Hypericum – St. John’s Wort (Hyperici herba)
|Latin name of the genus:||Hypericum|
|Latin name of herbal substance:||Hyperici herba|
|Botanical name of plant:||Hypericum perforatum l.|
|English common name of herbal substance:||St. john's wort|
Latin name of the genus: Hypericum
Latin name of herbal substance: Hyperici herba
Botanical name of plant: Hypericum perforatum L.
English common name of herbal substance: St. John’s Wort
- I.REGULATORY STATUS OVERVIEW1
- II.ASSESSMENT REPORT
- Hypericum perforatum L., herba
- II.1 I
- II.1.1 Description of the herbal substance(s), herbal preparation(s) or combinations thereof
- II.1.1.1 Herbal substance:
- Hyperici herba
- II.1.1.2 Herbal preparation(s):
- Consituents of Hyperici oleum
- Influence of the extraction solvent on the composition of the extract:
- II.1.1.3 Combinations of herbal substance(s) and/or herbal preparation(s)
- II.1.1.4 Vitamin(s)
- II.1.1.5 Mineral(s)
- II.1.2 Information on period of medicinal use in the Community regarding the specified indication
- II.1.2.1 Type of tradition, where relevant
- II.1.2.2 Bibliographic/expert evidence on the medicinal use
- II.126.96.36.199 Evidence regarding the indication/traditional use
- Traditional indications for oral use of herbal teas, liquid extracts (extraction solvent ethanol) and dry extracts
- Traditional indications for oral use of liquid extracts (extraction solvent vegetable oil)
- a) Aqueous extracts (herbal teas), liquid extracts prepared with ethanol, dry extracts:
- b) Liquid extracts prepared with vegetable oil (Hypericum oil):
- Traditional indications for cutaneous use of liquid extracts (extraction solvent vegetable oil)
- Traditional indications for cutaneous use of liquid extracts (extraction solvent ethanol)
- Traditional indications for cutaneous use of liquid extracts (extraction solvent water)
- II.188.8.131.52 Evidence regarding the specified posology
- Oral administration
- Cutaneous administration
- II.2.1 Pharmacology
- II.2.1.1 Overview of available data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- II.184.108.40.206 Effects associated with depression
- Effects of constituents (
- Effects of extracts (examples of publications)
- II.220.127.116.11 Antidepressant activity in animal models
- Forced swimming test (FST)
- Learned-helplessness paradigm
- Model of escape deficit
- II.18.104.22.168 Anxiolytic effects
- II.22.214.171.124 Neuroprotection, memory impairment, nootropic effects
- II.126.96.36.199 Support in smoking cessation
- II.188.8.131.52 Treatment of alcoholism
- II.184.108.40.206 Antibacterial activity
- II.220.127.116.11 Antiinflammatory activity
- II.18.104.22.168 Wound healing
- II.22.214.171.124 Photodynamic therapy
- II.126.96.36.199 Other effects
- II.2.1.2 Assessor’s overall conclusions on pharmacology
- II.2.2 Pharmacokinetics
- II.2.2.1 Overview of available data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- II.2.2.2 Assessor’s overall conclusions on pharmacokinetics
- II.2.3 Toxicology
- II.2.3.1 Overview of available data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
- II.188.8.131.52 Single-dose toxicity
- II.184.108.40.206 Repeated-dose toxicity
- II.220.127.116.11 Mutagenicity
- II.18.104.22.168 Carcinogenicity
- II.22.214.171.124 Phototoxicity
- II.126.96.36.199 Reproductive Toxicity
- II.2.3.2 Assessor’s overall conclusions on toxicology
- II.3.1 Clinical Pharmacology
- II.3.1.1 Pharmacodynamics
- II.188.8.131.52 Overview of available data regarding the herbal substance(s)/herbal preparation(s) including data on constituents with known therapeutic activity.
- II.184.108.40.206 Assessor’s overall conclusions on Pharmacodynamics
- II.3.1.2 Pharmacokinetics
- II.220.127.116.11 Overview of available data regarding the herbal substance(s)/herbal preparation(s) including data on constituents with known therapeutic activity.
- II.18.104.22.168 Assessor’s overall conclusions on pharmacokinetics
- II.3.2 Clinical Efficacy3
- II.3.2.1 Dose response studies
- II.3.2.2 Clinical studies (case studies and clinical trials)
- II.22.214.171.124 Studies on the treatment of depression
- Overall meta-analysis
- II.126.96.36.199 Somatoform disorders
- II.188.8.131.52 Schizophrenia
- II.184.108.40.206 Nootropic effects
- II.220.127.116.11 Subacute atopic dermatitis
- II.18.104.22.168 Premenstrual syndrome
- II.22.214.171.124 Menopausal symptoms
- II.3.2.3 Clinical studies in special populations (e.g. elderly and children)
- Assessor’s conclusion on the use in the paediatric population:
- II.3.2.4 Assessor’s overall conclusions on clinical efficacy
- II.3.3 Clinical Safety/Pharmacovigilance
- II.3.3.1 Patient exposure
- II.3.3.2 Adverse events
- II.3.3.3 Serious adverse events and deaths
- II.3.3.4 Laboratory findings
- II.126.96.36.199 Phototoxicity
- Dry extracts
- Hypericum oil
- II.188.8.131.52 Limited liver function
- II.3.3.5 Safety in special populations and situations
- II.184.108.40.206 Intrinsic (including elderly and children) /extrinsic factors
- II.220.127.116.11 Drug interactions
- Interactions with benzodiazepines:
- Interactions with oral contraceptives:
- Interaction with SSRIs:
- Interactions with voriconazole
- Interactions with methadone
- Interactions with digoxin:
- Interactions with theophylline:
- Interaction with finasteride
- Interaction of the herbal tea
- II.18.104.22.168 Use in pregnancy and lactation
- II.22.214.171.124 Overdose
- II.126.96.36.199 Drug abuse
- II.188.8.131.52 Withdrawal and rebound
- II.184.108.40.206 Effects on ability to drive or operate machinery or impairment of mental ability
- II.3.3.6 Assessor’s overall conclusions on clinical safety
- Benefit – Risk – Assessment
I.REGULATORY STATUS OVERVIEW1
MA: Marketing Authorisation;
TRAD: Traditional Use Registration;
Other TRAD: Other national Traditional systems of registration;
Other: If known, it should be specified or otherwise add ’Not Known’
1This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products in the MSs concerned.
2Not mandatory field
BASED ON ARTICLE 10A OF DIRECTIVE 2001/83/EC AS AMENDED
BASED ON ARTICLE 16D(1) AND ARTICLE 16F AND 16H OF DIRECTIVE 2001/83/EC AS
II.1.1 Description of the herbal substance(s), herbal preparation(s) or combinations thereof
II.1.1.1 Herbal substance:
Hyperici herba (European Pharmacopoeia)
Hyperici herba consists of the whole or cut, dried flowering tops of Hypericum perforatum L., harvested during flowering time. It contains not less than 0.08% of total hypericins expressed as hyericin calculated with reference to the dried drug.
Consituents (Wichtl 2002; Bradley 2006, Hänsel & Sticher 2007, figure 1)
Procyanidines: e.g. procyanidine B2, tannins with catechin skeletal
Xanthones: in trace amounts
Other constituents: include small amounts of chloregenic acid and other caffeoylquinic and
II.1.1.2 Herbal preparation(s):
St. John’s wort dry extract, quantified extract (Pharm. Eur. ref. 07/2008:1874)
Extraction solvents ethanol
Wurglics et al. (2001a, 2002, 2003) report that in commercial batches the content of hypericin is between 0.16 and 0.32%, the content of hyperforin is <0.2% (Ze 117) or in the range between 1.5 and 4.4% (partly with considerable differences between batches [Wurglics et al. 2001b, Wurglics et al. 2003]). The content of total flavonoids is between 6 and 8%. Dissolution test revealed considerable differences in the dissolution of flavonoids between authorized products in Germany.
Herbal preparations with evidence of tradition according Dir. 2004/24:
A)Dry extract, DER
B)Liquid extract (DER
According to the German “Ergänzungsbuch” to the German Pharmacopoeia 6
the fermentation the glass has to be sealed. It is then stored at a sunny place for about 6 weeks until the oil is bright red. The herbal substance has to be pressed out, the oil is dried with sodium sulphate (6 parts).
According to Swiss Pharmacopoeia (Pharm. Helv. 8 2001): The comminuted fresh flowering tops of H. perforatum are overflowed with 40.0 g refined sun flower oil. The mixture is reshuffled frequently; extraction and fermentation take place at a temperature of
According to the company ‘Caelo’, Germany: the dried herbal substance (according to Pharm. Eur.) is macerated with olive oil in a DER of 1:20. The mixture is agitated under light exposure for at least 40 hours. The content of hypericin is at least 0.005% (spectrophotometric determination).
Consituents of Hyperici oleum
Hyperici oleum does not contain hypericin. By using the sunlight maceration method described in the supplement to DAB 6 (EB 6), lipophilic breakdown products of this compound are obtained which lend the oil its red colour. The stability of hyperforin is limited; sufficient
As a consequence the spectrophotometric determination used for the specification of the St. John’s wort oils mentioned above detects primarily artefacts of hypericin.
Schempp et al. (2000) used for the test of the influence of Hypericum extracts on skin sensitivity Hypericum oil containing 110 µg/ml hypericin. It is not transparent, whether the authors determined hypericin or the oil derivatives.
C)Liquid extract (DER 1:13), extraction solvent maize oil: on the market in DE at least since 1976. Hypericin: approximately 0.0013%; hyperforin: approximately 0.01% (Müller et al. 2004)
D)Tincture (DER 1:10), extraction solvent ethanol
E)Tincture (DER 1:5), extraction solvent ethanol 50% v/v: mentioned in Bradley (2006). The evidence of tradition of this tincture has to be proved.
F)Liquid extract DER 1:2, extraction solvent ethanol 50%
“Rote Liste”. The first clinical study with this liquid extract is published 1979, therefore the extract is in medicinal use at least 30 years at the time of publication of the monograph.
H)Expressed juice from the fresh herb (DER
I)Comminuted herbal substance: cut herbal substance used for tea preparation; powdered herbal substance in solid dosage forms for oral use on the market in DE at least since 1976. Hypericin: approximately
Further dry extracts:
Dry extract (DER
Dry extract (DER
Both extracts are covered by dry extracts mentioned under
Further liquid extracts:
Since the edition 1993 of Hager’s Handbuch (Hänsel et al. 1993) a liquid extract with a DER 1:6, extraction solvent ethanol 70% is mentioned. This type of extract is not mentioned in previous literature. The period of 30 years of medicinal use is therefore not fulfilled.
