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Herbal Extract Series 1.
Hypericum
Extract
Use in Depression
HERBAL EXTRACTS SERIES 1. HYPERICUM
2
Introduction
is a company specialized in botanical extracts and active
principles which will be later used as phytomedicines within the
pharmaceutical field. devotes itself to the development
and production of these therapeutically active raw materials.
For that purpose the botanical raw materials are subject to a strict
selection and control, and the products are manufactured
following production methods developed by the company, which include controls in process in order to assure a
standard quality according to the latest knowledge of the state of
art in different fields: R&D, analysis, processes and facilities,
therapeutical usages on a scientific basis.
assures the quality of the products with the background
of broad phytochemical know-how.
HERBAL EXTRACTS SERIES 1. HYPERICUM
3
Table of Contents page
1 Hypericum Extract: General Information 4 1.1 Description 4
1.2 Indications 4
1.3 Extract Specification 4
1.4 Dosage and Methods of Administration 5
1.5 Contraindications and Interactions 5
1.6 Side-Effects 5
2 From Plant to Extract 7 2.1 St John’s Wort (Hypericum perforatum L.):
Botanical Information 7
2.2 Historic Use 9
2.3 Chemistry of the Plant Substances 10
2.4 Preparation of the Extract and Quality Assurance 11
2.5 Standardization 14
3 Depressive States 15
4 Pharmacology 19 4.1 Antidepressant Effect 19
4.1.1 Blocking the Resorption of Serontin 19
4.1.2 Slight Blocking of Monoamine oxidase (MAO) 21
4.1.3 Blocking of Catechol-O-methyltransferase (COMT) 22
4.1.4 Modulation of Cytokin Release 22
4.2 Pharmacokinetics 23
5 Toxicology 24
6 Clinical Pharmacology 25 6.1 Influence on Evoked Potentials and Resting EEG 25
7 Proof of Clinical Effectiveness 27 7.1 Meta-Analysis of the Clinical Trials of the use of
St John’s Wort Extract for Psychovegetative Complaints 27
7.2 Clinical Trials with Placebos 28
7.3 A Comparison of Clinical Trials and Standard Conditions 31
7.4 Drug-Monitoring Trials 33
7.5 Effect on Patients’ Responses 35
7.6 Therapeutic Safety 36
8 Bibliography 37
HERBAL EXTRACTS SERIES 1. HYPERICUM
4
1 Hypericum Extract:
General Information
1.1 Description
Absolutely natural Extract of Hypericum is a standardized herbal
extract of St John’s Wort (Hyperici herba).
Herbal
antidepressant
The herbal antidepressant Hypericum extract has
a mood-enhancing and drive-improving effect as
well as relieving both anxiety and tension.
General capacity for enjoying life is increased.
Extract of Hypericum does not cause tiredness or
affect responses. Because it does not interact with
other drugs and is so well tolerated it is suitable
for patients of all age groups as well as for
patients with multiple diagnoses.
1.2 Indications
Indications for the therapeutic use of Hypericum
extract are depressive states and psychovegetative
disorders as well as anxiety and/or nervous
agitation.
1.3 Extract Specifications
Hypericum extract is an extract of St John’s Wort
containing between 0.1 - 0.3 % hypericin. St
John’s Wort preparations usually contain circa
250 - 300 mg Hypericum extract (available from
).
HERBAL EXTRACTS SERIES 1. HYPERICUM
5
1.4 Dosage and Methods of Administration
A daily oral dose of 500 - 900 mg Hypericum
extract is usual. Usual length of therapy is 1 - 6
months. Discontinuation does not lead to side
effects. Physicians monitoring is advised. Table 1
(page 6) provides an overview over the
Hypericum-preparations of the market.
1.5 Contraindications and Interactions
None known.
1.6 Side-effects
Hypericum extract is generally well tolerated. In
clinical trials rare cases of gastro-intestinal
irritations occurred in the same percentage as in
the placebo-group. In rare cases, especially in
fair-skinned people, photosensitization can occur
(increased sensitivity of the skin to sunlight).
Well tolerated
HERBAL EXTRACTS SERIES 1. HYPERICUM
6
Tab. 1: Preparations containing Hypericum extract with a
standardized content of hypericin.
