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DRUG RECORD

 

SKULLCAP

(SCUTELLARIA LATERIFLORA)

OVERVIEW
Skullcap

 

Introduction

Skullcap is Native American plant, the dried leaves and stems of which are used as an herbal medication and in teas to treat anxiety, stress and insomnia.  Skullcap has been linked to several instances of clinically apparent liver injury, but usually in combination with other botanicals.

 

Background

Skullcap is a flowering perennial plant native to North America (Scutellaria lateriflora) used for centuries by Native Americans to treat menstrual disorders, nervousness, digestive and kidney problems.  The name skullcap refers to the flower’s resemblance to helmets worn by European soldiers.  Skullcap was used formerly for nervous disorders, including hysteria, nervous tension, epilepsy and chorea.  It is now used largely as a sedative and sleeping pill, often in combination with other herbs such as valerian.  Skullcap extracts are prepared from the aerial parts of the Scutellaria lateriflora plant and contain large amounts of flavonoids, including scutellarin and baicalin, which are believed to be the active components accounting for its sedative and antispasmodic activity.  It is thought that the flavonoid compounds may act as gamma amino butyric acid (GABA) agonists similar to the benzodiazepines.  There are more than 200 species of Scutteria which have different components and activities as well as potential toxicities.  Skullcap is available as a powder to prepare in tea, as a liquid solution and in capsules.  Scutellaria is listed as a component in many commercially available, over-the-counter herbal mixtures.

 

Hepatotoxicity

Skullcap has been implicated in rare instances of clinically apparent liver injury, although in most cases multiple herbal medications were being taken and the role of skullcap in the hepatic damage was unclear.  Furthermore, in some instances phytochemical analysis has identified significant adulterants (germander) or mislabelling in cases of suspected skullcap hepatotoxicity.  In reported cases, the onset of symptoms and jaundice occurred within 6 to 24 weeks of starting skullcap, and the serum enzyme pattern was typically hepatocellular.  Immunoallergic and autoimmune features were usually absent, although low titers of autoantibodies were not infrequent.  Recovery was rapid once the herbal was discontinued, but some cases have resulted in acute liver failure.  Chinese skullcap is a different species, but may also have adverse effects on the liver.  There have been several reports and small case series of acute liver injury with jaundice arising after 1 to 3 months of starting herbals or dietary supplements with Chinese skullcap (Scutellaria biacalensis), the liver injury resembling that associated with North American skullcap (Scutellaria lateriflora).

 

Mechanism of Injury

The mechanism of skullcap hepatotoxicity is not known.

 

Outcome and Management

Hepatotoxicity from skullcap is rare, and is usually mild to moderate in severity and resolves rapidly once the botanical is stopped.  There have been no instances of chronic liver disease, cirrhosis or vanishing bile duct syndrome linked to skullcap administration.

Other Names:  Blue pimpernel, Helmet flower, Hoodwort, Mad weed, Quaker bonnet, Scullcap, Scutellaria

 

Drug Class:  Herbals and Dietary Supplements

 

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CASE REPORT
Skullcap

 

Case 1.  Acute hepatitis due to combination of skullcap and valerian.
[Modified from:  Caldwell SH, Feeley JW, Wieboldt TF, Featherston PL, Dickson RC. Acute hepatitis with use of over-the-counter herbal remedies. Va Med Q 1994 Winter; 121(1): 31-3. PubMed Citation].

 

