Wiener Medizinische Wochenschrift
Wien Med Wochenschr (2007) 157/13–14: 356–361
DOI 10.1007/s10354-007-0440-8
St. John’s wort: Role of active compounds for its mechanism of action and
efficacy
Veronika Butterweck1 and Mathias Schmidt2
1
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville,USA
2
Herbresearch, Tussenhausen, Germany
Received March 20, 2007; accepted May 10, 2007
© Springer-Verlag 2007
Johanniskraut – Beiträge der Inhaltsstoffe zu
Wirkmechanismen und Wirksamkeit
Zusammenfassung. Johanniskraut (Hypericum per-
foratum L., SJW) enthält viele Verbindungen mit doku-
mentierter biologischer Aktivität. Zu den Inhaltstoffen, die
das größte Interesse ausgelöst haben, zählen die Naph-
thodianthrone Hypericin und Pseudohypericin, eine große
Zahl von Flavonoiden sowie die Phloroglucinole Hyperfo-
rin und Adhyperforin. Nach dem aktuellen Stand der wis-
senschaftlichen Erkenntnisse muss der Gesamtextrakt als
der eigentliche Wirkstoff betrachtet werden. Trotz einiger
offener Fragen ergibt sich aus der Gesamtdatenlage, dass
mehrere Inhaltstoffgruppen zur antidepressiven Wirksam-
keit des Pflanzenextraktes beitragen.
Schlüsselwörter: Hypericum perforatum, Wirkstoffe,
Pharmakologie, Klinische Wirksamkeit.
Summary. St. John’s wort (Hypericum perforatum L.,
SJW) contains numerous compounds with documented
biological activity. Constituents that have stimulated the
most interest include the naphthodianthrones hypericin
and pseudohypericin, a broad range of flavonoids, and the
phloroglucinols hyperforin and adhyperforin. According to
the actual state of scientific knowledge the total extract
has to be considered as the active substance. Although
there are some open questions, the bulk of data suggests
that several groups of active compounds are contributing
to the antidepressant efficacy of the plant extract.
Key words: Hypericum perforatum, active constitu-
ents, pharmacology, clinical efficacy.
Correspondence: Dr. Veronika Butterweck, Department of
Pharmaceutics, College of Pharmacy, University of Florida,
Gainesville, FL 32608, USA.
Fax: ++1-352-3924447
E-mail: butterwk@cop.ufl.edu
Printed in Austria
Introduction
The antidepressant efficacy of Hypericum perforatum L.
(Clusiaceae), commonly known as St. John’s wort (SJW),
has been confirmed in numerous clinical studies, and was
assessed in metaanalyses [1, 2]. The pharmacological
actions of SJW have likewise been extensively reviewed
[3–6].
Flavonol glycosides represent with an amount of up
to 4% the largest group of secondary metabolites in H.
perforatum. The major components are rutin, hyperoside,
isoquercitrin, quercitrin, miquelianin, and in smaller
amounts the aglycon quercetin [7]. Biflavonoids such as
I3,II8-biapigenin and amentoflavone exclusively occur in
the flowering part of SJW [8]. The naphtodianthrones
hypericin and pseudohypericin occur in the flowers and
leaves of the crude drug material in concentrations of
0.03 to 0.3% [9]. The amount of pseudohypericin in SJW
is approximately 2 to 4 times higher than that of hyperi-
cin [10]. In some extracts this ratio may even be 10:1.
The main representative of the phloroglucinol group of
constituents is hyperforin. Together with adhyperforin it
occurs exclusively in the generative parts of the plant,
especially in the unripe fruits. Consequently, plant mate-
rial collected at the end of the flowering period, when
fruits are developing, will contain more hyperforin than
material collected during the flowering time (as request-
ed by monographs) [11]. Hyperforin occurs in amounts
up to 2–5% in the crude drug material and can reach
about 6% in some extracts, whereas other extracts and
traditional SJW preparations are practically devoid of
hyperforin [12].
Antidepressant activity was reported for the phloro-
glucinol derivative hyperforin, for the naphthodian-
thrones hypericin and pseudohypericin, and for several
flavonoids. The role and the mechanisms of these differ-
ent compounds is still a matter of debate. However, based
on recent results it seems that the prevailing simplistic
view of one plant → one active compound → one mech-
anism of action is incorrect. It is more likely that the mul-
tiple bioactive compounds contribute to the antidepress-
 Butterweck and Schmidt, Active constituents of Hypericum perforatum
Fig. 1. Flavonoids from SJW
ant activity of the crude plant extract in a complex man-
ner.
A. SJW Constituents in Preclinical Studies
in vitro
MAO inhibition
Initial in vitro experiments with St. John’s wort suggest-
ed that inhibition of monoamine oxidase (MAO) is the
main mechanism of antidepressant action of SJW extract.
MAO-inhibition was demonstrated for quercetin, kaem-