Preparation
Name
method of
extraction
Content of
Hypericum Extract
[mg]
Total
Extract/day
[mg]
Content of
Hypericin
[mg]
Total
Hypericin/Day
[mg]
Jars
in 3
00
met
han
oli
c3
00
90
00
,92
,7
Rem
oti
vet
han
oli
c2
50
50
00
,51
,0
Ari
sto
fora
tet
han
oli
c1
20
-18
04
80
-72
00
,31
,2
Div
inal
Sed
aet
han
oli
c1
80
-22
07
20
-66
00
,30
,9
Esb
eric
um
fo
rte
25
05
00
0,5
1,0
Hel
ariu
m
Hy
per
icu
m
eth
ano
lic
25
5-2
85
76
5-8
55
0,9
2,7
Her
ban
eu
rin
fo
rte
eth
ano
lic
20
8-2
50
41
6-5
00
0,5
1,0
Kir
a1
35
-22
54
05
-67
50
,30
,9
Psy
cho
ton
in f
ort
eet
han
oli
c1
00
-12
02
00
-24
00
,51
,0
HERBAL EXTRACTS SERIES 1. HYPERICUM
7
2 From Plant to Extract
2.1 St John’s Wort (Hypericum perforatum
L.): Botanical Information
St John’s Wort, Hypericum perforatum L., is one
of the family of Hypericaceae (synonym
Guttiferae). The perennial, leafy plant reaches a
height of about 60 cm and has 5-petalled, yellow
flowers dotted with black hypericin glands. A
blood-red latex oozes from the glands when the
flower is rubbed.
The flowers contain
red hypericin
The name St John’s Wort comes from the fact
that the plant flowers around St John’s Day which
falls on 24 June. The ovate-elliptical leaves are
dotted with translucent oil glands. The plant’s
perforated appearance led to the species name
perforatum. The stem has two characteristic
vertical strips.
The leaves have a
characteristic
perforated
appearance
St John’s Wort is native to all of Europe, west
Asia, the Canary Islands and North Africa.
The part which is used medicinally is the herb,
Hyperici herba, consisting of the aerial parts
Hypericum perforatum L. harvested during the
flowering season and then dried [16, 32, 48, 55,
56].
HERBAL EXTRACTS SERIES 1. HYPERICUM
8
Fig. 1: St John’s Wort (Hypericum perforatum L.).
HERBAL EXTRACTS SERIES 1. HYPERICUM
9
2.2 Historic Use
St John’s Wort is a very old medicinal plant
which was used particularly in the treatment of
external wounds and burns. Hippocrates and
Paracelsus praised its healing powers including in
the treatment of ”mad fantasies“. The plant was
repeatedly described in the medieval herbals.
Many of the indications are still relevant in folk
medicine today [7, 32, 55].
Ancient medicinal
plant
The use of St John’s Wort has been well-
documented and recognized continuously up to
the present day. This is reflected in the
monograph [6, 11]. St John’s Wort is known as
an antidepressant used in the treatment of
psychovegetative disturbances for exhaustion,
nervous headaches, agitation, anxiety, lacklustre,
melancholy and apathy as well as for secondary
psychological climacteric symptoms. Because of
its relaxing effect St John’s Wort can be used for
problems of insomnia especially in elderly
patients [9].
St John’s Wort is used as an astringent tannic
drug in mouth washes for the treatment of
gingivitis and as an antidiarrhoeal agent. It is used
internally (as an infusion) for disorders of the
gastrointestinal tract [48], e.g., disease of the gall-
bladder and gastritis, but also in the treatment of
bronchitis and asthma [16].
HERBAL EXTRACTS SERIES 1. HYPERICUM
10
Further areas of use are bed-wetting, rheumatism
and gout. Its use as a diuretic is attributed to its
flavonoid content [9, 55, 56]. Its effectiveness as
a vermicide is attributed to the phloroglucin
derivatives. Procyanidine is thought to be the
active ingredient in the treatment of dyspeptic
complaints [24].
2.3 Chemistry of the Plant Substances
St John’s Wort (Hyperici herba) contains several
groups of substances. They are identified and
quantified according to modern scientific
analytical methods [8, 13, 29, 30, 33, 49].