The request for marketed products in the EU revealed that numerous further extracts are on the market. However, they neither do fulfil the criteria for traditional use nor are they supported by clinical evidence.
Influence of the extraction solvent on the composition of the extract:
When using extraction solvents containing more than 50% of ethanol or methanol in water the content of hypericin in the extract seems to be very similar independent of the actual concentration of the extraction solvent. In contrast the extraction of hyperforin and adhyperforin depends strongly on the concentration of the extraction solvent. Best yield (60% of the hyperforin in the herbal substance, 45% of adhyperforin in the herbal substance) is achieved with 70% (e.g. ethanol), while with 50% ethanol only 20% of hyperforin and no adhyperforin are extracted (Meier 1999).
II.1.1.3 Combinations of herbal substance(s) and/or herbal preparation(s)
II.1.2 Information on period of medicinal use in the Community regarding the specified indication
II.1.2.1 Type of tradition, where relevant
II.1.2.2 Bibliographic/expert evidence on the medicinal use
II.220.127.116.11 Evidence regarding the indication/traditional use
Traditional indications for oral use of herbal teas, liquid extracts (extraction solvent ethanol) and dry extracts
Nervous system disorders, psychiatric disorders:
Traditional indications for oral use of liquid extracts (extraction solvent vegetable oil)
Discussion and assessment of traditional indications for oral use:
Since the Hypericum oil differs considerably in the nature of the constituents from aqueous and ethanolic liquid extracts these types of herbal preparations are discussed separately.
a) Aqueous extracts (herbal teas), liquid extracts prepared with ethanol, dry extracts:
Infusions prepared with water are widely used in the traditional medicine at least in Central Europe (Gerlach 2008). The indication ‘depression’ is unknown in traditional medicine; Hypericum is used in order to ‘strengthen the nerves’, to restore emotional balance. The wording which is found in literature reflects this fact, although put into different words. This traditional indication is plausible because of the pharmacological and clinical data which are available for isolated compounds and alcoholic extracts of H. perforatum.
The numerous further traditional indications mentioned in the literature for these kinds of extracts are not plausible.
Since for the indication of a traditional herbal medicinal product terms like ‘depression’ or ‘depressed mood’ are not suitable, special care is taken to the wording.
The main feature is repeated presentation of physical symptoms together with persistent requests for medical investigations, in spite of repeated negative findings and reassurances by doctors that the symptoms have no physical basis. If any physical disorders are present, they do not explain the nature and extent of the symptoms or the distress and preoccupation of the patient.
Considerable cultural variations occur in the presentation of this disorder, and two main types occur, with substantial overlap. In one type, the main feature is a complaint of increased fatigue after mental effort, often associated with some decrease in occupational performance or coping efficiency in daily tasks. The mental fatigability is typically described as an unpleasant intrusion of distracting associations or recollections, difficulty in concentrating, and generally inefficient thinking. In the other type, the emphasis is on feelings of bodily or physical weakness and exhaustion after only minimal effort, accompanied by a feeling of muscular aches and pains and inability to relax. In both types a variety of other unpleasant physical feelings is common, such as dizziness, tension headaches, and feelings of general instability. Worry about decreasing mental and bodily
States of subjective distress and emotional disturbance, usually interfering with social functioning and performance, arising in the period of adaptation to a significant life change or a stressful life event. The stressor may have affected the integrity of an individual’s social network (bereavement, separation experiences) or the wider system of social supports and values (migration, refugee status), or represented a major developmental transition or crisis (going to school, becoming a parent, failure to attain a cherished personal goal, retirement). Individual predisposition or vulnerability plays an important role in the risk of occurrence and the shaping of the manifestations of adjustment disorders, but it is nevertheless assumed that the condition would not have arisen without the stressor. The manifestations vary and include depressed
mood, anxiety or worry (or mixture of these), a feeling of inability to cope, plan ahead, or continue in the present situation, as well as some degree of disability in the performance of daily routine. Conduct disorders may be an associated feature, particularly in adolescents. The predominant feature may be a brief or prolonged depressive reaction, or a disturbance of other emotions and conduct.
All these three types of disorders reflect partly the traditional oral use of H. perforatum. The definition of the somatoform disorders includes characteristics which are not suitable for THMPs. Particularly the persistent request for medical investigation is in contrast to the concept that the products are intended for use without medical supervision.
The traditional use seems to be covered in a most suitable way by the definition of ‘neurasthenia’. However, the very broad definition also includes symptoms which should be treated under medical supervision. Therefore the indication should be restricted to ‘temporary mental exhaustion’.
The plausibility of the efficacy in this traditional indication is supported by an observational study (Grube et al. 1996). Hypericum dry extract LI 160 was administered corresponding to 900 µg hypericin daily (= approximately 540 mg extract) to patients with mild temporary depressed mood.
Additionally the indication should be clearly different from the proposed health claims for food supplements (contributes to emotional balance and general wellbeing; contributes to optimal relaxation; helps to support relaxation and mental and physical wellbeing; helps to maintain a healthy sleep; helps maintain a positive mood).
Proposed traditional indication (oral use, aqueous extracts, liquid ethanolic extracts, dry extracts)
Traditional herbal medicinal product for the relief of temporary mental exhaustion.
The product is a traditional herbal medicinal product for use in the specified indication exclusively based upon
In addition the herbal tea is a traditional medicinal product in Poland used for treatment of digestion disorders.
Traditional herbal medicinal product for the symptomatic relief of mild gastrointestinal discomfort.
The product is a traditional herbal medicinal product for use in the specified indication exclusively based upon
b) Liquid extracts prepared with vegetable oil (Hypericum oil):
The indications mentioned in the references cannot be explained by the constituents of the Hypericum oil, data from pharmacological experiments are lacking. Therefore the mentioned indications are not plausible. There is no traditional indication for the oral use of Hypericum oil.
Traditional indications for cutaneous use of liquid extracts (extraction solvent vegetable oil)
Skin and subcutaneous tissue disorders:
Traditional indications for cutaneous use of liquid extracts (extraction solvent ethanol)
Skin and subcutaneous tissue disorders:
Traditional indications for cutaneous use of liquid extracts (extraction solvent water)
Skin and subcutaneous tissue disorders:
Discussion and assessment of traditional indications for cutaneous use:
The traditional use of liquid preparations of Hypericum for wound healing is supported by pharmacological data. Antiinflammatory activity, analgesic activity, astringent activity and antibacterial activity are documented,
traditional use for the treatment of symptoms caused by an injury or related to rheumatism is not yet plausible. Antiviral effects are documented for several types of viruses, but not for Varicella zoster. Therefore the traditional use in the treatment of shingles cannot be supported.
Proposed traditional indication (cutaneous use, liquid extracts, extraction solvents vegetable oil, ethanol or water)
Traditional herbal medicinal product for the symptomatic treatment of minor inflammations of the skin (such as sunburn) and as an aid in healing of minor wounds.
The product is a traditional herbal medicinal product for use in the specified indication exclusively based upon
II.18.104.22.168 Evidence regarding the specified posology
Comminuted herbal substance for tea preparation:
The single dose for tea preparation is 1 teaspoon per cup, which is equivalent to 1.8 to 2 g of herbal substance. The recommendation of the daily dose is
Proposal for the posology of the comminuted herbal substance for tea preparation: Adults, elderly: single dose
Children and adolescents: Since no data on the safe traditional use in children are available the use in children and adolescents is not recommended.
The powdered herbal substance is in medicinal use in solid dosage forms longer than 30 years. The proposed posology (single dose
Dry extracts: Traditionally dry extracts are administered in considerably lower doses than those used for the treatment of mild to moderate depression.
Tincture (DER 1:5):
Tincture (DER 1:5) (= ESCOP 2003, posology with reference to a product from Steigerwald):
Tincture (DER 1:10), 45% ethanol:
Tincture (DER 1:2): Single dose
Tincture (DER not given):
The posology of the further mentioned herbal preparations reflects the posology of the authorized products.
Children and adolescents: Since no data on the safe traditional use in children are available the use in children and adolescents below 18 years of age is not recommended.
Strength of the preparations:
Hypericum oil is administered undiluted.
Hypericum tea prepared with a DER of 1:5 (WHO monographs 2002)
Children and adolescents: Since no data on the safe traditional use in children are available the use in children below 12 years of age is not recommended.
II.2.1.1 Overview of available data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
II.22.214.171.124 Effects associated with depression
The mechanisms of action as well as the responsible compounds of Hypericum extracts are still under discussion. Several actions contributing to clinical efficacy are reported: Blockade of the reuptake of serotonin
Effects of constituents (primarily according to a review from Butterweck & Nahrstedt 2003a
In vitro the flavonols inhibit the monoaminooxidase (MAO), a fraction rich in flavonols also inhibits the
Amentoflavon, which occurs only in traces in the flowers, inhibits in very low concentrations the binding of flumazenil on the benzodiazepine binding sites of the GABA receptor (Baureithel et al.
1997) as well as to the
A flavonoid fraction, free of hypericins and hyperforin, induces a reduction of the
It is not known whether the flavonoids or their metabolites are responsible for these effects.
Hyperosid directly stimulates the endocytosis of
Pure naphthodianthrones are only poorly soluble in water. The solubility is increased by letter compounds of the extract. For example procyanidines are able to increase the solubility in water 10- fold. Rutin and hyperoside may also contribute to the better solubility of hypericin in extracts.
Hyperoside and the procyanidines increase the serum level of hypericin considerably.
Isolated hypericin has no influence on the
Hypericin alters the concentration of several neurotransmitters after 8 weeks of treatment comparable to imipramine. Eight weeks treatment also increases the serotonin concentration in the hypothalamus, while the concentration of metabolites of dopamine is reduced. Hypericin induces a reduction of the
Hypericin reduces, similar to imipramine, the expression of mRNA of the corticotrophin releasing hormone in the hypothalamus as well as the ACTH and corticosterone levels in the plasma of rats. An overview presenting chemical and biological properties of hypericin has been published by Lavie et al. (1995).
Müller et al. (1998) and Chatterjee et al. (1998) revealed that hyperforin plays an important role in the inhibition of neurotransmitter reuptake. In vitro the IC50 value for the inhibition of the synaptosomal
reuptake of serotonin, dopamine, noradrenaline, GABA and glutamate caused by hyperforin is in the range of 80 to 1234 nM. After a daily intake of 900 mg of Hypericum extract a blood level of 180 nM of hyperforin was detected. Therefore it could be concluded that sufficient amounts of hyperforin for the inhibition of the reuptake of some neurotransmitters could be achieved during therapy.
