St. John's Wort (Hypericum perforatum)
1. History
St. John’s wort is a yellow flowering plant that derives its name from flowering around June 24th which is St. John the Baptist’s Day. The use of St. John’s wort dates back to the ancient Greeks as well as the Roman military of the 1st century AD.. Interestingly, during the Middle Ages, St. John’s Wort was used as a component of magical potions, where the belief was held it would protect humans from magical beings, such as witches, demons, and evil diseases (Poldinger). Interestingly, beyond its magical uses, St. John’s wort was also used in construction of “Freikugel,” which is a magical bullet thought to always hit its target (St. John's Wort). It was also historically used to treat anxiety and depressive disorders for which many find its use now.
2. Medicinal and non-medicinal use
Medicinal: St. John’s wort is a commonly used herbal supplement for depression and anxiety disorders and has been studied in clinical trials for the treatment of depression, specifically mild to moderate depression (Ehrlich). It has also been used in malaria, for sedation, as a balm for wounds, burns, and insect bites, and sleep disorders (St. John's Wort NCCAM). Other complementary and alternative medicine (CAM) indications are antiviral, antibacterial topically and systemically, analgesic, wound healing, and for the treatment of oral herpes simplex (St. John’s Wort NCCAM).
Non-medicinal use: A concentrated extract is made from the yellow flower of the plant, which is used to make teas, tablets, and capsules (St. John’s Wort NCCAM).
3. Major component(s) hypothesized to be the active ingredient(s). Include chemical entities if applicable
Components of St. John’s wort extract are hypericin, pseudohypericin, flavonoids (hyperoside, rutin), biflavones, hyperforin, tannins, procyanidins, chlorogenic acid, isoquercitrin, quercitrin, quercetin, 13,II8-biapigenin, and amentoflavone (St. John’s Wort Micromedex).
4. Theorized mechanism of action:
The active agents of St John’s Wort are probably either hypericin or hyperforin. The mechanism is not known, although there are many proposed mechanisms. The antidepressant effects may be due to reuptake inhibition of serotonin, norephinephrine, or dopamine. In vitro and in vivo T Cell suppression was observed, and inhibition of free radicals has been observed in vitro. This may explain St. John’s Wort’s immunosuppressive effects in the treatment of skin disorders. St. John’s wort is bacteriostatic for two types of gram positive bacteria: B. subtilis and B. cereus (Barrette).
5. Clinical issues; DDIs, suggested dose, adverse effects, pharmacokinetics, overdose, use in special population (pregnant women, elderly...etc.) (Hammerly, Rouse, Spoerke)
Drug-Drug Interactions: oral contraceptives, cyclosporine, digoxin, indinavir (including other anti-virals), irinotecan, antiepileptics such as phenobarbital and phenytoin, warfarin, SSRIs, SNRIs, and MAOIs. St. John’s wort is a P450 inhibitor so it will interact with many drugs affected with this metabolic enzymatic system.
Adverse effects: Photosensitivity, anxiety, dry mouth, dizziness, gastrointestinal upset, constipation, diarrhea, fatigue, headache, edema, pruritus, or sexual dysfunction.
Pharmacokinetics:
In the treatment of depression, the therapeutic drug concentration of pseudohypericin is 8.5mcg/L and 100ng/ml for hyperforin where both pseudohypericin and hyperforin have a time to peak concentration of 3 hours when administered orally. Hypericin has a time to peak concentration of 4-6 hours. The oral bioavailability of St. John’s wort tablets is unknown. The distribution half-life of hyperforin is 3 hours, and the elimination half-life 28.1-41.7 hours for hypericin and 9-22.8 hours for hyperforin. Metabolism of another constituent of St. John’s wort, hypericin, is through the liver, but the percent metabolized hepatically is unknown. Total body clearance for St. John’s wort occurs at a rate of 200-340 ml/min (Hammerly, Rouse, Spoerke).
Dosing:
Adult-Depression
capsule or tablet administered orally: 300mg three times daily
dried herb taken orally: 2-4g three times daily
tea taken orally: 2-3g brewed and taken as a single dose
liquid extract with 25% ethanol taken orally: 2-4mL three times daily
tincture in 45% ethanol: 2-4mL three times daily
PMS
capsule/tablet administered orally: 300mg daily
Seasonal affective disorder
capsule/tablet given orally: 300mg three times daily
Pediatric-Depression (6-12 years)
extract given orally: 200-400mg per day given in divided doses only under medical supervision
Overdose:
Research on chronic toxic effects of St John’s wort has been performed in animals and in vitro. These studies found the maximal effective dose of St John’s Wort to be 5,000 mg/kg in mice and rats. Nonspecific side effects, including weight loss, were observed, but no other major side effects or mutagenic effects were observed. Various case studies report toxic effects from ingesting large amounts of St John’s Wort, including hepatotoxicity, photosensitivity, convulsions, and hypertensive crisis (St. John’s wort Natural).