pferol and luteolin [7]. However, the concentration of the
flavonoids showing activity is too low in Hypericum to
be responsible for the therapeutic efficacy of SJW extract
[13]. Micromolar concentrations of hypericin could irre-
versibly inhibit MAO-A and MAO-B activity in vitro
[14]. However, the hypericin sample was later shown to
have been impure, and containing at least 20% of other
constituents of the extracts, among these flavonoids. In
fact, the MAO inhibitory effects of hypericin could not
be confirmed in subsequent studies [15–17].
Receptor binding
Amentoflavone was found to bind to brain benzodiaze-
pine receptors with an affinity comparable to diazepam
[18, 19]. Amentoflavone had also remarkable affinity for
the δ-opioid receptor subtype (Ki = 36.5 nM) [20]. An
affinity of hypericin to δ-receptors was likewise found
[21, 22], however, the effect size was only modest.
Amentoflavone significantly inhibited binding at 5-
HT1D, 5-HT2C, and dopamine D3 receptors [20]. Further
striking actions were observed for quercetin with an
affinity to the D4 receptor at Ki = 7.8 nM, miquelianin to
the α2C receptor at 4 nM and rutin to α2A and α2C recep-
tor at 9 nM [20]. Hypericin had no affinity for adrener-
gic, GABA, or adenosine receptors, and only modest
affinity for muscarinic cholinergic receptors [22]. An
affinity of hypericin for NMDA-receptor was described
[16], but could not be confirmed in another study [20].
Hypericin showed, however, high affinity for the D3-
dopamine receptor [20].
357
Hypericin showed a potent binding inhibition to
human CRF1 receptor with an IC50 value of 300 nM [23].
However, in a subsequent experiment measuring CRF-
stimulated cAMP-formation in recombinant Chinese
hamster ovary cells (CHO), only pseudohypericin was
found to selectively antagonize CRF [24].
Re-uptake of neurotransmitters
A CO2-extract enriched in hyperforin as well as pure
hyperforin inhibited serotonin-induced responses and
uptake of neurotransmitters in vitro [25, 26]. Hyperforin
and adhyperforin were capable of inhibiting the re-uptake
of serotonin (5-HT), norepinephrine (NE), dopamine
(DA) and/or choline at a potency comparable or even
superior to that of conventional 5-HT and NE inhibitors
and synthetic antidepressants [27–29]. However, the
effect was only confirmed in micromolar concentrations
[29–32].
Hyperforin does not relevantly inhibit [3H]citalopram
binding [30]. It was therefore speculated that the inhibi-
tory effects on synaptosomal 5-HT accumulation might
be due to a reserpine-like mechanism. The apparent inhi-
bition of neurotransmitter uptake may be an artifact due
to the interaction of the high concentration of the tested
compounds with monoamine storage vesicles. Similarly,
the inhibition of DA-uptake by hyperforin and adhyper-
forin was not due to a direct interaction with the typical
binding site of antidepressants at the DA transporter, but
rather to a non-competitive interaction [29]. The appar-
ent inhibition of serotonin uptake observed with SJW
extract and hyperforin in vitro might be also due to an
interaction of the compounds with Na+ channels or
Na+/H+ exchangers, leading to an increase in free intra-
cellular sodium-concentrations [32, 33]. Such nonselect-
ive effects might explain why SJW extracts and hyperfo-
rin blocked the synaptosomal uptake of multiple neuro-
transmitters [25, 30, 32, 34].
Recent work indicated that hyperforin may also
influence calmodulin-dependent mechanisms [35], and
modulate voltage and ligand-gated ion channels known
to be involved in neurotransmitter release [36, 37]. Quer-
citrin was detected as a potent inhibitor of ATP-induced
conductance; biapigenin inhibited both the acetylcholine-
and ATP-induced conductance, whereas hyperoside
blocked currents activated by ATP and AMPA. Hypericin
was inactive in all cases.
Conclusions from in vitro-studies
In summary, the data from in vitro studies allocate inter-
esting pharmacological properties to hypericin, but simi-
larly to the flavonoids. The therapeutic relevance of these
findings needs verification by in vivo experiments. How-
ever, with regard to the contradictory effects of hyperi-
cin in various test models it should be pointed out that
the pharmacological evaluation of hypericin in most in
vitro and in vivo studies is hampered by its poor solubil-
ity in aqueous solutions.
Reported IC50 values for hyperforin as an inhibitor of
synaptosomal uptake of serotonin have ranges from 120
nM to 3.300 nM. In human volunteers receiving daily
doses of 900 mg SJW extract, plasma steady-state con-
358 Butterweck and Schmidt, Active constituents of Hypericum perforatum