A 53 year old woman developed worsening insomnia, anxiety and jaundice 4 weeks after starting an herbal preparation for sleep that contained skullcap (Scutellaria) and valerian root (Valeriana officianalis) for sleep.  She had no history of liver disease, alcohol abuse or risk factors for viral hepatitis.  She took no other medications except for a cup of herbal tea 2 to 3 times weekly which contained chaparral leaf (Larrea tridentate), and rare use of other miscellaneous herbals.  On examination, she was jaundiced but had no fever, rash or signs of chronic liver disease.  Laboratory testing showed a serum bilirubin of 9.0 mg/dL with marked increases in serum aminotransferase levels (ALT 1208 U/L, AST 1082 U/L), and modest increase in alkaline phosphatase (298 U/L) and normal prothrombin time and serum albumin (Table).  The white count and differential were normal.  Tests for hepatitis A, B and C were negative as were autoantibodies.  Immunoglobulin levels revealed a slight increase in IgG (2240 mg/dL), but normal IgA and IgM.  An anti-CMV IgM assay was positive, but urine cultures were negative and serial titers of anti-CMV were stable.  Abdominal ultrasound showed no evidence of gallstones or biliary obstruction.  A liver biopsy was not done.  She was monitored on no therapy and improved steadily.  One month later, the jaundice had resolved and 3 months after stopping the herbal, all liver tests were normal.


Key Points

Medication:Skullcap and valerian (4 capsules nightly)
Pattern: Hepatocellular (R=8.5)
Severity: 3+ (jaundice, hospitalization)
Latency: 4 weeks
Recovery: 12 weeks
Other medications:None, except occasional herbal tea containing chaparral leaf

Laboratory Values

Time After Starting Time After Stopping ALT (U/L) Alk P (U/L) Bilirubin (mg/dL) Other
Started sleeping aid with skullcap and valerian root
4 weeks 0 1208 298 9.0 Admission, herbals stopped
8 weeks 4 weeks 161 Normal
16 weeks 12 weeks Normal Normal Normal
Normal Values <65 <136 <1.2

Comment

The case history is entirely compatible with drug induced liver injury caused by one of the several botanicals that she was taking.  Skullcap (Scutellaria lateriflora) has been associated with cases of clinically apparent liver injury, but largely in association with other botanicals that have also been implicated in causing hepatotoxicity.  Valerian has been reported to cause an acute hepatitis-like syndrome alone or in combination with skullcap, both of which have purported sedative qualities leading to their mixture in herbal preparations claimed to help sleep.

 

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REPRESENTATIVE TRADE NAMES
Skullcap – Generic

 

DRUG CLASS
Herbals and Dietary Supplements

 

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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Skullcap 94279-99-9 Herbal mixture Not applicable

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REFERENCES
Skullcap

 

References updated: 02 January 2014

 

  1. Zimmerman HJ. Unconventional drugs. Miscellaneous drugs and diagnostic chemicals. In, Zimmerman, HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott,1999: pp. 731-4.  (Expert review of hepatotoxicity published in 1999; hepatotoxicity of herbals is discussed, but skullcap is not specifically mentioned).

  2. Seeff L, Stickel F, Navarro VJ. Hepatotoxicity of herbals and dietary supplements. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 631-58.  (Review of hepatotoxicity of herbal and dietary supplements [HDS]).

  3. Scullcap. In, PDR for Herbal Medicines. 4th ed. Montvale, New Jersey: Thomson Healthcare Inc. 2007: pp. 739.  (Compilation of short monographs on herbal medications and dietary supplements).

  4. Harvey J, Colin-Jones DG. Mistletoe hepatitis. Br Med J(Clin Res Ed) 1981; 282: 186-7. PubMed Citation  (49 year old woman developed fatigue and abdominal pain on two occasions after a few weeks of taking an herbal containing mistletoe and skullcap [bilirubin 2.5 mg/dL, ALT >250 U/L, Alk P 123 U/L], resolving in 6 to 24 weeks, the authors attributed the injury to mistletoe).

  5. Mizoguchi Y, Miyajima K, Sakagami Y, Yamamoto S. [A severe case of drug-induced allergic hepatitis in herbal medicine]. Nippon Naika Gakkai Zasshi 1986; 75: 1453-6. Japanese. PubMed Citation  (A 27 year old developed jaundice 6 weeks after taking Kinshigan, a Kampo herb with rapid recovery, but recurring with a more severe course 2 weeks after restarting [bilirubin 28.5 mg/dL, ALT 166 U/L, Alk P 1.5 times ULN, 1% eosinophils]; among 18 ingredients of the product was Scuttelariae radix).