Several mechanisms for these effects are in discussion: Inhibition of calcium channels of the
Isolated hyperforin does not influence the density of
Hyperforin directly causes the endocytosis of
Due to the low content of xanthones in the herbal substance (about 0.0004%) it is not likely that the experimentally documented inhibition of MAO A and B is of clinical relevance.
Effects of extracts (examples of publications)
The results on MAO inhibition are controversial. At concentration of
The inhibition of synaptosomal reuptake of several neurotransmitters could be demonstrated for different kinds of extracts (different extraction solvent, different amounts of hypericin, hyperforin).
Misane & Ogren. (2001) found that an ethanolic extract given in high doses affects the neuronal
Calapai et al. (2001) investigated an extract standardised to 50% flavonoids, 0.3% hypericin and 4.5% hyperforin. After acute oral administration (250 – 500 mg/kg)
The down regulation of
A methanolic extract (4.5% hyperforin) interacted with a GABA A receptor, an extract rich in hyperforin did not show an interaction. Data on the inhibition of specific bindings to the dopamine transporters indicate that the hyperforin content cannot explain effects of extracts on receptors (Gobbi et al. 2001).
A methanolic extract could also inhibit the binding of flumazenil to the benzodiazepine binding site of the GABA A receptor in vitro.
Simbrey et al. (2004) used quantitative radioligand receptor binding studies to examine the effects of
Hypericum extract inhibited the binding of naloxone to the µ- and
II.126.96.36.199 Antidepressant activity in animal models
Forced swimming test (FST)
In the FST pure naphthodianthrones were active in high concentrations only, after addition of a fraction rich in procyanidines (which itself is inactive in the FST) hypericin was active in a concentration of 0.009 mg/kg (Butterweck et al. 1998).
Hyperoside, isoquercitrin and miquellianin showed activity in low concentrations (0.6 mg/kg) in the FST. Rutin, when administered as isolated compound, has no activity in the FST. However, extracts with a low content of rutin show only a weak activity in the FST, but when pure rutin is added to the extract, an activity could be demonstrated. Unfortunately the contents of the naphthodianthrones were not presented in the study (Butterweck et al. 2000).
Daily administration of 3 mg/kg isorhamnetin, a main metabolite from quercetin, for 9 days induced a statistically significant decrease in the immobility time in the FST (Paulke et al. 2008).
Noldner & Schotz (2002) found that an ethanolic extract (doses
Beijamini & Andreatini (2003) investigated the same methanolic extract. The rats received 150 to 500 mg/kg extract in 3 portions starting 24 hours before the experiment. All doses significantly reduced the immobility time.
Two different hydroethanolic extracts (4.5% and 0.5% hyperforin) and a stable salt of hyperforin were tested in the forced swimming test by Cervo et al. (2002). All test substances caused a significant reduction of immobility; the effect was more pronounced in the extract containing more hyperforin. The authors therefore conclude that hyperforin plays an important role in the
Calapai et al. (2001) found that an extract standardised to 50% flavonoids, 0.3% hypericin and 4.5% hyperforin was able to reduce the immobility time by about
Chatterjee et al. (1998) compared an ethanolic extract (4.5% hyperforin) and a supercritical CO2 extract (38.8% hyperforin). Oral doses of 300 mg/kg/day of the ethanolic extract and 30 mg/kg/day of the CO2 extract were almost equieffective to 10 mg/kg/day of imipramine (52% reduction).
Model of escape deficit
Usai et al. (2003) compared 2 hydroethanolic extracts (4.5% hyperforin, 7.47% hyperforin). Both extracts exhibit a strong protective effect to prevent the development of escape deficit in rats. The extract with 4.5% hyperforin was effective in doses 8 times lower than of the other extract.
II.188.8.131.52 Anxiolytic effects
Kumar et al. (2000) reported anxiolytic effects of a Hypericum extract (ethanol 50%) of Indian origin in animal models, the dosage was relatively high (100 and 200 mg / kg p.o.).
Flausino et al. (2002) investigated the effects of acute and chronic oral treatment with H. perforatum L. (HP LI 160,
The aim of a study from Beijamini & Andreatini (2003) was to evaluate the putative antipanic/anxiolytic effect of standardised H. perforatum extract (LI 160) on rats tested in the elevated
Grundmann et al. (2006) used exposure to an open field (OF) as inescapable stressor to mice. Exposure of male BL6/C57J mice to OF stress significantly increased body temperature (DeltaT = 1.8 +/- 0.13 degrees C, p < 0.05). Anxiolytic drugs (the benzodiazepine diazepam; 5 mg/kg, and the 5HT (1A) receptor agonist buspirone; 10 mg/kg) significantly reduced DeltaT, whereas antidepressants (imipramine and fluoxetine) had no effect on DeltaT. Oral administration of Hypericum extract significantly reduced DeltaT in doses of 250 and 500 mg/kg. Higher doses (750 and 1000 mg/kg) as well as a lower dose (125 mg/kg) did not affect DeltaT after stress, indicating a
II.184.108.40.206 Neuroprotection, memory impairment, nootropic effects
Kaltschmidt et al. (2002) analyzed the effect of hypericin on nuclear factor kappa B
Extracts of H. perforatum exhibited upgrading and significant protective effects on the trauma of PC12 cells induced by 200 µM H2O2 in a
Genovese et al. (2006) evaluated the effect of H. perforatum (given at 30 mg/kg) in an experimental animal model of spinal cord injury, which was induced by the application of vascular clips to the dura via a
Froestl et al. (2003) studied the effect of hyperforin on the processing of the amyloid precursor protein (APP) in rat pheochromocytoma PC12 cells, stably transfected with human wildtype APP. The authors observed transiently increased release of secretory APP fragments upon hyperforin treatment. Unique features, like a strong reduction of intracellular APP and the time course of soluble APP release, distinguished the effects of hyperforin from those of alkalizing agents and phorbol esters, well known activators of secretory processing of APP. Carbonyl cyanide
Silva et al. (2004) assessed the neuroprotective role of a H. perforatum ethanolic extract and obtained fractions in
The major protein constituent of amyloid deposits in Alzheimer’s disease (AD) is the amyloid beta- peptide (Abeta). Dinamarca et al. (2006) have determined the effect of hyperforin on
by the capacity of hyperforin to disaggregate amyloid deposits in a dose and
Acute administration of Hypericum extract (4.0, 8.0, 12.0, and 25.0 mg/kg i.p.) in mice before retrieval testing increased the
The effects of a Hypericum extract and hyperforin sodium salt were evaluated in rat and mouse avoidance tests by Klusa et al. (2001). In a conditioned avoidance response (CAR) test on the rat, oral daily administration of hyperforin (1.25 mg/kg/day) or of the extract (50 mg/kg/day) before the training sessions considerably improved learning ability from the second day onwards until the day 7. In addition, the memory of the learned responses acquired during 7 consecutive days of administration and training was largely retained even after 9 days without further treatment or training. The observations made using different doses indicate that these
Kumar et al. (2000, 2002) found that orally administered extracts of H. perforatum of Indian origin (doses 100 mg and 200 mg/kg) to rats showed effects which could be interpreted as possible nootropic action.
Administration of H. perforatum (350 mg / kg daily for 21 days) significantly enhanced recall of passive avoidance behaviour (PAB), but had no effect on the acquisition of conditioned avoidance responses (CARs). Rats stressed chronically (2 h daily for 21 days) displayed diminished recall of the PAB and this effect was abolished by St John’s wort. Chronic administration of the “equivalent” to the stress dose of exogenous corticosterone (5 mg/kg daily for 21 days) also impaired recall of PAB, and
this effect was also reversed by H. perforatum. None of the treatments produced significant motor coordination impairments as tested in a ‘chimney’ test. It appears that H. perforatum prevents stress- induced deterioration of memory in rats (Trofimiuk et al. 2005, 2006).
Mohanasundari et al. (2006, 2007) tested the effect of an extract of H. perforatum in chemically induced Parkinson’s disease in mice. Treatment with H. perforatum extract resulted in an inhibition of monoamine
Sanchez Reus et al. (2007) designed a study to investigate the
II.220.127.116.11 Support in smoking cessation
Catania et al. (2003) investigated the effects of an extract of H. perforatum
Mannucci et al. (2007) investigated the possible involvement of
II.18.104.22.168 Treatment of alcoholism
Several studies were performed in order to investigate the influence of Hypericum extracts on alcohol intake in animals (Rezvani et al. 1999, Perfumi et al. 1999, Perfumi et al. 2005, Perfumi et al. 2005a, Coskun et al. 2006). All studies report beneficial effects on ethanol withdrawal symptoms,
additionally a reduction of alcohol intake in alcohol preferring animals was observed. Hypericum extracts and opioid receptor antagonists act synergistically (Perfumi et al. 2003).
The changes in the alcohol drinking behaviour may be caused by hyperforin (Perfumi et al. 2001, Wright et al. 2003). In contrast, De Vry et al. (1999) reported a reduction in alcohol preference after administration of an extract with very low hyperforin content. Clinical data are missing (Uzbay 2008).
II.22.214.171.124 Antibacterial activity
Gibbons et al. (2002) screened extracts of 34 species and varieties of the genus Hypericum for activity against a clinical isolate of
II.126.96.36.199 Antiinflammatory activity
Schempp (2000) investigated the alloantigen presenting function of human epidermal cells (EC) exposed to Hypericum ointment in vivo in a mixed epidermal cell lymphocyte reaction (MECLR). The effect of Hypericum ointment was compared with the immunosuppressive effect of
Three preparations of H. perforatum L. (a hydroalcoholic extract, a lipophilic extract and an ethylacetic fraction) and the pure compounds hypericin, adhyperforin, amentoflavone, hyperoside, isoquercitrin, hyperforin dicyclohexylammonium (DHCA) salt and dicyclohexylamine were evaluated for their topical
Eckert & Müller (2001) tested the effects of hyperforin on the fluidity of crude brain membranes from young guinea pigs. Hyperforin modifies specific membrane structures in different ways. It decreases the flexibility of fatty acids in the membrane hydrocarbon core, but fluidizes the hydrophilic region of membrane phospholipids. Relatively low concentrations of hyperforin (0.3 µmol/l) significantly decreased the annular fluidity of lipids close to membrane proteins. These findings are remarkable, as inhibition of several
of hyperforin with specific membrane structures that probably contribute to its pharmacological properties.
