94390). However, a single dose of danshen has the opposite effect, increasing maximum concentrations of midazolam by 87% (94390).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Danshen might alter the levels of drugs cleared by p-glycoprotein.  Details Pharmacokinetic research in healthy volunteers suggests that danshen might affect p-glycoprotein activity. Taking danshen extract 1 gram three times daily for 10 days prior to receiving fexofenadine 60 mg increases peak levels of fexofenadine, a p-glycoprotein substrate, by 27.4% and area under the curve (AUC) by 37.2% (94391).

ROSUVASTATIN (Crestor) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, danshen might increase the levels and clinical effects of rosuvastatin.  Details Animal research shows that a single dose of danshen increases levels of rosuvastatin at least 2-fold, possibly by increasing absorption and/or decreasing elimination (94395). So far, this interaction has not been reported in humans.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, danshen may increase the risk of bleeding if used with warfarin.  Details There have been several case reports of increased international normalized ratio (INR) after concomitant use of danshen and warfarin. Elevations in INR have occurred as early as 3-5 days after start of danshen (611,612,2237,5883,5884). However, a clinical trial in adults taking warfarin with stable INR found that the addition of compound danshen dripping pills, containing danshen extract, Panax notoginseng, and borneol, 270 mg three times daily for 4 weeks did not alter INR levels or the average required warfarin dose when compared to baseline (96438). These findings are consistent with animal research, which found no change in warfarin pharmacokinetics with the use of danshen (94388,94397,94399). Other research in healthy adult males also shows that taking a combination of danshen and kudzu with warfarin does not increases plasma warfarin area under the curve, but may reduce plasma soluble thrombomodulin levels (105517). However, other research shows that danshen might increase the rate of absorption and decrease the elimination rate of warfarin (5884,6048,94398). Also, research in healthy adult males shows that taking a combination of danshen and kudzu with warfarin increases plasma area under the curve of danshensu, a constituent of danshen, by approximately 29.5-fold (105517). Danshen should be used cautiously in patients taking warfarin.

(Read more about DANSHEN)

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)

CAFFEINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, pagoda tree might reduce the clearance of caffeine.  Details Pagoda tree contains genistein. Taking genistein 1 gram daily for 14 days seems to inhibit caffeine clearance and metabolism in healthy females (23582). This effect has been attributed to inhibition of the cytochrome P450 1A2 (CYP1A2) enzyme, which is involved in caffeine metabolism. It is unclear if this effect occurs with the lower amounts of genistein found in pagoda tree.

(Read more about PAGODA TREE)

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)

(Read more about SELF-HEAL)

General ...Orally, Baikal skullcap seems to be well-tolerated. There is currently a limited amount of information on the adverse effects of intravenous and topical Baikal skullcap.
Most Common Adverse Effects:
Orally: Abdominal pain, constipation, diarrhea, erythema, nausea, pruritus, and vomiting.
Intravenously: Skin reactions.
Topically: Dermatitis.
Serious Adverse Effects (Rare):
Orally: Hepatotoxicity and hypersensitivity pneumonitis have been reported with a specific combination product (Limbrel, Primus Pharmaceuticals) containing extracts of Baikal skullcap and catechu.

Cardiovascular ...Orally, in a small clinical study evaluating the safety of baicalein, a constituent of Baikal skullcap, in healthy adults, elevated triglyceride levels occurred in 1 of 10 patients who received 400 mg every 8 hours and 2 of 10 patients treated with 600 mg every 8 hours, compared with 0 of 10 patients who received 200 mg every 8 hours and 0 of 6 patients who received placebo. Triglyceride elevations were considered mild and resolved after discontinuation (110023).

Dermatologic ...Orally, taking Baikal skullcap may cause erythema and pruritus (105867). Intravenously, Baikal skullcap as part of a Tanreqing injection has been associated with reports of skin reactions in some pediatric patients (96281).
Topically, several cases of allergic contact dermatitis have been reported after applying sunscreen containing Baikal skullcap extract (105869,105870). Allergic contact dermatitis has also been reported after applying a facial cream (Resveratrol BE, Skinceuticals) containing Baikal skullcap root extract 0.5% and resveratrol 1%. Patch testing identified a positive reaction to both ingredients (110024). Baikal skullcap-induced dermatitis appears to respond to treatment with a topical corticosteroid and calcineurin inhibitor (105870).

Gastrointestinal ...Orally, use of Baikal skullcap has been associated with epigastric pain, abdominal pain, constipation, diarrhea, nausea, and vomiting (101738,105867).