  6. MacGregor FB, Abernethy VE, Dahabra S, Cobden I, Hayes PC. Hepatotoxicity of herbal remedies. BMJ 1989; 299: 1156-7. PubMed Citation  (Four cases of hepatitis attributed to herbals, all women, ages 41-57, developed jaundice 2 to 8 weeks after starting herbals for stress [“Neurelax” and “Kalms”] believed to contain skullcap and/or valerian [bilirubin 13.5-28.3 mg/dL, ALT 293-1165 U/L, Alk P 97-730 U/L], resolving 2-19 months after stopping).

  7. Miskelly FG, Goodyer LI. Hepatic and pulmonary complications of herbal medicines. Postgrad Med J 1992; 68: 935. PubMed Citation  (77 year old woman developed fatigue followed by jaundice 6 months after starting an herbal product with comfrey and skullcap [bilirubin 3.5 mg/dL, AST 520 U/L, Alk P 390 U/L], resolving within 6 months of stopping).

  8. Bruseth S, Enge A. [Scullcap—liver damage. Mistletoe hepatitis]. Tidsskr Nor Laegeforen 1992; 112: 2389-90. Norwegian. PubMed Citation  (Letter mentioning that mistletoe has been implicated in causing liver injury, but that the patient was also taking skullcap; mistletoe has been used in more than 30,000 cancer patients with no evidence of liver injury, although allergic reactions have been reported).

  9. Caldwell SH, Feeley JW, Wieboldt TF, Featherston PL, Dickson RC. Acute hepatitis with use of over-the-counter herbal remedies. Va Med Q 1994; 121: 31-3. PubMed Citation  (53 year old woman developed jaundice 4 weeks after starting an herbal for sleep containing skullcap and valerian given as 4 capsules nightly [bilirubin 9 mg/dL, ALT 1208 U/L, Alk P 298 U/L, protime 13.5 sec], resolving within 3 months of stopping: Case 1).

  10. Hullar TE, Sapers BL, Ridker PM, Jenkins RL, Huth TS, Farraye FA. Herbal toxicity and fatal hepatic failure. Am J Med 1999; 106: 267-8. PubMed Citation  (28 year old man developed jaundice after taking skullcap and pau d’arco for 6 months for his multiple sclerosis [bilirubin 29.0 mg/dL, ALT 3917 U/L, Alk P 106 U/L, protime 20 seconds, ANA 1:640], progressing to liver failure and liver transplant 5 weeks later, dying shortly thereafter; explant showed sinusoidal obstruction syndrome).

  11. Stickel F, Seitz HK, Hahn EG, Schuppan D. [Liver toxicity of drugs of plant origin]. Z Gastroenterol 2001; 39: 225-32, 234-7. German. PubMed Citation  (Review of hepatotoxicity of botanicals including pyrrolizidine alkaloids, germander, celandine, chaparral, Chinese herbs and pennyroyal).

  12. Stedman C. Herbal hepatotoxicity. Semin Liver Dis 2002; 22: 195-206. PubMed Citation  (Review and description of patterns of liver injury, including discussion of potential risk factors, and herb-drug interactions; skullcap is listed as potentially causing veno-occlusive disease).

  13. Whiting PW, Clouston A, Kerlin P. Black cohosh and other herbal remedies associated with acute hepatitis. Med J Aust 2002; 177: 440-3. PubMed Citation  (6 cases of severe hepatitis in patients taking herbal medications, including one on black cohosh alone and 5 taking multiple herbals including skullcap [n=3], valerian [n=2], chaparral [n=1] and greater celandine [n=1] for 1-14 weeks, presenting with jaundice [bilirubin 9.9-62.7 mg/dL, ALT 1293-3764 U/L, Alk P 80-219 U/L], 1 on black cohosh alone requiring liver transplantation, the other 5 resolving in 7-25 weeks; 3 were treated with prednisone for prolonged cholestasis).

  14. Schiano TD. Hepatotoxicity and complementary and alternative medicines. Clin Liver Dis 2003; 7: 453-73. PubMed Citation  (Comprehensive review of herbal associated hepatotoxicity, including common patterns of presentation; mentions two reports of hepatotoxicity due to skullcap).

