Lavandula – Lavender (Lavandulae flos)

Latin name of the genus:Lavandula
Latin name of herbal substance:Lavandulae flos
Botanical name of plant:Lavandula angustifolia mill. (l. officinalis chaix)
English common name of herbal substance:Lavender
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Latin name of the genus: Lavandula
Latin name of herbal substance: Lavandulae flos
Botanical name of plant: Lavandula angustifolia Mill. (L. officinalis Chaix)
English common name of herbal substance: Lavender

Lavandula - Lavender - Lavandula angustifolia Mill. (L. officinalis Chaix)

Table of Contents

1. Introduction

1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof

Herbal substance(s)

Lavender flower consists of the dried flowers of Lavandula angustifolia Miller (Lavandula officinalis Chaix) (European Pharmacopoeia 2008a).

Herbal preparation(s)

Essential oil obtained by steam distillation from the flowering tops of Lavandula angustifolia Miller (Lavandula officinalis Chaix) (European Pharmacopoeia 2008b).

The species is regularly confused with other lavender species L. x intermedia Emeric. (Lavandin) and L. latifolia MEDIK. (Spiklavender). If no detailed quality specifications are mentioned, the herbal substance consists of flowers from different flower species (Hänsel et al. 1993).

Combinations of herbal substance(s) and/or herbal preparation(s) including a description of vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products assessed, where applicable.

Not applicable.

Constituents

Lavender flower contains not less than 13 ml/kg of essential oil, calculated with reference to the dried drug.

Lavender flower

Essential oil (1-3%)

Coumarin derivatives: umbelliferon, herniarine

Flavonoids

Sterols (traces): cholesterol, campesterol, stigamsterol, β-sitosterol

Triterpenes (traces): mictomeric acid, ursolic acid

Tannins: up to 13% in the herbal substance

Phenylcarboxylic acids such as rosmarinic acid, ferulic acid, isoferulic acid, α-cumaric acid, p-cumaric acid, gentisinic acid, p-OH-benzoic acid, caffeic acid, melilotic acid, sinapinic acid, sytingic acid, vanillinic acid.

Lavender oil

The main components of the essential oil are monoterpene alcohols (60-65%) such as linalool (20- 50% of the fraction), linalyl acetate (25-46% of the fraction). Others include cis-ocimen (3-7%), terpinene-4-ol (3-5%), limonene, cineole, camphor, lavandulyl acetate, lavandulol and α-terpineol, β- caryophyllene, geraniol, α-pinen. Non-terpenoid aliphatic components: 3-octanon, 1-octen-3-ol, 1- octen-3-ylacetate, 3-octanol (ESCOP 2009; Hänsel et al. 1993; Bruneton 1999).

1.2. Information about products on the market in the Member States

Regulatory status overview

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’

This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products in the MSs concerned.

Composition of preparations

1.3. Search and assessment methodology

For this assessment report the following sources were used: – Allied and alternative medicine

– Biosis

– Chemical abstracts (since 1967)

– Current contents search – bibliographic records – Derwent drug file

– Derwent drug file backfile – Excerpta Medica

– International pharmaceutical abstracts – Medline

– Pascal

– PubMed

– Standard reference books

These sources were searched on the following terms (alone or in combination):

Lavandula, lavender, essential oil, stress, anxiety, relaxation, sleep, sleeping, disorder

2. Historical data on medicinal use

2.1. Information on period of medicinal use in the Community

In the 15th century when the technique of steam distillation was developed, Hildegarde von Bingen, Matthiolus and Paracelsus described the use of distilled water saturated with the essential oil of lavender as a sedative (‘Nervinum’) and against tooth- and headache (Kroeber 1935, Madaus 1938). The oil was traditionally used by evaporating it into rooms to calm ‘excited’ children. Even narcotic effects have been described when high concentrations were used (Guillemain et al. 1989). Rembertus Dodonaeus (1608) mentioned already the use of lavender water as a calming agent, even in case of epileptic seizures.

Pabst (1888) describes the oil as belonging to strongly toxic substances.

Indications can also be related to gastro-intestinal complaints and musculoskeletal disorders. Some sources mention posologies for oral use: five drops of essential oil on a cube of sugar, two times a day (Fischer 1939). Lavender is also used in behavioural therapy (Pelikan 1958).