II.188.8.131.52 Wound healing
II.184.108.40.206 Photodynamic therapy
Hypericin is considered as a potential agent in the photodynamic therapy of cancer (Agostinis et al. 2002). However, since only isolated hypericin and not extracts have been tested, this approach is out of the scope of this assessment.
II.220.127.116.11 Other effects
A dry extract prepared by successive extraction with petroleum ether,
Capasso et al. (2005) evaluated the effect of Hypericum on rat and human vas deferens contractility. Hypericum extract (1 to 300 microM) decreased in a concentration dependent manner the amplitude of electrical field stimulation and agonist induced contractions with the same potency, suggesting direct inhibition of rat vas deferens smooth muscle. Of the chemical constituents of Hypericum extract tested hyperforin but not hypericin or the flavonoids quercitrin, rutin and kaempferol inhibited phenylephrine induced contractions. Hypericum extract and hyperforin also inhibited phenylephrine induced contractions in human vas deferens. These results might explain delayed ejaculation described in patients receiving Hypericum extract.
Effects of different extracts of H. perforatum on the kindling epileptic discharges were analyzed by Ivetic et al. (2002). The experiment was carried out on Chinchilla rabbits with chronically implanted electrodes in cortical structures and hippocampus. Water,
Hypericin, pseudohypericin and hyperforin at doses as low as 2.5 µmol/l are potent antioxidants in the
Free radical scavenging and antioxidant activities of a standardized extract of H. perforatum were examined for inhibition of lipid peroxidation, for hydroxyl radical scavenging activity and interaction with
Antioxidative and radical scavenging effects are also reported for the flavonoid fraction of H. perforatum (Zou et al. 2004) and for several commercially available formulations (Hunt et al. 2001). The antioxidative properties protect human neuroblastoma cells against induced apoptosis (Jang et al. 2002).
Genovese et al. (2006) evaluated the effect of H. perforatum extract on acute pancreatitis induced by cerulein administration in male CD mice. The degree of pancreatic inflammation and tissue injury (histological score), expression of
Following the traditional use of Hypericum against viruses of the Herpes family in Greece Axarlis et al. (1998) found antiviral activity of a methanolic extract against Human Cytomegalovirus.
Panossian et al. (1996) concluded that the antiviral, antiinflammatory and antitumor effects of hypericin may result from the inhibition of the
II.2.1.2 Assessor’s overall conclusions on pharmacology
There are numerous pharmacological findings published which propose a similar pharmacology to established synthetic antidepressant drugs. However, the discussion on the responsible compounds in the extract is still ongoing. Since several hydroethanolic and hydromethanolic extracts with different contents of hypericin and hyperforin have been tested positively, it could be concluded that the naphthodianthrones and the phloroglucine derivatives are of minor relevance for the antidepressant activity.
II.2.2.1 Overview of available data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
Wurglics et al. (2006) published a review on pharmacokinetic data of compounds of Hypericum extracts. The hyperforin plasma concentration in humans was investigated in a small number of studies. The results of these studies indicate a relevant plasma concentration, comparable with that used in in vitro tests. Furthermore, hyperforin is the only ingredient of H. perforatum that could be determined in the brain of rodents after oral administration of alcoholic extracts. The plasma concentrations of the hypericins were only
The intestinal absorption characteristics of protohypericin were studied and compared with those of hypericin by Kamuhabwa et al. (1999). The
significant cellular accumulation
Investigations by Sattler et al. (1997) indicate that a significant accumulation of hypericin in the cell membrane and the cell nucleus membrane of
Plasma levels of hypericin in rats in the presence and absence of procyanidin B2 or hyperoside were determined by reversed phase HPLC using fluorimetric detection (Butterweck et al. 2003). Both compounds increased the oral bioavailability of hypericin by ca. 58% (B2) and 34% (hyperoside). Procyanidin B2 and hyperoside had a different influence on the plasma kinetics of hypericin; median maximal plasma levels of hypericin were detected after 360 min (Cmax : 8.6 ng/ml) for B2, and after 150 min (Cmax : 8.8 ng/ml) for hyperoside. It can be speculated that, when administered together with these compounds, a significant accumulation of hypericin in rat plasma in the presence of both polyphenols might be responsible for the observed increased in vivo activity.
Juergenliemk et al. (2003) examined the pathway of miquelianin (quercetin
Paulke et al. (2008) suggested that not the genuine flavonoid glycosides reach the plasma. After oral uptake they are deglycosylated in the small intestine, after absorption the quercetin aglycone is glucuronidated (yielding e.g. miquelianin). Further methylation is possibly leading to isorhamnetin and tamarixetin. These metabolites have the ability to penetrate the
Hyperforin is a high affinity ligand for pregnan x receptor (PXR) and activates the promoters of CYP3A4 and CYP2B6 through activation of PXR and
II.2.2.2 Assessor’s overall conclusions on pharmacokinetics
The few data on pharmacokinetics do not allow a final conclusion about absorption, distribution, metabolism and excretion of the constituents of Hypericum extracts. Additionally it is not clear whether putative active constituents of Hypericum extracts reach the brain tissue in sufficient concentration.
II.2.3.1 Overview of available data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
For a methanolic extract (DER
Intravenous application of hypericin was well tolerated by rhesus monkeys at a dose of 2 mg/kg, at 5 mg/kg transient severe photosensitivity rash occurred (Fox et al. 2001). The amount of hypericin administered daily in usual therapeutic dosages is not more than 3 mg for adults (= 0.04 mg/kg).
The genotoxicity testing of ethanolic extracts showed weak positive results in the
Okpanyi et al. (1990) tested an ethanolic extract (DER
Tests on the carcinogenic potential have not been published.
In order to estimate the potential risk of phototoxic skin damage during antidepressive therapy, Bernd et al. (1999) investigated the phototoxic activity of hypericin extract using cultures of human keratinocytes and compared it with the effect of the
Schempp et al. (2002) assessed the phototoxic and
Wilhelm et al. (2001) investigated the phototoxic potential of three H. perforatum extracts from different sources as well as some of its main constituents. H. perforatum extracts demonstrated cytotoxicity and photocytotoxicity in a dose and
Clinical evidence suggests that administration of H. perforatum extracts containing the
Schmitt et al. (2006a) examined the cytotoxicity of H. perforatum extracts prepared in solvents ranging in polarity, fractions of one extract, and purified compounds in three cell lines. All extracts exhibited significant cytotoxicity; those prepared in ethanol (no hyperforin, 3.6 microM hypericin, and 134.6 microM flavonoids) showed between 7.7 and 77.4% cell survival (p < 0.0001 and 0.01), whereas the chloroform and hexane extracts (hyperforin, hypericin, and flavonoids not detected) showed approximately 9.0 (p < 0.0001) and 4.0% (p < 0.0001) survival.
A study of Traynor et al. (2005) used HaCaT keratinocytes to investigate the photoclastogenic ability of hypericin on irradiation with UVA. The results show that although the combination of hypericin and UVA light increased the genotoxic burden, when all factors are taken into account, the risk of significant photogenotoxic damage incurred by the combination of H. extracts and UVA phototherapy may be low in the majority of individuals.
To determine if hypercin could be phototoxic to the eye, He et al. (2004) exposed human lens epithelial cells to
Wahlman et al. (2003) found that the total accumulated protein leakage was positively correlated (r = 0.9) with variability in focal length. Lenses treated with hypericin and irradiated with UVB had an increase in focal length variability as compared with the lenses that were only
To determine if hypericin might be phototoxic to the human retina, Wielgus et al. (2006) exposed human retinal epithelial cells to
II.18.104.22.168 Reproductive Toxicity
Ondrizek et al. (1999) incubated
Gonzalez et al. (1999) studied the impact of antenatal Hypericum exposure on cognition in mice. Hypericum (182 mg/kg/day) was consumed for 2 weeks before mating and throughout gestation. This dose has antidepressant efficacy in mice. Prenatal exposure to a therapeutic dose of Hypericum did not have a major impact on selected cognitive tasks in mice offspring.
Assessor’s comment: No details were published about the nature of the Hypericum preparation.
Cada et al. (2001) investigated the influence of Hypericum extract on gestation and offspring of rats. 35 rats were exposed to diets containing 0, 180, 900, 1800 or 4500 ppm Hypericum extract (0.3% hypericin) (=
Chan et al. (2001) studied the influence of hypericin on rat embryos. Embryos from
After ingestion of 1800 mg Hypericum extract the mean peak plasma hypericin concentration was 29.5 ng/ml with a range of
Assessor’s comment: In the setting of the study hypericin comes into direct contact with the embryos, while in situ embryos are protected by the placental barrier.
Rayburn et al. (2000) studied the effect of antenatal exposure to Hypericum on neurobehaviour of developing mice. The extract was standardised to 0.3% hypericin. 0.75 mg extract was mixed with each gram of feed (= 180 mg/kg/day). In a randomized and
In a following study with similar design (Rayburn et al. 2001) no effect on long term growth and physical maturation of exposed mouse offspring was detectable. With the same herbal preparation Rayburn et al. (2001a) found that prenatal exposure to a therapeutic dose for Hypericum did not have a major impact on certain cognitive tasks in mice offspring.
The purpose of a study of Gregoretti et al. (2004) was to investigate the effects of a treatment with Hypericum administered prenatally and during breastfeeding (from 2 weeks before mating to 21 days after delivery) in Wistar rats. Two doses of the extract were chosen, 100 mg/kg per day, which, based on surface area, is comparable to the dose administered to humans, and 1000 mg/kg per day. A microscopic analysis of livers, kidneys, hearts, lungs, brains, and small bowels was performed. A severe damage was observed in the livers and kidneys of animals euthanized postnatally on days 0 and 21. The lesions were more severe with the higher dose and in animals that were breastfed for 21 days; however, an important renal and hepatic damage was evident also with the dose of 100 mg/kg per day. In addition, similar serious hepatic and renal lesions were evident also in animals that were exposed to Hypericum only during breastfeeding. In particular, a focal hepatic damage, with vacuolization, lobular fibrosis, and disorganization of hepatic arrays was evident; in the kidney, a reduction in glomerular size, disappearance of Bowman’s space, and hyaline tubular degeneration were found. All important
Borges et al. (2005) treated inseminated rats orally with a methanolic extract of H. perforatum. A dosage of 36 mg/kg was given on days
signs of maternal toxicity were found. In the administered dose Hypericum extract did not interfere with the progress of gestation during organogenesis in rats.
