Salvia – Sage Oil (Salviae officinalis aetheroleum)
|Latin name of the genus:||Salvia|
|Latin name of herbal substance:||Salviae officinalis aetheroleum|
|Botanical name of plant:||Salvia officinalis l.|
|English common name of herbal substance:||Sage oil|
Latin name of the genus: Salvia
Latin name of herbal substance: Salviae officinalis aetheroleum
Botanical name of plant: Salvia officinalis L.
English common name of herbal substance: Sage Oil
- I.REGULATORY STATUS OVERVIEW1
- II.ASSESSMENT REPORT
- SALVIA OFFICINALIS L., FOLIUM and
- SALVIA OFFICINALIS L., AETHEROLEUM
- II.1 I
- II.1.1 Description of the herbal substance(s), herbal preparation(s) or combinations thereof
- II.1.3 Search and assessment methodology
- The Cochrane Library:
- II.2.1 Information on period of medicinal use in the Community
- II.2.2 Information on traditional/current indications and specified substances/preparations
- II.2.3 Specified strength/posology/route of administration/duration of use for relevant preparations and indications
- II.3.1 Composition Constituents:
- II.3.2 Non-clinical pharmacology
- II.3.3 Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- II.3.4 Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
- II.3.5 Overall conclusions on non-clinical data
- Indication a) Traditional herbal medicinal product for symptomatic treatment of mild dyspeptic, complaints such as heartburn and bloating:
- Indication b)
- Indication c)
- II.4.1 Clinical Pharmacology
- II.4.1.1 Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
- Methods/Study design
- Inclusion criteria:
- Exclusion criteria:
- II.4.1.2 Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
- II.4.2 Clinical Efficacy
- II.4.2.1 Dose response studies
- II.4.2.2 Clinical studies (case studies and clinical trials)
- II.4.2.3 Clinical studies in special populations (e.g. elderly and children)
- II.4.3 Overall conclusions on clinical pharmacology and efficacy
- II.5.1 Overview of toxicological/safety data from clinical trials in humans
- II.5.2 Patient exposure
- II.5.3 Adverse events and serious adverse events and deaths
- II.5.4 Laboratory findings
- II.5.5 Safety in special populations and situations
- II.5.6 Overall conclusions on clinical safety
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.
SALVIA OFFICINALIS L., FOLIUM and
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
Sage leaf consists of the whole or cut dried leaves of Salvia officinalis L. It contains not less than 15 ml/kg of essential oil for the whole drug and minimum 10 ml/kg of essential oil for the cut drug, both calculated with reference to the anhydrous drug. Sage leaf oil is rich in thujone (Ph. Eur., 2008).
Sage tincture produced from 1 part of comminuted sage leaf and 10 parts of ethanol (70% V/V) is a separate monograph in the European Pharmacopoeia. The tincture produced from sage leaf should contain minimum 0.1% m/m essential oil. The European Pharmacopoeia also has a monograph on
The essential oil has a very variable composition depending on the source, time of harvesting and other factors (Bradley, 2006). Principal components of the essential oil, in addition to thujone, are cineol and camphor. In addition, the leaves contain tannins, diterpene bitter principles, triterpenes, steroids, flavones, and flavonoid glycosides (Blumenthal et al., 2000).
Comminuted herbal substance. Liquid extract (1:1), ethanol 70% V/V
Liquid extract (1:7.2), extraction solvent: liquor wine : ethanol 96% V/V (38.25 : 61.75 m/m) Tincture (1:10), extraction solvent: ethanol 70% V/V
Combinations of herbal substance(s) and/or herbal preparation(s)Salvia officinalis L. is used in combinations with many other herbal substances/herbal preparations. Combination products in member states consists of Salvia officinalis L. in combination with:
This monograph refers exclusively to products containing only Salvia officinalis L..
Vitamin(s): Not applicable Mineral(s):
The contents of sodium, potassium, magnesium, calcium, iron, manganese, zinc and copper have been determined in dry sage leaves, and the kinetics of extraction of these metals have been studied with cold water, hot water, 0.05 M and 0.01 M citric acid solutions, 0.1 M ascorbic acid and 70% ethanol by Zimna et al., (1984). The leaves have been found to be very rich in iron and magnesium especially. The total contents of the eight elements were determined in a commercial specimen of sage leaves and in sage leaves collected in the Garden of Medicinal Plants at the Medical Academy in Gdansk in Poland. The results were :
(ppm = parts per million. 1 ppm = 0.0001%)
Zimna et al. (1984) also specified the quantities of the metals present in a decoction prepared under usual conditions: a glass (= 250 ml) of hot water poured onto 10 g of dried leaves and set aside for 30 minutes. According to Zimna et al. (1984) the decoction contains about:
Brand names have been deleted. This table is based on information provided by the National Competent Authorities.
II.1.3 Search and assessment methodology
Databases assessed (date, search terms) and other sources used
The following electronic databases were searched on 16th of June 2008 with the search term “Salvia officinalis, Salvia officinalis folium OR Garden Sage OR Dalmatian Sage OR True Sage”.
Salvia officinalis: 239 references
Salvia officinalis folium: 4 references (No case report of safety concern)
Garden Sage: 10 references (No case report of safety concern)
Dalmatian Sage: 3 references (One case report of safety concern)
True Sage: 25 references (No case report of safety concern)
Salvia officinalis: 101 references
Salvia officinalis folium: 3 references (No case report of safety concern)
Garden Sage: 7 references (No case report of safety concern)
Dalmatian Sage: 10 references (One case report of safety concern )
True Sage: 4 references (No case report of safety concern)
Salvia officinalis: 3430 references
Salvia officinalis folium: 37 references (No case report of safety concern when phrase “toxicity” and “safety” were combined)
Garden Sage: 2045 references (Several case reports of safety concern
True Sage: 388 references (No case report of safety concern when phrase “toxicity” and “safety” were combined)
Assessors comment: Since this database covers both chemical abstracts and Medline, some references may be cited twice
The Cochrane Library:
Salvia officinalis: 4 references
Salvia officinalis folium: 1 reference
Garden Sage: 0 references
Dalmatian Sage: 0 references
True Sage: 5 references
This report is based on a scientific review of the scientific and traditional literature referring to
Salvia officinalis L.