Flowers and essential oil of Lavandula officinalis have been used for their sedative activity throughout Europe (Weiss & Fintelmann 1999). Leclerc (1966) has mentioned the use of lavender flowers in phytotherapeutic practice in France.

According to information on marketed products, lavender oil has been marketed for use as bath additive since 1976. Since 2009, soft capsules with lavender oil have been marketed as an authorised product in Germany. This practice has been preceded by a long-standing tradition of administering the essential oil as drops on a piece of sugar (ESCOP 2009; British Herbal Pharmacopoeia 1983, referring to the British Pharmaceutical Codex BPC 1973).

2.2. Information on traditional/current indications and specified substances/preparations

Peroral use

Soft capsules with Lavandulae aetheroleum have been authorised in Germany since 2009.

– Therapeutic indications: WEU

For treatment of anxious restlessness or for treatment of restlessness due to anxiety. – Posology

For adults ≥ 18 years: soft capsules containing 80 mg, 1 capsule per day.

Use as bath additive

Bath additives with Lavandulae aetheroleum have been authorised in Germany since at least 1976.

– Therapeutic indications: TU

Herbal medicinal product traditionally used to improve feeling in state of exhaustion. – Posology

For adults and adolescents over 12 years: 15 to 30 ml bath additive containing 7 to 10% (w/w) Lavandulae aetheroleum per full bath at 35-38°C during 10-20 minutes.

A bath additive with 5% Lavandulae aetheroleum has been on the market in Austria since 1994. The posology is the same as for the preparations in Germany.

Cutaneous use

There is a tradition for direct cutaneous use of lavender oil in diluted (mostly 10%) preparations. This use is for supportive treatment in conditions of nervous or physical tension which can show as:

restlessness

difficulties falling asleep

gastro-intestinal (abdominal) complaints, e.g. cramps and wind (flatulence)

periodic pains.

The product is a traditional herbal medicinal product for use in the specified indications exclusively based upon long-standing use in anthroposophic medicine in Germany.

There exists indeed a lot of written protocol data survey of cutaneous anthroposophic practice. This practice goes back more than 30 years and can be considered as traditional (Fischer 1939). The translation into exact instructions seems to be of a more recent date.

The first document mentioning a detailed use of the 10% lavender oil diluted with olive oil dates from 1999. Under posology, it reads:

… if no other instructions are given, 2-3 times per day 3-5 drops of essential oil should be gently rubbed on the skin area affected or applied on a gauze …

… in case of balance disturbance, difficulties to fall asleep and functional heart disease and circulatory difficulties, the left part of the thorax should be rubbed with essential oil …

… in case of flatulence the essential oil should be rubbed clockwise on the belly …

… in case of dysmenorrhoea the essential oil must be applied on the belly and in the lumbar region …

… for baby’s and small children up to 5 years old, the essential oil should not be directly rubbed as a 10% preparation but applied on a gauze …

This information specifies the places where to rub the skin with the diluted (10%) lavender oil. It is even specified that in case of flatulence the rubbing should be done clockwise on the belly. There also does not seem to be an age limit.

With regard to the dose used for compresses the number of drops to be put on the gauze proposed cannot be retrieved in a written source.

Conclusion on the cutaneous use: there is a long-lasting tradition for cutaneous use. However the modalities cannot yet be considered as traditional, especially not for children.

2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications

According to the ESCOP monograph (2009)

Indications

Mood disturbances such as restlessness, agitation or insomnia

Posology

– Lavender flower

An infusion is made of 1-2 teaspoons (approximately 0.8 to 1.6 g) in 150 ml of water. The number of doses is not specified.

Tincture (1:5 in 50% v/v ethanol), 60 drops per day

– Lavender oil

1-4 drops (approximately 20-80 mg) e.g. on a sugar cube

According to Blumenthal et al. (2000) (referring to Commission E monographs)

Indications

Internal use: restlessness or insomnia and nervous stomach irritation, Roehmheld’s syndrome (stomach discomfort), meteorism and nervous intestinal discomfort.

For balneotherapy: treatment of functional circulatory disorders.

The German standard license for lavender tea lists it for restlessness, sleeplessness, lack of appetite, nervous irritable stomach, meteorism and nervous disorders of the intestines.