The naphthodianthrones hypericin and pseudo-
hypericin are characteristic substances of St
John’s Wort and of pharmacological interest.
Hypericin Pseudohypericin
Fig. 2: Hypericin and pseudohypericin found in St John’s
Wort (Hyperici herba) [39].
The following table provides an overview of the
whole spectrum.
HERBAL EXTRACTS SERIES 1. HYPERICUM
11
Tab. 2: Substances found in St John’s Wort [4, 9, 16, 22,
39, 48, 56].
Active and Other Substances
• essential oil (0.05 - 0.3 %, n-alkannin, α-pinene,
cineole)
• anthraquinone (skyrine)
• carotenoids (epoxyxanthophyll)
• cumarin (umbelliferone, scopoletin)
• flavonoids (0.5 - 1.0 %, flavonols, flavonolglyco-
sides and biflavones including hyperoside and
rutin)
• naphthodianthrones (0.1 - 0.3 %, including up to
80 or 90 % hypericin and pseudohypericin)
• carbolic acids (including chlorogenic acid, caffeic
acid, ferulic acid, gentisic acid)
• phloroglucins (up to 3 % hyperforin)
• phytosterol
• proanthocyanidins (circa 10 % catechin tannins)
• wax (paraffins and wax alcohols)
• xanthones (mangostin)
Hypericin is
considered the
main substance of
St John’s Wort
2.4 Preparation of the Extract and Quality
Assurance
The plant material used for Hypericum
extract originates primary from cultivations. An
Agreement with the suppliers is established in
order to fix the conditions of cultivation, harvest,
drying and storage, which assure the quality of the
product.
Previous
agreements with
the suppliers about
controls of the drug
HERBAL EXTRACTS SERIES 1. HYPERICUM
12
St John’s Wort extract is formed by many
substance groups the individual active ingredients
of which are largely known. The hypericins are
considered to be the main characteristic active
substances. The level of the hypericin and
pseudohypericin is measured experimentally in
order to optimize the production process and to
assure quality of Hypericum extracts [36, 53].
Control of the drug
upon its arrival at
When the plant material arrives at an
exhaustive control of the raw material is carried
out according to the methods included in the
current pharmacopoeia [8], paying special
attention to the hypericin content in order to
assure the quality of the final product.
Furthermore, evaluates the eventual
contamination of the drug; in doing so, the
company assures that the limits fixed by the
international norms or literature are not
surpassed.
Pesticides: in compliance with the limits
established in Ph. Eur. 3rd ed.,
2.8.13 (1997)
Aflatoxins: the contamination with these
mycotoxins is controlled by
legal limits worldwide
Heavy metals: the contamination with
heavy metals is controlled
by atomic absorption
spectrophotometry
Microbiology: in compliance with the limits
established in Ph. Eur. 3rd ed.,
5.1.4 (category 4B), (1997)
HERBAL EXTRACTS SERIES 1. HYPERICUM
13
Only high-quality raw plant material chosen
according to the strictest criteria is selected. The
extraction process is carried out using methods
which avoid unnecessary damage and with
continuous in-process checks in order to
guarantee the quality, e.g. the HPLC (Fig. 3).
Strict quality
assurance of the
extracts
Fig. 3: HPLC-profile of Hypericum perforatum extract [4].
Hypericum extract from satisfies the
highest standards of quality thus enabling it to
meet the requirements for the effectiveness and
safe use of the medication.
HERBAL EXTRACTS SERIES 1. HYPERICUM
14
2.5 Standardisation
Consistent quality The consistent quality of the Hypericum extract is guaranteed by the standardized
production process.
An extract of the
whole herb is used
Hypericin is the main substance of St John’s Wort
with which the uptake and elimination of
Hypericum extract can be determined. Other
substances apart from hypericin, however, are
also responsible for the effectiveness of the
extract such as, for instance, hyperforin, the
flavonoids, xanthone and the essential oil. For
this reason the extract is taken from the whole of
Hyperici herba.