  15. Pittler MH, Ernest E. Systematic review: hepatotoxic events associated with herbal medicinal products. Aliment Pharmacol Ther 2003; 18: 451-71. PubMed Citation  (Systematic review of published cases of hepatotoxicity due to herbal medications listing 52 case reports or case series, most common agents being celandine [3], chaparral [3], germander [8], Jin Bu Huan [3], kava [1], Ma Huang [3], pennyroyal [1], skullcap [2], Chinese herbs [9], valerian [1]).

  16. Estes JD, Stolpman D, Olyaei A, Corless CL, Ham JM, Schwartz JM, Orloff SL. High prevalence of potentially hepatotoxic herbal supplement use in patients with fulminant hepatic failure. Arch Surg 2003; 138: 852-8. PubMed Citation  (Among 20 patients undergoing liver transplantation for acute liver failure during 2001-2, 10 were potentially caused by herbals: 3 Ma Huang, 3 kava, 2 LipoKinetix, 1 chaparral, 1 skullcap and 2 miscellaneous Chinese herbs).

  17. Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug-induced liver injury in the United States. Liver Transpl 2004; 10: 1018-23. PubMed Citation  (Among ~50,000 liver transplants reported to UNOS between 1990 and 2002, 270 [0.5%] were done for drug induced acute liver failure, including 7 [5%] for herbal medications, but skullcap not mentioned as a cause).

  18. Seeff LB. Herbal hepatotoxicity. Clin Liver Dis 2007; 11: 577-96. PubMed Citation  (Review of herbal induced hepatotoxicity, with a review of two reports of acute liver injury attributed to skullcap in the literature).

  19. García-Cortés M, Borraz Y, Lucena MI, Peláez G, Salmerón J, Diago M, Martínez-Sierra MC, et al. [Liver injury induced by “natural remedies”: an analysis of cases submitted to the Spanish Liver Toxicity Registry]. Rev Esp Enferm Dig 2008; 100: 688-95. Spanish. PubMed Citation  (Among 521 cases of drug induced liver injury submitted to Spanish registry, 13 [2%] were due to herbals, but none were attributed to skullcap).

  20. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation  (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, 9% of cases were attributed to herbal medications, skullcap is not listed).

  21. Lin LZ, Harnly JM, Upton R. Comparison of the phenolic component profiles of skullcap (Scutellaria lateriflora) and germander (Teucrium canadense and T. chamaedrys), a potentially hepatotoxic adulterant. Phytochem Anal 2009; 20: 298-306. PubMed Citation  (Herbal extracts of skullcap [S. lateriflora]) have occasionally been contaminated with germander [T. chamaedrys], but mass spectrometry can separate the two by demonstration of phenylethanoid components of germander).

  22. Navarro VJ. Herbal and dietary supplement hepatotoxicity. Semin Liver Dis 2009; 29: 373-82. PubMed Citation  (Overview of the regulatory environment, clinical patterns, and future directions in research with HDS; skullcap is not discussed).

  23. Morgan SL, Baggott JE, Moreland L, Desmond R, Kendrach AC. The safety of flavocoxid, a medical food, in the dietary management of knee osteoarthritis. J Med Food 2009; 12: 1143-8. PubMed Citation  (Among 59 patients with osteoarthritis treated with flavocoxid [a medical food that contains baicalin extracted from Scutellaria baicalensis] vs placebo for 12 weeks, side effects were minor, and mean ALT or AST values did not change).

  24. Levy R, Khokhlov A, Kopenkin S, Bart B, Ermolova T, Kantemirova R, Mazurov V, Bell M, Caldron P, Pillai L, Burnett B. Efficacy and safety of flavocoxid compared with naproxen in subjects with osteoarthritis of the knee- a subset analysis. Adv Ther 2010; 27: 953-62. PubMed Citation  (Among 220 patients with osteoarthritis treated with flavocoxid [a medical food that contains baicalin] or naproxen for 12 weeks, rates of ALT elevations were similar and none were >5 times ULN or associated with symptoms or jaundice).

