1. St. John’s Wort Does it do anything?

2. Taxonomy Kingdom Plantae Kingdom Plantae Subkingdom Tracheobionta Subkingdom Tracheobionta Superdivision Spermatophyta Superdivision Spermatophyta Division Magnoliophyta Division Magnoliophyta Class Magnoliopsida Class Magnoliopsida Subclass Dilleniidae Subclass Dilleniidae Order Theales Order Theales Family Clusiaceae Family Clusiaceae Genus Hypericum L. Genus Hypericum L. Species Hypericum perforatum L. Species Hypericum perforatum L. Common Names--St. John's wort, hypericum, Klamath weed, goat weed Common Names--St. John's wort, hypericum, Klamath weed, goat weed

3. Botanical Information Considered a weed in many areas Considered a weed in many areas Perennial Perennial Rhizomous Rhizomous Native to Europe Native to Europe Found in Europe, North America, & Asia Found in Europe, North America, & Asia Grows well in sandy, dry soil with few nutrients as long as it has ample sun Grows well in sandy, dry soil with few nutrients as long as it has ample sun

4. Distribution and Use Leaves are used for antidepressant and other purposes Leaves are used for antidepressant and other purposes Flowers are used to promote wound healing Flowers are used to promote wound healing Alcoholic extracts commonly available in your local grocery store Alcoholic extracts commonly available in your local grocery store Usually in pill form or tea- ointments or other dermal applications also used Usually in pill form or tea- ointments or other dermal applications also used Typical Dose: ~2g of herb or 500-1800 mg extract per day Typical Dose: ~2g of herb or 500-1800 mg extract per day Over $200 million in sales in the US. Over $500 million worldwide Over $200 million in sales in the US. Over $500 million worldwide

5. Chemical Constituents Substances found and described using various chromatographic methods (esp. HPLC). Flavonol derivatives Biflavones Proanthocyanidines Xanthones Phloroglucinols* Naphthodianthrones* *Most notable: hypericin and hyperforin

6. Pharmacokinetics Metabolized by cytochrome P450 in the liver (like many drugs) Metabolized by cytochrome P450 in the liver (like many drugs) Hypericin may not cross the blood-brain barrier, hyperforin more likely an active ingredient Hypericin may not cross the blood-brain barrier, hyperforin more likely an active ingredient Most of the purported active ingredients are heterocyclic and are metabolized quickly (half life < 6 hrs). Most of the purported active ingredients are heterocyclic and are metabolized quickly (half life < 6 hrs).

7. Pharmacodynamics Weak Inhibitor of MAO Weak Inhibitor of MAO Weak Reuptake Inhibitor of NE, DA, & 5-HT Weak Reuptake Inhibitor of NE, DA, & 5-HT Weak direct agonist of GABA A, GABA B, adenosine, & glutamate receptors Weak direct agonist of GABA A, GABA B, adenosine, & glutamate receptors Causes upregulation of 5-HT 2 receptors and downregulation of β-adrenergic receptors Causes upregulation of 5-HT 2 receptors and downregulation of β-adrenergic receptors These effects exerted by a combination of These effects exerted by a combination of hypericin, hyperforin and several flavonoids.

8. Animal Models Extracts increased performance of rats in forced swim test. Extracts increased performance of rats in forced swim test. Protected against effects of stress in learned helplessness experiments (also rats) Protected against effects of stress in learned helplessness experiments (also rats) These effects observed using methanol extracts containing These effects observed using methanol extracts containing hypericin, hyperforin and several flavonoids. Pure hypericin was ineffective. Reduced alcohol withdrawal in rats

9. Clinical Trials Big 2001 study funded by NIMH and Pfizer found St. John’s Wort did not relieve major depression any more than a placebo Big 2001 study funded by NIMH and Pfizer found St. John’s Wort did not relieve major depression any more than a placebo Herbalists slam big 2001 study funded by NIH Herbalists slam big 2001 study funded by NIH Older studies mixed; review finds “inconsistent an confusing results” Older studies mixed; review finds “inconsistent an confusing results” Dropout rates/side effects Dropout rates/side effects Mixed results may be due to poorly characterized St. John’s Wort, as well as inconsistent measurements of depressive symptoms… Mixed results may be due to poorly characterized St. John’s Wort, as well as inconsistent measurements of depressive symptoms…