Available handbooks have been searched for relevant references and information. Bibliographic searches have been done after the same procedure as described for the bibliographic review of safety data.
II.2.1 Information on period of medicinal use in the Community
Salvia officinalis L. is a perennial plant (subshrub), native to the Mediterranean region, especially in the area of the Adriatic Sea and is cultivated to some extent in different European countries. The material of commerce originates from south eastern European countries (Blumenthal et al., 2000).
Sage leaf was mentioned in the writings of Hippocrates, Paracelsus, Hildegard von Bingen, and Lonicerus, Bock and Matthiolus (Madaus, 1938). Its cultivation in northern Europe dates back to medieval times, and it was introduced to North America during the 17th century. Sage was used in ancient Egyptian, Greek and Roman medicines. Ancient Egyptians used it as a fertility drug. The Greeks used it to stop bleeding of wounds and to clean ulcers and sores, towards hoarseness and cough, enhancing memory functions, for gargles to treat sore mouths and throats.
Its uses in traditional Greek medicine spread to India, where the dried leaf
Sage is well known for carminative, antispasmodic, antiseptic, astringent and antihidrotic properties. Pharmacognostical handbooks describe that traditionally, sage has been used to treat flatulent dyspepsia, pharyngitis, uvulitis, stomatitis, gingivitis, glossitis (internally or as a gargle/mouthwash), hyperhydrosis, and galactorrhoea (Barnes et al., 2007). The herbals of Gerard, Culpeper and Hill credit sage with the ability to enhance memory. The German Commission E approved the internal use of sage for dyspeptic symptoms and excessive perspiration, and the external use for inflammation of mucous membranes of mouth and throat.
II.2.2 Information on traditional/current indications and specified substances/preparations
II.2.3 Specified strength/posology/route of administration/duration of use for relevant preparations and indications
The following herbal substances and herbal preparations have been on the European market for a period of 30 years and are proposed for the monograph on traditional use:
a)Comminuted herbal substance.
b)Liquid extract (1:1), ethanol 70% V/V
f)Liquid extract (1:7.2), extraction solvent: liquor wine : ethanol 96% V/V (38.25 : 61:75 m/m)
g)Tincture (1:10), extraction solvent: ethanol 70% V/V
Posology and indications for traditional herbal substance and preparations of Salvia officinalis L. folium
There is a lack of safety and toxicity data for the
Furthermore, in order to harmonize with similar indications in other monographs, the duration of use is limited as followed:
Oromucosal use: Not more than 1 week Oral use: Not more than 2 weeks
II.3.1 Composition Constituents:
Some constituents mentioned in other handbooks are borneol, bornyl acetate, isorosmanol (Wichtl, 2004), linalyl acetate,
Numerous articles concerning the compositions of Salvia officinalis L. and Salvia fructicosa Miller have been published regarding the composition of the essential oil. The considerable variation found may be due to the quality of the plant material (influence of harvest time, different chemical types, use of fertilizers etc.) as well as to the methods used for analysis. Essential oil obtained by steam distillation is influenced to some extent by
The boiling temperature (corresponding to the ion content of the water) and the degree of grinding have a significant effect on the result (Länger et al., 1996, with reference to Iconomou et al., 1982).
An analysis of 50 randomly chosen leaves of a commercial sample of sage leaf showed an considerable inhomogeneity, some leaves showing more
From the top to the base of an individual plant, the relative contents of
In a study on the relationship of camphor biosynthesis to leaf development in sage, a plot of leaf pair surface area and camphor content as a function of time, clearly indicated that the increase in camphor content closely paralleled leaf expansion. Examination of the second and third leaf pairs as they expanded
provided similar results, although the levels of camphor were generally higher from beginning to end, reaching approximately 0.7 mg/leaf pair on full expansion (Croteau et al., 1980).
An excess of the (1R,
According to information from handbooks, Salvia officinalis L., folium is often used as an infusion in dosages ranging from 1 to 9 g daily. As pointed out by Bradley, 2006, sage contains up to 3% essential oil. The essential oil consists of
These results show that the amount extracted varies according to the wide range of
Based on these calculations and data from one unpublished study, we have limited the posology to 6 g Salvia officinalis L., folium daily, a lower daily dose than used traditionally.
Antibacterial, fungistatic ,antiseptic and virustatic effects
Sage oil has antimicrobial properties, attributed principally to the presence of thujones (Bradley, 2006; Newall et al., 1996).
Inhibitory activity of the oil against
versus Pseudomonas aeruginosa (Bradley, 2006). Wichtl, 2004, also mentions antimicrobial activity against Aspergillus flavus.
Microencapsulation of the oil into
Horiuchi et al. (2007) found that crude extract from Salvia officinalis L. leaves showed antimicrobial activity against
The effective compound was identified as oleanolic acid. Also ursolic acid showed antimicrobial activity against VRE. The minimum inhibitory concentrations (MICs) of oleanolic acid and ursolic acid were 8 and 4 µg/ml, respectively. These two compounds also showed antimicrobial activity against Streptococcus pneumonia and
From a study by
The antibacterial efficiency of essential oils is diminished when they are added to more complex materials (such as food products).This must be taken into account when essential oils are applied as antibacterials in foods.
An aqueous and a
The antiviral action has been attributed to the essential oil according to Wichtl (2004).
In a study performed by Chang et al. 1977, a decrease in the rate of formation of peroxides was used as a measurement of the antioxidant activity of rosemary and sage extracts. The antioxidant activity of the purified antioxidant prepared from sage was shown to be comparable to that of rosemary. It appeared that the rosemary extract is as effective as the commercial antioxidant Tenox VI (Tenox VI is a mixture of BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), propyl galate, and citric acid) when used in animal fat and is superior to Tenox VI in vegetable oils. The antioxidants also appeared to be able to improve the flavour stability of soybean oil, as well as the flavour stability of potato chips.
The antioxidant activity of six isolated compounds
The antioxidant activity of eight aromatic herbs was assessed by the
showed high antioxidant activity in the tests performed and were regarded as promising sources of natural antioxidants.