Special Populations:
St. John’s wort is given a Briggs risk factor of C but is also listed as contraindicated during pregnancy with the risk of acting as an abortifacient and sufficient scientific data is lacking. For lactation, there is not enough scientific data to determine the safety of St. John’s wort.
6. Efficacy vs. safety
Since St. John’s wort is an herbal medication and carries the classification as a supplement, the United States does not require regulation of the manufacture or purity of ingredients so the safety if often not known (Hammerly, Rouse and Spoerke). The safety of St. John’s wort has been given a class 2d rating by the American Herbals product association due to its effects on MAOIs (Hammerly, Rouse and Spoerke). Natural Standard’s Efficacy Rating System gives St. John’s Wort an “A” grade (strong scientific evidence of benefit) for only one indication, depression. All other indications for St. John’s Wort were given a B, C, or D grade (good, conflicting, or fair evidence) by Natural Standard (Barrette).
7. Information about the standard of the various preparations available
St. John’s wort is supplied capsule, tablet, liquid extract, or tea (Micromedex). The standard of St. John’s wort formulations is hypericin or hyperforin; however, this is not to disclude other chemical components of St. John’s wort that may be effective (Hammerly, Rouse, and Spoerke).
8. Cost (compare to prescription medication):
From GNC, the cost for GNC Herbal Plus brand (100 capsules) is $19.99 (GNC). From Walgreens, the cost for Sundown Naturals brand St. John’s wort (150 capsules) is $13.99 (Sundown).
For 25mg of sertraline, the cost according to Pharmacy Checker is anywhere from $30.00 to $74.90 for 100 tablets/capsules from online pharmacies. For 50mg of sertraline, the cost for 100 tablets/capsules is anywhere from $37.99 to $157.09. For 100mg of sertraline, the cost for 100 tablets/capsules is anywhere from $36.00 to $216.94 (Sertraline).
9. Prevalence of use
In a 2002 FDA study of supplement use in the U.S., 6.5% of respondents reported using St. John’s Wort in the past year. St. John’s wort was the seventh most commonly used herbal or nonvitamin dietary supplement, according to the study (Timbo).
10. Evidence-based studies
A randomized, double-blind, multi-site study was conducted testing St. John’s wort against placebo for use in moderate depression in 340 subjects. In this same study, St. John’s wort was tested against the active comparator, sertraline. The primary outcomes analyzed were improvements (as indicated by a reduction) in the Hamilton Depression Scale (HAM-D) and response to treatment (using a reduction in the HAM-D scale and Clinical Global Impressions-Improvement Scale (CGI-I) score). Those receiving St. John’s wort, experienced a reduction of 8.7 points in the HAM-D scale when compared to the placebo group, who had a reduction of 9.2 points and compared to sertraline which had a reduction of 10.5 points. The results for the response to treatment were 24% for St. John’s wort, 32% for placebo, and 25% for sertraline. The primary outcomes of the trials yielded results that were not statistically significant, but it is important to note that a lack of statistical significance is common for trials testing antidepressants (“Study Shows St. John’s wort”).
In another study, a meta-analysis was performed based on twenty-three trials, found St. John’s wort to be superior to placebo and comparable to the active comparator. The patients analyzed in each trial were reported to suffer from mild to moderately severe depression. Thirteen of the twenty-three trials compared St. John’s wort, more specifically a hypericum extract, to placebo where there were 94 (22.3%) responders to placebo compared to 225 (55.1%) responders to the hypericum extract (95% CI 1.78 to 4.01). Nine trials of the thirteen provided data based on the Hamilton depression scale where results indicated a 4.4 points better in the hypericum group compared to the placebo group (95% CI 3.5 to 5.3). In five trials comparing hypericum extract to an active comparator, there were 101 responders (63.9%) to single preparation hypericum compared to 93 responders (58.5%) to the active comparator antidepressant (CI 0.93 to 1.31). There were 88 responders (67.7%) to combination hypericum preparations compared to 66 responders (50%) for the active comparator antidepressant (CI 0.78 to 2.94). The result of this trial was not statistically significant due to a lack of power from the sample size, so while St. John’s wort preparations may work better than placebo or may be no worse than the active comparator antidepressant, the results are inconclusive (Linde).
