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Shrivastava and Dwivedi, IJPSR, 2015; Vol. 6(12): 1000-07. E-ISSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 1000
IJPSR (2015), Vol. 6, Issue 12 (Review Article)
Received on 30 May, 2015; received in revised form, 24 July, 2015; accepted, 29 September, 2015; published 01 December, 2015
THERAPEUTIC POTENTIAL OF HYPERICUM PERFORATUM: A REVIEW
Mansi Shrivastava* and L. K. Dwivedi
Institute of Biomedical Sciences, Bundelkhand University, Jhansi-284128, UP, India.
ABSTRACT: The irreversible effects of modern therapies and
increasing drug resistance have augmented our reliance on medicinal
plants for herbal remedy against the deadly and infectious diseases.
Hypericum perforatum or St. John’s wort (SJW) family Clusiaceae has
been used to treat depression, mental disorders, wounds, peptic ulcers,
malaria, gout and arthritis. Various compounds of the plant are known
as sedative, diuretic and expectorant according to their effects. The
flowers and the aerial parts are commonly used in the preparations of
traditional medicines. Hypericum perforatum with identified active
compounds like Hypericines, Hyperforins is being studied for its anti-
depressant activity in both humans and animals. It is also used in the
treatment of pulmonary complaints, bladder troubles in suppression of
urine, dysentery, worms, diarrhoea, hysteria and other haemorrhages
and jaundice. Most of its therapeutic effects with mechanism of action
are critically reviewed in the present paper.
INTRODUCTION: The Genus Hypericum L.
(Guttiferae/Clusiaceae/Hypericaceae) containing
465 species globally 41, 48, 49 is a large family of
plants with potential medicinal value. However, H.
perforatum is mainly studied for its bioactivities
due to its popularity among the depression patients.
Hypericum perforatum commonly known as St.
John’s wort is named so because of the traditional
collection of its flower at the feast of St. John the
Baptist on June 24th 48. It is a perennial herb native
to Asia and Europe 4, 38 but known globally for its
traditional and modern uses. The use of this species
as an herbal remedy to treat a variety of internal
and external ailments dates back to the time of the
ancient Greeks.
QUICK RESPONSE CODE
DOI:
10.13040/IJPSR.0975-8232.6(12).1000-07
Article can be accessed online on:
www.ijpsr.com
DOI link: http://dx.doi.org/10.13040/IJPSR.0975-8232.6(12).1000-07
Since then, it has remained a popular treatment for
anxiety, infection, and wound healing 38, 56, 57. In
last couple of decades, the majority of research on
H. perforatum was based on its use as anti-
depressant, which has expanded its popularity and
made it among the top selling dietary supplements
in the market 4, 14. Pharmaceutical companies,
particularly in Europe, prepare standard
formulations of this herb that are taken by millions
of people. Moreover, it has also attracted the
scientists’ brain for its anti-inflammatory and anti-
microbial properties against the inflammatory
diseases 14, 24.
Recent research suggests the effectiveness of this
herb in treating other ailments including cancer,
inflammation related disorders, and bacterial and
viral diseases, and used as an antioxidant and
neuro-protective agent. Of the total 400 species,
distributed in the temperate regions of the world,
about 25 species are found in the Indian Himalayan
Region (IHR). Amongst the species, Hypericum
perforatum, grows in Himalayas at higher altitudes
Keywords:
Hypericum perforatum, St. John’s
wort, Anti-depressant agent,
Hypericines, Hyperforins.
Correspondence to Author:
Mansi Shrivastava
Institute of Biomedical Sciences,
Bundelkhand University, Jhansi-
284128, UP, India
E-mail: bubms02@gmail.com
Shrivastava and Dwivedi, IJPSR, 2015; Vol. 6(12): 1000-07. E-ISSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 1001
and in the hills of central parts of the country is a
prospective herb to be used as a anti-depressant,
anti-cancer, anti-tumour and anti-viral agent.
Considering its anti-viral property, the plant is
widely studied for its effect against the HIV
species. Some biologically active constituents like
hyperforin and adhyperforin (phloroglucinols),
hypericin and pseudohypericin
(naphthodianthrones), flavonoids, xanthones,
oligomeric procyanidines, and amino acids have
been detected in Hypericum 4, 38.
