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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.


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


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

).


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


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


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].


8

Fig. 1: St John’s Wort (Hypericum perforatum L.).


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].


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.


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


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)


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.


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.


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


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].


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


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


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


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.


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].


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.


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].


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].


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


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].


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].


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].


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].


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].


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].


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].


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


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].


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


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


37

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