HERBAL EXTRACTS SERIES 1. HYPERICUM
15
3 Depressive States
Depression is the most common psychiatric
disorder [18]. About 3 - 5 % of the global
population (well over 100 million people) suffer
from depressive mood disturbances requiring
treatment. Up to 19% of patients seeking medical
help suffer from symptoms of depression [5].
More than 90 % of the patients suffering from
depression are treated by medical practitioners
rather than clinics [52].
Most common
psychiatric disorder
Every fourth adult suffers at least once in their
lives from severe depression, women being more
affected than men. There are four main kinds of
depression [47]:
• reactive depression, brought on, for example,
by unemployment or the loss of a partner
• endogenous depression, which develops for no
apparent reason from within
• endoreactive depression, a mixture of
endogenous and reactive depression
• neurotic depression, which can be
characterized as abnormal behaviour within
the framework of intrapsychic tensions
Every fourth adult
is affected
A deficiency of catecholamines (e. g.,
noradrenaline) or serotonin to specific receptors
in the CNS is believed to be the cause of
depression [57].
There is a large range of psychological and
physical symptoms of depression (Tab. 3) [47]:
Large range of
symptoms
HERBAL EXTRACTS SERIES 1. HYPERICUM
16
Tab. 3: Symptoms of Depression [47].
Psychological Symptoms:
• anxiety
• agitation
• poor memory and lack of concentration
• feelings of hopelessness
• apathy and indecisiveness
• reduction in drive
• melancholy
Physical Symptoms:
• sleeplessness
• loss of appetite
• tightness in the chest
• dry mouth
• impaired potency
• constipation
According to WIECK the depression causes
feelings of guilt, anxiety and melancholy [44]:
Fig. 4: Diagram of depression according to WIECK. The
patient expresses feelings of melancholy in association with
the present linked with guilt about the past and anxiety
about the future [44].
HERBAL EXTRACTS SERIES 1. HYPERICUM
17
However, about a third of depressions respond
poorly or not at all to treatment with synthetic
drugs (therapeutically resistance depression) [2].
In the past, unwelcome cholinergic side-effects
have been observed, in particular to tricyclic
antidepressants in non-hospitalized patients, such
as dryness of the mouth and difficulty in focusing,
disturbances of the cardiovascular and central
nervous systems. Within 14 days almost half of
the patients treated had their effective dosage
reduced or completely stopped. The potential
danger at the workplace and in traffic as well as
interaction with alcohol reduced the compliance
with tricyclic antidepressants [1, 5, 47].
Nowadays, less and less patients are prepared to
accept undesirable side-effects and expect to be
prescribed drugs which are both effective and
carry a low risk when taken over a long period
[21]. Therapeutic treatment with St John’s Wort
extract has no cholinergic or sedative side-effects
so that neither driving or operating machines at
work is not effected [59].
No sedative side-
effects
HERBAL EXTRACTS SERIES 1. HYPERICUM
18
St John’s Wort has rightly become a standard
medication in the treatment of depression and is
well regarded by medical practitioners. The
emphasis of the treatment is on the symptomatic
and reactive depressions as well as on neurotic
depression and psychovegetative syndrome. It
should be remembered that these conditions are
chronic and always necessitate long-term therapy.
The positive effect of St John’s Wort on patients’
moods does not become evident for at least two to
three weeks. Therapy should last for at least two
to three months [1, 55].
St John’s Wort:
respected by
medical
practitioners
Long-term
treatment
recommended
HERBAL EXTRACTS SERIES 1. HYPERICUM
19
4 Pharmacology
4.1 Antidepressant Effect
The antidepressant effect of St John’s Wort
extract is not based on a single mechanism but
rather, as is the case with many herbal remedies,
is brought about by many different mechanisms.
Many different
mechanisms
account for
effectiveness
4.1.1 Blocking the Resorption of Serotonin
The effect observed under the influence of
Hypericum extract of the reduced availability of
serotonin receptors and the associated possible
resorption of the neurotransmitter serotonin into
the cell could be an example of the antidepressant
mechanism of the Hypericum extract. Using
fluorescent microscopic methods to examine
them, nerve cells which had been incubated with
Hypericum extract displayed significantly less
serotonin receptors on their surface then before
incubation [34].