Botanical Description:
The genus name Hypericum is derived from the
Greek words hyper (above) and eikon (picture), in
reference to the plant's traditional use in warding
off evil by hanging plants over a religious icon in
the house during St John's day (24th June). The
species name perforatum refers to the presence of
small oil glands in the leaves that look like
windows, which can be seen when they are held
against the light 33. Hypericum consists of herbs
and shrubs having yellow or coppery flowers with
four to five petals, numerous stamens, and a single
pistil 10 and free branching typically range from 40
to 80 cm in height16, 36. The stems and branches are
densely covered by oblong, smooth margined
leaves that range from 1 to 3 cm long and 0.3-1.0
cm wide. The leaves are interrupted by minute
translucent spots that are evident when held up to
the light. The upper portions of mature plants can
produce several dozen five petaled yellow flowers
that are typically 1.0-2.0 cm wide. The edges of the
petals are usually covered with black dots. Crushed
flowers produce a blood red pigment. By late
summer, the flowers produce capsules that contain
dozens of tiny, dark brown seeds. It thrives in poor
soils, and is commonly found in meadows, fields,
waste areas, roadsides, and abandoned mines and
quarries 16, 27, 36. Due to concerns over phototoxicity
to livestock, H. perforatum is listed as a noxious
weed in seven western states in the United States.
Programs promoting its eradication are underway
in Canada, California, and Australia.
Chemical Constituents:
Chemical investigations have detected seven
groups of medicinally active compounds in H.
Perforatum 38. They include naphthodianthrones,
phloroglucinols, and flavonoids (such as
phenylpropanes, flavonol glycosides, and
biflavones), as well as essential oils 2, 4, 11, 46. There
two major active constituents have been identified:
hypericin (a naphtodianthrone) and hyperforin (a
phloroglucinol).
Naphthodianthrones:
The class of compounds isolated from H.
perforatum which is the most researched is the
naphthodianthrones 17, 18, 47. They include
hypericin, pseudohypericin, isophypericin, and
protohypericin 2, 11. Of these, hypericin—an
anthraquinone derived pigment that is responsible
for the red color of SJW oils. Hypericin is found in
the flowers in the form of black dots that are
located along the petals. Due to its chemical
structure, hypericin is highly photoreactive.
Flavonoids:
Flavonoids in SJW range from 7% in stems to 12%
in flowers 11 and leaves 18. Flavonoids include
flavonols (kaempferol, quercetin), flavones
(luteolin), glycosides (hyperside, isoquercitrin, and
rutin), biflavones (biapigenin), amentoflavone,
myricetin, hyperin, oligomeric proanthocyanadins,
and miquelianin, all of which are biogenetically
related 2, 47.
Lipophilic compounds:
Extracts of SJW contain several classes of
lipophilic compounds with demonstrated
therapeutic value, including phloroglucinol
derivatives and oils. Hyperforin, isolated in
concentrations of 24.5% 8, 47, is a prenylated
phloroglucinol. Hyperforin is unstable in the
presence of both light and oxygen 23. Other
phloroglucinols include adhyperforin (0.2%1.9%),
furohyperforin, and other hyperforin analogs 2, 11, 18,
21. Essential oils are found in concentrations
ranging from 0.05% to 0.9% 21. They consist
mainly of mono and sesquiterpenes, specifically 2-
methyloctane, nnonane, α and β pinene, α terpineol,
geranil, and trace amounts of myrecene, limonene,
and caryophyllene 21, 46.
Additional compounds:
These include tannins (ranging from 3% to 16%),
xanthones (1.28 mg/100g), phenolic compounds
(caffeic acid, chlorogenic acid, and pcoumaric
acid), and hyperfolin. Additional compounds
Shrivastava and Dwivedi, IJPSR, 2015; Vol. 6(12): 1000-07. E-ISSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 1002
include acids (nicotinic, myristic, palmitic, and
stearic), carotenoids, choline, pectin, hydrocarbons,
and long chain alcohols 11.
Pharmacological activities:
Anti-depressant:
St. John's wort (Hypericum perforatum L.) has been
used for centuries to treat a number of common
ailments (such as neuralgia, sleep disorders, wound
healing, and hemorrhoids), but it is best known for
its use in the treatment of mild to moderate
depression 39.
Responsible Compounds:
SJW is known to have several active ingredients
including cyclopseudohypericin, hypericin,
hyperforin, isohypericin, protohypericin,
pseudohypericin and several other flavonoids 5, 13.
Each of these active components appears to have
differing levels of contribution to its anti-
depressant properties 5.
Mechanism of action: One of the proposed
mechanisms of St. John's wort in the treatment of
depression is the inhibition of the uptake of
serotonin (5HT), dopamine (DA) and
norepinephrine (NE) from the synaptic cleft of
interconnecting neurons 8, 40. A second contributing
mechanism is the ability to bind to the major neuro-
inhibitory receptor, gamma amino butyric acid
(GABA A and GABA B) receptors, to block the
binding of GABA3, 54. This reduction in GABA
ligand binding results in decreased central nervous
system (CNS) depression. A third mechanism is an
increase in the number or density of 5HT2
receptors in the frontal cortex of the brain, which is
potentially beneficial when treating depression 37.
