Hypericum perforatUln: Nature's mood stabilizer - Semantic Scholar

Indian Journal of Ex perimental Biology Vol. 38, November 2000, pp. 1077- 1085

Review Article

Hypericum perforatUln: Nature's mood stabilizer Vikas Kumarl.2, P N Singh 1, A V Muruganandam 2 & S K Bhattacharya 1• 1

Pharmacology Laboratory, Department of Pharmaceutics, Institute of Technology,

2

Neuropharmacology Laboratory, Department of Pharmacology, Institute of Med ical Sciences, Banaras Hindu University, Varanasi 22 1 005, Indi a

Hypericum pe1Jorauun (HP), better known as St. John ' s Wort, has been used clini call y for centu ries. Modern usage is still quite diverse and includes kidney and lung ailments, insomnia and depression. Standardised extracts of HP are widely used in the treatment of psychovegetative di sorders and es pecially for mild forms of depression. Several bioacti ve constituent s of thi s plant may play importan t role 111 its well-known antidepressant acti vity, which arc discussed in the present article. Furthermore, emphasis is also given on its botany, chemi stry, pharmacology and clini cal efficacy.

The name Hypericum is a de rivation of two Greek words, hyper and eikon which translate "over" and " icon" as in "over an apparition ," alluding to its use in anci e nt times for protec tin g aga inst de moni c possess ion and its reported ability to protect one from "evil spirits." The species name fJe lj'oratum is based on the pe rforated appearance of the leaves due to their translucent leaf gland s which ca n be observed when he ld up to li ght. Hypericum pe!fora tum (HP) is also known as St. John 's W ort because its fl owers bl oom around St. John 's Day (June 24) and red pi gme nt s whi c h a re ex uded whe n the buds and fl owers are sq ueezed were associated with the blood 1 o f St. John the Bapti st • HP is a perenni a l p lant belonging to the Guttiferae fami ly. Some taxonomi sts c lass ify th e ge nu s Hype ricum in a separate family, the Hyperi caceae. The genu s Hypericum e ncompasses app rox imate ly 400 spec ies, of whi ch ten morp ho logica ll y and 2 chemically distinct spec ies grow in central Europe . HP is di stributed in Europe,- Asia, North Afri ca and North America. Indi an HP (THp) is a rhizomatu s pe renni a l herb grow in g up to a he ight o f 3 reet di stributed in the western Himalayas at altitudes of 3000-10,500 feet. Hypericum spec ies were already known to anci e nt communi ti es as useful medicinal plants. HP has been known si nce Gree k and Roman times. Closer to our 1 times , Mattioli a lso wrote of Hypericum in Discorsi . The use of HP in particul ar, as a re medy was described and recommended throughout th e Middl e * Correspondent author E-mail: salil @banaras .eJnet. in

Ages . The primary ancient medical he rbali sts , includin g Hippocrates, Pliny, Di osco rides, Th eophrastu s and G alen wrote abou t the medi cina l prope rti es of St. John 's wort, noting its use as a vulne rary (wound hea lin g) and for treatment of neura lgic conditi ons suc h as sciatica and hip pain . Matt io li wrote of its use as an e mme nagogue, diure tic 4 and antimalarial . The most co mmon use of Hype ricum has been for th e treatme nt of depression and vari ous psycho logical and neuralgic di sorders, as an anthelminti c for worms , a vu lne rary for minor he morrh ages, for bedwettin g in c hildre n, and as a 58 diuret ic - . Bes ides it has been also used as balm 9 for wounds, burns, ul cers and bites .