Studies using synaptosomes from rat brains
showed that with a concentration of Hypericum
extract of 6.2 µg/ml the serotonin resorption was
reduced by 50 % (IC50 value). This has been taken
to mean that the antidepressant activity of the
Hypericum extract is due to a blocking of the
serotonin resorption by post-synaptic receptors
(see following graph) [37].
Blocking of the
serotonin
resorption
HERBAL EXTRACTS SERIES 1. HYPERICUM
20
Fig. 5: Uptake of 3H-serotonin (5-HT) by rat synaptosomes
as a function of incubation time. Five experiments for each
value were performed. The results have been corrected with
respect to the passive transport of serotonin [37].
Fig. 6: Effect of Hypericum extract on the 2H-serotonin (5-
HT) uptake by rat synaptosomes. The incubation period
after addition of serotonin was 20 min. Five experiments for
each value were performed.
HERBAL EXTRACTS SERIES 1. HYPERICUM
21
The hypericins are said to have a further effect on
the serotonin metabolism. They are supposed to
work by increasing light utilization and
influencing the serotonin-melatonin metabolism.
As a colour pigment hypericin absorbs light in the
long-wave section of the light spectrum and thus
helps the patient to use whatever light is available
more effectively, which often leads to a lifting of
depressive moods. Hypericin also raises the
concentration of melatonin, a hormone which is
formed in the pineal gland of the brain out of
serotonin and has a sleep-regulating function
[47]. In addition the hypericins are said to have an
antiviral effect [24].
4.1.2 Slight Blocking of the Monoamine
oxidase (MAO)
The enzyme monoamine oxidase (MAO) is to a
large part responsible for the breakdown of the
neurotransmitter noradrenalin. The initial
strengthening of noradrenalin probably leads to an
adaptive alteration of the receptor systems
localized on the postsynaptic side and to
transduction mechanisms. Since MAO is also
responsible for the intraneuronal breakdown of
serotonin, MAO blockers at the serotoninergic
synapsis lead to similar effects as at noradrenergic
synapsis. An in vitro model of the proof of the
effectiveness of the Hypericum extract showed a
slight blocking effect of the resorption of the
neurotransmitter. It was also shown that hypericin
alone cannot be responsible for the effect [35].
HERBAL EXTRACTS SERIES 1. HYPERICUM
22
Flavonoids and
cumarin block the
MAO side-effects
Fractionated extracts have, however, shown both
in vitro and ex vivo that flavones and flavonols
(e.g. quercetin and quercetrin) are MAO A-
blockers while the cumarin fraction blocks MAO-
B [3, 16, 24]. A molecular modelling study has
shown that MAO-blocking effects are
conceivable for the flavonoids contained in
Hypericum but that this is unlikely to be a
mechanism of hypericin [23]. The side-effects
which are sometimes associated with strong
MAO blockers do not occur with Hypericum
Extract.
4.1.3 Blocking the Catechol-O-methyl-
transferase (COMT)
A further enzyme involved in the breakdown of
the neurotransmitter is catechol-O-
methyltransferase (COMT). Hypericum, an
extract made from the whole herb blocks COMT
in a concentration of 10-4 M. The COMT-
blocking fraction contains for the most part
flavonols and xanthone [51]. In other in vitro
experiments quercetin and rutoside were also
shown to have a blocking effect [16].
4.1.4 Modulation of Cytokine Release
A modulation of the release of cytokine has also
been discussed as having a further antidepressant
effect. Cytokines (including interleukins) are
important components in the psycho-
neuroimmuno-endocrinal communication
between cells outside the immune system, in
particular the nervous system.
HERBAL EXTRACTS SERIES 1. HYPERICUM
23
Hypericum extract acts in vitro as a direct
modulator of interleukin-6. In vivo it was thus
possible to indirectly control the secretion of the
corticotropin releasing hormone (CRH) with
Hypericum extract and to activate its
antidepressant effect using this mechanism [4,
51].
Blocking the
release of cytokine
4.2 Pharmacokinetics
The extract of St John’s Wort is a complex
compound mixture. Pharmacokinetic experiments
on the extract of the whole herb are, therefore,
difficult and have primarily been carried out for
the main substances hypericin and
pseudohypericin [46].