A fourth and possibly fifth separate contributing
mechanism is St. John's wort ability to inhibit the
activity of both monoamine oxidase (MAO) and
catechol O-methyl transferase (COMT) enzymes 37,
55. Active form of both of these CNS enzymes
metabolize dopamine precursors into inactive
products and allows dopamine to metabolized to
norepinephrine (NE) in the brain. Thus, inhibition
of these enzymes in the CNS favors the metabolism
of Dopamine and the formation of NE (Fig.1).
FIG.1: ANTI-DEPRESSIVE MECHANISM OF ST. JOHN’S WORT EXTRACT (SJW).
Anti-bacterial and anti-viral:
Extracts of H. perforatum have been used to treat
cuts, abrasions, and other wounds for thousands of
years. It is useful in reducing inflammation and is
well known for its ability to serve as an
antibacterial agent. Hyperforin, the main
antibacterial component was determined to inhibit
Shrivastava and Dwivedi, IJPSR, 2015; Vol. 6(12): 1000-07. E-ISSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 1003
the growth of certain types of microorganisms
especially for all Gram positive bacteria. However,
no growth inhibitory effects were seen in the gram
negative bacteria 6.
The SJW extracts have long been regarded as being
effective against various classes of viruses.
Flavonoid and catechin containing fractions of SJW
are active against influenza virus 34. Hypericin
inactivates enveloped viruses at different points in
their life cycle 28, and their fusion with cell
membranes 10, 28. Considering to that Hypericin is
used as natural candidate to inactivate several
enveloped viruses present in human blood and to
treat Acquired Immunodeficiency Syndrome
(AIDS) patients 22, 33. Other reverse-transcribed
viruses like hepatitis virus B and C (HBV and
HCV) have been found to be inhibited by hypericin
in vitro 37, 55. It was found hypericin ineffective
against the hepatitis C virus in a doses study 25.
Some recent reports showed that isoquercetrin in H.
perforatum extract could inhibit H1N1 influenza
virus replication in MDCK cells. However, most
observations of anti-viral activity of Hypericum
were acquired from in vitro studies and a limited
number of animal studies, while human clinical
trials often showed little or no significant effect.
Studies on other viruses have shown the hypericin
induced in-vitro inactivation of Bovine Diarrhea
Virus (BVDV) in the presence of light 43.
Anti HIV Property:
Hypericin induced changes in p24 protein and the
p24 containing gag precursor, p55 and the
formation of an anti p24 immuno-reactive material
which inhibit the release of reverse transcriptase
activity 10. However, in a phase I clinical trial, it
was found that hypericin had no beneficial effect
on administration to 30 HIV infected patients with
CD4 counts less than 350 cells/mm3 20. Recently, in
a study, 3hydroxy lauric acid was found in the field
grown H. perforatum which has shown better anti
HIV activity 43.
Mechanism of action:
With no apparent effect on viral nucleotide,
transcription and translation being observed, the
authors speculated that the anti-viral mechanism of
the Hypericum was having a direct interference
with virus infection and shedding, or inactivation of
virus, or disruption of virus lipid membrane.
However, conclusive clinical evidence has yet to be
found to support the in vivo efficacy of hypericin
and H. perforatum against HIV.
The Janus kinase/signal transducers and activators
of transcription (JAK/STAT) pathway are
responsible for transmitting signals from a myriad
of cytokine and hormone receptors 45. Negative
regulation of the JAK/STAT pathway is carried out
through suppressor of cytokine signaling (SOCS)
proteins, whose transcription is controlled by
STATs 44. Although SOCSs are important to
contain inflammation, they are also manipulated by
pathogens such as influenza virus regulating
SOCS3 expression by the biological components
found in H. perforatum extract may inhibit the viral
infection.
Anticancer:
Hyperforin and hypericin have also been examined
for their anticancer properties. Hyperforin inhibits
tumor cell growth in vitro 51. Studies demonstrated
that hyperforin in conjunction with polyphenolic
procyanidin B2 effectively inhibited the growth of
leukemia in K562 and U937 cells, brain
glioblastoma cells LN229, and normal human
astrocytes 23. Hypericin also inhibits the growth of
cells derived from a variety of neoplastic tissues,
including glioma, neuroblastoma, adenoma,
mesothelioma, melanoma, carcinoma, sarcoma, and
leukemia15. Hypericin being photodynamic
compound whin photoactivated with white light or
ultraviolet light or both could induce nearly
complete apoptosis (94%) in malignant cutaneous
T cells and lymphoma T cells 15. Exposing tumors
cells to hypericin in conjunction with laser
irradiation led to toxic effects on human prostatic
cancer cell lines 9, human urinary bladder
carcinoma cells 26, and pancreatic cancer cell lines
29 in in-vitro systems.