11. More Clinical Trials Limited research on anxiety disorders Limited research on anxiety disorders No better than a placebo at treating social phobia No better than a placebo at treating social phobia Ineffective in treating neuropathic pain Ineffective in treating neuropathic pain “Subthreshold” depression “Subthreshold” depression 9 current trials funded by NCCAM 9 current trials funded by NCCAM Antiviral studies Antiviral studies

12. Toxicology Allergic Reactions (rare but serious) Allergic Reactions (rare but serious) Photosensitization Photosensitization Hypericism in animals-causes severe skin irritation and loss of appetite Hypericism in animals-causes severe skin irritation and loss of appetite Alters pharmacokinetics of other drugs by inducing CYP3A4 and altering P- glycoprotein Alters pharmacokinetics of other drugs by inducing CYP3A4 and altering P- glycoprotein Interaction with medication-including antidepressants Interaction with medication-including antidepressants Rarely toxic in humans Rarely toxic in humans

13. References Butterweck V, Wall A, Lieflaender-Wulf U, et al. 1997. Effects of the total extract and fractions of Hypericum perforatum in animal assays for antidepressant activity. Pharmacopsychiatry, 30 Suppl. 2, 117-24 Butterweck, V. 2003. Mechanism of action of St John’s wort in depression: What is known?, CNS Drugs, 17(8), 539-562 Butterweck, V. 2003. Mechanism of action of St John’s wort in depression: What is known?, CNS Drugs, 17(8), 539-562 Coskun, I., Uzbay, I., Ozturk, N., & Ozturk, Y. 2006. Attenuation of ethanol withdrawal syndrome by extract of Hypericum perforatum in Wistar rats. Fundamental and Clinical Pharmacology, 20(5), 481- 488. Coskun, I., Uzbay, I., Ozturk, N., & Ozturk, Y. 2006. Attenuation of ethanol withdrawal syndrome by extract of Hypericum perforatum in Wistar rats. Fundamental and Clinical Pharmacology, 20(5), 481- 488. Gambrana C, Ghiglieri O, Tolu P, et al. 1999. Efficacy of an Hypericum perforatum (St John’s wort) extract in preventing and reverting a condition of escape deficit in rats. Neuropsychopharmacology, 21(2), 247-54 Hypericum Depression Trial Study Group. 2002. Effect of Hypericum perforatum (St. John's wort) in major depressive disorder: a randomized controlled trial. Journal of the American Medical Association. 287(14), 1807–1814. Hypericum Depression Trial Study Group. 2002. Effect of Hypericum perforatum (St. John's wort) in major depressive disorder: a randomized controlled trial. Journal of the American Medical Association. 287(14), 1807–1814.

14. More References Linde K, Mulrow CD, Berner M, Egger M. 1998. St John's Wort for depression. Cochrane Database of Systematic Reviews Linde K, Mulrow CD, Berner M, Egger M. 1998. St John's Wort for depression. Cochrane Database of Systematic Reviews Schulz, V. 2006. Safety of St. John's Wort extract compared to synthetic antidepressants. Phytomedicine, 13(3), 199-205. Schulz, V. 2006. Safety of St. John's Wort extract compared to synthetic antidepressants. Phytomedicine, 13(3), 199-205. Sindrup, S., Madsen, C., Bach, F., Gram, L., & Jensen, T. 2001. St. John's wort has no effect on pain in polyneuropathy. Pain, 91(3), 61-65. Sindrup, S., Madsen, C., Bach, F., Gram, L., & Jensen, T. 2001. St. John's wort has no effect on pain in polyneuropathy. Pain, 91(3), 61-65. Wonnemann M, Singer A, Siebert B, et al. 2001. Evaluation of synaptosomal uptake inhibition of most relevant constituents of St John’s wort. Pharmacopsychiatry, 41 Suppl. 1, S148-S51. Wurglics, M. & Schubert-Zsilavecz, M. 2006. Hypericum perforatum: A modern herbal antidepressant: pharmacokinetics of active ingredients. Clinical Pharmacokinetics, 45(5), 449-469. Wurglics, M. & Schubert-Zsilavecz, M. 2006. Hypericum perforatum: A modern herbal antidepressant: pharmacokinetics of active ingredients. Clinical Pharmacokinetics, 45(5), 449-469.