Coptis Relieve Toxicity Formula by Eastern Currents Distributing 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

• Anxiety. Although there has been interest in using oral gardenia for anxiety, there is insufficient reliable information about the clinical effects of gardenia for this purpose.
• Dementia. Although there has been interest in using oral gardenia for dementia, there is insufficient reliable information about the clinical effects of gardenia for this purpose.
• Depression. Although there has been interest in using oral gardenia for depression, there is insufficient reliable information about the clinical effects of gardenia for this purpose.
• Diabetes. Although there has been interest in using oral gardenia for diabetes, there is insufficient reliable information about the clinical effects of gardenia for this purpose.
• Hypertension. Although there has been interest in using oral gardenia for hypertension, there is insufficient reliable information about the clinical effects of gardenia for this purpose.
• Influenza. Although there has been interest in using oral gardenia for influenza, there is insufficient reliable information about the clinical effects of gardenia for this purpose.
• Insomnia. Although there has been interest in using oral gardenia for insomnia, there is insufficient reliable information about the clinical effects of gardenia for this purpose.
• Stroke. Although there has been interest in using oral gardenia for stroke, there is insufficient reliable information about the clinical effects of gardenia for this purpose. More evidence is needed to rate gardenia for these uses.

(Read more about GARDENIA)

There is insufficient reliable information available about the effectiveness of goldthread.

(Read more about GOLDTHREAD)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. It is unclear if topical phellodendron is beneficial in patients with acne. Details: A small clinical study in patients with mild to moderate acne shows that applying a facial mask containing an unknown dose of phellodendron for 15-20 minutes daily for 3 days, then every other day for 8 weeks, reduces the number of acne lesions when compared to baseline. About 33% of patients showed a moderate improvement and 11% showed an excellent improvement in overall lesions at week 8. However, no significant difference in the total number of lesions was seen (97317).
• Benign prostatic hyperplasia (BPH). Oral phellodendron has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with BPH shows that taking five tablets of a specific traditional Chinese medicine product containing phellodendron bark, gardenia fruit, licorice root, safflower, Indian long pepper, and other ingredients three times daily with conventional therapy for 6 months improves storage-related lower urinary tract symptoms, such as urinary frequency, urinary urgency, and nocturia, when compared with placebo plus conventional therapy. However, this product did not appear to improve voiding-related symptoms (109450).
• Diabetes. Although there has been interest in using oral phellodendron for diabetes, there is insufficient reliable information about the clinical effects of phellodendron for this purpose.
• Diabetic foot ulcers. Topical phellodendron has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large clinical study in adults with diabetic foot ulcers shows that applying gauze soaked in a Traditional Chinese Medicine (TCM) solution containing phellodendron, forsythia, honeysuckle, dandelion, and Scolopendra once daily for 4 weeks is associated with a higher rate of clinical efficacy and greater reduction in wound area when compared with applying gauze soaked with a Kangfuxin control solution (106438). Kangfuxin is an herbal TCM solution commonly used in the treatment of diabetic foot ulcers. The validity of these findings is limited by the unclear reporting of outcomes and discrepancies in the data. Additionally, it is unclear how these findings would compare with the use of standard care. A small clinical study in adults undergoing negative pressure wound aspiration therapy (NPWT) for diabetic foot ulcers shows that the addition of liquid compound phellodendron TCM irrigation to NPWT for 30 days improves wound symptom scores and wound healing and bacterial cultures compared with saline control (112389). A moderate size clinical study in adults undergoing ultrasonic debridement for diabetic foot ulcers shows that rinsing the wound with a liquid compound phellodendron TCM for 4 weeks reduces wound area and bacterial cultures and improves healing rate and efficacy compared with a Kangfuxin control solution (112390). The lack of blinding and randomization limits the validity of these findings. Additionally, in all three trials the phellodendron solution contained other TCM ingredients such as forsythia, honeysuckle, dandelion, golden cypress, and centipede (106438,112389,112390). Thus, it is unclear if the effects are due to phellodendron, other ingredients, or the combination.
• Obesity. Oral phellodendron has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in overweight individuals shows that taking a specific blend of phellodendron and sweet orange extracts (Citrofen, Next Pharmaceuticals) 740 mg twice daily for 8 weeks reduces body weight by 3.7% when compared with placebo (94902,94903). This blend also seems to reduce levels of low-density lipoprotein (LDL) cholesterol by about 30% and triglycerides by about 14% when compared with placebo. It also appears to reduce systolic and diastolic blood pressure and fasting glucose (94902). Another specific combination product containing a combination of extracts of phellodendron plus magnolia (Relora, Next Pharmaceuticals) has been evaluated for weight loss in females who have a tendency to eat during stressful situations. One small clinical study in overweight, postmenopausal individuals shows that taking this product 250 mg three times daily for 6 weeks prevents weight gain when compared with placebo (14349). However, another small clinical study in overweight, postmenopausal individuals shows that taking this product at the same dose for 6 weeks does not decrease appetite, caloric intake, body weight, or waist or hip circumference when compared with placebo (94901).
• Osteoarthritis. Oral phellodendron has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with osteoarthritis of the knee shows that taking a specific blend of phellodendron and sweet orange extracts (Citrofen, Next Pharmaceuticals) 740 mg twice daily for 8 weeks improves functional measures of joint pain and movement by 16% to 41% when compared with placebo (94903).
• Peptic ulcers. Although there has been interest in using oral phellodendron for peptic ulcers, there is insufficient reliable information about the clinical effects of phellodendron for this purpose.
• Stress. Oral phellodendron has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with moderate stress shows that taking a specific product containing a combination of extracts of phellodendron plus magnolia (Relora, Next Pharmaceuticals) 250 mg twice daily for 4 weeks improves stress and mood by 11% when compared with placebo (94904).
• Tuberculosis. Although there has been interest in using oral phellodendron for tuberculosis, there is insufficient reliable information about the clinical effects of phellodendron for this purpose.
• Wound healing. Topical phellodendron has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate sized clinical trial in adults recovering from anal fistulotomy shows that using 200 mL of compound phellodendron decoction in 1.8 liters of warm water for fumigation and sitting (sitz) bath for 7 days reduces pain, wound edema and exudation, and total wound healing time compared with fumigation and sitz bath with warm water alone (112391). Four other herbs were in the decoction, so it is unclear if the effects are due to phellodendron, other ingredients, or the combination. More evidence is needed to rate phellodendron for these uses.