Posology

Infusion: 1-2 teaspoons (approximately 0.8-1.6 g) in 150 ml water

Essential oil: 1-4 drops (approximately 20-80 mg) e.g. on a sugar cube

Bath additive: 20-100 g dried flowers for a 20 liter bath

According to the British Herbal Pharmacopoeia (1979 and the 1983 compilation)

Posology

Internally as a tea: dried flowers 1-2 g by infusion 3 times daily

Tincture (1:5) in 60% ethanol, 2-4 ml 3 times daily

Lavender oil BPC (1973), 0.06–0.2 ml 3 times daily

According to Leclerc (1966)

Lavandulae flos is used in case of asthma, whooping cough, influenza and laryngitis. An infusion is made of 5 parts per 100 (w/w) and 4 cups a day are prescribed.

According to Valnet (since 1964)

Indications

Internal use:

Irritability, spasms, insomnia

Fever blasts, infectious diseases

Neurasthenia, melancholy

Respiratory diseases: asthma, whooping cough, influenza, bronchitis due to whooping cough

Oliguria

Rhumatism

Instability during childhood

Atonic stomach or intestinal atony

Migraine, vertigo, hysteria, sequellae of paralysis

Typhoid enteritis (diarrhoea)

Cystitis, blennorrhoea

Dermal eruptions

Intestinal parasites

Metrorrhagia, leucorrhoea

Hypertension

Posology

Infusion: 1 teaspoon in a cup of boiled water, infusion during 10 minutes: 3 cups per day between meals.

Alcoholature: 40 drops 4 times daily in water (no detailed composition of alcoholature communicated).

Essential oil: 2-5 drops in honey or in an alcoholic solution. In case of anaesthesia: 1 g aids at mentally relaxing, without losing intellectual capacity.

Vaporisation: make a solution of 2% in water. To be vaporised in public rooms.

According to Madaus (1938)

Indications

Internal use: Lavender mildly acts on the nervous system, especially in case of migraine. It is used against neurasthenia, vertigo, nervous tachycardia, general nervous tension, hysteria, spasms, weakness and sleeplessness. Lavender has been used against affections of the stomach like gastritis, against meteorism and oedema.

External use: Lavender flowers are used as a bath additive. Lavender oil is used for local massage in case of rheumatism, gout, neuralgia, ischias and scabies. Rinsing fluid is made in case of fluor albus.

Posology

Essential oil: 8 drops (without further specification)

Tincture (strength not given): 10-15 drops

Infusion: 2-3 teaspoons (= 3-4.5 g) daily

3. Non-Clinical Data

3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof

In vitro studies

Antimicrobial effects

Lavender oil had an antimicrobial activity against Escherichia coli, Bacillus subtilis, Candida albicans and Staphylococcus aureus, but not against Pseudomonas aeruginosa. The model used was the plate diffusion test. No details about the concentrations used are mentioned. Linalool was active against Streptococcus mutans with a MIC of 1600 µg/ml which is a rather high concentration (Kubo et al. 1993).

Eight essential oils were examined using the agar dilution method, including Carum carvi, Citrus aurantium var. amara, Foeniculum vulgare dulce, Illicium verum, Lavandula angustifolia, Mentha arvensis, Mentha x piperita, and Trachyspermum copticum. Doubling dilutions of the essential oils were tested against 12 species of intestinal bacteria, which represent the major genera found in the human gastrointestinal tract (GIT). Carum carvi, Lavandula angustifolia, Trachyspermum copticum, and Citrus aurantium var. amara essential oils displayed the greatest degree of selectivity, inhibiting the growth of potential pathogens at concentrations that had no effect on the beneficial bacteria examined. The most promising essential oils for the treatment of intestinal dysbiosis are Carum carvi, Lavandula angustifolia, Trachyspermum copticum, and Citrus aurantium var. amara. The herbs from which these oils are derived have long been used in the treatment of gastrointestinal symptoms and the in vitro results of this study suggest that their ingestion will have little detrimental impact on beneficial members of the GIT microflora. For lavender was among the oils displaying the highest degree of selectivity. Concentrations varied from 0.55 to 4.5% (v/v). More research is needed, however, to investigate tolerability and safety concerns, and verify the selective action of these agents (Hawrelak et al. 2009).