Resorption occurs quickly and in concentrations
proportional to the dose administered. The
maximum concentration cmax of 4.3 ng/ml was
achieved after tmax = 2.5 hours. After the
resorption phase the exponential elimination
followed with a half-life value of 6 hours [54].
Fast resorption
Fig. 7: Hypericin concentration in the plasma after the
administration of 600 mg Hypericum extract. Mean of 12
test subjects [54].
HERBAL EXTRACTS SERIES 1. HYPERICUM
24
5 Toxicology
Phototoxic effect is
unlikely
Hypericin is responsible for the photodynamic
effect and the hypericism seen in grazing animals
[38]. Studies have shown, however, that the usual
therapeutic doses of Hypericum extracts used are
below the threshold of phototoxicity by a factor
of between 30 and 50 [45].
HERBAL EXTRACTS SERIES 1. HYPERICUM
25
6 Clinical Pharmacology
6.1 Influence on Evoked Potentials and
Resting EEG
In double-blind trials using placebos the
neurophysiological effect profile and the effects
of the Hypericum extract on the subjective
symptoms as well as on the cognitive
performance parameters were studied in healthy
volunteers. Pharmaco-EEG-examinations
(electro-encephalo-graphy) were carried out and
both the acoustic and visually evoked potentials
deduced at two week intervals.
The pharmacodynamic trials demonstrated that a
neurophysiological profile similar to that of a
„classical“ antidepressant such as imipramine or
maprotiline, which have relaxing and CNS
activating characteristics, was achieved with high
doses of St John’s Wort extract (reduction in the
alpha spectrum accompanied by an increase in the
slower theta and faster beta waves = dissociative
frequency displacement). Along with its mood-
enhancing characteristics St John’s Wort extract
also has a positive effect on cognitive abilities
[26, 28].
Similar action to
classical
antidepressants
HERBAL EXTRACTS SERIES 1. HYPERICUM
26
Fig. 8: Effect on resting EEGs after 6 weeks of treatment
with the verum and the placebo. Such changes are typical
for tricyclic antidepressants [26].
The effects of Hypericum extract (as available
from ) in comparison with those brought
about by maprotilin were looked at in a
randomized study with 24 healthy trial volunteers.
In the resting EEG opposite effects were seen in
the theta area for the two drugs while very similar
changes were seen in the alpha and beta areas.
Measurement of evoked potentials in the theta
and beta range supported these findings. The
results point to a general improving effect on the
cognitive abilities during treatment with
Hypericum extract [27].
HERBAL EXTRACTS SERIES 1. HYPERICUM
27
7 Proof of Clinical Effectiveness
7.1 Meta-analysis of the Clinical Trials of
the Use of St John’s Wort Extract for
Psychovegetative Complaints
The effectiveness of Hypericum extract was
demonstrated in a meta-analysis and systematic
overview of over 20 randomized trials including
patients with mainly mild or moderately severe
depressive disorders. 14 placebo-controlled trials
showed the significant superiority of St John’s
Wort extract over the placebo. 6 studies describe
St John’s Wort extract as having the same
antidepressant effect as standard medication.
The trials used various methods to measure and
rate treatment effects. The most consistently used
instruments were the HAMILTON depression scale
(HAMD) and the clinical global impressions
index (CGI).
The HAMILTON depression scale is an observer-
rated scale focusing mainly on somatic symptoms
including 17 items. The clinical global
impressions index is an observer-rated instrument
with three items (severity of illness, global
improvement and an efficacy index) [31].
HERBAL EXTRACTS SERIES 1. HYPERICUM
28
7.2 Clinical Trials with Placebos
In Section 7.1 on meta-analysis it was stated that
14 placebo-controlled double-blind trials demon-
strated the effectiveness of St John’s Wort. Some
of these trials are described below.
In a randomized, placebo-controlled double-blind
trial 39 patients suffering from depressive moods
with accompanying psychovegetative symptoms
in the form of a masked depression were treated
for four weeks. The group receiving the verum
were given 300 mg St John’s Wort extract three
times daily. 70 % of the patients showed no
symptoms after 4 weeks. Symptoms which
reacted particularly well to treatment were
lacklustre, exhaustion, fatigue and sleep
problems [25].
