St. John’s St. John’s WortWortDoes it do anything?Does it do anything?

TaxonomyTaxonomy KingdomKingdom Plantae Plantae SubkingdomSubkingdom Tracheobionta Tracheobionta SuperdivisionSuperdivision Spermatophyta Spermatophyta DivisionDivision Magnoliophyta Magnoliophyta ClassClass Magnoliopsida Magnoliopsida SubclassSubclass Dilleniidae Dilleniidae OrderOrder Theales Theales FamilyFamily Clusiaceae Clusiaceae GenusGenus Hypericum L. Hypericum L. SpeciesSpecies Hypericum perforatum L. Hypericum perforatum L. Common Names--St. John's wort, Common Names--St. John's wort,

hypericum, Klamath weed, goat weedhypericum, Klamath weed, goat weed

Botanical Botanical InformationInformation

Considered a weed in many Considered a weed in many areasareas

PerennialPerennial RhizomousRhizomous Native to EuropeNative to Europe Found in Europe, North Found in Europe, North

America, & AsiaAmerica, & Asia Grows well in sandy, dry Grows well in sandy, dry

soil with few nutrients as soil with few nutrients as long as it has ample sunlong as it has ample sun

Distribution and UseDistribution and Use

Leaves are used for Leaves are used for antidepressant and other antidepressant and other purposespurposes

Flowers are used to Flowers are used to promote wound healingpromote wound healing

Alcoholic extracts Alcoholic extracts commonly available in commonly available in your local grocery storeyour local grocery store

Usually in pill form or tea-Usually in pill form or tea-ointments or other dermal ointments or other dermal applications also usedapplications also used

Typical Dose: ~2g of herb Typical Dose: ~2g of herb or 500-1800 mg extract or 500-1800 mg extract per dayper day

Over $200 million in sales Over $200 million in sales in the US. Over $500 in the US. Over $500 million worldwidemillion worldwide

Chemical Chemical ConstituentsConstituents Substances found and

described using various chromatographic methods (esp. HPLC).

Flavonol derivatives Biflavones Proanthocyanidines Xanthones Phloroglucinols* Naphthodianthrones* *Most notable: hypericin

and hyperforin

PharmacokineticsPharmacokinetics

Metabolized by cytochrome P450 in Metabolized by cytochrome P450 in the liver (like many drugs)the liver (like many drugs)

Hypericin may not cross the blood-Hypericin may not cross the blood-brain barrier, hyperforin more likely brain barrier, hyperforin more likely an active ingredientan active ingredient

Most of the purported active Most of the purported active ingredients are heterocyclic and are ingredients are heterocyclic and are metabolized quickly (half life < 6 metabolized quickly (half life < 6 hrs).hrs).

PharmacodynamicsPharmacodynamics Weak Inhibitor of MAOWeak Inhibitor of MAO Weak Reuptake Inhibitor of NE, DA, & 5-HTWeak Reuptake Inhibitor of NE, DA, & 5-HT Weak direct agonist of GABAWeak direct agonist of GABAAA, GABA, GABABB, ,

adenosine, & glutamate receptorsadenosine, & glutamate receptors Causes upregulation of 5-HTCauses upregulation of 5-HT22 receptors receptors

and downregulation of and downregulation of ββ-adrenergic -adrenergic receptorsreceptors

These effects exerted by a combination of These effects exerted by a combination of hypericin, hyperforin and several flavonoids.

Animal ModelsAnimal Models

Extracts increased performance of rats in Extracts increased performance of rats in forced swim test.forced swim test.

Protected against effects of stress in learned Protected against effects of stress in learned helplessness experiments (also rats)helplessness experiments (also rats)

These effects observed using methanol These effects observed using methanol extracts containing extracts containing hypericin, hyperforin and several flavonoids. Pure hypericin was ineffective.