II.2.3.2 Assessor’s overall conclusions on toxicology
The few data available on acute and subchronic toxicity do not reveal signs of a risk to the patient. The weak positive outcome of tests on mutagenicity of ethanolic extracts can be explained with the presence of quercetin in the extracts. Numerous publications deal with the potential phototoxicity of hypericin and Hypericum extracts. Extracts exert less phototoxicity than pure hypericin. Considering the outcome of clinical tests on phototoxicity herbal preparations of H. perforatum can be considered as safe when administered in the proposed dosage. The data on reproductive toxicity are contradictory. Tests on reproductive toxicity demonstrated no differences between Hypericum extract (108 mg/kg) and placebo in mice. However, isolated hypericin seems to have teratogenic properties. For safety reasons the oral use of Hypericum during pregnancy and lactation should not be recommended.
II.3.1 Clinical Pharmacology
II.22.214.171.124 Overview of available data regarding the herbal substance(s)/herbal preparation(s) including data on constituents with known therapeutic activity.
An EEG study with the extract Ze 117 (Böttcher et al. 2000) showed marked increase in the amplitude of delta and theta waves indicating typical antidepressant profile.
In a placebo controlled design the neurophysiological effects of Hypericum extract LI 160 were compared with respect to the subjective state as well as to the performance (Johnson et al. 1992). The authors suggest that Hypericum shows central effects (cognitive activation) similar to known antidepressants.
II.126.96.36.199 Assessor’s overall conclusions on Pharmacodynamics
There is limited data published which would confirm the findings of in vivo pharmacological testing in humans.
II.188.8.131.52 Overview of available data regarding the herbal substance(s)/herbal preparation(s) including data on constituents with known therapeutic activity.
Biber et al. (1998) investigated the pharmacokinetics of hyperforin after oral administration of 300, 600 and 1200 mg of two different ethanolic extracts (5% and 0.5% hyperforin). Maximum plasma levels of hyperforin were reached after 2.8 to 3.6 hours. The 5% extract yielded a total
Schempp et al. (1999) describe the HPLC detection of hypericin and semiquantitative detection of pseudohypericin in human serum and skin blister fluid after an oral single dose (1 x 6 tablets) or after
serum level of total hypericin (hypericin + pseudohypericin) was 43 ng/ml and the mean skin blister fluid level was 5.3 ng/ml. After
Schulz et al. (2005b) investigated pharmacokinetic parameters of the Hypericum extract STW3 (612 mg extract per dose) in 18 volunteers. Data were collected after single dose or multiple doses over 14 days.
Single dose administration:
Hypericin: Cmax 3.14 ng/ml, elimination
Quercetin: Cmax1 47.7 ng/ml, Cmax2 43.8 ng/ml, elimination
The same study design was applied for the Hypericum extract STW
Single dose administration:
Hypericin: Cmax 3.8 ng/ml, elimination
Quercetin: Cmax1 89.5 ng/ml, Cmax2 79.1 ng/ml, elimination
A study from Johne et al. (2004) evaluated the influence of cimetidine and carbamazepine on the pharmacokinetics of hypericin and pseudohypericin. In a
With the extract Ze 117 maximum hypericin plasma concentration of 0.21 to 1.33 µg/L were achieved
Wang et al. (2001) studied the influence of Hypericum extract (3 x 300 mg per day, 900 µg hypericin per capsule) on different types of cytochrome P450 enzymes. 12 healthy volunteers received tolbutamide (CYP2C9), caffeine (CYP1A2), dextrometorphan (CYP2D6), oral midazolam (intestinal wall and hepatic CYP3A4), and intravenous midazolam (hepatic CYP3A4) before, with
Whitten et al. (2006) concluded that in three studies in which the daily exposure to hyperforin was less than 4 mg, no significant effect on CYP3A4 could be detected. Brattström (2005, unpublished data, cited in Whitten et al. 2006) tested the extract ZE 117 in 16 females in a dose of 500 mg daily for
14 days. The women started 3 months prior to the study taking 20 µg ethinyl estradiol and 150 µg desogestrel daily. Pharmacokinetic testing on days 7 and 22 after the treatment with ZE 117 revealed no significant differences in ethinyl estradiol or
Arold et al. (2005) report from a pharmacokinetic interaction study with 240 mg Hypericum extract daily containing 3.5 mg hyperforin. After treatment for 11 days no significant changes in the primary kinetic parameters of alprazolam, caffeine, paraxanthine, tolbutamide,
CYP1A2 appears to be induced by Hypericum extract only in females, the activities of CYP2D6,
Dresser et al. (2003) studied the effects of Hypericum extract on CYP3A and multidrug resistance protein (MDR1 =
The disposition of all drugs was altered. Although a common molecular mechanism may be involved, the quantitative aspects of induction are complex and depend on the particular drug and the relative contributions of CYP3A and MDR1 in its disposition.
The elevated activity of CYP3A returns to basal level approximately 1 week after termination of Hypericum administration (Imai et al. 2008).
L’homme et al. (2006) conducted a phase I pharmacokinetic study. A single 200 mg dose of nevirapine was administered; in phase 2 of the study one group (4 participants) received Hypericum tea bid for 14 days.
Hypericum tea had no influence on the half life of nevirapine, which is explained by the low content of hyperforin (reference to Mueller SC et al. 2004 and Zhou et al. 2004).
The role of hyperforin for interactions with cyclosporine was studied by Mai et al. (2004). In a crossover study 10 renal transplant patients received cyclosporine and Hypericum extract (900 mg/day) either with a high amount of hyperforin (LI 160) or with a low amount (LI 160 after removal of hyperforin by extraction with supercritical carbon dioxide) for 2 weeks.
LI 160: One capsule contained 7.0 mg hyperforin (2.3%), 0.45 mg total hypericin, 16.16 mg total flavonoids (5.4%)
The low hyperforin extract did not alter significantly the pharmacokinetics of cyclosporine, while the high hyperforin extract reduced the plasma levels of cyclosporine significantly.
II.184.108.40.206 Assessor’s overall conclusions on pharmacokinetics
Pharmacokinetic data on the most compounds which are considered to contribute to the activity are available. The long elimination
II.3.2 Clinical Efficacy3
II.3.2.1 Dose response studies
II.3.2.2 Clinical studies (case studies and clinical trials)
II.220.127.116.11 Studies on the treatment of depression
3 In case of traditional use the
From several notes in publications it can be assumed that the content of hyperforin is in the range from 3 to 6%.
Wurglics et al. (2002) stated that although no significant difference between placebo and verum was detected, significant differences in the number of remissions and number of responders were observed. Patients included were severely depressed (duration of depression more than 10 years); the acute phase had a mean duration of 2 years. This is a clear difference to the clinical studies preformed in Europe. The authors point out the extremely low responder rate under placebo in this study.
Reference controlled studies: All studies included patients with major depression; similar or insignificantly less efficacy compared to standard antidepressants; in some studies no difference between Hypericum, reference medication and placebo. Only one study (Vorbach et al. 1997) was designed for proof of equivalence.
Placebo controlled studies: Tendency that in older studies (published before 2000) better outcome for Hypericum; modern studies also with negative outcome.
Studies including patients with more severe depressive episodes (daily dosage up to 1800 mg extract) do not show sufficient efficacy.
The extraction solvent and the declared amount of Hypericine of this extract are identical with that of LI 160.
Conclusion: All studies are well designed. All studies report superiority compared to placebo or non- inferiority compared to standard medication.
Comparison with LI 160:
In contrast to the recent studies published for LI 160 all modern studies for WS 5570 demonstrated a positive outcome for Hypericum. Since the extracts LI 160 and WS 5570 are very similar in their key parameters, it seems to be justified to combine the results. It can be concluded that the efficacy of this type of extract in the treatment of mild to moderate severe depression is well documented.
Information on the refinement of the extract in order to reduce the content of hyperforin is not available.
Conclusion: The superiorioty of the extract ZE 117 against placebo and the
Conclusion: An old study (inadequate study design) shows superiority against placebo. No data are available on a comparison to synthetic antidepressants.
Observational study: Demmling et al. (2004)
Post marketing observational study in 793 family care units, 4188 patients with psychovegetative disorders, depressive disturbances, anxiety, nervous restlessness were treated with Laif 900 (STW3- VI, DER
F 32.1: 32.7%
F 33.1: 10.9%
F 34.1: 5.9%
HAMD decreased from an average of 15.8 to 9.5 after 4 weeks and finally to 4.6. The percentage of responders was about 78%, even in the subgroup of patients with an HAMD baseline of ≥ 17 the percentage of responders was about 77%. 0.6% of the patients reported adverse events, severe adverse events were unrelated to the treatment. No drug interactions were reported (7.2% of the patients used oral contraceptives; 0.4% anticoagulants from the
Conclusion: An adequate study which demonstrates
Conclusion: In the context with the results of the other extracts this study contributes to the overall evidence on the use of Hypericum extracts for the improvement of depressive symptoms.
Conclusion: Superiority against placebo and
Extract identical to STEI 300, but different dosage form and posology.
Conclusion: 800 mg of
In a retrospective study (Singer et al. 2008) 154 responders of the clinical study by Gastpar et al. (2006) in patients with moderate depression (HAMD score
In 19.5% of the patients a relapse was observed with the highest ratio in the citalopram group (25.9%), followed by the placebo group (17.4%), the minimal relapse rate was in the Hypericum group (14.8%). The severity of the relapse was identical in all three groups.
Relapse + recurrence: Hypericum 44.4%, citalopram 48.1%, placebo 52.2%.
Duration until relapse, recurrence: Hypericum 1833 days, citalopram 1755, placebo 802 days. The authors suggest that the prognosis under Hypericum is better compared to citalopram.
Conclusions: Superiority against placebo and
Observational study: Lemmer et al. (1999):
6382 patients with mild to moderate depression were treated with WS 5672. In 59.6% the depression occurred for the first time, 31.5% had a relapse, 8.6% suffered from chronic depressive disorder. 0.7% adverse events, only 0.1% were considered causally related to medication.
Break through bleeding in 0.05% of women below 50 years of age, which is considered as the usual frequency in the untreated population.
No cases of interactions were observed.
Conclusion: WS 5572 is superior to placebo in the treatment of mild to moderate major depression.
The same extract was tested in an observational
Patients received 425 or 850 mg extract per day (no further information) Indication: Depressive mood disorder.
Assessment of efficacy by using HAMD and van Zerssen Depression Scale (more suitable for emotional disturbances). The author found a clear reduction of symptoms.