A multi-centre, randomized, double-blind,
placebo-controlled trial with 102 out-patients
suffering from a Major depression of mild to
moderate severity according to DSM-III-R
demonstrated the effectiveness of a Hypericum
extract (900 mg/day). The treatment lasted 4
weeks, with all the patients being given the verum
subsequent to the trial. The total score on the
HAMILTON depression scale (HAMD) had
dropped more significantly in the verum group
after 4 weeks than in the placebo group.
Significant differences were also measured on
von ZERSSENS depression scale (D-S). The
administration of the verum over a period of 2
weeks after completion of the placebo phase led
to a reduction in the symptoms. These results thus
confirmed the results of earlier trials [14, 15].
HERBAL EXTRACTS SERIES 1. HYPERICUM
29
Fig. 9: HAMILTON depression scale (HAMD). In the group
treated with the verum the score value dropped within 4
weeks from 21.0 to 8.9 and from 20.4 to 14.4 in the placebo
group. The differences between the verum and the placebo
groups after 2 and 4 weeks were highly significant (p<0.001
respectively). In the 5th and 6th week during which period
both groups were given the verum a marked improvement in
the original placebo group was seen [14].
Fig. 10: von ZERSSENS depression scale (D-S). After 4
weeks of treatment with the verum the levels considered as
the norm for healthy volunteers were reached (mean value
and standard deviation). In this case too subsequent
treatment of the placebo group with the verum (weeks 5 and
6) led to a reduction in symptoms, which with reference to
the scale value correspond at least to the verum group
(weeks 1 and 2) [14].
HERBAL EXTRACTS SERIES 1. HYPERICUM
30
In a further randomized, double-blind, placebo-
controlled trial in three practices of psychiatrists,
internists and general practitioners, the
effectiveness of a Hypericum extract in the
treatment of mild to moderately severe
depressions was documented. 105 non-
hospitalized patients suffering from neurotic
depression or short bouts of depressive mood
changes were treated with 900 mg/day of St
John’s Wort extract or with a placebo for a
duration of 4 weeks. Significant changes were
reported in the trial drug/placebo comparison for
the symptoms of depressives moods (feelings of
melancholy, hopelessness, helplessness, low self-
esteem, see Fig. 11), for the psychological anxiety
and the symptoms ”difficulty in getting to sleep”,
”heart complaints”, ”exhaustion” and
”headaches” [21].
Fig. 11: Depressive moods (feelings of melancholy,
hopelessness, helplessness, low self-esteem) according to
the HAMILTON scale. Statistically significant improvement
in the depressive moods in the verum group after 4 weeks of
treatment [21].
HERBAL EXTRACTS SERIES 1. HYPERICUM
31
The St John’s Wort extract provides doctors
treating patients suffering from depression with
an efficient herbal remedy which is well accepted
by them. It is a medication which has shown clear
superiority over placebos in placebo-controlled
double-blind trials [17].
7.3 A Comparison of Clinical Trials and
Standard Conditions
In a double-blind comparative trial 135
depressive patients were treated in 20 trial
centres. This trial included patients with
diagnoses ranging from typical depression with
single episodes and those with repetitive
episodes, depressive neurosis and adjustment
disorders with depressive mood alteration as
defined according to DSM-III-R. The dosage used
was 3 x 300 mg Hypericum extract or 3 x 25 mg
imipramine daily over a period of 6 weeks. The
reference criteria used were the HAMILTON-
depression scale (HAMD), von ZERSSENS
depression scale (D-S) and the clinical global
impressions index (CGI).
A similar reduction in the HAMILTON-Scores and
in the statistical D-S values occurred in both
treatment groups. The evaluation of the CGI
produced similar results for both groups. Less and
milder side-effects were reported in the
Hypericum group than in the imipramine
group [52].
HERBAL EXTRACTS SERIES 1. HYPERICUM
32
Comparison of the effectiveness and tolerability
of a Hypericum extract and maprotiline was
carried out in a multi-centre, randomized, double-
blind trial with 102 depressive patients. Over a
period of 4 weeks treatment was administered
with 3 x 300 mg Hypericum extract or 3 x 25 mg
maprotiline. A similar level of effectiveness was
reported after 4 weeks (Fig. 12). Less side-effects
were reported in the Hypericum group [19].