Lipid peroxidation in both
Two phenolic glycosides isolated from sage leaf,
Aqueous methanolic extracts of 9 spices were investigated for their phenolic compounds composition and antioxidant properties, amongst them Salvia officinalis L. The extract of sage (not specified to only concern folium) showed in the applied in vitro test system better antioxidant properties than ascorbic acid which was used as a control (Muchuweti et al., 2007).
To study the phytosterol components of Salvia officinalis L. infusion (sage tea) and its antioxidant and hypocholesterolemic function, rats were divided into 4 groups; normal control group I. Group II, in which animals were fed on normal diet and received sage tea in a dose of 35 mg/kg bw/day. Group III, where rats were maintained on high cholesterol diet for 4 wk. Group IV, in which rats were maintained on high cholesterol diet while receiving sage tea in a dose of 35 mg/kg bw/day for 4 wk. Blood plasma transaminases, cholesterol, triglycerides, LDL, and lipid peroxides, liver GSH, and its related enzymes,
Oleanolic acid also showed
Rosmarinic acid has been shown to have
In this study, rosmarinic acid acted as an inhibitor of the complement activation when the influence of rosmarinic acid on the function of porcine and human polymorphonuclear leucocytes was tested.
In a study to determine the effect of topical application (5% in vehicle) of the
The antitussive and immunomodulatory activities of pectin and hemicellulose polysaccharides orginated from sage was shown in a study performed by Sutovska et al. (2007). Sage polysaccharide complex A significantly decreased the number of the cough efforts (NE) and the intensity of inspiratory and expiratory cough attacks (IA– and IA+) of mechanically – induced cough reflex from both,
laryngopharyngeal and tracheobronchial areas of airways, without any side effects in
Furthermore, all fractions of isolated polysaccharides possessed ability to increase rat thymocyte proliferation, which confirmed their immunological property
The immunomodulatory activity of
Carminative, spasmolytic, stimulant and tonic effects on digestion and nervous system
Sage oil had only a relatively weak spasmolytic effect on isolated guinea pig tracheal and ileal smooth muscle in comparison with oils from other Labiatae such as melissa leaf or thyme (Bradley, 2006).
The spasmolytic effect of the total flavonoid fraction from Salvia officinalis L. was considerably weaker. It caused inhibition of the contractile
The spasmolytic activity of the components of essential oils probably affects the smooth muscle in direct and indirect ways and modifies the quantity of Ca2+(Taddei et al., 1988).
Cholinesterase (ChE) inhibiting properties of S. officinalis on mood, anxiety and performance were studied by Kennedy et al. (2006). The sage extract exhibited in vitro dose dependent
Studies on the effect of Salvia officinalis L. extracts showed a prolonged latency of the onset of sleep on hexobarbital anaesthesia in mice (Todorov et al., 1984).
Hypotensive activity in anaesthetized cats and
Extracts from Salvia officinalis L. contain biologically active substances possessing moderate and prolonged hypotensive action. Applied intravenously and duodenally,
Hypoglycaemic activity in vivo has been reported for mixed phytotherapy preparations involving various Salvia species including S. officinalis. Activity in normoglyaemic, hypoglyaemic and in
Some of the terpenoids of sage have demonstrated antimutagenic effects (Wichtl, 2004).
In a study by Patenkovic et al. (2009), the antimutagenic effects of Salvia officinalis tea have been estimated by the somatic mutation and recombination test (SMART) on Drosophila melanogaster. Methyl methanesulphonate (MMS) was used as the mutagen and positive control. Several types of treatment were performed: short acute treatment with sage infusion or MMS, longer (chronic) treatment with sage solution or MMS, and two combined treatments, i.e. short treatment with sage followed by a longer treatment with MMS and vice versa. Sage infusion used in the experiments showed antimutagenic effect by reducing the frequency of mutations induced by MMS. The study do not reveal which components of sage infusion are of particular antimutagenic potential.
Antimutagenic properties of terpenoid fractions of sage (Salvia officinalis) were tested by Vujosevic et al., 2004, in mammalian system in vivo. The ability of sage to decrease the frequency of aberrant cells induced by a potent mutagen was examined. First, groups of mice were treated with three concentrations of sage alone and it was established that the frequency of aberrant cells after treatment with a concentration of 25 μL/kg was not significantly different from the negative control (olive oil), while that found after treatment with the 50 μL/kg concentration differed significantly
Sage used at a concentration of 100 μL/kg was cytotoxic. Mitomycin C (MMC), known as a potent mutagen, was used for induction of chromosome aberrations.
Cirsiliol occurs on the leaf surface on Salvia officinalis L. and is a potent and relatively selective inhibitor of arachidonate
Results in a study with natural flavonoids on the inhibition of
A methanolic extract from sage leaf showed affinity to human brain benzodiazepine receptors (from postmortem frontal cortex) by competitive displacement of
II.3.3 Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
In vitro experiments
No pharmacokinetic (ADME) studies on extracts of Salvia officinalis L. were available.
Extract of Salvia officinalis L. from the commercial herbal medicinal product, Nosweat®, was assessed in vitro for its inhibitory potential on isolated human
In vivo experiments
In mice treated intraperitoneally with
After oral administration to male rabbits of a mixture of α- and
level of about
Camphor is easily absorbed in the gastrointestinal tract. In rabbits, orally administered d– and
In dogs, the major hydroxylation products of d– and
II.3.4 Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
Acute and repeated dose toxicity
An experimental study of the toxic properties of commercialized essential oil of sage has revealed that the convulsant action was of central nervous system origin in unanaesthetized rats. The dose limit from which the cortical events are subclinical is 0.3 g/kg for sage oil. Above 0.50 g/kg for sage oil, the convulsions appeared and became lethal above 3.2 g/kg (ESCOP, 2003). The toxicity appeared to be related to the presence of camphor and thujone in Salvia officinalis oil (Millet et al., 1981; Newall et al., 2002).
