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CNS Drugs 2006; 20 (4): 257-280 LEADING ARTICLE 1172-7047/06/0004-0257/$39.95/0 © 2006 Adis Data Information BV. All rights reserved. Aromatherapy in the Management of Psychiatric Disorders Clinical and Neuropharmacological Perspectives Nicolette Perry and Elaine Perry Medicinal Plant Research Centre, Universities of Newcastle and Northumbria, Newcastle upon Tyne, UK Aromatherapy is currently used worldwide in the management of chronic pain, Abstract depression, anxiety, some cognitive disorders, insomnia and stress-related disor- ders. Although essential oils have been used, reputedly effectively, for centuries as a traditional medicine, there is very little verified science behind this use. The pharmacology of the essential oils and/or their single chemical constituents, therefore, remains largely undiscovered. However, accumulating evidence that inhaled or dermally applied essential oils enter the blood stream and, in relevant molecular, cellular or animal models, exert measurable psychological effects, indicates that the effects are primarily pharmacological. This review includes evidence from the limited number of clinical trials that have been published of ‘psychoaromatherapy’ in relation to psychiatric disorders, together with evidence from mechanistic, neuropharmacological studies of the effects of essential oils in relevant in vitro and in vivo models. It is concluded that aromatherapy provides a potentially effective treatment for a range of psychiatric disorders. In addition, taking into account the available information on safety, aromatherapy appears to be without the adverse effects of many conventional psychotropic drugs. Investment in further clinical and scientific research is clearly warranted. 1. Background as ‘essential oil therapy’ and ‘phyto-essential- pharmacology’ might be more applicable. Aromatherapy is the therapeutic use of plant es- Essential oils are concentrated steam distillates sential oils, whether absorbed via the skin or olfacto- obtained from a range of aromatic plants, and also ry system. The term ‘aromatherapy’, intended to include expressions from the peel of citrus fruits. describe the compounds present in the essential oil Chemically, plant essential oils are heterogeneous that are aromatic (i.e. have an aroma), is not entirely mixtures (often hundreds in total) of, amongst precise, as effects are not necessarily related to the aromatic properties of the agent; further terms such others, the lipophilic volatile hydrocarbon monoter-

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Aromatherapy is currently used worldwide in the management of chronic pain,depression, anxiety, some cognitive disorders, insomnia and stress-related disorders. Although essential oils have been used, reputedly effectively, for centuriesas a traditional medicine, there is very little verified science behind this use. The pharmacology of the essential oils and/or their single chemical constituents, therefore, remains largely undiscovered. However, accumulating evidence that inhaled or dermally applied essential oils enter the blood stream and, in relevant molecular, cellular or animal models, exert measurable psychological effects, indicates that the effects are primarily pharmacological.

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  • CNS Drugs 2006; 20 (4): 257-280LEADING ARTICLE 1172-7047/06/0004-0257/$39.95/0 2006 Adis Data Information BV. All rights reserved.

    Aromatherapy in the Management ofPsychiatric DisordersClinical and Neuropharmacological Perspectives

    Nicolette Perry and Elaine Perry

    Medicinal Plant Research Centre, Universities of Newcastle and Northumbria, Newcastle uponTyne, UK

    Aromatherapy is currently used worldwide in the management of chronic pain,Abstractdepression, anxiety, some cognitive disorders, insomnia and stress-related disor-ders. Although essential oils have been used, reputedly effectively, for centuriesas a traditional medicine, there is very little verified science behind this use. Thepharmacology of the essential oils and/or their single chemical constituents,therefore, remains largely undiscovered. However, accumulating evidence thatinhaled or dermally applied essential oils enter the blood stream and, in relevantmolecular, cellular or animal models, exert measurable psychological effects,indicates that the effects are primarily pharmacological.

    This review includes evidence from the limited number of clinical trials thathave been published of psychoaromatherapy in relation to psychiatric disorders,together with evidence from mechanistic, neuropharmacological studies of theeffects of essential oils in relevant in vitro and in vivo models. It is concluded thataromatherapy provides a potentially effective treatment for a range of psychiatricdisorders. In addition, taking into account the available information on safety,aromatherapy appears to be without the adverse effects of many conventionalpsychotropic drugs. Investment in further clinical and scientific research is clearlywarranted.

    1. Background as essential oil therapy and phyto-essential-pharmacology might be more applicable.

    Aromatherapy is the therapeutic use of plant es-Essential oils are concentrated steam distillatessential oils, whether absorbed via the skin or olfacto-

    obtained from a range of aromatic plants, and alsory system. The term aromatherapy, intended toinclude expressions from the peel of citrus fruits.describe the compounds present in the essential oilChemically, plant essential oils are heterogeneousthat are aromatic (i.e. have an aroma), is not entirelymixtures (often hundreds in total) of, amongstprecise, as effects are not necessarily related to the

    aromatic properties of the agent; further terms such others, the lipophilic volatile hydrocarbon monoter-

  • 258 Perry & Perry

    penoids (grouped by their different functional ranging list of therapeutic activities. The pharmacol-ogy behind the actions of many essential oils re-groups into, for example, alcohols, oxides, phenols,mains undefined and it is certain to be a long andaldehydes and ketones) and the less volatile ses-complex path to full medicinal and pharmacologicalquiterpenoids (and their alcohols, oxides and al-understanding, paralleling that of medical herbalismdehydes) [see table I and examples in figure 1]. Theand unlike any conventional medicinal substance.myriad of chemical constituents that exist as essen-

    tial oils, combined with the chemical diversity be- Essential oils can be absorbed into the body intween essential oils, results in a potentially wide- three ways: (i) through the olfactory and respiratory

    systems (vapour inhalation); (ii) transdermally vialotions or compresses, often involving massage andduring bathing; or (iii) orally, via ingestion of essen-tial oils in capsules or as additives to food or medicalpreparations, for example. The latter option belongsmore to the realm of herbal medicine than aro-matherapy.

