ArthroMax Elite by Life Extension

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.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Exercise-induced muscle soreness. Oral catechu has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in healthy runners shows that taking a specific combination product (AmLexin, Unigen) containing extracts of catechu 67 mg and white mulberry 133 mg twice daily for 8 weeks during training and for 1 week after a half-marathon reduces muscle pain and stiffness on the first and third days post-race when compared with placebo (103270).
• Osteoarthritis. Oral catechu 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 combination product (Limbrel, Primus Pharmaceuticals) containing flavocoxid, a combination of flavonoid extracts from catechu and Baikal skullcap, 500 mg once or twice daily for up to 12 weeks reduces symptoms of osteoarthritis of the knee when compared to baseline. These studies found no significant difference between this combination product and naproxen 440 mg once daily or naproxen 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. More evidence is needed to rate catechu for these uses.

(Read more about CATECHU)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Androgenic alopecia. Although there has been interest in using oral white mulberry for androgenic alopecia, there is insufficient reliable evidence about the clinical effects of white mulberry for this purpose.
• Common cold. Although there has been interest in using oral white mulberry for symptoms of the common cold, including cough and sore throat, there is insufficient reliable evidence about the clinical effects of white mulberry for this purpose.
• Diabetes. While research is mixed, most small clinical studies suggest that oral white mulberry does not reduce fasting blood glucose or glycated hemoglobin (HbA1c) in patients with type 2 diabetes; however, it does seem to improve insulin resistance and postprandial blood glucose in these patients. Details: A meta-analysis of 4 small, mostly low-quality clinical studies in adults with impaired glucose tolerance or type 2 diabetes shows that taking white mulberry extract for 12 weeks does not reduce HbA1c when compared with placebo, dietary education, or no treatment. White mulberry extract also does not reduce fasting plasma glucose but may improve glucose intolerance (110480). However, studies utilized heterogeneous dosing regimens, with doses ranging from 500 mg twice daily to 4.6 grams three times daily and 1-deoxynojirimycin (DNJ) content in each dose ranging from 5-18 mg. Additionally, a small clinical study in adults with type 2 diabetes not included in the analysis above shows that taking white mulberry extract 300 mg twice daily for 12 weeks improves insulin resistance but does not reduce fasting blood glucose or HbA1c when compared with placebo (110481). Due to its small size, this study may have been inadequately powered to detect a difference between groups. One clinical study in adults with type 2 diabetes shows that taking powdered white mulberry leaf 1 gram three times daily for 4 weeks reduces fasting blood glucose levels by 27% compared with an 8% reduction with glyburide 5 mg daily. However, neither treatment significantly reduced HbA1c levels over the 4-week period (16494). The short study duration may explain the lack of significant HbA1c reduction. The effect of white mulberry on postprandial glucose levels has also been assessed. Taking a single 0.8-1.2 gram dose of powdered white mulberry leaf standardized to contain DNJ 1.5% or taking a single 250 mg dose of a specific white mulberry leaf extract (Reducose, Phynova Group) standardized to contain DNJ 4.5% to 5.5% reduces peak blood glucose levels after ingestion of 50-75 grams of sucrose when compared with placebo in adults with or without type 2 diabetes (16495,17051,105796).
• Hyperlipidemia. It is unclear if oral white mulberry is beneficial in patients with hyperlipidemia; the available research has mixed results. Details: A small clinical study in adults with type 2 diabetes shows that taking white mulberry extract 300 mg twice daily for 12 weeks does not decrease serum triglycerides, or levels of total, low-density lipoprotein (LDL), or very-low-density lipoprotein (VLDL) cholesterol when compared with placebo (110481). Due to its small size, this study may have been inadequately powered to detect a difference between groups. However, another small clinical study in adults with type 2 diabetes shows that taking white mulberry leaf 1 gram three times daily for 4 weeks reduces total cholesterol levels by 12%, triglycerides by 16%, LDL by 23%, and VLDL by 17% when compared to baseline. Plasma HDL was increased by 18% (16494). The validity of these findings is limited by the lack of a comparator group. White mulberry has also been studied in combination with other ingredients. In one small clinical study, taking a specific product (LopiGLIK, Akademy Pharma) containing white mulberry leaf extract 200 mg, berberine, and red yeast rice daily for 4 weeks reduced LDL cholesterol to less than 130 mg/dL in 57% of participants, compared with only 22% of those receiving a different combination product (Armolipid Plus, RottapharmSpA) that contains red yeast rice, berberine, and other ingredients, without white mulberry. Both products reduced triglycerides and total cholesterol to a similar extent (100624).
• Hypertension. Although there has been interest in using oral white mulberry for hypertension, there is insufficient reliable evidence about the clinical effects of white mulberry for this purpose.
• Impaired glucose tolerance (prediabetes). It is unclear if oral white mulberry is beneficial in patients with impaired glucose tolerance. Details: One small clinical study in obese patients with impaired glucose tolerance shows that taking white mulberry leaf powder 4.6 grams three times daily before meals for 12 weeks decreases fasting blood glucose by around 4 mg/dL and glycated hemoglobin (HbA1c) by 0.12% when compared to baseline. Neither measure was improved in the placebo group (103870). Although a statistically significant improvement in glycemic control was established, the observed reductions in fasting plasma glucose and HbA1c were modest and unlikely to be clinically meaningful.
• Joint pain. Although there has been interest in using oral white mulberry for joint pain, including joint pain associated with osteoarthritis and rheumatoid arthritis (RA), there is insufficient reliable information about the clinical effects of white mulberry for these conditions.
• Obesity. It is unclear if oral white mulberry can reduce body weight in patients who are obese or overweight. Details: A small clinical study in overweight and obese adults on a calorie-restricted diet shows that taking white mulberry extract 800 mg three times daily with meals for 90 days reduces body weight by about 10%, compared to a loss of about 3% with placebo (100627). However, a small clinical study in overweight and obese adults with type 2 diabetes shows that taking white mulberry extract 300 mg twice daily for 12 weeks does not decrease body weight when compared with placebo (110481).
• Osteoporosis. Although there has been interest in using oral white mulberry for osteoporosis, there is insufficient reliable evidence about the clinical effects of white mulberry for this purpose. More evidence is needed to rate white mulberry for these uses.