Psychotonin (Liquid extract, DER 1:
According to Linde (2007) all studies performed with this type of extract are not convincing from the current point of view. The methodology is inadequate, the number of included patients is small, and the
Roder et al. (2004) published a
The results demonstrate a significant superiority of Hypericum extracts over placebo (mean response: Hypericum: 53.3% and placebo: 32.7%). Compared to standard antidepressive Hypericum is similarly effective for the treatment of depression (mean response: Hypericum: 53.2%, synthetic antidepressive: 51.3%). In the subgroup of mild to moderate depression Hypericum showed better results against the standard antidepressive group (mean response: 59.5% / 52.9%) and a better
Relative risk of
Werneke et al. (2004) came to similar results. They found that the effect sizes in recent studies were smaller than those resulted form earlier studies.
Linde et al. (2005) concluded that the available data for major depression is confusing. While Hypericum has minimal beneficial effects over placebo, other trials suggest that Hypericum and standard antidepressants have equal efficacy.
Response to Hypericum extracts in depression. Results from
Response rates over time to a) Hypericum extracts and b) placebo (Linde 2007)
Response to Hypericum extracts in depression. Results from controlled trials stratified by type of comparison drug. Studies identified by first author and year, n: number of responders; N: number of patients per group; RR response rate ratio (Linde 2007)
In a further Cochrane review Linde et al. (2008) assessed the outcome of studies in which exclusively patients with major depression were included. 29 studies in 5489 patients met the inclusion criteria; the duration of treatment was 4 to 12 weeks.
Overall the Hypericum treatment was superior to placebo, similarly effective as standard antidepressants, and had fewer side effects than standard antidepressants. Studies from German speaking countries were more favourable to Hypericum compared to studies performed in other countries.
The cumulative evidence now suggests that Hypericum extracts have a modest effect over placebo in a similar range as standard antidepressants. An attempt of treating mild to moderate major depression with one of the Hypericum preparations positively tested in clinical trials is clearly justified.
However, the differences in the findings from different countries make
Overview of extracts with predominately positive study outcome (Superiority against placebo, equivalence to reference medication):
Wording of the indication:
According to the ‘Note for guidance on clinical investigation of medicinal products in the treatment of depression’ several facts should be considered:
Randomised double blind comparisons versus placebo are needed.
For licensing it should be shown that a
Recurrence prevention is not an obligatory part of a dossier.
Demonstration of an acceptable benefit/risk in moderately ill patients will be considered sufficient for a registration package to get a license for ‘Episodes of Major Depression”.
A 50% improvement on the usual rating scales is accepted as a clinically relevant response.
Data on relapse prevention are available from extract
Proposal of indication for these extracts:
Herbal medicinal product for the symptomatic treatment of mild to moderate depressive episodes.
Overall the clinical evidence is also positive for the other extracts as reviewed by Linde et al. (2008). Due to the lack of data on relapse prevention the indication should be clearly different.
Proposal of indication for the remaining extracts:
Herbal medicinal product for the short term treatment of mild to moderate depressive symptoms.
II.18.104.22.168 Somatoform disorders
Volz et al. (2002) conducted a multicentre, randomised, placebo controlled,
In a prospective, randomized,
Hypericum extract LI 160 has demonstrated a
II.22.214.171.124 Nootropic effects
A study from Elis et al. (2001) aimed to examine whether acute administration of a standardized Hypericum extract could exert a nootropic effect in normal human subjects. The study employed a
In a randomized,
II.126.96.36.199 Subacute atopic dermatitis
II.188.8.131.52 Premenstrual syndrome
19 women with premenstrual syndrome who were in otherwise good physical and mental health and not taking other treatments for premenstrual syndrome were investigated in a prospective, open,
uncontrolled, observational pilot study (Stevinson & Ernst 2000). The participants took Hypericum tablets for two complete menstrual cycles (1 x 300 mg Hypericum extract per day standardised to 900 µg hypericin). Symptoms were rated daily throughout the trial using a validated measure. The Hospital Anxiety and Depression scale and modified Social Adjustment Scale were administered at baseline and after one and two cycles of treatment. There were significant reductions in all outcome measures. The degree of improvement in overall premenstrual syndrome scores between baseline and the end of the trial was 51%, with over
Hicks et al. (2004) performed a randomized,
II.184.108.40.206 Menopausal symptoms
Additionally some clinical trials with fixed combinations are published (e.g., combination Hypericum + Cimicifuga racemosa Uebelhack et al. 2006, Chung et al. 2007). Although the authors report a positive outcome with regard to climacteric complaints, such publications are considered only marginally because the amount of the contribution of each combination partner to the overall efficacy cannot be estimated.
II.3.2.3 Clinical studies in special populations (e.g. elderly and children)
Depression in children
Hübner & Kirste (2001) investigated a Hypericum extract in children under 12 years with symptoms of depression and psychovegetative disturbances.
Based on the data available for analysis, the number of physicians rating effectiveness as ‘good’ or ‘excellent’ was 72% after 2 weeks, 97% after 4 weeks and 100% after 6 weeks. The ratings by parents were very similar. There was, however, an increasing amount of missing data at each assessment point with the final evaluation including only 76% of the initial sample. Tolerability was good and no adverse events were reported. The authors suggest that Hypericum is a potentially safe and effective treatment for children with symptoms of depression.
Findling et al. (2003) conducted an
Youths 6 to 16 years of age meeting
33 children with a mean age of 10.5 (2.9) years were enrolled. After 4 weeks of St. John’s wort therapy, 22 youths had their dose increased to 900 mg/day.
Assessor’s comment: The Hypericum extract is characterized improperly.
In an 8 week
Fegert et al. (2006) analyzed the prescription data of antidepressants in Germany in the years
Hypericum and tricyclic antidepressants accounted for more than 80% of antidepressant use. In all of the 4 years Hypericum was the preferably prescribed antidepressant in this age group: 2000: Hypericum 55.59%, Imipramine 16.25%
2001: Hypericum 52.24%, Imipramine 14.93%
2002: Hypericum 50.58%, Imipramine 11.85%
2003: Hypericum 40.36%, Omipramol 10.72%
Attention deficit, hyperactivity disorder
In a randomized,
Assessor’s conclusion on the use in the paediatric population:
Although there are no controlled studies with children and adolescents published it can be concluded that there is a widespread documented use of Hypericum extracts among adolescents. However, there are no data available on the efficacy and safety in this population. Therefore the use in children and adolescents below 18 years of age is not recommended.
II.3.2.4 Assessor’s overall conclusions on clinical efficacy
Dry extracts prepared with ethanol
There are several new therapeutic approaches (smoking cessation, treatment of alcoholism, menopausal symptoms …) published. However, at the moment the clinical evidence is insufficient in order to be considered in a community monograph.
The clinical data of the hyperforin cream demonstrate a great potential. However, the herbal preparation is less than 10 years in medicinal use; therefore
II.3.3 Clinical Safety/Pharmacovigilance
II.3.3.1 Patient exposure
II.3.3.2 Adverse events
Stevinson & Ernst (2004) reviewed systematically the clinical evidence associating Hypericum extract with psychotic events. Seventeen case reports associated the use of Hypericum extract with psychotic events. In 12 instances, the diagnosis was mania or hypomania. Causality is in most cases possible. In no case a positive rechallenge has been reported. These case reports raise the possibility that Hypericum extract may trigger episodes of mania in vulnerable patients.
Linde performed in his
Adverse events reported from clinical trials:
According to the review by Greeson et al. (2001) the overall incidence of ADR is in the range of 2%. The most commonly reported side effects were gastrointestinal irritations (0.6%), allergic reactions (0.5%), fatigue (0.4%) and restlessness (0.3%). In comparison, the overall ADR incidence for SSRIs is between 20% and 50%, including more serious side effects.
Additional case reports:
A case of acute neuropathy after taking 500 mg of Hypericum powder per day and exposure to sunlight was reported (Bove 1998).
O’Breasail & Argouarch (1998) published two cases where Hypericum (no details of the product) may be linked to the development of hypomania.
During the year 2001, poison control centres in US were contacted regarding 356 exposures involving Hypericum (Gryzlak et al. 2007). Only a minority (39) resulted in adverse events. 21% reported exposures were coded as intentional, 13% were reported as ‘suspected suicidal’.
Most of the reported exposures occurred among children of 5 years or younger. For patients ≥ 20 years of age exposures were more likely to be associated with adverse effects.
II.3.3.3 Serious adverse events and deaths
Several case reports document psychotic adverse reactions like mania and psychosis (review in Hammerness et al. 2003). The majority of the affected persons had histories of affected illness, in most cases Hypericum was combined with other psychopharmaceuticals. The symptoms remitted after discontinuation of the medication. As a precaution Hypericum extracts should not be taken by persons with a history of mania or psychosis. Seizures are reported after overdose only (Karalapillai & Bellomo 2007).
II.3.3.4 Laboratory findings
Schempp et al. (1999) describe the HPLC detection of hypericin and semiquantitative detection of pseudohypericin in human serum and skin blister fluid after oral
In a prospective randomized study Schempp et al. (2003) investigated the effect of the Hypericum extract LI 160 on skin sensitivity to ultraviolet B (UVB), ultraviolet A (UVA), visible light (VIS) and solar simulated radiation (SIM). Seventy two volunteers of skin types II and III were included and were divided into six groups, each consisting of 12 volunteers. In the
volunteers (n = 24) received an initial dose of 6 tablets (5400 mg hypericin), and subsequently 3 x 1 tablets (2700 mg hypericin) per day for 7 days. Photo testing was performed on the volar forearms prior to medication and 6 h after the last administration of Hypericum extract. The
The objective of a study by Schulz et al. (2006a) was to investigate the effect of two different Hypericum extracts (STW 3, STW
Köppel et al. (2008) investigated the effect of a dry extract (DER
Schempp et al. (2000) investigated the effects of Hypericum oil (hypericin 110 mg/ml) and Hypericum ointment (hypericin 30 mg/ml) on skin sensitivity to solar simulated radiation. Sixteen volunteers of the skin types II and III were tested on their volar forearms with solar simulated radiation for photosensitizing effects of Hypericum oil (n=8) and Hypericum ointment (n=8). The minimal erythema dose (MED) was determined by visual assessment, and skin erythema was evaluated photometrically. With the visual erythema score, no change of the MED could be detected after application of either Hypericum oil or Hypericum ointment (P>0.05). With the more sensitive photometric measurement, an increase of the
The mentioned content of hypericin is in contrast to investigations from Maisenbacher et al (1992), these authors found only artefacts of hypericin.