OH
OH
HO
HO O O
HO
OH

OH
O
OH O HO O

O OH O

O
HO

HO

I3,II8-Biapigenin Amentoflavone
Fig. 2. Biflavonoids from SJW

centrations of approx. 180 nM were measured [38]. Thus,
the blood levels of hyperforin after a daily dose of
900 mg Hypericum-extract may reach concentrations
needed to inhibit serotonin uptake in vitro. However, fur-
ther research is needed to measure the concentration of
SJW compounds available for action at central receptors
in vivo.
B. SJW Constituents in Preclinical Studies
in vivo
The potential antidepressant activity of some SJW fla-
vonoids, of hypericin and pseudohypericin and of hyper-
forin was confirmed in the forced swimming test (FST)
in rats. Interestingly, pure hypericin and pseudohypericin
did not reduce immobility time after acute pre-treatment
at doses comparable to the total extract; and only the
exceptionally high dose of 0.23 mg/kg (p.o.) of hypericin
was significantly active, whereas pseudohypericin indi-
cated some non-significant activity at about 0.5 mg/kg
(p.o.) [39].
Triple administration of hyperforin acetate
(5–20 mg/kg) significantly reduced the immobility time
of rats, while in the learned helplessness test a daily treat-
ment of 10 mg/kg for seven consecutive days was neces-
sary to elicit an antidepressant effect [40]. In the tail sus-
pension test in mice pure hyperforin significantly reduced
immobility time in a dosage of 4 and 8 mg/kg whereas it
was inactive in dosages below or above that [41]. In the
same study it was also shown that step by step removal
of either hyperforin or hypericin did not result in a loss
of pharmacological activity. The results clearly show that
the crude SJW extracts contains several constituents with
antidepressant activity.
An extract fraction containing a high amount of fla-
vonoids significantly reduced immobility time in the
FST. The effect was comparable to that of imipramine
[42]. Hyperoside, isoquercitrin and miquelianin were sig-
nificantly active in the FST after acute as well as after
repeated oral treatment [42], at doses comparable to their
amounts present in the crude drug material [13]. In addi-
tion, Butterweck et al. could show that, similar to imi-
pramine, hypericin and the flavonoids hyperoside, iso-
quercitrin as well as miquelianin significantly downreg-
ulated plasma ACTH and corticosterone levels after two
weeks of daily treatment [43, 44].
Hypericin (0.2 mg/kg) given daily by gavage for 8
weeks but not for 2 weeks significantly decreased levels
of corticotropin-releasing hormone (CRH) mRNA by
16–22% in the hypothalamic paraventricular nucleus
(PVN), and serotonin 5-HT1A receptor mRNA by 11–17%
in the hippocampus [45].
In the model of learned helplessness (rat), escape
deficits significantly and dose dependently decreased
after 150 and 300 mg/kg/day (p.o.) of an ethanolic SJW
extract (4.5% hyperforin). Comparable effects were
observed for a CO2-extract (38.8% hyperforin) in doses
of 15 and 30 mg/kg/day (p.o.) [25]. When tested in the
escape deficit paradigm, 25 mg, 50 mg and 75 mg/kg
(i.p.) of hyperforin significantly counteracted the effects
of acute stress in rats [46]. In how far other constituents
of St. John’s wort are active in this model needs to be
further elucidated.
Potential synergisms
When a fraction of procyanidins, which was not active in
the FST, was recombined with hypericin and pseucohy-
OH O OH
HO CH2R
HO CH3
OH O OH
R=H Hypericin
R = OH Pseudohypericin
Fig. 3. Naphthodianthrones from SJW
 Butterweck and Schmidt, Active constituents of Hypericum perforatum
H3C
CH3
H3C
O
CH3
CH3
O CH3
O cacy cannot be drawn from the conflicting results of this
CH3
H3C H3C
R blind trials with extracts containing a wide range of
R=H Hyperforin
R = CH3 Adhyperforin
Fig. 4. Phloroglucinols from SJW
pericin, the latter were significantly active at 0.028 and
0.166 mg/kg (p.o.), respectively. Flavonoids – especially
hyperoside – and procyanidins increased the water solu-
bility of hypericins up to 400 fold, which may lead to a
better bioavailability [47, 48]. The combination of inac-