Spasmolytic effects

The ileum of the guinea-pig and the rat uterus and phrenic nerve diaphragm were used as an experimental model. These isolated organs contract when exposed to acetylcholine, histamine or noradrenaline or electrically stimulated (field stimulation). Lavender oil inhibited the contractions of the isolated ileum by about 50%. Pure linalool had similar effects. In contrast with lavender oil, a concentration-effect relationship was studied with linalool: 5×10-5 to 2×10-4 g/ml on the diaphragm and 4×10-6 to 8×10-5 g/ml was used on the isolated ileum; both organs were electrically stimulated. However no concentration-effect curves were displayed.

The inhibition of the electrically stimulated contractions by lavender of guinea-pig ileum appeared to be postsynaptic and not atropine-like, as lavender inhibited the contractile responses due to acetylcholine and to histamine to a similar degree. The relaxation effect by isoprenaline was potentiated by linalool, which may indicate a phosphodiesterase inhibitory activity (Lis-Balchin & Hart 1997 and 1999).

Experiments were designed to investigate the relaxation mechanism of linalyl acetate as the major ingredient of lavender essential oil in rabbit carotid artery specimens. Linalyl acetate produced sustained and progressive relaxation during the contraction caused by phenylephrine. The relaxation effect of linalyl acetate at a concentration near the EC50 was partially but significantly attenuated by nitroarginine as an inhibitor of nitric oxide synthase, 1H-(1,2,4) oxadiazolo (4,3-a) quinoxaline-1-one as an inhibitor of guanylyl cyclase, or by the denudation of endothelial cells. In specimens without endothelium, the phenylephrine-induced contraction and phosphorylation of myosin light chain (MLC) were significantly attenuated after the pretreatment with linalyl acetate. The relaxation caused by linalyl acetate in the endothelium-denuded specimens was clearly inhibited by calyculin A as an inhibitor of MLC phosphatase, although not by ML-9 as an inhibitor of MLC kinase. Furthermore, suppression of the phenylephrine-induced contraction and MLC phosphorylation with linalyl acetate was canceled by the pretreatment with calyculin A. These results suggest that linalyl acetate relaxes the

vascular smooth muscle through partial activation of the nitric oxide/cyclic guanosine monophosphate pathway, and partial MLC dephosphorylation via activating MLC phosphatase (Koto et al. 2006).

Other effects

Cultures of cerebellar granular cells from rat pups were exposed to neurotoxic concentrates of glutamate (10-7 M). The neuroprotective effect of a dry aqueous extract from lavender flower (DER approximately 5:1) was tested at concentrations of 10 µg/ml, 100 µg/ml, 1 mg/ml and 10 mg/ml. At 100 µg/ml and 1 mg/ml, the extract significantly reduced glutamate-induced neurotoxicity from 37% to 29% (p<0.05) and 21% (p<0.001) respectively (Büyükokuroglu et al. 2003).

A study on MCF-7 human breast-cancer cells (positive for oestrogen receptors) demonstrated that lavender oil is weakly oestrogenic in concentrations of 0.01 and 0.03% (V/V), treated for 18 h. In MDA-kb2 cells (positive for androgen receptors) lavender oil was revealed to be weakly anti- androgenic in concentrations between 0.0001 and 0.01% (V/V) treated for 24 h (Henley et al. 2007).

Lavender oil concentration-dependently inhibited histamine release from peritoneal mast cells (p< 0.05):

stimulated by compound 48/80 (a synthetic phosphodiesterase and ATP-ase inhibitor) at dilutions of 1:500, 1:100, 1:10, 1:1 and undiluted

stimulated by anti-dinitrophenyl IgE at dilutions of 1:100, 1:10, 1:1 and undiluted.

It also had a significant inhibitory effect on anti-dinitrophenyl IgE-induced TNFα secretion from peritoneal mast cells at 1:1000, 1:100, 1:10 and undiluted (p<0.05) (Kim & Cho 1999).

Assessor’s comments:

The relevance of antimicrobial, spasmolytic as well as other effects is difficult to evaluate, as no detailed information about concentrations as such and concentration-effect relationship is available. For the inhibition of histamine release, highly concentrated dilutions or even pure oil have been used, which seems of poor relevance.

It is difficult to judge the human relevance of oestrogenic effects seen in vitro.