Hepatic ...A specific combination product (Limbrel, Primus Pharmaceuticals) containing flavocoxid, a mixture of Baikal skullcap flavonoid extract and catechu extract, has been linked to several reports of acute liver damage. There have been at least five published reports of liver damage associated with this product. In all cases, the patients were females aged 54-68 years taking doses of 250-500 mg twice daily for 1-3 months. Signs and symptoms included jaundice, pruritus, abdominal pain, fever, rash, and elevated serum bilirubin and liver transaminase levels. All patients fully recovered and levels normalized within 3 months after discontinuation (18009,96282). In addition to these published case reports, approximately 30 liver-related adverse events have been reported to the manufacturer of this product (18009). The mechanism of hepatotoxicity is unclear (18009,18010); it is estimated that the incidence of hepatotoxicity with this product is around 1 in 10,000, although the actual incidence is unknown (18010). In 2017, the US Food and Drug Administration (FDA) formally requested the recall of all non-expired lots of this product due to the risk for liver and lung injury (106042). It is unclear if these effects were due to Baikal skullcap, catechu, or the combination.
Hepatotoxicity has also been reported in two patients taking a specific dietary supplement (Move Free Advanced, Reckitt Benckiser) containing Baikal skullcap, black catechu, glucosamine, chondroitin, and hyaluronic acid (33460) and in a patient taking Baikal skullcap, elderflower, horseradish, and white willow (101737). The investigators determined that the hepatotoxicity was likely caused by Baikal skullcap in these cases (33460,101737). Additionally, cases of liver injury are reported in 4 of 37 patients taking various Kampo formulations containing Baikal skullcap and other herbs daily. Patients presented with elevated liver function tests 7 to 38 days after consumption (112179). It is unclear if this adverse effect is from Baikal skullcap, other ingredients, or the combination.
In a small study evaluating the safety of baicalein, a constituent of Baikal skullcap, in healthy adults, liver transaminase elevations occurred in 2 of 10 patients who received 400 mg every 8 hours for 6 days, compared with 0 of 6 patients who received placebo. No patients receiving either 200 mg or 600 mg every 8 hours experienced liver transaminase elevations. The elevations were considered mild and resolved after discontinuation (110023).

Pulmonary/Respiratory ...A specific combination product (Limbrel, Primus Pharmaceuticals) containing flavocoxid, a mixture of Baikal skullcap flavonoid extract and catechu extract, has been linked to several reports of hypersensitivity pneumonitis. Symptoms include fever, chills, headache, cough, chronic bronchitis, shortness of breath, weight loss, and fatigue. In 2017, the US Food and Drug Administration (FDA) formally requested the recall of all non-expired lots of this product due to the risk for liver and lung injury (106042). It is unclear if these effects were due to Baikal skullcap, catechu, or the combination.

Renal ...Orally, in a small clinical study evaluating the safety of baicalein, a constituent of Baikal skullcap, in healthy adults, proteinuria of undefined severity occurred in 1 of 10 patients who received 200 mg every 8 hours for 6 days, 3 of 10 patients who received 400 mg every 8 hours for 6 days, and 5 of 10 patients who received 600 mg every 8 hours for 6 days, compared with 1 of 6 patients who received placebo. The proteinuria was considered mild and resolved after discontinuation (110023).

(Read more about BAIKAL SKULLCAP)

General ...Orally, danshen seems to be well tolerated. There is limited reliable information available about the adverse effects of danshen when used intravenously.
Most Common Adverse Effects:
Orally or intravenously: Upset stomach, pruritus, and reduced appetite.

Cardiovascular ...Orally, in clinical trials, side effects of danshen preparations include palpitations; however, it is not known if these effects were due to danshen or other drugs (109370).

Dermatologic ...Orally or intravenously, danshen can cause pruritus (12,96440).

Gastrointestinal ...Orally or intravenously, danshen can cause upset stomach and reduced appetite (12). In clinical trials, side effects of danshen preparations include loose stools; however, it is not known if these effects were due to danshen or other drugs (109370).

Hematologic ...Orally or intravenously, side effects of danshen preparations reported in clinical trials include thrombocytopenia; however, it is not known if this effect was due to danshen or other drugs (15538).

Neurologic/CNS ...Orally or intravenously, in clinical trials, side effects of danshen preparations include drowsiness, dizziness, or headache; however, it is not known if these effects were due to danshen or other drugs (15538,109370).

(Read more about DANSHEN)

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, pagoda tree flower and fruit seem to be well tolerated. No adverse effects have been reported; however, a thorough evaluation of safety outcomes has not been conducted. The pagoda tree seed is possibly unsafe when consumed long-term.
Serious Adverse Effects (Rare):
Orally: With use of the seed, death and edema.

Other ...Orally, using pagoda tree seed long-term may cause edema and death (18).

(Read more about PAGODA TREE)

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

(Read more about REHMANNIA)

General ...Orally, self-heal has been reported to cause nausea, vomiting, and diarrhea. Orally and topically, self-heal has been reported to cause allergic reactions in sensitive individuals (12).

Gastrointestinal ...Orally, self-heal has been reported to cause nausea, vomiting, and diarrhea (12). A combination product containing self-heal, Clematis mandshurica, and Chinese cucumber has been reported to cause epigastric pain, abdominal discomfort, nausea, reduced appetite, and dyspepsia. It is not clear if these effects are due to self-heal, the other ingredients, or the combination (101041).

Immunologic ...Orally and topically, self-heal has been reported to cause allergic reactions, including rashes and swelling of the throat, lips, and tongue, in sensitive individuals (12).

(Read more about SELF-HEAL)