(Read more about PHELLODENDRON)

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)

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

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

(Read more about GARDENIA)

There is insufficient reliable information available about the safety of goldthread when used in adults in medicinal amounts.

CHILDREN: LIKELY UNSAFE
when used orally in newborns. The berberine constituent of goldthread can cause kernicterus in newborns, particularly preterm neonates with hyperbilirubinemia (2589).

PREGNANCY: LIKELY UNSAFE
when used orally. Berberine is thought to cross the placenta and may cause harm to the fetus. Kernicterus has developed in newborn infants exposed to berberine (2589). Preliminary evidence suggests that maternal intake of goldthread during the first trimester increases the risk of congenital malformations of the central nervous system (15129).

LACTATION: LIKELY UNSAFE
when used orally. Berberine and other harmful constituents can be transferred to the infant through breast milk (2589).

(Read more about GOLDTHREAD)

POSSIBLY SAFE ...when used orally and appropriately in combination with other ingredients, short-term. A specific product containing a combination of extracts of phellodendron plus magnolia (Relora, Next Pharmaceuticals) 250 mg 2-3 times daily has been used with apparent safety in clinical trials lasting up to 6 weeks (14349,94901,94904). Also, a specific product containing a combination of extracts of phellodendron plus sweet orange (Citrofen, Next Pharmaceuticals) 740 mg twice daily has been used with apparent safety for up to 8 weeks (94903). ...when used topically (97317). There is insufficient reliable information available about the safety of phellodendron when used orally as a single ingredient.

CHILDREN: LIKELY UNSAFE
when used orally in newborns. The berberine constituent of phellodendron can cause kernicterus in newborns, particularly preterm neonates with hyperbilirubinemia (2589).