Botanical description HP is glabrous throughout, gree n or sometimes glaucescent; the stems are erect, branched at top a nd 30 to I 00 em long; th e leaves are ova l or e lli ptic, sucordate, or rathe r narrow, obl ong- lin ear, subobtuse, revo lute-marginated with nume rous pellucid black glandul ar dots. The flowers are numerous, formin g a broadly pani c ulate, almost co rymbose infl orescence, 7-llcm long and 5- 11 em broad . The bracts are lanceo late, 0.5 e m lon g a nd ac ute. The ca lyx is deep ly parted , 5 mm long and about two to th ree ti mes shorte r than coro lla ; sepals are lanceo late 4-5 mm long, I mm broad , as long as ova ry, acute or acuminate, with blac k g la ndul a r mostly ova l dots. The petals are ob long to oblon g e lliptic, in equi lateral, 1.2 to 1.5 em long, 0.5 to 0 .6 em broad, with numerous black g landu lar dots and lines on margin of uppe r pa rt , surface w ith nume rou s ye ll ow glandular dots. The stame ns are nume rous, in 3

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bundles; the ovaries ovoid, 3-5 mm long; there are three styles. The seed is I mm long, cylindric, brow n, minute ly pitted longitudinally. Chemistry

Hypericum contains numerous compounds with documented biological activity. Most researchers consider its effects to be due to a variety of constituents rather than any single component. Constituents th at have stimulated the most interest include the napthodianthrones hyperici n and pseudohypericin, a broad range of flavonoids, including quercetin, quercitrin, amentoflavone and hyperin, the phloroglucinol s hyperforin and adhyperforin , essenti al oils and xanthones . Recently hyperforin has been considered as an important 10 11 antidepress ive constituent of HP ' . The following major groups of bioactive constituents will summarise the constituents of HP: Napth odianthrones- The napthodi anthrones present in HP include hyperic in ( 1.8%), pseudohypericin (relative abundance 3.9%), isohypericin and emodin-anthrone (precursor of hypericins). Protohypericin and protopseudohypericin were al so detected in fresh material, wh ich on exposure to light yields hypericin and pseudohypericin, respectively. An oxidation product of pseudohypericin, cyclopseudohypericin was also cited 12' 13 . Flavonoids-Flavonoids present in the HP include, flavonol glycosides, viz., rutin (0.3 %), quercitrin (0 .314 15 0 .524%), isoquercitrin (0.3%) ' , hyperin/hyperoside (0.7-1.1 %) 16 , and aglycones, viz., kaempferol, luteolin, myricetin and quercetin (2 %). Biflavones-The following biflavones: 3,8"-bia16 17 pigenin (0.1-0.5% ) · , amentoflavone/ 3',8"-biapigenin (0.0 1-0.05% in flowers) , were reported from the HP. Proanthocyanidins-The proanthocyanidins, consisting of dimers, trimers, tetramers, and high polymers of catechin and epicatechin, represent approximately 12% of the dried weight of the aerial portion of the plant" 18 , the highest values were observed during the flowering stage. Phenyl propanes-HP contain phenyl propanes in the form of esters of cinnamic acids, such as pcoumaric and caffeic acids (0.1%). Chlorogenic acids have been detected and found to less than I%. Ferulic, isoferulic and gentisic acids alongwith leucocyanidin have also been described 19-2 1.