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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.

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LIKELY SAFE ...when used orally in amounts commonly found in foods. Catechu has Generally Recognized As Safe (GRAS) status for use in foods in the US (4912). There is insufficient reliable information available about the safety of catechu when used orally in medicinal amounts. A specific product (Limbrel, Primus Pharmaceuticals) containing flavocoxid, a mixture of flavonoid extracts from catechu and Baikal skullcap, 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 catechu, Baikal skullcap, or the combination. There is insufficient reliable information available about the safety of catechu when used topically.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods. Catechu has Generally Recognized As Safe (GRAS) status for use in foods in the US (4912). There is insufficient reliable information available about the safety of catechu when used orally in medicinal amounts or when used topically during pregnancy and lactation.

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POSSIBLY SAFE ...when used orally and appropriately. White mulberry powdered leaf or leaf extract has been used with apparent safety at doses of up to 4.6 grams three times daily for up to 12 weeks (16494,17051,100627,103870,105796,110480). There is insufficient reliable information available about the safety of white mulberry berries.

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

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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.

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ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use with antihypertensive drugs might increase the risk of hypotension.  Details Catechu might lower blood pressure (14144).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black catechu may increase the levels and clinical effects of CYP1A2 substrates.  Details Animal research shows that black catechu can increase theophylline concentrations in the blood, possibly by inhibiting CYP1A2 (94560). Theophylline is a CYP1A2 substrate.

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, catechu might interfere with immunosuppressant therapy.  Details Animal and in vitro studies suggest that catechu has immunomodulating effects (103271).

THEOPHYLLINE Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, black catechu may increase the levels and clinical effects of theophylline.  Details Animal research shows that black catechu can increase theophylline concentrations in the blood, possibly by inhibiting cytochrome P450 1A2 (94560).

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, white mulberry leaf might increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Clinical research shows that white mulberry leaf can lower blood glucose levels (16494,16495,17051,103870,105796). Advise patients to monitor glucose levels closely.

ORGANIC CATION TRANSPORTER 2 (OCT2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, white mulberry leaf might slow the elimination and increase the adverse effects of drugs which are OCT2 substrates.  Details Animal research shows that coadministration of white mulberry leaf extract with metformin, an OCT2 substrate, slows the renal elimination of metformin via inhibition of OCT2 activity (103869). OCT2 is expressed in the kidneys and is responsible for transporting cationic drugs into tubular epithelial cells in order to be excreted in the urine.

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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).

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General ...There is limited reliable information available about the adverse effects of catechu when used orally or topically as a single ingredient. A specific combination product (Limbrel, Primus Pharmaceuticals) containing flavonoid extracts of catechu and Baikal skullcap has been associated with serious adverse effects, including liver and lung injury.

Hepatic ...A specific combination product (Limbrel, Primus Pharmaceuticals) containing flavocoxid, a mixture of flavonoid extracts from catechu and Baikal skullcap, has been linked to several reports of acute liver damage. In a case series, four reports of liver damage were described in patients taking this product. The patients involved 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 and liver transaminase levels. All patients fully recovered and levels normalized within 3 months after discontinuation (18009,18011). 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 catechu, Baikal skullcap, or the combination.
More recently, in another case report, a 54-year-old female reported to the emergency room with acute hepatitis possibly due to taking a preparation of catechu and Baikal skullcap for 2-4 weeks. Causation was unable to be established. After discontinuing the supplements and supportive treatment, liver function returned to normal (94563). It was unclear if the catechu product was the same specific combination product (Limbrel, Primus Pharmaceuticals) associated with previous reports of liver damage.

Pulmonary/Respiratory ...A specific combination product (Limbrel, Primus Pharmaceuticals) containing flavocoxid, a mixture of flavonoid extracts from catechu and Baikal skullcap, 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 catechu, Baikal skullcap, or the combination.

(Read more about CATECHU)

General ...Orally, white mulberry leaf seems to be well tolerated.
Most Common Adverse Effects:
Orally: Transient bloating, constipation, flatulence, and loose stools.

Gastrointestinal ...Orally, white mulberry leaf powder 4. 6 grams three times daily for 4 weeks was associated with bloating and flatulence in 50% of patients, loose stools in 25% of patients, and constipation in 21% of patients in one clinical study. However, reports of these adverse effects decreased over the course of the 12-week study, suggesting that for some patients the adverse effects may be transient in nature (103870).

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