Acute LD50 values for sage oil are documented as 2.6 g/kg in rats for oral administration (ESCOP, 2003; Bradley, 2006) and 5 g/kg in rabbits for intradermal administration (Newall et al., 2002).
Based on these values, the observed NOAEL of 250 mg sage oil/kg bw/day corresponds to camphor intakes of 18 and 125 mg/kg bw/day, respectively (EFSA 2008, accessible at: http://www.efsa.europa.eu/cs/BlobServer/Scientific_Opinion/afc_ej729_camphor_op_en.pdf?ssbinary=tru e).
Suggestions that thujone activates the CB1 cannabinoid receptor, based on structural similarities of thujone enol to tetrahydrocannibinol, have not been supported experimentally (Scientific Committee on Food 2003, with reference to Meschler &Howlett, 1999).
Subcutaneous LD50 values in mice were determined as 87.5 mg/kg body weight (bw) for
The oral LD50 of α- and β thujone (+) in rats was found to be 192 mg/kg and 500 mg/kg bw, respectively (Scientific Committee on Food 2003, with reference to Margaria, 1963). In subchronic toxicity tests in rats, thujone (α + β) given orally to rats at 10 mg/kg daily produced convulsions in only 1 out of 20 animals by the 38th day (ESCOP, 2003).
Thujone is much more acutely toxic after parenteral administration and the intravenous LD50 in the rabbit is stated to be 0.031 mg/kg bw (Scientific Committee on Food 2003, with reference to NLM, 1997)
In rats, i.p. injections of thujone induced
In a further study, thujone was administered to rats by gavage at doses of 0, 5, 10 or 20 mg/kg bw/day 6 times per week for 14 weeks. There were 3 deaths in females and 1 in males associated with convulsions at the top dose level. The NOEL for convulsions was reported to be 10 mg/kg bw in males and 5 mg/kg bw in females; no changes were reported in haematologic or histopathologic examinations (Scientific Committee on Food 2003, with reference to Margaria, 1963).
group; mortality was not increased in the lower dose groups. The increased mortality was associated with indications of neurotoxicity (hyperactivity, tremors, tonic seizures).
Histological changes observed only at the top dose level included only mild renal tubular dilatation/focal degeneration, increased haematopoiesis in spleen, and bone marrow myeloid cell hyperplasia. No increased mortality occurred in male rats but there was increased mortality (3/5 animals) in females of the top dose group. As in mice, the increased death rate was associated with convulsions/seizures.
Consumption of as much as 1 liter of an alcoholic beverage containing 5 mg/l, the maximum permitted level of thujone in alcoholic beverages with up to 25% alcohol, would result in an intake of about 0.08 mg thujone/kg bw for a 60 kg adult.
This intake is about 100 times lower than the NOEL derived from a 14 week study in rats (Scientific Committee on Food, 2003).
Although the toxic effects of thujone are evident, the concentrations found in sage leaves are low according to calculations made by Länger et al.,1996.
Investigations showed that only 17% of the genuine thujone content could be extracted with hot water corresponding to 2.5 mg thujone per cup of tea (the most common preparation of sage leaves). A cup of tea prepared from 3.0 g sage leaves and 150 ml boiling water contained 3.8 mg thujone, which is approximately only 17% of the thujone present in the herbal substance.
Negative results have been reported from
Thujone was tested at 1.5 and 3% in DMSO (dimethyl sulfoxide) for its effect on the mutagenicity of aflatoxin B1 in Salmonella typhimurium strain TA100. The plates treated with thujone showed evidence of colony damage which indicates some mutagenic activity on the part of thujone (Kim et al. 1992).
No mutagenic effect was found with (+) camphor, citral, citronellal,
The results from this study therefore suggest that, with the exception of terpineol, the monoterpenoid compounds tested are not mutagenic in the Ames test.
A rosemary extract, and its main active components, carnosic acid and carnosol, were checked for their potential mutagenicity in the bacterial Ames test. Purified carnosol and carnosic acid were not mutagenic in the test (EFSA, 2008).
Other studies with rosemary extract and carnosic acid has demonstrated antimutagenic activity in bacteria (EFSA, 2008 with reference to Minnuni et al., 1972; Santamaria et al., 1987) and in in vitro human liver and bronchial cell models (EFSA 2008, with reference to Offord et al., 1997).
Camphor did not show mutagenic activity in Salmonella typhimurium strains TA 1535, TA 1538, TA 98 and TA 100 with and without S9 activation (Anderson and Styles, 1978). No mutagenic effect was found with
Herbal preparations of Salviae folium
Bradley (2006) and ESCOP (2003) refer to tests on genotoxicity performed with sage leaf tincture and sage essential oil. In the study by Zani et al. (1991) genotoxic properties of essential oils from different herbs, including Salvia officinalis L. and one of its varieties were tested.
ESCOP (2003) with reference to Schimmer et al., 1994) describe that a sage leaf tincture (Salviae tinctura German Pharmacop. 6th ed.) at doses up to 200 µl/plate showed no mutagenic activity in the Ames test using Salmonella typhimurium strains TA98 and TA 100 with or without S9 metabolic activation system.
The study with the essential oil as published by Zani et al. (1991) cannot be interpreted because of deficiencies in the performance and analysis of the tests.
Results from tests with the essential oil are not transferable to the herbal substance or other preparations of
Salvia officinalis L. folium.
The testing of sage leaf tincture by Schimmer et al. 1994 with two strains is not complete (3 strains are missing).
Based on the available data for the tincture, the requirements for a list entry are not fulfilled.
Reproductive and developmental toxicity:
No studies with Salvia officinalis L., neither essential oil nor extracts, were available. No experimental data on thujone were available (Scientific Committee on Food, 2003)
No adverse effects on foetal growth, viability, or morphological development were reported on camphor (EFSA 2008, with reference to NTP, 1992b).
No studies with Salvia officinalis L., either essential oil or extracts, were available.
No oral studies on chronic toxicity or carcinogenicity with camphor are available. In a pulmonary tumour response test
II.3.5 Overall conclusions on
Salvia officinalis L. and some of its constituents have been investigated in several preclinical studies.