Phloroglucinols- Two

closely related phloroglucinol derivatives; hyperforin and 22 adhyperforin, were reported from the HP . The amount of hyperforin was found be 2% in flowers and 4.5 % in the unripe fruit s while the amount of adhyperforin was found to be 0.2% (flowers) and 24 1.6% (unripe fruits) 2 " . These hyperforin s were lipophilic, un stable toward heat and light either on storage or in solution. One of the products of degradation was 2-methyl-3-buten-2-ol, probably generated by oxidative cleavage of isoprenyl side chains of hyperforin and adhyperforin. Recently, an unu sual compound with combined structure of cadinan sesquiterpene and hyperforin, hydroperoxy5 cadiforin (0.0006%i , and furohyperforin (ca. 5% of 26 hyperforin concentration) were isolated and characterized from HP. Xanthones-A xanthanolignoid, kielkorin (0 .0 1% in roots) 27 , and I ,3 ,6,7-tetrahydroxy xanthone (i n trace amounts in leaves and stems) 2 x were reported in HP. Essential oil-The essential oil consists mostly of 19 monoterpenes (pinenes) and sesqu iterpines . Of these, the primary compounds include the saturated hydrocarbons, 2-methyl-octane ( 16.4% and a-pinene (I 0.6% ). Also present were traces of 2-methyldecane, 2-methyl-butenol and undecane, b-p inene, atocopherol, geraniol, myncme, linolene, caryophillene, humulene, C 16 and C24 n-alkanes, and 29 31 C24, C26 and C28 n-alkanol s - . Add itional compounds include choli ne, carotenoids (lutein, luteoxanthin, violaxanthin, cis-throllixanthin, throllichromone), b-sitosterol, pectin, phlobaphene and rhodan ; isovalerianic, lauric, myristic, nicotinic (0.12% in leaves, palmitic and steari c acids, amino acids; including cysteine, GABA (0.7 mg/g), glutamine, leucine, lysine, orn ithine, proline, threonine, scopoletin, umbelliferone, and vitamin ci 6. 19J I-34 .

The pharmacological act1v1ty of constituents are summarised in Table I.

various

Biological properties Hypericum perforatum has been widely researched for its antidepressant effects. Recent interest has focused on its potential as an antiviral agent. There is some data confirming its traditional wound-healing effects. Hypericum contains several compounds of biological interest, including the napthodianthrones, hypericin and pseudohypericin , and a broad spectrum

KUMAR eta/.: HYPERICUM PERFORATUM

Table !-Pharmacological activity of constituents of Hypericum

Constituent

Activity

AmentoO avo ne (13 ', I 18-biapigenin )

Anti-inflammatory, anti-u lcerogeni c35

GABA

Sedative31

Hyperforin

Antibacterial against gram-positive bacteria, wound healing 22 ·23 ·3"; neurotransmitter inhibitor 31, potenti al anti carcinogenic·17

Hypericin

AntiviraJ 3x-40

I 3, I I 8-biapigenin

Probably sedative 35

2-methyl-butenol

Sedative31

Proanthocyanid ins

Antiox idant , antimicrobial, antiviral, vasorelaxant 31

Pseudohypericin

Antiviralw

Quercitrin

In vitro MAO inhibiting acti vity2x

Xanthones

Antidepressant, ant imicrobial, antiviral, diuretic, cardi otoni c, MAOA inhibitor2R,Jl ,41 ,42

of flavonoid s. Although investi gation s continue, these are considered to be primarily responsible for HP 's activities.

Antidepressant activity A commercial standardi zed extract of HP (Psychotonin®) was tested in several animal models 3 predictive of psychotropic activit/ . These activities included two, used for antidepressants, increased activity in water wheel test in mi ce and reduced aggressiveness in isolated mal e mtce. The pharmacological models most commonly used to demonstrate a potential antidepress ive activity of Hypericum ex tracts are the examination of the 1 behaviour of mice in an unknown environmen{ 44 forced swim test , and the measurement of bi ogeni~ 45 amines metabolites in urine . A corre lation can be established between the excretion in urine of 3methoxy-4-hydroxy phenyl glycol (MHPG), the main metabolite of noradrenaline, and the initiation of the therapeutic activity of HP as an antidepressant agent. 44 46 Butterweck et al. ' compared the Hypericum extract, LI 60, with bupropion, a sy nthetic antidepressant . Results indicated si mil ar effects of both the drugs in the tail suspension test (mi ce) and