In vivo studies

Anticonvulsive effects

Anti-inflammatory and analgesic effects

3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof

3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof

Acute toxicity

The acute oral LD50 of lavender oil in rats was found to be >5 g/kg b.w. Other authors reported the oral LD50 in male rats as 6.2 ml/kg and in female rats as 5.0 ml/kg; the oral LD50 in male rats as 5 ml/kg and in female rats as 3 ml/kg.

Furthermore an oral LD100 in male rats as > 7 ml/kg and in female rats as >6 ml/kg was reported. In an earlier study the acute oral LD50 of lavender oil was determined as 9 g/kg (Buchbauer et al. 1991; Delaveau et al. 1989; von Skramlik 1959).

Acute oral LD50 values in rodents have been reported as 2.2-3.9 g/kg b.w. for linalool and 5.0-

48.8 g/kg for linalyl esters. The dermal LD50 of linalool in rabbits exceeded 5 g/kg. No adverse effects were reported from administration of linalool to female mice via a stomach tube at 94, 188 or

375 mg/kg/day for 5 days (Bickers et al. 2003).

Subacute toxicity

In a 90-day chronic dermal toxicity study in rats (20 per group), linalool was applied daily at 250, 1000 and 4000 mg/kg b.w.. At 250 mg/kg no changes were observed except decreased activity and transient erythema; at 1000 mg/kg weight gain and activity were reduced; at the highest dose level, 11 animals died (Bickers et al. 2003).

In a 90-day study, a 1:1 mixture of linalool and citronellol was added to the diet of rats to provide an intake of about 50 mg/kg/day of each substance. A slight retardation of body weight gain was

observed in the males, but no effects were evident from histopathology, haematology, clinical chemistry or urine analysis at weeks 6 and 12 (Bickers et al. 2003).

Investigations on rats showed that the acute toxicity of essential oil of lavender (OL), given p.o. in olive oil, was relatively low, while when given to mice pharmacological tests demonstrated that it had anxiolytic effects and prolonged sleep induced by i.p. pentobarbital Na, though the latter effect was reduced after repeated p.o. administration. Impaired balance, piloerection and hypersalivation sometimes occurred. The authors concluded that, if its chronic toxicity is also low, OL might be used instead of more active anxiolytics or tranquilizers for minor conditions (Delaveau et al. 1989).

Undiluted lavender oil was not irritant when applied to the backs of hairless mice or pigs, but was slightly irritant on intact or abraded rabbit skin under occlusion for 24 h (Opdyke 1976).

Undiluted linalool caused slight to severe irritation to guinea pigs and rabbits when applied to open or occluded skin; no irritation was observed at 10% dilution. Undiluted linalyl acetate caused slight to severe irritation in guinea pigs and rabbits; at 5% dilution it was slightly irritating to rabbits (Bickers et al. 2003).

Mutagenicity

Linalool and linalyl acetate showed no mutagenic potential in the Ames mutagenicity test, with or without metabolic activation (Eder et al. 1980; Eder et al. 1982a; Eder et al. 1982b; Ishidate et al. 1984).

In the mouse lymphoma assay, no effects were seen with linalool in the absence of metabolic activation at concentrations up to 300 µg/ml; weak positive effects were observed in the presence of metabolic activation at doses of 200 µg/ml and above (Bickers et al. 2003).

Linalool did not induce chromosomal aberrations when incubated with Chinese hamster fibroblast cells at concentrations up to 0.25 mg/ml (Ishidate et al. 1984) nor with Chinese hamster ovary cells at concentrations up to approximately 300 µg/ml (Bickers et al. 2003).

No induction of unscheduled DNA synthesis in rat hepatocytes was evident at concentrations of linalool up to 50 µg/ml or linalyl acetate up to 300 µg/ml (Bickers et al. 2003).

Evrandi et al. (2005) studied the antimutagenic activity of lavender essential oil in the bacterial reverse mutation assay using Salmonella typhimurium TA98 and TA100 strains and in Escherichia coli WP2 uvrA strain, with and without an extrinsic metabolic activation system, without pre-incubation. Lavender essential oil had no mutagenic activity on the two tested Salmonella strains or on E. coli, with or without the metabolic activation system. Lavender oil exerted strong antimutagenic activity, reducing mutant colonies in the TA98 strain exposed to the direct mutagen 2-nitrofluorene. Antimutagenicity was concentration-dependent: the maximal concentration (0.80 mg/plate) reduced the number of histidine-independent revertant colonies by 66.4%. Lavender oil (0.80 mg/plate) also showed moderate antimutagenicity against the TA98 strain exposed to the direct mutagen 1- nitropyrene.