Indication a) Traditional herbal medicinal product for symptomatic treatment of mild dyspeptic, complaints such as heartburn and bloating
The indication is supported by the fact that it has been an indication for the traditional use of Salvia officinalis L. for a period of at least 30 years in Europe. Further preclinical studies are necessary to clarify this effect.
Indication b) Traditional herbal medicinal product for relief of excessive sweating:
The indication is supported by the fact that it has been an indication for the traditional use of Salvia officinalis L. for a period of at least 30 years in Europe. Further preclinical studies are necessary to clarify this effect.
Indication c) Traditional herbal medicinal product for the symptomatic treatment of inflammations in the mouth or the throat, and minor inflammations of the skin:
Many preclinical studies have been performed investigating the antibacterial and
Several other preclinical studies on different plausible effects from sage leaf have also been performed, but further studies are necessary.
Based on the limited data available on pharmacokinetics for the herbal substance, no conclusion can be made.
There is a lack of safety and toxicity data for the
No studies on reproductive toxicity or carcinogenity are available for Salvia officinalis L. There is no suspicion for a carcinogenic potential. Inclusion to the Community list of traditional herbal substances, preparations and combinations thereof for use in traditional herbal medicinal products can not be recommended for any preparations.
II.4.1 Clinical Pharmacology
II.4.1.1 Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
Excessive sweat induced by pilocarpine was inhibited by a dialysate of an aqueous extract of fresh sage. In an open study, 40 patients were given dried aqueous extract of sage (440 mg, equivalent to 2.6 g herbs) and 40 were given infusion of sage (4.5 g herb daily). Reduction of sweat (less than 50%) was achieved in both groups of patients with idiopathic hyperhidriosis (the secretion of an abnormally large amount of sweat). It should be noted however, that this study did not include a control group (Barnes et al. 2007, with reference to ESCO 2003).
Several open studies, carried out mainly in the 1930s on patients or healthy volunteers but also including a larger study from 1989 (unpublished) on 80 patients with idiopatic hyperhidrosis, supported the longstanding assumption that sage leaf aqueous extracts have
In folk medicine, sage is used to promote menstruation (unproven) (Wichtl, 2004).
Healthy people in a
When Salvia was used diluted, as in a 10% plant substance preparation, Salvia “Teep” mite, one tablet three times daily, duration of administration not specified, the inhibitory effect was strong (Madaus, 1938).
In folk medicine, sage is used to facilitate weaning due to a
In a randomized, double blind,
In a randomized,
Compared with the placebo condition (which exhibited the characteristic performance decline over the day), the
The overall pattern of results is consistent with a
In a double blind, placebo controlled, crossover study, 30 healthy young volunteers (17 males, 13 females; mean age 24 years) were given, on three separate days at
Simulator (DISS) computerized multitasking battery. The DISS comprises a set of four cognitive and psychomotor tasks presented concurrently on a split (quartered) screen layout, to which responses had to be made with an external mouse, giving attention simultaneously to all four tasks while monitoring the cumulative score (reflecting accuracy and speed of response) in the centre of the screen. The DISS engenders increases in
The anticholinesterase activity of several Salvia species and their constituents have been investigated in the search for new drugs for the treatment of Alzheimer`s disease. The inhibition of acetylcholinesterase in vitro by an ethanolic extract of S. officinalis. L (2.5 mg/ml) was 68%, and by oils of S. officinalis L. and S. lavandulaefolia (0.1 µg/ml) was 52% and 63% respectively. The monoterpenes
Symptomatic relief of inflammations of the mouth and throat
Hubbert et al., 2006, compared the efficacy and tolerability of a new sage product presented as a pump spray in a glass flacon against placebo in the treatment of patients with acute viral pharyngitis. The therapeutically active principle is a sage leaf fluid extract (1:1, extraction solvent ethanol 70% V/V). The product contains 15% of the extract in an aqueous solution. Placebo was identically composed regarding ethanol and excipient concentration and contained a pharmacologically inactive amount of 0.3 % sage leaf extract for appropriate blinding. According to this article there are no similar approved products available on the European market. No information about any marketing authorization has been submitted from the member states. Switzerland is therefore assumed to be the first country to market this spray. The Swiss Agency for Therapeutic Products have the following product information on a spray for similar use available on their website www.swissmedic.ch (retrieved
Salviae extractum ethanolicum liquidum 150 mg, DER: 1:1, excipiens ad solutionem pro 1 g, corresp. ethanolum 19% V/V.
Methods/Study design: A randomised,
Inclusion criteria: were male and female patients aged 18 years and older with symptoms of acute pharyngitis existing for max. 48 hours. Typical signs (spontaneous pain, local inflammation) of pharyngitis were confirmed by the study physician. All participants had to document their spontaneous pain intensity on a VAS with a minimum value of 40 mm on a VAS 100 mm.
Exclusion criteria: were a positive test on group A
Measurements/Endpoints: The primary efficacy variable in both study parts was the change of throat pain intensity documented every 15 minutes within the first 2 hours after the first application as compared to baseline (using VAS, area under curve (AUC), and pain intensity differences (PID).
The secondary endpoints in both study parts were
–meaningful pain relief (MPR): max. 50% of the baseline value on VAS
–complete pain reduction after first application
–change of throat pain intensity during study treatment (according to patient’s diary)
–number of patients with early treatment discontinuation due to lack of efficacy
–overall efficacy assessment both by the physician and by the patient
–overall safety assessment both by the physician and by the patient
–adverse events (AE)
Results: The efficacy analysis demonstrated according to Hubbert et al. (2006), that the 15% spray was significantly superior in throat pain reduction, whereas for the 30% and the 5% preparation results made superiority over placebo unlikely in the final analysis. It was not possible to show any dose dependency of the sage spray in the first study part and the authors suggested that a
Regarding MPR and complete pain reduction within the first 2 hours after the first application, no significant superiority could be shown. A ca 44% pain reduction within 2 hours following the first application was found in both study parts for the 15 % spray, compared to ca 34% pain reduction in the placebo group. The author’s states that this difference can be contributed to the sage fluid extract itself since the placebo contained the same amount of alcohol as the 15% spray.