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the forced swim test (rats). Since Hypericum treatment was antagonized by drugs known to reduce dopamine functional activity (haloperidol, sulpiride, a-methyltyrosine and g-butyrolactone) the authors concluded that Hypericum exerted its activity via dopaminergic activation. Hypericum extract, LI 160, subchronic treatment (250 mg/kg for two weeks) resulted in a 15 % down regulation of ~- adrenerg ic receptors in the rat frontal cortex. In the same study, a 25% down regul ation was observed after the 47 imipramine treatment . Many question s exist about the composition, pharmacology and mechanisms of action of HP. In fact the active constituent is still unclear. While previous studies report that hypericin inhibits MAO 48 at concentrations of 50 flg/mL , others have fail ed to 49 5 1 confirm thi s effect - . Some of the research work on the identification of the active antidepressant constituent has been performed using computer modelling. Out of the fl avonoids, xanthones and hypericins compared best. Overlap was obtained with flavonoid derivatives and suggest fla vonoid s as the most likely MAO inhibitor fraction, due to structural similarity to toloxone and brofaromine, two known 49 52 inhibitors of MAO-A . Bladt and Wagner reported that the Hypericum fraction s with the greatest MAO inhibition contains the hi ghest concentration of flavonoids . In another study, the xanthone fract ion 28 was particularly strong inhibitor of MAO-A in vitro . However, the MAO inhibition shown by Hypericum may not be pharmacolog ically re levant since it has 49 not been confirmed in vivo. Bladt and Wagner reported that no MAO inhibition was seen in vivo after administration of 300 mg/kg Hype ricum ex tracts to rats . Other proposed mechani sms involve effects on serotonin. Muller and Rosso l53 reported that Hypericum ex tract inhibits serotonin receptor ex press ion at 50 f.!M (- 25 flg/mL) and Perovic and 54 Muller reported inhibiti on of serotonin uptake (IC 50 = 6.2 flg/ml). The concentration required for the former effect could never be achieved in the whole animal and even the latter concentrations see m 47 unlike ly . As a reference co mparison, Mull er et a/. reported an IC 50 for the syntheti c antidepressant , clomipramine, of 0.9 nM (- 0.3 ng/ml ) for seroton in uptake inhibition . In addition, an inhibition of both synaptosomal GABA uptake (IC 50 = I flg/ml , LI 160) and GABAA-receptor binding (TC 50 = 3 flg/mL) was noted.

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Through an National Institute of Mental Health (NIMH, USA) sc reening co ntract (Novasc reen, Baltimore, Maryl and) a commercially availab le crude extract from the fresh flowers and buds of HP was subjected to in vitro assays in a battery of 39 receptor types and two enzyme systems. The receptor assays showing 50% di spl acement of radioligand (or 50% inhibition of MAO) were considered "hits". Concentration-response curves (IC 50) were then performed for the hits. The crude ex tract of HP had significant receptor affinity for adenosine, GABAA, GABAB, serotonin , benzodi azepine, inos itol 55 triphosphate (IP 3), and MAOA.B . The inhibiti on of MAO by crude Hypericum extracts is consistent with . previous repo rts48 ·49 ··s I . u nI"1ke the cru de ex tract, syntheti c hyperi cin (95%) lacked significant MAOA or MAOB inhibition at concentrat ions up to I 0 ~M . Hypericin had affinity only for NMDA receptors (Ki-1 ~M ) and thi s may play a role in its reported anti viral activity since NMDA antagoni sts prevent gp 120-induced neurotoxic ity56 . These data are co nsistent with the recent pharmaco logical ev idence suggesting that oth er constituents of this plant may be more important for the reported psychotherapeutic acti vity. More recently , hyperforin, a prenylated phloroglucinol present in this plant, has been focused as primarily respons ible for the ant idepressa nt . .Ity of tI1e HPI O·II ··'i7-60 . M any o f tI1e ex pen. menta I act iV studi es 60 have confi rmed the and cli nical antidepressant activity of hyperforin . Hyperforin was shown to inhi bit uptake of serotonin (5-HT), dopamine (DA), noradrenaline (NA), GABA and Lglutamate with IC.'io val ues of about 0.05 - 0.10 ~t g/ml (5-HT, NA, DA , GABA) and about 0.5 ~g/ml (Lgl utamate) in synaptosomal preparation 11 . Recentl y, Indian Hyp ericum pe1joratum (IHp) extract standard ised for hyperforin lacked MAO A and B inhibitory acti vi t/ 1• Additionally, IHp showed . I . 61 anti"d epressant 6?-, anx10 yt1c · and nootrop1.c 64 ·6S· activities. Another novel proposal is th at Hypericum ex tract reduces cytokine ex press ion (i nterl eukin-6)66 . The hypothes is is that interleukins can induce depress ion in susceptible indi vidual s67 . The lin k between depression and the immune system is we ll establi shed 67 . In addition to the antidep ressant effects, Hypericum has hi storically been used for a wide variety of neurol ogical conditi ons, including anxiety, insomni a due to restlessness, irritability, neuralgia,