Fig. 12: Mean value of the total score on the HAMILTON
depression scale. There was a drop of around 50 % in both
trial groups during the 4 week period of treatment [19].
An extremely low-
risk alternative to
synthetic
antidepressants
A variety of more recent double-blind trials
demonstrate the clinical effectiveness of high
doses of St John’s Wort preparations in the
symptomatic treatment of depression. It has been
shown to be more effective than a placebo and
when compared with standard medication to be
just as effective. When the mild or non-existent
side-effects are taken into account St John’s Wort
extract must be seen as medication of first choice
in the treatment of mild and moderately severe
depression [2, 10].
HERBAL EXTRACTS SERIES 1. HYPERICUM
33
7.4 Drug Monitoring Trials
In an observation study of its clinical use, the
effectiveness and tolerability of a 5-week course
of treatment with a St John’s Wort preparation
was demonstrated in subjects suffering from
psychological depressive states. Typical
psychological and somatic symptoms were
reduced both in their severity and frequency [12].
Symptoms recede
A drug monitoring trial was carried out in
association with the treatment of over 1000
patients under the care of a total of 270 medical
practitioners. The patients were suffering from
mild to moderately severe depression and were
treated over a period of 4 weeks. The
effectiveness and assessment of the tolerability of
the St John’s Wort preparation were standardized
using, for example, the HAMILTON depression
scale (HAMD) and von ZERSSENS scale (D-S
scale). After 4 weeks of treatment a marked
clinical reduction in the symptoms was observed.
More than three quarters of the patients exhibited
no further symptoms of depression. In 90% of the
cases tolerability was positively assessed [1].
Depressions recede
HERBAL EXTRACTS SERIES 1. HYPERICUM
34
Effectiveness and tolerability of a 4-week course
of treatment with Hypericum extract administered
to 3259 patients was monitored by 663 medical
practitioners. The typical symptoms receded in
both frequency and severity by about 50 %.
Around 80 % of the patients improved or were
completely symptom-free during treatment. Only
2.4 % of the patients complained of side-effects
[59].
Fig. 13: Absolute frequency of the specific symptoms in
3259 depressive patients before and after treatment with
Hypericum extract [59].
HERBAL EXTRACTS SERIES 1. HYPERICUM
35
7.5 Effect on Patients’ Responses
A double-blind trial including a placebo group
was carried out on the medically measurable
traffic responses of 60 patients. Hypericum
extract was shown to have no negative effect on
responses [41, 43].
No negative effect
on patients’
responses
In a placebo-controlled double-blind trial using
the cross-over design, the interaction of
Hypericum extract with alcohol during treatment
was tested. No such interaction was observed.
This finding is of particular importance for non-
hospitalized patients on antidepressant therapy
who continue to work and drive during treatment
[42].
No interaction with
alcohol
St John’s Wort does not have a sedative effect. It
leads instead to mild relaxation in the patient
while at the same time activity and attention are
increased.
No sedative effect
HERBAL EXTRACTS SERIES 1. HYPERICUM
36
7.6 Therapeutic Safety
High level of
therapeutic safety
Hypericum extract is notable for its particularly
high level of clinical safety. To date no acute
cases of Hypericum extract poisoning have been
reported [16]. Hypericum extract is a particularly
safe form of treatment for patients diagnosed as
having depression which could lead to attempted
suicide.
High level of
compliance
Particular emphasis should be put on the high
level tolerability of St John’s Wort preparations
which leads to a high level of treatment
compliance because of the almost total absence of
side-effects. This absence of sides-effects means
that here is also no impairment of function when
operating machines or when driving in traffic
[40].
In contrast to many synthetic antidepressants the
extract of St John’s Wort does not have a sedative
effect and can be recommended without
restrictions for patients who are working and all
patients who require full concentration for driving
and for operating machines [44]. The mood-
enhancing St John’s Wort does not carry with it a
danger of addiction, its effect is not increased by
alcohol and it well accepted by patients.
No danger of
addiction
HERBAL EXTRACTS SERIES 1. HYPERICUM
37
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