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

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

(Read more about PHELLODENDRON)

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)

STIMULANT LAXATIVES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, gardenia might increase the effects and adverse effects of stimulant laxatives.  Details Animal research shows that geniposide, a glucoside found in gardenia fruit, may function as a laxative and cause diarrhea when taken orally (26534).

(Read more about GARDENIA)

(Read more about GOLDTHREAD)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron might increase the risk of bleeding when used with anticoagulant or antiplatelet drugs.  Details Phellodendron contains berberine. In vitro and in vivo research suggest that berberine can inhibit platelet aggregation (33660,33694). Theoretically, phellodendron might also inhibit platelet aggregation.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron may increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Phellodendron contains berberine. Clinical research shows that berberine may lower blood glucose levels (20579,34247,34265,34282). Theoretically, phellodendron might also lower blood glucose levels.

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron might have additive effects with antihypertensive drugs.  Details Phellodendron contains berberine. Animal research suggests that berberine can have hypotensive effects (33692,34308). Also, a clinical study suggests that taking berberine in combination with amlodipine can lower systolic and diastolic blood pressure when compared with amlodipine alone (91956). Theoretically, phellodendron might also reduce blood pressure.

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron might increase the sedative effects of CNS depressants.  Details Phellodendron contains berberine. Animal research suggests that berberine may have sedative effects (13519,33650,33664,33692). Theoretically, phellodendron might also have CNS depressants effects.

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron might increase blood levels of cyclosporine.  Details Phellodendron contains berberine. Preliminary clinical research shows that berberine can reduce metabolism of cyclosporine and increase serum levels, likely through inhibition of cytochrome P450 3A4 (CYP3A4), which metabolizes cyclosporine (13524). Theoretically, phellodendron might also reduce the metabolism of cyclosporine.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron might increase serum levels of drugs metabolized by CYP2C9.  Details Phellodendron contains berberine. Preliminary clinical research shows that berberine can inhibit CYP2C9 (34279). Theoretically, phellodendron might also inhibit CYP2C9.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron might increase serum levels of drugs metabolized by CYP2D6.  Details Phellodendron contains berberine. In vitro research and preliminary clinical evidence show that berberine can inhibit CYP2D6 (21117,34279,34297). Theoretically, phellodendron might also inhibit CYP2D6.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron might increase serum levels of drugs metabolized by CYP3A4.  Details Phellodendron contains berberine. In vitro research and preliminary clinical research show that berberine moderately inhibits CYP3A4 (13524,21114,34279,34297). Theoretically, phellodendron might also inhibit CYP3A4.

DEXTROMETHORPHAN (Robitussin DM, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron may increase serum levels of dextromethorphan.  Details Phellodendron contains berberine. Preliminary clinical research shows that berberine can inhibit cytochrome P450 2D6 (CYP2D6) activity and reduce the metabolism of dextromethorphan (34279). Theoretically, phellodendron may also inhibit the metabolism of dextromethorphan.

LOSARTAN (Cozaar) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron might reduce the therapeutic effects of losartan by decreasing its conversion to its active form.  Details Phellodendron contains berberine. Preliminary clinical research suggests that berberine can inhibit cytochrome P450 2C9 (CYP2C9) activity and reduce metabolism of losartan (34279). Theoretically, phellodendron might also inhibit the metabolism of losartan.

METFORMIN (Glucophage) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron might increase the therapeutic and adverse effects of metformin.  Details Phellodendron contains berberine. In vitro and animal studies show that berberine can increase the systemic exposure and half-life of metformin, potentially increasing metformin's effects and side effects. This interaction seems to be most apparent when berberine is administered 2 hours prior to metformin. Taking berberine and metformin at the same time does not appear to increase systemic exposure to metformin (103195). It is unclear if phellodendron might have this same effect.

MIDAZOLAM (Versed) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron might reduce metabolism of midazolam, which might increase the risk of severe adverse effects.  Details Phellodendron contains berberine. Preliminary clinical research shows that berberine can inhibit cytochrome P450 3A4 (CYP3A4) activity and reduce metabolism of midazolam (34279). Theoretically, phellodendron might also inhibit the metabolism of midazolam.