trigeminal neural gia, neuroses, mi graine headac hes, fibrosis, dyspepsia (oi l), and sc iatica6'>· 7 1•74 . Wound healing properties Hypericum has hi stori call y been one of the most relied upon botani ca ls for the treatment of wounds. Part of thi s activity is due to Hypericum's antimicrobi al act ivity, which is attributed to the essential oil , phloroglucinol s and flavo noids. The essential oil and th e water-soluble fraction of an alcoholi c ex tract ex hibit minor antifun gal and significant antibacteri al activity. A res in fraction of the alcoholic ex tract has also been shown to be effecti ve aga inst gram-posi ti ve organi sms 72 . The tannins and fl avo noids were reported to in acti vate 74 Escherichia coli at diluti on of I :400 or I :20073. . Hyperforin and ad hyperforin have bee n reported to possess an chemotherapeuti c effect greater than th at of sulfanilamide 75 . An ointment prepared by ex tracting the fresh fl owers (5 g) with oli ve oiI ( I 00 g) (for I 0 days at 20.C) was used in th e treatment of I ' 1, 2"0, and 3"1 degree bu rns. First degree burn s healed in 48 hours. Second and third degree burn s healed atleast three times faster th an burn s treated with co nven ti onal methods and keloid formation was inhibited 76 . A commercial preparation containing 0.4 12% quercitrin (Novoimamin) was found to be effecti ve aga inst Staphylococcus au reus in fection 75 and its effects have been reported to be greater than conventi onal treatment with sulfanilamide77 . A tin cture ( 1: 10) of Hypericum was studied for its wound healing properti es and compared with calendul a, anothe r widely used wound hea ling herb . The effect of orally ad mini stered tincture of Hypericum was more pronounced than topical application of Calendula tinc ture in the healing of incision, exc ision and dead space woun ds, as evidenced by an increase 111 epithel isati on and wound-breaking strength 7 . Antiviral acti vity Hypericin is currentl y in earl y clinical tri al in the USA as an antiviral agent 4 · 3'J. In an open pilot stud y, 18 patients with acq uired immune deficiency syndrome (AIDS class ification s; 3 with CDC II, 8 with CDC IVB and 3 with CDC IVCI) were treated with an i.v. Hypericum pe1joratum preparation (Hyperforat; 2x2ml week ly) plus additional Hypericum tablets of undefin ed dosage. Sixteen out of 18 pati ents with good study compliance showed