The magnitude of the mean pain reduction of the 15% spray in the second study part was in the same range as the placebo effect in the first study part on the mm on the VAS. Possible explanations given by the authors are that “pain” is a very subjective parameter which makes interpretation of such studies challenging, and that the two collectives were different to some extent. Also a possible contribution from the
Only minor side effects such as dry pharynx or burning of mild intensity were seen.
Assessors comment : The product used in this study by Hubert et al., 2006, has a concentration of 15%. This does not correspond to the concentration for similar formulations with a marketing authorisation, i.e. the gargle, for external use in the Comission E monograph of
Therefore, this study can not be assessed as documentation for
II.4.1.2 Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
No data available regarding the herbal substance.
In humans admitted to hospital in a state of acute intoxication after ingestion of
the latter being conjugated with glucuronic acid (EFSA 2008, with reference to Köppel et al., 1982) (Accessible at: http://www.efsa.europa.eu/cs/BlobServer/Scientific_Opinion/afc_ej729_camphor_op_en.p df?ssbinary=true)
II.4.2 Clinical Efficacy
The following traditional uses, dosages, method and duration of administrations have been recorded for Salvia officinalis L., folium in the handbooks:
II.4.2.1 Dose response studies
There are no dose response studies available
II.4.2.2 Clinical studies (case studies and clinical trials)
Some clinical studies are performed as specified in II.4.1.1
II.4.2.3 Clinical studies in special populations (e.g. elderly and children)
In a randomized clinical study, 15 elderly patients treated with 60 drops/day of sage leaf liquid extract (1:1.45% ethanol) for 16 weeks experienced slightly more mild gastrointestinal complaints than those receiving placebo, but the differences were not statistically significant (Bradley, 2006).
The oral use of sage is not recommended in children due to the lack of adequate data, and the presence of compounds (such as thujone and camphor) with neurotoxic effects. A warning is recommended for the use in children and adolescents because data are not sufficient and medical advice should be sought when children have such symptoms.
The recommended dosage for adults and children over 12 years for oral use is supported by use in member states. There are no studies in adolescents between 12 and 18 years available.
Oromucosal use in children over 4 years is also listed under the reported posologies from the European Member States.
Background for marketing authorisation for oromucosal use in children:
No clinical studies in children are available, but oromucosal use in children was accepted in one member state in 2004 in accordance with the national regulations for the described oromucosal posology. A single dose for oromucosal use was in this safety assessment stated to contain no more than 0.5 mg thujone in 150 ml of water. The absorption is estimated to be negligible and children older than 4 years of age are considered able to rinse or gargle without swallowing.
II.4.3 Overall conclusions on clinical pharmacology and efficacy
Several clinical studies have been conducted to determine the effectiveness of herbal preparations of Salvia officinalis L. Based on these results it is plausible that sage has effects that support the traditional indications, however, the clinical data cannot be considered to fulfil the criteria required for “well- established medicinal use” according to directive 2001/83/EC. According to the information available, products used in the studies cannot be considered to be corresponding to any of the products available within the Community for the required time period of at least 10 years. More studies are needed and this is also mentioned by Barnes et al., 2007. Overall the existing data are not sufficient at present to show efficacy of sage in a
Based on the limited data available on pharmacokinetics for the herbal substance, no conclusion can be made.
II.5.1 Overview of toxicological/safety data from clinical trials in humans
II.5.2 Patient exposure
Products containing Salvia officinalis L., folium is widely available. The products have various regulatory status. A considerable patient/consumer exposure must be anticipated as sage is widely used as a natural
source of food flavouring (Barnes et al., 2007) and in herbal medicinal products on the market in the European Member States. .
II.5.3 Adverse events and serious adverse events and deaths
Sage essential oil:
After prolonged use of alcoholic extracts or of the pure essential oil, epileptiform convulsions can occur (Wichtl, 2004, with reference to The German Commission E monograph, 1990).
Convulsant activity in humans (and animals) has been documented for sage oil. Clinical intoxications were characterized by
A case of human poisoning has been documented following ingestion of sage oil for acne.
There are several anecdotal and case study reports of the acute effects of essential oils containing
thujone causing seizures in humans, indicating that the animal data are of relevance to humans. In most cases, the doses are not well determined but one case was associated with about twelve drops of the essential oil of sage, which caused a generalized
More than a few drops of the oil can be toxic due to the high thujone content. Thujone is a nervous system stimulant that may cause convulsions at high doses (http://extoxnet.orst.edu/newsletters/n42_83.htm). Sage oil is reported to be a moderate skin irritant and is not recommended for use in aromatherapy (Barnes et al., 2007; Newall et al., 2002).
Sage leaf herbal tea:
Case Report: A previously healthy 18
Allergic contact dermatitis caused by spices is well documented; however, commercial patch tests are unavailable. Between October 1991, and August 1992, a series of
II.5.4 Laboratory findings
None known concerning Salvia officinalis L.
II.5.5 Safety in special populations and situations
Pregnancy and lactation: Sage is
The pure essential oil and alcoholic extracts should not be taken during pregnancy (Wichtl 2004, with reference to the German Commission E monograph), (Blumenthal et al., 2000).
Assessors comment: Safety during pregnancy and lactation has not been established.
In the absence of sufficient data, the use during pregnancy and lactation is not recommended.
Use in children:
No data about Salvia officinalis L. are available. Use in children and adolescents under 18 years of age is not recommended because data are not sufficient and medical advice should be sought.
The American Academy of Pediatrics concluded that although adults recovered from ingestions of as much of 42 g camphor, the ingestion of 2 g generally produces dangerous effects. In children, ingestions of 0.7 to 1.0 g of camphor have proven fatal (EFSA 2008, with reference to AAP, 1994). In the pediatric population, exposure to as little as 500 mg camphor is cited as a cause of mortality. More commonly, 750 to 1000 mg is associated with the development of seizures and death. Currently available products with 10% camphor contain 500 mg in 5 ml. It is concluded that small doses are dangerous. In children less than 6 years of age, exposure to 500 mg or more requires rapid triage to the closest health care facility.