As a matter of attention, hypericin alone has only a
weak inhibitory effect on cancerous cell growth,
whereas methanolic extract of SJW together with
hypericin leads to long lasting inhibition of cell
growth, induces apoptosis, and decreases
phototoxicity 50, 52. Considering the encouraging
results of hyperforin and hypericin as anticancer
Shrivastava and Dwivedi, IJPSR, 2015; Vol. 6(12): 1000-07. E-ISSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 1004
agents, more research is needed to evaluate their
efficacy, mode of action, and adverse interactions.
Mechanism of action: The mechanism involves
induction of apoptosis (programmed cell death)
through the activation of caspases, which are
cysteine proteases that trigger a cascade of
proteolytic cleavage in mammalian cells. Hypericin
with its greater photodynamic properties1 acts as a
powerful natural photosensitizer in the presence of
oxygen and light. It generates superoxide radicals
that form peroxide or hydroxyl radicals, or singlet
oxygen molecules that kill tumor cells. Hence, in
future, hypericin can be used as a component of
photodynamic therapy (PDT).
Neuroprotective:
H. perforatum serves as a neuroprotective agent
against MPTP (1methyl 4phenyl 1,2,3,6
tetrahydropyridine) induced Parkinson's disease in
mice 35. H. perforatum extract led to the inhibition
of MAOB activity and decreased astrocyte
activation in striatal area of (MPTP) induced mice.
The flavonols quercetin and kaempferol provide
neuroprotective action by decreasing oxidation of
the mitochondrial lipid membrane and maintaining
mitochondrial transmembrane electric potential 53.
They lower the ability of mitochondria to absorb
calcium. Extracts of SJW protect against cell death
caused by amyloid P peptides (Abeta) that form
plaques in the brains of those suffering from
Alzheimer's disease. Hypericin may interfere with
the processes of polymerization of the beta-amyloid
peptide responsible for the onset of Alzheimer’s
diseas 19.
Other Activities:
H. perforatum shows promise as an anti-
inflammatory agent. Rats fed doses of SJW showed
decreased levels of blood and bowel enzymes
associated with colonic inflammation 12, and had
lower incidences of gastric ulcers 12.
The extracts of H. perforatum decrease oxidative
stress and consequently prevent neurotoxicity,
inflammation, and gastrointestinal problems. H.
perforatum extract has been used over thousands of
years as a wound healing agent. The chicken
embryonic fibroblasts exposed to SJW extract
enhanced collagen production, followed by the
polygonal shape activation of fibroblast cells that is
responsible for wound closure 42.
Future Perspectives:
In recent years, many studies have proven the
efficacy of some HP extracts in the treatment of
depression, bacterial and viral infection,
neurological disorders, etc. It has also received
special attention due to its pharmacological
properties, including antiseptic, spasmolytic, tonic,
diuretic and anesthetic remedies. Despite the
dozens of clinical, in vivo, and in vitro studies
conducted on the medicinal attributes of SJW,
several unanswered questions still prevail regarding
its therapeutic value, mechanisms of action, and
adverse interactions. The future research must
focus on resolving the apparent contradictions
related to this herbal plant. Additional research is
needed regarding the therapeutic value of SJW as
anti-cancerous, anti-HIV, immuno-modulatory
agent and so on. Moreover, the potency of
hypericin, hyperforin, and flavonoids must be
further elucidated.
Anti-bacterial property of SJW is reported against
the gram positive bacteria but it is still to be
thoroughly studied against the gram negative
bacteria. Hypericin was tested as anti-HIV drug,
but some more studies are required to understand
its mechanism of action and efficacy in serious
AIDS patients. The anti-retroviral activity of 3-
hydroxy lauric acid reported to be found in the field
grown SJW extract may further be studied for its
in-vivo effects. As anti-cancer agent evaluation of
efficacy, mode of action and adverse effects of
hypericin and hyperforin is needed.
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How to cite this article:
Shrivastava M and Dwivedi LK: Therapeutic Potential of Hypericum Perforatum: A Review. Int J Pharm Sci Res 2015; 6(12): 1000-
07.doi: 10.13040/IJPSR.0975-8232.6(12).1000-07.