KUMAR eta/.: HYPERICUM PERFORATUM

increasing counts of absolute CD4 values over a 40month period . Also observed were improvements in CD4/CD8 ratios in the majority of patients. In addition only 2 of the 16 patients experienced an opportumst1c infection during the 40-month observation period. The other 14 of the 16 patients remained clinically stable78 . Studies have shown that two of HP' s primary components, hypericin and pseudohypericin, inhibit a variety of encapsulated viruses, including herpes simplex types I and 240 ' 79 and the human immunodeficiency virus type I (HIV -1) v1rus associated with AIDS 39 ·80 ' 81 . While the later ·researchers have concluded that hypericin and pseudohypericin display a unique and effective antiviral activity, Weber et al. 40 suggest that it may be due to non-specific association with cellular and viral membranes. In vitro antiviral activity has also been reported against murine cytomegalovirus, parainfluenza 3 virus, Sindbis virus 8 1, vesicular stomatitis virus 79 , and equine infectious anemia virus 82 . The antiviral activity appears to involve a photoactivation process 8 1-85 which forms singlet oxygen and inactivates viral fusion and syncytia formation 86-88 . While hypericin does show antiviral activity in vivo (mice), these photodynamic properties may limit its potential usefulness as an antiretroviral agent 89 . However, besides singlet oxygen production , hypericin can photoreduce oxygen to superoxide radicals and can form semiquinone radicals in the absence of li ght 38 . These authors speculate that thi s ability to form semiquinones might account for the antiviral activity. Protein kinase C inhibition Hypericin has been reported inhibit the growth of glioma cell lines in vitro and to be a potent inducer of glioma cell death due to inhibition of protein kinase C (PKC) as measured by ['H] thymidine uptake 90 . The anti-PKC activity doses are reported to be below those associated with clinical hypericism90 . Other researchers report a PKC-inhibiting activity with both hypericin and pseudohypericin (TC 50 of 1.7 Jlg/ml and 15 Jlg/ml, respectively) 9 1. Receptor tyrosine kinase activity of epidermal growth factor has also been reported to be inhibited hypericin 92 . These effects have been linked to both the antiviral and antineoplastic activities 38'93 . In addition, the PKC inhibition may also contribute to the antiinflammatory effects hi storically associated with

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Hypericum as hypericin has been found to inhibit the 3 release of arachidonic acid and leukotriene B/ • Other effects Hypericum has been reported to have number of additional effects. In one study the procyanidin fraction of Hypericum was tested in an isolated guinea pig heart preparation 94 and found to enhance coronary flow in the same way as the procyanidin from Crataegus (Hawthorn) . The procyanidins fractions also antagonized histamine or prostaglandin F2a-induced atrial contractions in porcine isolated . 95 coronary artenes . In another study, a significant increase in the production of nocturnal melatonin was observed after administration of 90 drops of the commercial preparation, Hyperforat. These effects were observed after a three week period 96 . Other researchers report that Hypericum may be useful in the treatment of chronic tension headaches 97 , while a hepatoprotective activity of a water/alcohol extract has also been reported in animals 98 . Pain and inflammation of nerve origin may also respond to Hypericum which can be administered both topically and orally 99- 101 . Recent study with IHp in our lab confirms its antiinflammatory and analgesic activiti 02 . Clinical studies Hypericum has become increasingly popular in Germany, where physicians routinely prescribe herbal medicines. In 1994, 66 million daily doses of HP were prescribed there for use in the treatment of depression 103 . This phytomedicine has been tested in more than 3,000 patients against placebo and various . me d.!CatiOns . 104- 109 G active . erman researc hers recent 1y published a meta-analysi s of 23 randomized trial s of Hypericum with a total of I ,757 outpatients with mild to moderately severe depressive disorders. They concluded that the herb was significantly superior to placebo and appeared comparably effective to standard antidepressants (maprotiline, 1m1pramine and amitriptyline) while producing fewer side effects 6. Pharmacokinetic studies Detailed pharmacokinetic studies have been performed with the standardized Hypericum extract, Ll 160 (Jarson® 300), one of several officially recognized formulations (containing 300 mg of the dried extract of HP, yielding 0.24-0 .32% total