From traditional use of Hypericum oil it is known that the exposure to sunlight of treated parts of the skin would lead to skin irritations. In traditional medicine it is recommended to protect treated skin from sunlight.
II.220.127.116.11 Limited liver function
Johne et al. (2002) investigated the influence of impaired liver function on the pharmacokinetic data of major constituents of Hypericum. 8 Patients with mild and 8 with moderate liver cirrhosis received a single dose of the extract LI 160 (900 mg) and for 12 days 3 x 300 mg of this extract. The data were compared to 8 healthy volunteers. The authors conclude that moderate liver cirrhosis may increase plasma levels of hypericin, pseudohypericin and hyperforin.
Although statistically significant (testing for significance using data from such a small population should be questioned), the very broad ranges overlap for all constituents and groups with the exception of pseudohypericin in patients with moderate liver cirrhosis. It is common knowledge that impaired liver function alters the metabolism of the majority of drug substances. Nevertheless it is unusual to mention this in the SPC. Since the proposed indication for
II.3.3.5 Safety in special populations and situations
II.18.104.22.168 Intrinsic (including elderly and children) /extrinsic factors
Fegert et al. (2006) analyzed the prescription data of antidepressants in Germany in the years
Hypericum and tricyclic antidepressants accounted for more than 80% of antidepressant use. In all of the 4 years Hypericum was the preferably prescribed antidepressant in this age group: 2000: Hypericum 55.59%, Imipramine 16.25%
2001: Hypericum 52.24%, Imipramine 14.93%
2002: Hypericum 50.58%, Imipramine 11.85%
2003: Hypericum 40.36%, Omipramol 10.72%
Assessor’s comment: From this data it can be concluded that there is a documented widespread use of Hypericum extracts among adolescents. However, there are no data available on the efficacy and safety in this population. Therefore the use in children and adolescents below 18 years of age is not recommended.
Kaye et al. (2000) evaluated data from 1017 hospital patients. 30% used Hypericum. The authors propose that pseudoephedrine, MAOIs and SSRIs should be avoided in these patients.
Larkin (1999) proposes to stop herbal supplements 2 weeks before elective surgery. Hypericum should be stopped 5 days before, because it may prolong the effects of some narcotics and anaesthetics (Larkin 2001).
Assessor’s comment: The mentioned interaction with narcotics and anaesthetics is hypothetical, there are no reports published.
II.22.214.171.124 Drug interactions
The extent of induction of CYP3A varies among St. John’s wort products and depends on hyperforin dose (Mueller SC et al. 2006, Gutmann et al. 2006). Products that do not contain substantial amounts of hyperforin (<1%) have not been shown to produce clinically relevant enzyme induction (Madabushi et al. 2006). Hypericin may be assumed to be the
Volz & Zeller. (2000) report from a observational trial (11.296 patients receiving
The causality of some of the published interactions is questioned by Schulz (2006b), particularly the combinations with serotonin reuptake inhibitors and digoxin.
The elevated activity of CYP3A returns to basal level approximately 1 week after termination of Hypericum administration (Imai et al. 2008). This should be considered when in the case of elective surgery substances will be used which may be influenced.
Interactions with benzodiazepines:
Moody et al. (2004) states that P450 3A4 is extensively involved in many pathways of oxidative metabolism of benzodiazepines.
Assessor’s comment: This statement supports the proposal to include benzodiazepines in general to the interaction section.
20 healthy male volunteers received low hyperforin extract for 2 weeks (Mueller et al. 2009). Midazolam plasma concentration time profiles were analyzed on the day before and on day 14 of Hypericum medication.
Study medication: 2 x 500 mg Hypericum powder per day. Content per capsule: 0.06 mg hyperforin, 0.6 mg hypericin, 17.77 mg flavonoids. No significant changes were observed.
Interactions with oral contraceptives:
Hypericum has been also reported to cause bleeding and unwanted pregnancies when concomitantly administered with oral contraceptives.
Hall et al. (2003) studied the interactions between an oral contraceptive
Concomitant use resulted in a significant increase of oral clearance of norethindrone (8.2 ± 2.7 L/h to 9.5 ± 3.4 L/h, P = 0.42) and a significant reduction in the
No ovulation was found. Therefore an increase of breakthrough bleeding is not necessarily associated with a loss of contraceptive efficacy. The authors interpret the changes in pharmacokinetics of norethindrone and ethinylestradiol as ‘modest’.
Murphy et al. (2005) studied the interactions between a low dose oral contraceptive and Hypericum. 16 healthy women received an oral contraceptive (20 µg ethinyl estradiol and 1 mg norethindrone) for two consecutive cycles; treatment with Hypericum extract (3 x 300 mg, Hypericum Byuers Club, alcoholic extract, 0.3% hypericin, 3.7% hyperforin) was added for two additional cycles.
Results: The authors observed a significant
Pharmacokinetic data of ethinyl estradiol:
Author’s conclusion: Women taking oral contraceptives should be cautioned that the use of Hypericum might reduce the effectiveness of their birth control method.
Pfrunder et al. (2003) studied the interaction between Hypericum and
No change in follicle maturation, serum estradiol or progesterone concentrations were found. Significantly more subjects reported intracyclic bleeding, the AUC and Cmax of ethinyl estradiol remained unchanged, whereas the AUC and Cmax of
There was no evidence of ovulation, but intracyclic bleeding episodes may adversely affect compliance to oral contraceptives. The decrease in serum
Assessor’s comment: The amount of hypericin in the extract must be questioned. The duration of treatment seems to be too short compared with the usual duration of use of Hypericum.
Interaction with SSRIs:
When combined with serotonin reuptake inhibitors, antidepressants (e.g. sertaline, paroxetine, nefazodone) or buspirone, Hypericum extracts can cause a serotonergic syndrome.
Gordon (1998) published a case report of a complication: A female patient (50 years old) stopped taking paroxetine 40 mg and started taking Hypericum powder 600 mg per day. After 10 days she took 20 mg paroxetine additionally. She was found to be incoherent, groggy,
This case was classified by the author as an interaction between the SSRI paroxetine and the MAO inhibitor Hypericum.
Assessor’s comment: The role of Hypericum as MAO inhibitor is discussed controversially. Butterweck et al 2003 summarize that MAO inhibitors are present in Hypericum. Their relatively high inhibition concentrations do not suggest any relevance of
Five cases of clinically diagnosed central serotonergic syndrome among elderly patients who combined prescription antidepressants with St. John’s wort are described by Lantz et al. (1999). Cases 1, 3, 4: 50 mg sertraline, 900 mg Hypericum
Case 2: 75 mg sertraline, 900 mg Hypericum Case 5: 200 mg nefazodone, 900 mg Hypericum
Assessor’s comment: The Hypericum preparations are not properly characterized. In view of the problems associated with the diagnosis of serotonergic syndrome the cases are very poorly described.
Bonetto et al. (2007) report a case of a suspected serotonin syndrome. The Hypericum preparation is not mentioned
A 28 year old woman was on fluoxetine 60 mg/day for 1 year (bulimia), eletriptan 40 mg/day previous 3 days (migraine), and on Hypericum for one month.
Symptoms: Epileptic fit with clonic convulsions, mental slowness, tremor of fingers, slightly elevated temperature, diffuse myalgia. Highly elevated levels of creatine kinase and
Evans (2008) replied to the findings by Bonetto et al. (2007). In the opinion of Evans the authors did not rule out other possible reasons for the presented symptoms. In the opinion of Evans the symptoms would fit much better to an infectious aetiology than to a serotonin syndrome.
The author revised all cases reported from the FDA on serotonin syndrome. Out of the alleged 29 cases only 7 cases met the Sternbach criteria for serotonin syndrome, but no case met the Hunter criteria. In the opinion of Evans it is premature to give a warning when more than 1 million patients have been exposed to the drug combinations (triptans and SSRI) with only 7 cases meeting just one set of criteria.
Assessor’s comment: Bonetto is of the opinion that Hypericum is an inhibitor of CYP3A4 like fluoxetine. This wrong fact is used by Bonetto to make the serotonin syndrome more plausible. In fact Hypericum should counteract the inhibition of CYP3A4 by fluoxetine.
Waksman et al. 2000 published a case report of an assumed serotonin syndrome. The patient took Hypericum 600 mg/day (no further details), discontinued 3 days prior to presentation and paroxetine 20 mg on the day of presentation. Symptoms: restlessness, uncontrollable movements of all four extremities. These symptoms were classified as serotonin syndrome.
Assessor’s comment: It is more than doubtful that after discontinuation of Hypericum such symptoms are causally related to Hypericum. The mentioned adverse reactions are known for paroxetine too.
Based on the original descriptions of serotonin syndrome (fatal reactions to serotonergic compounds) in animal studies and fatal human cases with interactions between MAO inhibitors and serotonergic compounds Fischer (1995) proposes to use the term ‘serotonergic reaction’ for such cases and reserve the term ‘serotonin syndrome’ for the most severe
The interpretation of the results of
Interactions with voriconazole
In a controlled,
Day 15: Extensive reduction of voriconazole exposure
Interactions with methadone
Interactions with digoxin:
Johne et al. (1999) performed a single blind, placebo controlled parallel study.
After achievement of a steady state for digoxin healthy volunteers received 0.25 mg digoxin per day either with placebo (n = 12) or combined with 900 mg Hypericum extract (LI 160, n = 13) for further 10 days.
10 days of Hypericum treatment resulted in a decrease of digoxin AUC by 25%. After multiple dosing a reduction in trough concentration (33%) and Cmax (26%) was observed, the effects were time- dependent.
Mueller SC et al. (2004) studied the pharmacokinetics of digoxin determined in 96 healthy volunteers before comedication and after 14 days of comedication with Hypericum.
Medication, per day:
LI 160: 28.9 mg hyperforin, 2.5 mg hypericin, 95.4 mg flavonoids
4 g per day: 21.1 mg hyperforin, 4.8 mg hypericin, 117.8 mg flavonoids
Hypericum oil: 3 x 2 capsules containing 200 mg oil extract each. 0.13 mg hyperforin, 0.016 mg hypericin, 0.007 mg flavonoids per day.
Tea (prepared from 1.75 g): 2 x 1 cup. 0.04 mg hyperforin, 0.6 mg hypericin, 71 mg flavonoids per day.