According to a recently published case report, a
1000 mg of camphor is a concerning exposure in the child under 6 years of age (Love et al., 2004) Exposure to camphor should not exceed 2 mg/kg bw on a single day in any age group (EFSA, 2008). According to the extraction rate of 35.4% for camphor shown in the study of Länger et al., 1996, a toxic amount for children and adults will theoretically not be reached in a
Drug interactions: No drug interactions are documented clinically. However, the potential for preparations of sage to interact with other medicines administered concurrently, is the basis for giving this precautionary information about potential interactions. According to the available information, it is given as a precautionary advice that concomitant use of other
Potential for clinically relevant interactions based on the pharmacodynamic properties and in vivo pharmacokinetic studies of the medicinal product, with a particular emphasis on the interactions, which result in a recommendation regarding the use of this medicinal product can be useful. This also includes in vivo interaction results which are important for extrapolating an effect on a marker (‘probe’) substance such as
Other sources has also mentioned the hypoglycemic effects (Newall et al., 1996), but due to limited evidence from preclinical studies of hypoglycemic activity (Barnes et al., 2007) this information is not included in the monograph.
A sense of heat, tachycardia, feelings of vertigo and epileptiform convulsions can occur following prolonged intake of ethanolic extracts of the drug or volatile oil, or through overdose (corresponding to more than 15 g of the sage leaves) (Fleming, 1999; Blumenthal et al. 2000; Wichtl, 2004). A case of human poisoning has been documented following ingestion of sage oil for acne (Barnes et al. 2007 with reference to Centini et al. 1987).
Not many Lamiaceae poisonings are known. The essential oils of Lamiaceae can be dangerous when ingested in large doses. The most noxious are those, like official sage oil (Salvia officinalis L.), that contain monoterpenoid ketones like thujones
From the study of Dettling et al. (2004), it can be assumed that at least a concentration of
Sage can be added to foodstuffs providing the concentration of thujones (α and β) present in the final product does not exceed current Regulatory Status on Thujone (Scientific Committee on Food, 2003)
Annex II of Directive 88/388/EEC (EEC, 1988) on flavourings sets the following maximum levels for thujone (α and β) in foodstuffs and beverages to which flavourings or other food ingredients with flavourings properties have been added: 0.5 mg/kg in foodstuffs and beverages
with the exception of
5 mg/kg in alcoholic beverages with not more than 25% volume of alcohol 10 mg/kg in alcoholic beverages with more than 25% volume of alcohol 25 mg/kg in foodstuffs containing preparations based on sage
35 mg/kg in bitters.
Thujone may not be added as such to food.
Thujone is not authorized for use as a flavouring substance in the USA.
Estimates of intakes of thujone have been made in France and the United Kingdom. In France, the mean and 97.5th percentile daily intakes were estimated to be 15.6 and 44.3 µg/kg bw/day respectively. The intakes in the United Kingdom were estimated to be somewhat lower at 3.9 and 14.2 µg/kg bw/day respectively. Both estimates were based on the maximum limits proposed by the CoE (Council of Europe, 2000). The major dietary contribution to thujone intake appeared to derive from sage and
Dietary exposure to camphor arises from the consumption of foods flavoured by using either
herbs (e.g. basil, coriander, marjoram, rosemary, sage), their essential oils or the chemically defined flavouring substance
The dietary exposure to camphor was estimated to be 1.5 mg/person/day (Council of Europe, 2001). Assuming an average body weight of 60 kg, this corresponds to an exposure of 25 μg/kg bw/day
The Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food (Panel) have assessed the toxicity risks associated with the exposure to camphor in various food commodities (EFSA 2008).
In humans, signs of camphor intoxication include central nervous stimulation, oral and gastric irritation, nausea and vomiting, excitement, hallucinations, delirium, muscular excitability, tremors, convulsions and urinary retention (EFSA 2008, with reference to Opdyke, 1978). Locally it can produce irritation of skin, eyes and mucous membranes of the respiratory tract (EFSA, 2008)
Intoxications from camphor have been frequently reported in literature, mostly involving the accidental ingestion of camphorated oil (20% camphor in cottonseed oil). For example 20 children aged 1 to 4 years who became ill after ingestion of 1 to1.5 tablespoons of camphorated oil equivalent to about 3 to 4.5 g camphor. Most of them had seizures, but recovered (EFSA 2008, with reference to Benz, 1919).
As little as 1 g camphor ingested in 1 teaspoonful of camphorated oil was fatal in a
“The probable lethal oral bolus dose has been reported to be in the range of 50 to 500 mg/kg bw. No acute toxicity was reported after doses lower than 2 mg/kg bw and clinically insignificant signs of toxicity may be seen in sensitive individuals at doses of 5 mg/kg bw and higher, whereas clinically manifest toxicity in sensitive persons would require doses higher than 30 mg/kg bw.” Although acute exposure estimates via food for children and adults are about
Due to variations of thujone and camphor it is difficult to set an exact value on the maximum amount of sage leaves which could result in a overdose based on the available data.
Drug abuse: Only experimental use or abuse due to the reputed effects of another species, Salvia divinorum L. (Lamiaceae) has been used for centuries by the Mazatecan culture This species has gained popularity due to its potent hallucinogenic effects (Grundmann et al., 2007).
Withdrawal and rebound: No reactions reported.
Ability to drive or operate machinery or impairment of mental ability: No known effects on ability to drive and use machines (ESCOP, 2003), however according to the study performed by Dettling et al. (2004) it was shown that attention performance was changed under the influence of high thujone concentrations.
Dettling et al. (2004), determined if the impacts of thujone (absinthe) on attention performance and mood were different from those experienced with beverages that contain only alcohol.
The calculated total amount of thujone consumed was 0.28 mg/kg and 0.028 mg/kg for men and 0.24 mg/kg and 0.024 mg/kg for women. The alcohol content was adjusted to 16 g/l in all beverages. The amount of liquid to be consumed depended on the weight of the subject, It was tried to attain a maximum
blood alcohol concentration of 0.05% (= 0.5‰) for each subject. Before drinking every subject received a small standard meal; the beverage had to be drunk then within 10min. All tests were performed before drinking (T0) and 30 (T1) and 90 min (T2) after drinking.