11. Comparable prescription or non-prescription medications
St. John’s Wort has been compared in systematic reviews and meta-analyses to SSRIs (fluoxetine, citalopram, sertraline, and paroxetine) tricyclic antidepressants, and benzodiazepines. Many studies found that St. John’s Wort is more effective than placebo treatment and approximately as effective as standard antidepressive therapy (Barrette).
12. Any regulatory issues
There are almost no regulations regarding the use of St. John’s wort or the amounts of St. John’s Wort in products imported from other countries. St. John’s Wort is not included on the FDA’s GRAS (Generally Regarded as Safe) List. The U.S. Cosmetic Ingredient Review Expert Panel determined that there is not enough data to justify the use of St. John’s Wort in cosmetic products (Barrette). In 2000, the FDA issued a health alert concerning St. John’s wort and the potential for dangerous interactions with prescription medications such as indanavir, cyclosporine, and oral contraceptives (Lumpkin). An FDA-funded randomized controlled study found no difference between St. John’s wort and placebo to treat moderately severe depression; however, the study also found no difference between placebo and sertraline. This study indicates that St. John’s wort is not an effective treatment for depression (“Questions and Answers”).
References
Ehrlich, Steven D. St. John's wort. 24 June 2013. 30 January 2014
GNC Herbal Plus® Standardized St. John's Wort. 30 January 2014 <http://www.gnc.com/GNC-Herbal-Plus-Standardized-St-Johns-Wort/product.jsp?productId=2133911>.
Hammerly, M. MD, J. ND Rouse and D. MS, RPh Spoerke. "St. John's wort." March 2004. Micromedex. 4 February 2014 <http://www.micromedex.com/products/altmeddex/samples/stjohnswort.pdf>.
Pöldinger, W. "History of St. John's wort." Praxis (Bern 1994). 89.50 (2000): 2012-9.
Sertraline. 30 January 2014 <http://www.pharmacychecker.com/compare-drug-prices-online-pharmacies/sertraline-100+mg/19288/31428/>.
St. John's Wort. 23 November 2012. 4 February 2014 <nccam.nih.gov/health/stjohnswort/ataglance.htm>.
"St. John's Wort." Micromedex. Truven Health Analytics. 4 February 2014 <www.micromedex.com/products/altmeddex/samples/stjohnswort.pdf>.
"St. John's wort (Hypericum perforatum)." Natural Standard. Natural Standard Professional Monograph. 4 February 2014 <http://www.naturalstandard.com.proxy.lib.umich.edu/databases/herbssupplements/stjohnswort.asp?#dosingtoxicology>.
"Study Shows St. John's Wort Ineffective for Major Depression of Moderate Severity." 9 April 2002. Nationcal Center for Alternative and Complementary Medicine. 30 January 2014 <http://nccam.nih.gov/news/2002/stjohnswort/pressrelease.htm>.
Sundown Naturals St. John's Wort 300 mg Herbal Supplement Capsules. 30 January 2014 <http://www.walgreens.com/q/st-johns-wort>.
Timbo, Babgaleh, Ross, Marianne, McCarthy, Patrick, Lin, Chung-Ting. “Dietary Supplements in a National Survey: Prevalence of Use and Reports of Adverse Events.” 2006. Journal of the American Dietetic Association 106:12. 30 January 2014
Linde, Klaus, Ramirez, Gilbert, Mulrow, Cynthia, Pauls, Andrej, Weidenhammer, Wolfgang and Melchard, Dieter. “St John’s wort for depression- an overview and meta-analysis of randomised clincial trials.” 24 April 1996. BMJ 313:253. 30 January 2014
Barrette, EP, editor. “St John’s Wort Natural Standard Professional Monograph.” 2013. Natural Standard. 4 February 2014
Lumpkin, Murray and Alpert, Susan. “Risk of Drug Interactions with St. John’s Wort and Indinavir and other Drugs.” 10 February 2000. U.S. FDA. 4 February 2014 <http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm052238.htm>.
“Questions and Answers: A Trial of St. John’s Wort (Hypericum perforatum) for the Treatment of Major Depression.” 8 March 2013. National Center for Complementary and Alternative Medicine. National Institutes of Health. 4 February 2014
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