  25. Pillai L, Burnett BP, Levy RM; GOAL Study Cooperative Group. GOAL: multicenter, open-label, post-marketing study of flavocoxid, a novel dual pathway inhibitor anti-inflammatory agent of botanical origin. Curr Med Res Opin 2010; 26: 1055-63. PubMed Citation  (Among 1005 patients with osteoarthritis treated with flavocoxid [a medical food that contains baicalin] in an open label study, only one subject had liver test abnormalities, but no details given).

  26. Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute
    liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. PubMed Citation  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 [11%] were attributed to drug induced liver injury of which 12 [9%] were due to herbals, but none were attributed to skullcap).

  27. Linnebur SA, Rapacchietta OC, Vejar M. Hepatotoxicity associated with Chinese skullcap contained in Move Free Advanced dietary supplement: two case reports and review of the literature. Pharmacotherapy 2010; 30: 750, 258e-62e. PubMed Citation  (Two patients developed liver injury within weeks of taking “Move Free Advanced”, which contains Chinese skullcap [Scutellaria baicalensis] for arthralgias, resolving upon stopping).

  28. Stickel F, Kessebohm K, Weimann R, Seitz HK. Review of liver injury associated with dietary supplements. Liver Int 2011; 31: 595-605. PubMed Citation  (Review of current understanding of liver injury from herbals and dietary supplements focusing upon herbalife and hydroxycut products, green tea, usnic acid, noni juice, Chinese herbs, vitamin A and anabolic steroids; skullcap is not discussed).

  29. Yang L, Aronsohn A, Hart J, Jensen D. Herbal hepatoxicity from Chinese skullcap: A case report. World J Hepatol 2012; 4: 231-3. PubMed Citation  (78 year old woman developed jaundice 3 weeks after starting an herbal mixture of glucosamine, chondroitin, black catechu and Chinese skullcap [Scutellaria baicalensis] [bilirubin 7.2 mg/dL, ALT 1626 U/L, Alk P 354 U/L], resolving on stopping and recurring within 2 weeks of restarting).

  30. Kwon H, Lee SH, Kim SE, Lee JH, Jee YK, Kang HR, Park BJ, et al. Spontaneously reported hepatic adverse drug events in Korea: multicenter study. J Korean Med Sci 2012; 27: 268-73. PubMed Citation  (Among 9360 drug adverse reports made during 2007 and 2008 to a Korean pharmacovigilance center, 567 were hepatic of which only 3 were due to herbal medications, specific ingredients of which were not given).

  31. Chalasani N, Vuppalanchi R, Navarro V, Fontana R, Bonkovsky H, Barnhart H, Kleiner DE, et al. Acute liver injury due to flavocoxid (Limbrel), a medical food for osteoarthritis: a case series. Ann Intern Med 2012; 156: 857-60. PubMed Citation  (Flavocoxid, a medical food that contains Scutelleria baicalensis and Acacia catechu, was implicated in 4 cases of clinically apparent liver injury in women, ages 57 to 68 years, arising within 1-3 months of starting [bilirubin 2.0-20.8 mg/dL, ALT 741-1540 U/L, Alk P 286-770 U/L], resolving within 1-3 months of stopping).

  32. Teschke R, Wolff A, Frenzel C, Schulze J, Eickhoff A. Herbal hepatotoxicity: a
    tabular compilation of reported cases. Liver Int 2012; 32: 1543-56. PubMed Citation  (A systematic compilation of all publications on the hepatotoxicity of specific herbals identified 185 publications on 60 different herbs, including 4 reports that mention skullcap: MacGregor [1989], Calwell [1994], Hullar [1999], Estes [2003]).

  33. Bunchorntavakul C, Reddy KR. Review article: herbal and dietary supplement hepatotoxicity. Aliment Pharmacol Ther 2013; 37: 3-17. PubMed Citation  (Review of literature on hepatotoxicity due to herbals and dietary supplements; skullcap is mentioned, but not specifically discussed).

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OTHER REFERENCE LINKS
Skullcap

 

  1. PubMed logoRecent References on Skullcap

  2. Clinical Trials logoTrials on Skullcap

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