The results between
Assessors comment: The study by Dettling et al. (2004) showed that approximately 15 mg thujone/person (60 kg) leads to changes in the in attention performance, while intake of approximately 1.5 mg thujone/person gave no such changes in attention performance. Accordingly for safety reasons, 1.5 mg /person in a single dose is suggested as a limit for thujone content in thujone containing herbal medicinal products.
Further clinical studies are needed for assessment of effects on ability to drive or operate machinery or impairment of mental ability, and precautions are included in the monograph.
II.5.6 Overall conclusions on clinical safety
The essential oil of Salvia officinalis L. contains constituents like thujone and camphor, which have toxic effect in high doses. Most studies have been performed in vivo in animals, and toxicological dose limits have been set based on the available toxicological data, case reports and clinical studies. The toxic effect appears to be of central nervous origin. Maximum apparent doses of rectal or oral preparations regarding the camphor content of sage leaf are up to about 500 mg/day, which may cause insignificant effects in sensitive individuals. Highest estimates of exposure via food are 0.34 mg/kg bw (adults, about 20 mg/day) and 0.83 mg/kg bw (children).
The camphor content in sage leaf preparations for oral and oromucosal use, are not expected to cause safety concern if dose recommendations are followed.
The study by Dettling et al. (2004) showed that approximately 15 mg thujone/person (60 kg) leads to changes in the in attention performance, while intake of approximately 1.5 mg thujone/person gave no such changes in attention performance. Accordingly for safety reasons, 1.5 mg /person in a single dose is suggested as a limit for thujone content in thujone containing herbal medicinal products.
The presence of thujone in sage leaf preparations in the monograph is restricted to a daily intake of 5.0 mg/person for a maximum duration of 2 weeks as no data were retrieved for more serious conditions that could alter the benefit/risk assessment. There is a lack of safety and toxicity data for the
During the meetings of the MLWP after the public consultation, the following points led to amendments in the monograph and the assessment report:
Since this is not a new chemical, but an herbal preparation, a reduced safety factor is accepted based on the extensive traditional use of a variety of herbal sage leaf preparations covered by the monograph. The safety data available for assessment are from single constituents, and not from sage leaf as a whole. Even when acknowledging that thujone containing essential oils are amongst the essential oils associated with the highest risk, the recommended posology of the preparations covered by the monograph and the restricted duration of use will provide a sufficient safety margin. An intake of about 0.08 mg thujone/kg bw for a 60 kg adult are assessed as safe when used occasionally in foodstuff and beverages. This exposure level is not a recommended daily intake proven safe. However, as serious side effects on the nervous system and the liver, remains to be shown in clinical studies and in traditional use, we consider that a precautionary approach is taken with a maximum thujone content of 5.0 mg/day and a duration of use of maximum 2 weeks.
Products exceeding the recommended maximum thujone limit cannot be recommended for marketing without supplementary safety studies and a detailed benefit/risk assessment.The MLWP discussion focused on the lack of adverse drug reactions indicating that thujone could be less neurotoxic than thought in the past. The potential danger of the substance is possibly overrated because of the problems encountered with the consumption/misuse of liquors. There are no side effects reported for the Salviae folium.
The importance of limiting the exposure of thujone must also be seen together with the background intake of thujone from the use of Sage leaf based spices and other sources of thujone such as alcoholic beverages based on Absinth.
Preparations with less than 5.0 mg thujone/day:
Herbal medicinal products complying with the monograph must have a specification showing that the daily amount of thujone does not exceed the set limit with the approved posology.
Preparations with more than 5.0 mg thujone/day:
These herbal preparations should provide safety studies and a detailed benefit/risk assessment .
The thujone content in sage leaf preparations for oral and oromucosal use, are not expected to cause safety concern if dose recommendations are followed and the specified maximum limits of thujone are not exceeded.
Sage leaf can be recognized as safe when used in recommended dosages under specified conditions. If dose recommendations are followed in relation to camphor and the specified maximum limits of thujone content are kept, sage leaf should not be a safety concern in adults. However, exposures of children will be limited to be sure that doses causing significant toxic effects are avoided.
The maximum daily dose of 5.0 mg thujone/day is supposed to be divided according to listed posologies in the monograph. Therefore the single dose is always lower than the amount postulated as the lowest described limit of thujone action in the study by Dettling et al., 2004. The content of thujone must be shown for every batch.
There are sufficient data available to develop a Community monograph on the traditional use of sage leaf. Traditional use has shown that sage leaf can be recognised as safe when used in recommended dosages under the conditions specified in the monograph.
The clinical data cannot be considered to fulfil the criteria required for
Traditional medicinal use of sage leaf has been found to fulfil the requirement of medicinal use for at least 30 years (15 years within the Community) according to Directive 2004/24/EC for following indications:
1)Traditional herbal medicinal product for symptomatic treatment of mild dyspeptic complaints such as heartburn and bloating.
2)Traditional herbal medicinal product for symptomatic treatment of excessive sweating
3)Traditional herbal medicinal product for symptomatic treatment of inflammations in the mouth or the throat
4)Traditional herbal medicinal product for relief of minor skin inflammations..
Concomitant use of other
As minimum required data on mutagenicity (Ames’ test) are not available, an inclusion to the Community list of traditional herbal substances and preparations can not be recommended.
Sage essential oil is characterised by high levels of thujone. Consumption of sage essential oil in single ingredient products involves a high risk of exceeding the maximum recommended daily intake of thujone. Thujone is toxic and may cause seizures at high doses as shown in animal studies and indicated from case reports. The available clinical and toxicological data on sage essential oil can not be considered adequate to fulfil the criteria required for developing a Community herbal monograph. For this reason, no monograph will be made on sage essential oil before supplementary information on clinical and toxicological data for sage essential oil are considered adequate to fulfil those criteria.
2According to the ‘Procedure for the preparation of Community monographs for traditional herbal medicinal products’ (EMEA/HMPC/182320/2005 Rev.2)
3According to the ‘Procedure for the preparation of Community monographs for herbal medicinal products with