tive rutin with likewise inactive extracts resulted in a
strong pharmacological effect in the FST [49], possibly
through an improved bioavailability of hypericin. In fact,
the oral bioavailability of hypericin in rats was increased
by ca. 58% with procyanidin B2, and by 34% with hyper-
oside [50] These interesting pharmacokinetic properties
would explain why conflicting data were obtained in
most in vitro experiments with hypericin.
C. SJW Constituents in Clinical Studies
The usual dose range of hypericin applied with the rec-
ommended daily doses of SJW extracts is 1–2 mg of
hypericin per day. The pharmacokinetic properties of
hypericin from typical doses of SJW preparations are
well known [51]. Hypericin reaches relevant plasma con-
centrations to contribute to the overall antidepressant
efficacy of SJW preparations.
Little data is available on flavonoid quantities in SJW
preparations applied in clinical trials. Flavonoids have
been shown to be abundant in SJW tea (4.1%) and
extracts (up to 22.3%) [52]. Although pharmacological
data strongly suggests an importance of flavonoids for
the overall antidepressant efficacy of SJW, there is as yet
no clinical correlate linking flavonoid contents to clini-
cal efficacy.
Hyperforin was attributed major importance for the
antidepressant efficacy of SJW preparations. However,
even in the most recent trials data on hyperforin contents
are rarely ever reported. A study that analyzed 33 SJW
products available on the German market showed distinct
variations of the hyperforin content from < 0.5 mg/unit
(< 0.02% in the extract) to 24.87 mg/unit (5.85% in the
extract) [12].
The as yet only evidence of differential effects of
SJW extracts with a different content of hyperforin was
359
found in a clinical trial where an extract with 5% hyper-
forin was compared to a reference with 0.5% hyperforin.
Superiority was demonstrated for the high dose over pla-
cebo on the Hamilton depression score, but neither for
the comparison for the low dose extract over placebo, nor
for the comparison of the high and low dose extract [53].
Since no sufficient information was provided for the
comparability of both treatments with regard to other
constituents, i.e. flavonoids and hypericin, definite con-
clusion regarding the role of hyperforin for clinical effi-
study.
Positive study outcomes were obtained from double
hyperforin contents, with hyperforin contents ranging
from practically absent to the most frequently encoun-
tered content of 1.5–3%, and extracts with up to 6%.
Since clinical efficacy has been demonstrated in at least
three older double-blind trials using a hyperforin-free
SJW tincture [54–56], and further studies with a hyper-
forin-free dry extract [57–59], hyperforin may well con-
tribute to the antidepressant efficacy, but is obviously not
an essential component.
Whereas more conclusive data is needed to establish
a correlation between hyperforin and efficacy, such a cor-
relation has by now become evident for the participation
of hyperforin in pharmacokinetic interactions triggered
by SJW [60, 61]. In conclusion, the overall importance
of hyperforin for clinical efficacy and its positive contri-
bution to the benefit-risk ratio may have been overesti-
mated.
Conclusions
Hyperforins and hypericins represent the best investi-
gated group of constituents in SJW, whereas for the fla-
vonoids there is still an increased demand for further
research. Flavonoids not only represent pharmacologi-
cally active compounds, but hence can act as co-effect-
ors to improve the biopharmaceutical properties of hyper-
icin.
Known bioactive compounds in SJW represent
approximately 50–70% of the known phytochemical con-
stituents. Still 30–50% of the compounds present in SJW
extracts are as yet not structurally assigned – among them
could be further constituents directly or indirectly con-
tributing to the overall clinical efficacy. The total extract
must still be regarded as the active constituent of SJW.
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