2 g per day: 0.3 mg hyperforin, 2.4 mg hypericin, 58.9 mg flavonoids
Fresh plant juice: 2 x 10 ml. 3.56 mg hyperforin, 0.58 mg hypericin, 93.6 mg flavonoids per day. Ze117: 0.38 mg hyperforin, 0.34 mg hypericin, 55.8 mg flavonoids
Comedication with 2 g powder without hyperforin, tea, juice, oil extract,
Comedication with LI 160: reduction of AUC
Interactions with theophylline:
Nebel et al. (1999) report a case of a 42 year old women who was stabilized to 2 x 300 mg theophylline daily. After some time the dosage was increased to 800 mg bid because the plasma concentrations were lower than desired. She took several other drugs, but the only change was the new addition of Hypericum extract (300 mg/day). After stopping Hypericum the plasma concentration of theophylline increased about 100% after 7 days.
As a consequence of this report Morimoto et al. (2004) investigated 12 Japanese male volunteers who received 3 x 300 mg Hypericum extract (TruNature), labelled as containing 0.3% hypericin. After 14 days they received a single oral dose of 400 mg theophylline. The treatment of Hypericum produced no significant difference compared to the control group.
Assessor’s comment: Theophylline is metabolized via CYP1A2, which is not influenced by Hypericum (Wang et al 2001). There is no rationale for a pharmacokinetic interaction between Hypericum and theophylline.
Interaction with finasteride
Lundahl et al. (2009) investigated the influence of Hypericum extract (300 mg, bid, hyperforin content 4%) given for 2 weeks on the pharmacokinetic profile of finasteride. Hypericum lowered the Cmax to 42%, the AUC to 66% and the elimination
Interaction of the herbal tea
Alscher & Klotz (2003) published a case report that drinking of a herbal tea containing Hypericum resulted in a significant decrease of the blood level of cyclosporine in a kidney transplant patient. Five days after stopping tea intake the blood levels returned to previous levels.
Assessor’s comment: No data are provided on the composition of the herbal tea and the dosage frequency. The data are in contradiction to other publications on the interaction potential of Hypericum tea.
II.126.96.36.199 Use in pregnancy and lactation
Grush et al. (1998) report of two pregnant women taking Hypericum extract (not more characterized, 900 mg/day). No signs of toxicity or other harmful effects are reported. Nonetheless the authors are concerned about the use of Hypericum instead of an established effective treatment because safety of Hypericum in pregnancy and lactation has not been established.
Klier et al. (2002) report from a mother with
Lee et al. (2003) conducted a prospective, observational cohort study. 33 breastfeeding women received Hypericum (704.9 ± 463.6 mg/day, no further characterization) compared with 101 disease matched and 33 age and
No statistically significant differences in milk production, maternal adverse events and infant weight over the first year of life were observed.
Five mothers who were taking 300 mg of Hypericum extract (LI 160) 3 times daily and their breastfed infants were assessed by Klier at al (2006).
In a review Dugoua et al. (2006) searched 7 electronic databases and compiled data according to the grade of evidence found. The authors found very weak scientific evidence based on a case report that St Johns wort is of minimal risk when taken during pregnancy. There is in vitro evidence from animal studies that St John’s wort during pregnancy does not affect cognitive development nor cause long- term behavioural defects, but may lower offspring birth weight. There is weak scientific evidence that the use of St. John’s wort during lactation does not affect maternal milk production nor affect infant weight, but, in a few cases, may cause colic, drowsiness or lethargy. There is weak scientific evidence that St John’s wort induces CYP450 enzymes, which may lower serum medication levels below therapeutic range; this may be of concern when administering medications during pregnancy and lactation. Caution is warranted with the use of St John’s wort during pregnancy until further high quality human research is conducted in order to determine its safety. The use of St John’s wort during lactation appears to be of minimal risk, but may cause side effects. Caution is warranted when using medications along with St John’s wort.
Moretti et al. (2009):
In Canada 54 women who were exposed to Hypericum preparations during pregnancy were observed and the data compared to 108 women in 2 control groups (other medication for depression and healthy women). No difference in the rates of major malformations compared to the general population was observed (Moretti et al. 2009). No data on the type of the preparations and the posology are available.
The data are not sufficient to recommend Hypericum during pregnancy.
Karalapillai & Bellomo (2007) reported a case of overdose in suicidal intention of a
In a personal communication the author confirmed that there is a typing error in the publication. The product contained 300 mg extract per tablet. These symptoms occurred therefore after ingestion of 4500 mg extract per day over a period of 2 weeks (approximately the
II.188.8.131.52 Drug abuse
II.184.108.40.206 Withdrawal and rebound
Beckman et al. (2000) conducted a telephone survey of 43 subjects who had taken Hypericum extract to assess demographics, psychiatric and medical conditions, dosage, duration of use, reason for use, side effects, concomitant drugs, professional consultation, effectiveness, relapse, and withdrawal effects. Most subjects reported taking Hypericum extract for depression, and 74% did not seek medical advice. Mean dosage was
Details on the type of products used are missing. Data from a telephone survey should be assessed reluctantly.
II.220.127.116.11 Effects on ability to drive or operate machinery or impairment of mental ability
Friede et al. (1998) studied potential sedative effects of Hypericum in a
Study medication: Ze117, 250 mg per coated tablet 2 times daily.
Ze 117 was shown to have no sedative effect in mental performance and reaction time tests under controlled conditions, so no impairment of the ability to drive vehicles or operate machinery is anticipated. In addition, cognition was not further impaired when Hypericum was administered concomitantly with alcohol (0.5‰ blood alcohol level).
Schmidt (1991) found in a
The authors did not find differences between placebo and verum.
Schmidt et al. (1993) investigated in a
Group 1: 3 x 300 mg LI160 per day for 7 days; then 7 days placebo Group 2: first placebo, then active treatment
After consumption of alcohol (blood alcohol concentration between 0.045 and 0.08%) psychometric tests were performed on day 7 and on day 14. Interactions between Hypericum and alcohol on the level of psychomotor and mental performance can be ruled out. The authors suggest that Hypericum can be used safely when driving or using machines.
Assessor’s comment: The conclusions are only partly correct. The data suggest that additionally to alcohol there is no impairment on mental performance. Only the studies of Friede et al (1998) and Schmidt (1991) studied the influence of Hypericum alone.Considering the small number of treated persons and the findings on sedation in animals of Girzu et al (1997) it can be concluded that adequate studies in order to clarify this aspect are missing.
II.3.3.6 Assessor’s overall conclusions on clinical safety
The adverse events observed in clinical trials which are most probably linked to the study medication are in general mild, the frequency is considerably lower in comparison to synthetic antidepressants. The induction of CYP3A4 is well documented; the amount is directly correlated with the content of hyperforin in the herbal preparation. Pharmacokinetic interactions are documented for several drug substances metabolised via CYP3A4 having with a narrow therapeutic range. Hypericum extracts should not be used concomitantly with these substances. Adequate studies with extracts with low hyperforin content which could justify exemptions in the wording of contraindications, special warnings and in the interactions section of the monograph are missing. Nevertheless, the risk / benefit assessment favours the benefits of the Hypericum dry extracts.
The induction of the CYP3A4 is reversible within approximately 1 week after stopping ingestion of
No influence on the mental performance at least in case of
The only risk of the cutaneous application of Hypericum oil seems to be the phototoxicity when treated skin is exposed to intense sunlight. A special warning should inform the patient.
Dry extracts of H. perforatum demonstrated superiority over placebo and non inferiority against standard medication in mild to moderate major depression in several controlled clinical trials. Therefore these types of extracts are proposed for
Benefit – Risk – Assessment
Numerous clinical trials have shown the efficacy of herbal preparations containing Hypericum in the respective indications. A comparison with therapeutic alternatives reveals that for many herbal preparations containing Hypericum a
Hyperforin, which may be present in the herbal preparations, is responsible for interactions with other drug substances which are metabolized by certain CYP450 isoenzymes. Nevertheless, the rate and severity of adverse effects was clearly lower for Hypericum than for synthetic antidepressants (Schulz 2006c). Therefore the
At least in the alpine regions of Central Europe H. perforatum is the most important and most frequently used herb in traditional medicine.
The considerable appreciation of Hypericum in traditional medicine and pharmacological data make the use in the proposed indication plausible.
Possible risks with the oral administration of preparations of Hypericum are related with pharmacokinetic interactions which are caused by the constituent hyperforin. The extent of the induction of the metabolic enzymes is
Interaction studies with digoxin (e.g. Mueller SC et al. 2004) revealed that a daily intake of less than about 5 mg hyperforin did not induce the enzyme activity significantly. The amounts of hyperforin administered with the herbal tea, the expressed juice or the powdered herbal substance are clearly below this limit.
The liquid extracts and tinctures are prepared with ethanol 50% (v/v). With this extraction solvent only about 20% of the hyperforin present in the herbal substance can be extracted (Meier 1999). The usual content of hyperforin in the herbal substance is about 0.5%, however amounts up to 4% are published. The calculation in the table below indicates that in the case of 20% extraction rate the daily intake of hyperforin is clearly below 5.3 mg when a typical herbal substance is used for extraction. But even in the worst case (4% hyperforin in the herbal substance) the amounts are only slightly above the limit. In this calculation the poor stability of hyperforin in liquid extracts is not considered. Therefore the actual amounts will be clearly lower.
It is known that extracts prepared with ethanol 50% (v/v) contain less than 1% of hyperforin (Blaschek et al. 2008). With the extraction solvent ethanol 38% (m/m) (= ethanol 45% v/v) not more hyperforin should be expected in the traditional herbal preparation A. At the maximum daily dosage of 360 mg an amount of 3.6 mg hyperforin will be administered.
For comparison: With a typical daily dose of 900 mg of hyperforin containing dry extracts approximately 27 mg of hyperforin are administered.
It can be concluded that the daily intake of hyperforin of all herbal preparations listed under traditional use are unlikely to induce enzyme activity when administered in the proposed posology and not longer than 2 weeks. However, a safety margin should be considered. Therefore the daily uptake of hyperforin with traditional herbal medicinal products should be limited to a maximum of 1 mg. With the low intake of hyperforin combined with the short duration of use clinically relevant interactions
are not likely to occur based on the current scientific knowledge. Under these circumstances the risk associated with traditional herbal preparations is acceptable.
The use of liquid Hypericum preparations in the mentioned indication is documented for a long period. Based on pharmacological data the use in the indication is plausible. Beside the risk of increased photosensitivity of the treated skin areas no concerns are known. The risk is at an acceptable level for traditional herbal medicinal products.
4According to the ‘Procedure for the preparation of Community monographs for traditional herbal medicinal products’ (EMEA/HMPC/182320/2005 Rev.2)
5According to the ‘Procedure for the preparation of Community monographs for herbal medicinal products with