Reduced alcohol withdrawal in rats

Clinical TrialsClinical Trials

Big 2001 study funded by NIMH and Pfizer Big 2001 study funded by NIMH and Pfizer found St. John’s Wort did not relieve major found St. John’s Wort did not relieve major depression any more than a placebodepression any more than a placebo

Herbalists slam big 2001 study funded by Herbalists slam big 2001 study funded by NIHNIH

Older studies mixed; review finds Older studies mixed; review finds “inconsistent an confusing results”“inconsistent an confusing results”

Dropout rates/side effectsDropout rates/side effects Mixed results may be due to poorly Mixed results may be due to poorly

characterized St. John’s Wort, as well as characterized St. John’s Wort, as well as inconsistent measurements of depressive inconsistent measurements of depressive symptoms…symptoms…

More Clinical TrialsMore Clinical Trials

Limited research on anxiety disordersLimited research on anxiety disorders No better than a placebo at treating No better than a placebo at treating

social phobiasocial phobia Ineffective in treating neuropathic painIneffective in treating neuropathic pain ““Subthreshold” depressionSubthreshold” depression 9 current trials funded by NCCAM9 current trials funded by NCCAM Antiviral studiesAntiviral studies

ToxicologyToxicology Allergic Reactions (rare but serious)Allergic Reactions (rare but serious) PhotosensitizationPhotosensitization Hypericism in animals-causes severe Hypericism in animals-causes severe

skin irritation and loss of appetiteskin irritation and loss of appetite Alters pharmacokinetics of other Alters pharmacokinetics of other

drugs by inducing CYP3A4 and drugs by inducing CYP3A4 and altering P-glycoprotein altering P-glycoprotein

Interaction with medication-including Interaction with medication-including antidepressantsantidepressants

Rarely toxic in humansRarely toxic in humans

ReferencesReferences 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 Butterweck, V. 2003. Mechanism of action of St John’s wort in depression: What is known?, in depression: What is known?, CNS Drugs,CNS Drugs, 1717(8), 539-562(8), 539-562

Coskun, I., Uzbay, I., Ozturk, N., & Ozturk, Y. 2006. Coskun, I., Uzbay, I., Ozturk, N., & Ozturk, Y. 2006. Attenuation of ethanol withdrawal syndrome by extract of Attenuation of ethanol withdrawal syndrome by extract of Hypericum perforatumHypericum perforatum in Wistar rats. in Wistar rats. Fundamental and Fundamental and Clinical Pharmacology, 20Clinical Pharmacology, 20(5), 481-488.(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 Depression Trial Study Group. 2002. Effect of Hypericum perforatumHypericum perforatum (St. John's wort) in major depressive (St. John's wort) in major depressive disorder: a randomized controlled trial. disorder: a randomized controlled trial. Journal of the Journal of the American Medical AssociationAmerican Medical Association. . 287287(14), 1807–1814. (14), 1807–1814.

More ReferencesMore References

Linde K, Mulrow CD, Berner M, Egger M. 1998. St John's Linde K, Mulrow CD, Berner M, Egger M. 1998. St John's Wort for depression. Wort for depression. Cochrane Database of Systematic Cochrane Database of Systematic ReviewsReviews

Schulz, V. 2006. Safety of St. John's Wort extract Schulz, V. 2006. Safety of St. John's Wort extract compared to synthetic antidepressants. compared to synthetic antidepressants. Phytomedicine, Phytomedicine, 1313(3)(3),, 199-205. 199-205.

Sindrup, S., Madsen, C., Bach, F., Gram, L., & Jensen, T. Sindrup, S., Madsen, C., Bach, F., Gram, L., & Jensen, T. 2001. St. John's wort has no effect on pain in 2001. St. John's wort has no effect on pain in polyneuropathy. polyneuropathy. Pain, 91Pain, 91(3), 61-65. (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. Wurglics, M. & Schubert-Zsilavecz, M. 2006. Hypericum Hypericum perforatumperforatum: A modern herbal antidepressant: : A modern herbal antidepressant: pharmacokinetics of active ingredients. pharmacokinetics of active ingredients. Clinical Clinical Pharmacokinetics, 45Pharmacokinetics, 45(5), 449-469.(5), 449-469.