Rahimifard et al. (2010) investigated the mutagenic and antimutagenic activities of lavender (and cardamom) oil by reverse mutation assay in the same strains of Salmonella typhimurium with and without S9 (microsomal mutagenesis assay) for 7 dilutions. For lavender oil, the concentration per plate varied from 0.13 to 0.80 mg/plate. No mutagenicity was seen. On the contrary, there was a antimutagenic effect when 0.4 mg lavender essential oil per plate was applied.

3.4. Overall conclusions on non-clinical data

Most of the experiments were done with Lavandulae aetheroleum, the herbal preparation that is used in clinical conditions. Lavender flowers were used for investigating a diuretic action.

Experimental pharmacological data point to an activity in the central nervous system: anticonvulsive effects, sleep prolongation, locomotor activity, explorative or anticonflict behaviour and anxiety. Well known inflammatory and nociceptive experimental models were used. As far as these interventions are concerned, high doses of lavender oil were used to obtain pharmacological effects. These doses mostly cannot be extrapolated to human conditions. On the other hand, dose-response relationship could be demonstrated in some investigations. The outcomes are mostly positive. This may be due to a publication bias. The effect on enzyme induction by linalool is difficult to translate to metabolic consequences.

The experimental pharmacokinetic data are limited. Most probably, oil constituents are excreted by the urine as glucuronic conjugates.

Toxicity of lavender oil is not a major concern. Some components like linalool and linalyl acetate are not mutagenic. The essential oil did not demonstrate mutagenic activity towards two strains of Salmonella typhimurium and one of Escherichia coli with and without metabolic activation. The number of strains used for testing and the procedure used are not according to the recent regulatory guidelines. A Community list entry cannot be established for Lavandula.

4. Clinical Data

4.1. Clinical Pharmacology

4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents

Effects on the central nervous system and neuronal activity

Antioxidative activity

4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents

4.2. Clinical Efficacy

4.2.1. Dose response studies

Not applicable.

4.2.2. Clinical studies (case studies and clinical trials)

Anxiety

Sleeping disorders

4.2.3. Clinical studies in special populations (e.g. elderly and children)

4.3. Overall conclusions on clinical pharmacology and efficacy

The anxiolytic activity of lavender oil has been studied in different conditions. Patients can be considered as representative for ambulatory practice. The number of patients per study is low, only in some trials a critical mass is obtained. Lavender oil is administered in dosage forms or nebulised as aromatherapy. The former is more reliable as compared to the latter. It will always remain difficult to assess clinical activity when no exact ingested dose can be calculated. Moreover, a significant change towards baseline does not automatically mean that the difference between control and lavender groups differs significantly. When combined treatments are used or co-medication was allowed, the clinical relevance of the results is more safety related.

Abstraction made from these limitations and weaknesses, independently from the form administered, lavender oil seems to positively influence anxiety and stress-related restlessness. However, the peroral use of lavender oil cannot be accepted as well-established use, as the essential factors to be taken into account in order to establish a well-established medicinal use (according to Annex I of Directive 2001/83/EC) are not fulfilled. So only for completeness, this assessment report presents also one of the most recent studies (Woelk & Schläfke, 2010), where patients with general anxiety disorder are included. The study is organised according to good clinical practice. Patients are well characterised, capsules with lavender oil are directly compared with lorazepam, and primary and secondary outcomes are clearly distinguished. Before entering, there was a one-week screening phase. Results were calculated using the full analysis set (Intention to treat or ITT) as well as per protocol (PP). However, the number of patients is low and no power calculation is made. Furthermore, no placebo arm was included. Therefore it is not possible to grant a well-established use for lavender. More studies with the same preparation and positive outcome will be necessary to ponder a well-established use.

Lavender oil has been studied in special populations like newborn children, children with autistic behaviour, psychogeriatric patients and hospitalised patients with positive outcomes. However the study populations are small and might be too diverse.