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hypericin) in Germany for the treatment of mild to moderate depression. Oral administration of this preparation was given to twelve healthy male subjects 110 • Hypericin and pseudohypericin were determined in plasma using an HPLC technique (limit of detection 0.2 ng/ml) after oral administration of single doses of 300, 900 and 1800 mg total extract. Blood levels were measured for up to three days after a single dose. Peak plasma concentrations were seen with hypericin after 2.0 to 6.0 hours and with pseudohypericin between 0.4 to 0.6 hours . Peak concentrations of hypericin were 1.5, 7.5 and 14.2 ng/ml , respectively, for the three doses of the extract. Pseudohypericin attained concentrations of 2.7, 11.7 and 30.6 ng/ml, res pectively. The elimination half-life of hypericin was between 24.8 and 26.5 hours. The elimination half-life of pseudohyperici n ranged from 16.3 to 22.8 hours. Repeated doses over 14 days (3x300 mg/day) resulted m steady state (level at which the constituents accumulate to reach a steady concentration) after four days. The peak concentration of hypericin was 8.5 ng/ml and 5.8 ng/ml for pseudohypericin. Trough concentrations ( 14 hours after the last dose) were between 5.3 and 11 0 3.7 ng/ml for both compounds . Earlier pharmacokinetic data on mice report that maximum plasma concentrations of hypericin and pseudoh ypericin were reached at 6.0 hours and maintained for atleast 8.0 hours. The aqueousethanolic extract used contained 1.0 mg of hyperi cin. The same researchers also tested the concentration of hypericin in one human test subject after a single dose of the same extract. The concentrations found in human serum were comparable to those fou nd in the · Ill m1ce Pharmaco kinetic studies of Hypericwn ex tracts containing hypt>rforin revealed th e half-li fe and clearance values as 6 hour and 70 ml/min/kg respective ly . After oral administration of 300 mg/kg Hypericum extract (WS 5572, contai nin g 5% hyperforin) to rats maximum plasma le ve ls of approx imately :no ng/ml (approx. 690 nM ) were reached after 3 h, as quantified by HPLC and UV detection meth od. Conclusion Hypericum ts a clearly one of the leading psychotherapeutic phytomedicines for the treatment of mild to moderat e depression. The shortcomin gs of

the current controlled clinical triaL of Hypericum have been pointed out in the review by Linde et al. 6 and by Ernst 11 2 • They include lack of wellcharacterised severely depressed patients populations, heterogeneity of diagnoses, lack of intent-to-treat analyses, lack of long term studies, lack of control over compliance, and low dosages of comparison medications. Despite the extensive use of thi s plant extract as an antidepressant , the chemical nature of its bioactive principles still remains unclear. Earlier, in vitro studies with hypericin and pseudoh ype ricin as MAO inhibitory agents suggested that hy pericin may be responsibl e for the antidepressant activity of this plant. Consequently, the pharmaceutical preparati ons were standardized on the basis of their hyperi cin contents. However, in later studi es, these earlier results cou ld not be confirmed. Flavonoids present in the HP were also shown to inhibit MAO-A, but a therapeutic efficacy of this class of compounds appeared doubtful due to th eir low plasma levels after oral administration" '. Recently, hyperforin, a preny lated phloroglucinol present in this plant, has been fo cused as the major component responsible for the antidepressant activity of HP. The lack of viable pharmaco logical mechani sm or the assurance of which components within th e plant are critical for therapeutic effect (necessary in order to standardi se formulations) will continu e to create skepticism among psychopharmacologists and regul atory aut horiti es. However, continued research is needed to identify the constituents most responsible for Hypericum 's activity so that preparation s can be optimall y standardised. While determin ing the pharmacological profile of all major components of Hype ricum wi ll be a difficult task, it wi ll surely add to the body of know ledge regarding the biochemi st ry of depress ion . The presence of significant anxiolyt ic activity of HP extract63, suggest that co-existence of anxio lytic-antidepressant act ivity may help in its clinical profile since anxiety and depress ion often coex ist. References I Upton R, St. Joh n' s wo rt monograph, American Herbal Pharmacopoei a, Sant a Cruz, CA, USA, 1997. 4. 2 Hoelzl J, lnhaltssto llc und Weitschrift des johanniskratutes, Zeitschrift fur Phytothcrapie, 14 ( 1993) 255. 3 Mattioli I, Disco rsi- Venezia, ( 1557) 447. 4 Bornbardelli E & Morazzoni P, Hypericum pe1joratwn. Fitoterapia , 66 ( 1995) 43.