PENTOBARBITAL (Nembutal) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron might increase the sedative effect of pentobarbital.  Details Phellodendron contains berberine. Animal research shows that berberine can prolong pentobarbital-induced sleeping time (13519). Theoretically, phellodendron might increase the sedative effects of pentobarbital.

TACROLIMUS (Prograf) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, phellodendron might increase blood levels of tacrolimus.  Details Phellodendron contains berberine. In a 16-year-old patient with idiopathic nephrotic syndrome who was being treated with tacrolimus 6.5 mg twice daily, intake of berberine 200 mg three times daily increased the blood concentration of tacrolimus from 8 to 22 ng/mL. Following a reduction of the tacrolimus dose to 3 mg daily, blood levels of tacrolimus decreased to 12 ng/mL (91954). It is unclear if phellodendron might have this same effect.

(Read more about PHELLODENDRON)

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 ...There is currently a limited amount of information on the adverse effects of gardenia.
Most Common Adverse Effects:
Topically: Allergic contact dermatitis in sensitive individuals.

Dermatologic ...Topically, exposure to gardenia fruit extract or the whole plant has been associated with allergic contact dermatitis (26518,49078).
Orally, there is a case report of blue-gray skin pigmentation associated with taking a product containing the extracts of gardenia fruit, phellodendron bark, and licorice for 7 years in a 77-year-old female. The pigmentation was thought to be due to melanin deposition enhanced by genipin, a constituent of gardenia. The patient gradually improved over 9 months after stopping this treatment (102698).

Gastrointestinal ...Orally, there are case reports of mesenteric phlebosclerosis, a thickening of the walls of the intestine and mesenteric veins, which can lead to obstruction and occlusion. Typical presenting symptoms are paroxysmal abdominal pain with nausea and vomiting, and imaging studies reveal thickening and stiffening of the walls of the ascending and transverse colon, with dark purple discoloration of the colonic and rectal mucosa, and linear calcification of the mesenteric veins. Treatment is supportive and conservative, leading to a slow resolution of signs and symptoms. In one case a 61-year-old female had been taking a Chinese herbal combination containing extracts of gardenia fruit, Baikal skullcap root, goldthread, phellodendron bark, honeysuckle, rhubarb, anemarrhenae, and trichosanthis root for 8 years (112954). In another case, a 77-year-old female took a product containing extracts of gardenia fruit, phellodendron bark, and licorice for 7 years. Mesenteric phlebosclerosis is thought to be caused by genipin, formed from geniposide after hydrolysis by intestinal bacteria. It is absorbed from the intestine, reacting with proteins in mesenteric veins, leading to progressive fibrosis, calcification, and venous occlusion (102698,112954).

Immunologic ...Topically, exposure to gardenia fruit extract or the whole plant has been associated with allergic contact dermatitis (26518,49078).

(Read more about GARDENIA)

General ...No adverse effects have been reported in adults. However, a thorough evaluation of safety outcomes has not been conducted.

(Read more about GOLDTHREAD)

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

Endocrine ...Orally, a combination product containing extracts of phellodendron plus magnolia has been associated with one report of thyroid dysfunction in one clinical trial (14349,94901). However, it is unknown if this is related to phellodendron or some other factor.

Gastrointestinal ...Orally, a combination product containing extracts of phellodendron plus magnolia has been associated with one report of heartburn in one clinical trial (14349,94901). However, it is unknown if this is related to phellodendron or some other factor.

Genitourinary ...Orally, a combination product containing extracts of phellodendron plus magnolia has been associated with one report of sexual dysfunction in one clinical trial (14349,94901). However, it is unknown if this is related to phellodendron or some other factor.

Neurologic/CNS ...Orally, a combination product containing extracts of phellodendron plus magnolia has been associated with single reports of shaking hands, perilabial numbness, fatigue, and headache in clinical research (14349,94901). However, it is unknown if this is related to phellodendron or some other factor.

(Read more about PHELLODENDRON)