5. Clinical Safety/Pharmacovigilance

5.1. Overview of toxicological/safety data from clinical trials in humans

In clinical studies involving patients treated orally with a lavender flower tincture (Buchbauer et al. 1993b), and patients or healthy volunteers treated with lavender oil either topically (Dale & Cornwell 1994; Yip & Tse 2004; Dunn et al. 1995) or by inhalation of the odour (Diego et al. 1998; Louis & Kowalski 2002; Kane et al. 2004), only a few mild adverse events have been reported.

At a concentration of 16% in petrolatum, lavender oil did not produce any irritation after 48 h in the closed-patch test and produced no sensitization reactions in the maximisation test (Opdyke 1976).

From evaluation of linalool and linalyl acetate for skin irritation in male volunteers, no irritation was observed with 20% linalool or up to 32% linalyl acetate, while mild irritation was observed with 32% linalool. No sensitization reactions were observed in the human maximisation test with linalool at concentrations of 8% or 20% in 50 volunteers, nor with 10% linalyl acetate in 131 volunteers. With linalyl acetate at 12% and 20% no reactions were observed in 25 subjects (Bickers et al. 2003).

In very rare cases allergic reactions have been reported due to contact with lavender oil. Coulson & Khan (1999) described two case reports of mild facial ‘pillow’ dermatitis due to lavender oil allergy. Lavender oil does not seem to be a major sensitizing substance (Hausen & Vieluf 1997). A case of allergic reactions have been reported in young students (20 years). When an aromatherapy student started massaging the feet of a client with a mixture of Lavandula, Origanum and Juniperus oil, her hands started to tingle and became swollen with redness to her arms and throat area. Shortness of breath occurred within 3 minutes of exposure. The symptoms were reversible upon cleaning the skin of lavender oil (Maddocks-Jennings 2004).

Another case of contact dermatitis was reported after rubbing the face with hands that were not cleaned from a massage gel, containing 5% benzylamine and lavender fragrance. Erythema, followed by acute vesicular dermatitis developed (Rademaker 1994).

Three cases of gynecomastia in prepubertal boys were seen after topical application of products that contained lavender and tea tree oils. The boys were between 4 and 10 years old. Exposure was as a ‘healing balm’ with lavender on the skin, styling gel containing lavender on hair and scalp and the use of lavender-scented soap. Gynecomastia resolved after discontinuing of the therapy. No re-application is mentioned. Nevertheless, causality was accepted between the topical use of the plant species mentioned and the gynecomastia (Henley et al. 2007).

5.2. Patient exposure

Lavender flowers and essential oil have been used for centuries. Exact exposure data related to the use of registered preparations have not been retrieved.

5.3. Adverse events and serious adverse events and deaths

There have been reports of contact dermatitis associated with lavender oil in shampoo, and facial dermatitis after application of the oil to pillows for its sedative properties (Sweetman 2009).

5.4. Laboratory findings

No data available.

5.5. Safety in special populations and situations

No data available.

5.6. Overall conclusions on clinical safety

There is no major concern about human toxicity due to lavender essential oil or lavender flowers. Contact dermatitis may be possible in rare cases.

6. Overall conclusions

Lavender essential oil as well as the dried lavender flowers can be considered as safe. There is no major concern about the quality of the herbal substance and the herbal preparation thereof.

Experimental as well as clinical evidence converge to central nervous effects, more particularly related to anxiety. There are many small- and larger-scale studies available with a patient population representative for ambulatory practice, including children and elderly. Some criticism can be given to the doses and the method of administration. Especially inhalation is difficult to quantify, although the substances will be more directly delivered to the circulation. There are no major concerns on the safety of lavender flowers or essential oil.

Lavender oil and flowers have been used for more than 30 years in the EU. A well-established use cannot be proposed for lavender flowers and oil in the treatment of general anxiety disorders (cf. ICD- 10 F 41.1). Although the quality of the studies has increased with time, the number of patients treated with essential oil of lavender in RCTs is too low. No structured clinical research has been done on the cutaneous use of Lavandula preparations. The use as bath additive of the oil is considered as traditional.

The regulatory position of lavender flowers was discussed. There is a long-standing use of the flowers, in a very wide range of therapeutic indications. Moreover, no authorised preparations with flowers were reported in the EU countries. However, the effects for the relief of mild symptoms of mental stress and exhaustion and to aid sleep are plausible on the basis of long-standing use and tradition, thus a monograph is established.

As the genotoxicity of lavender flowers and total essential oil was not appropriately tested, a Community list entry cannot be established.

Annex

List of references

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