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5 Fernie WT, Herbal Simples, John Wiel y & Co, Bristol , 1897. 6 Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W, Melchart , D : St. John 's wort for depression - an overview and meta-analysis of randomi zed clinical tri als, British Medical Journal, 3 13 ( 1996) 253. 7 Rao SG, Laxminarayan AU , Saraswathi LU , Padma GM, Ganesh R & Kuk arni DR , Calendula and Hypericum: two homeopathi c drugs promoting wound healing in rats, Fitoterapia , 6 ( 199 1) 508. 8 Vickery AR, Traditional uses and folklore Hypericum in British Isles, Economic Botany, ( 1981 ) 289. 9 Gerard J, The Herbal, Revi sed and enl arged T Johnson, Reprinted by Dover Publications Inc, New York , 1975, 1633. 10 Mull er WE, Singer A, Wonnemann M, Hafner U, Rolli M & Schafer C, Hyperforin represents the neurotransmitter reuptake inhibiting constituent of hyperi cum extract, Pharmacopsychially, 3 1 ( 1998) 16. II Chatterjee SS , Bhattacharya SK, Wonnemann M, Singer A & Muller WE, Hyperforin as a possible antidepressant component of Hypericum extracts, Life Sciences, 63 ( 1998) 499. 12 DAC, Deutscher Arzneimillel - Codex, 3rd Supplement 9 1 ed, 1986. 13 ESCOP, Monograph St. John 's wort, European Scientic Cooperative for phytomedici nes, The Netherlands, Meppel, 1996. 14 Dorosseiv I, Determinati on of fl avonoids in Hypericum 11e1foratum , Pharmazie, ( 1985) 585. 15 Kogel TA, Determination of amount of quercitrin in Hypericum pe~foratum , Khimiya Prirodnykh Suedin enii, 2 (1987) 185. 16 Hansel R, Keller K, Rimpler H & Schneider G, Hagers Hcmdbuc/1 der Plwrmazeutischen Praxis , val 5, (Springe rVerl ag, Berlin), 1993. 17 Berghofer R & Hol zl J, Biflavonoids in Hypericum perforatum, Part I. Isolation of 13, 11 8 - biapigen in . Plallla Medica, ( 1987) 2 16. 18 Akhtardzhiev K & Kit anov G, Catechin composi ti on of Hypericum petforatum. Farmatsiya (Sophia), 24 ( 1974) 17. 19 Bcnigni R, Capra C & Cattorini PE, Hypericum , Piwlle Medicina/i: Chimica, Farmaco /ogia e Terapia, Mil ano, ln verni and Dell a BeiTa, 197 1. 20 Seabra RM , Vasconcelos MH , Costa MA & Alves AC, Phenolic compou nds from Hypericum petjoratu111. L and H undulatum , Fitoterapia, 63 ( 1992) 473 . 21 Stoyanova A, Popova M & Georgiev E, Thin-l ayer chromatography of extracts of Hypericum petforatU III , Fannatsiya (Sofia), I ( 1987) 8. 22 Bystrov NS, Chernov BK, Dobryn in VN & Kolosov MN, The structure of hyperforin , Tetrahedran Le/1, 32 ( 1975) 2791 . 23 Maisenbacher P & Kovar AK, Adhypcrforin : a homologue of hyperforin for Hypericum petforatum , Plan/a Med, ( 1992) 291. 24 Maisenbacher P & Kovar AK, Analysis and stab ility of Hyperi ci oleum. Planta Med, ( 1992) 35 1. 25 Ruecker G. Manns D, Hartmann R & Bon scls U, A C-50hydropcr-ox idc from Hypericum per{oratu111, A rch Pharm (We inheim ), 328 ( 1995) 725.

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