    The aromatic oils have been used for over 5000years; ancient Egyptians used them as perfumes,[3]and there are nearly 200 references in the Bible totheir use for mental, spiritual and physical healing.[7]Modern aromatherapy originated in Germany in the16th century.[8] Gattefosse, a French chemist, inves-tigated the antibacterial and healing properties ofessential oils during World War I to treat woundedsoldiers[9] and Valnet, a French army surgeon, fur-ther revived the application of aromatherapy duringWorld War II.[7]

    The effects of an aroma can be instantaneous andinclude both direct and indirect psychological ef-fects even thinking about a smell may have asimilar effect to the smell itself. However, accumu-lating evidence that inhaled or dermally appliedessential oils enter the blood stream and, in relevantmolecular, cellular or animal models, exert measur-able psychological effects, indicates that the effectsare primarily pharmacological. This conclusion issupported by increasingly reported benefits ofaromatherapy using specific essential oils in themanagement of chronic pain, depression, anxietyand some cognitive disorders, as well as insomniaand stress-related disorders.[10] The subjective ef-fects of aromatic plant oils relevant to CNS/cerebral

    1,8-Cineole(monoterpene oxide)

    Salvia lavandulaefolia (21%)

    O

    Alpha-pinene(monoterpene hydrocarbon)Rosmarinus officinalis (22%)

    Linalool(monoterpene alcohol)

    Lavandula angustifolia (38%)

    OH

    Linalyl acetate(acetate of linalool)

    Lavandula angustifolia (45%)

    O

    O

    Camphor(monoterpene ketone)Salvia officinalis (12%)

    O

    O

    Geranial(monoterpene aldehyde)Melissa officinalis (32%)

    H

    Caryophyllene oxide(sesquiterpenoid)

    Lavandula latifolia (2.4%)

    H

    H

    O

    Fig. 1. Examples of frequently occurring essential oil terpenoidsfrom the different chemical classes. % indicates the amount ofterpenoids present in each oil, e.g. Lavandula angustifolia is 38%linalool.

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    Table I. Subjective effects and chemical constituents of aromatic essential oils relevant to cerebral functionaEssential oil Latin name Reported subjective effects Main chemical constituentsbBergamot Citrus bergamia Antidepressant, calming, relaxing, sedative Limonene 38%, linalyl acetate 28%, linalool 8%,

    gamma-terpinene 8%, beta-pinene 7%Chamomile-Roman Chamomelium nobilis Analgesic, hypnotic, relaxing, sedative Isobutyl angelate 36%, 2-methylbutyl angelate 15%,

    methyl angelate 9%Linalyl acetate 49%, linalool 24%, germacrene D 3%,alpha-terpineol 3%, geranyl acetate 3%

    Geranium Pelargonium graveolens Analgesic, antidepressant, uplifting Citronellol 21%, geraniol 17%, linalool 13%, citronellylformate 8%, geranyl formate 8%

    Jasmine Jasminum grandiflorum Antidepressant, aphrodisiac, euphoric, relaxing, Benzyl acetate 22%, benzyl benzoate 15%, phytylstimulating acetate 10%, linalool 6%, methyl cis-jasmonate 3%

    Juniper Juniperus communis Analgesic, aphrodisiac, mentally clearing Alpha-pinene 33%, myrcene 11%, beta-farnesene 11%,gamma-elemene 3%, beta-caryophyllene 3%

    Lavender Lavandula angustifolia Analgesic, antidepressant, anticonvulsant, Linalyl acetate 40%, linalool 32%, (Z)-beta-ocimene 7%,anxiolytic, calming, hypnotic, relaxing, sedative beta-caryophyllene 5%, lavandulyl acetate 4%

    Lemon Citrus limonum Mentally stimulating, reviving Limonene 70%, beta-pinene 11%, gamma-terpinene8%, citral 2%, trans-alpha-bergamotene 0.4%

    Mandarin Citrus deliciosa Sedative, uplifting Limonene 71%, gamma-terpinene 19%, alpha-pinene2%, alpha-sinensal 0.2%, octanal 0.2%

    Marjoram Origanum majorana Analgesic, anxiolytic, aphrodisiac, comforting, Terpinen-l-ol 15%, Sabinene 8%, mycene 5%, gamma-sedating terpine 17%, linalool 5%

    Melissa Melissa officinalis Anxiolytic, calming, hypnotic, sedative, Geraniol 40%, neral 35%, 6-methyl-5-heptan-2-ol 3%,stimulating, uplifting beta-caryophyllene 2%, citronellal 2%

    Neroli Neroli bigarade Sedative, uplifting Linalool 37%, limonene 26%, beta-pinene 12%, geraniol4%, linalyl-acetate 3%

    Patchouli Pogostemon cabin Calming, sedative, uplifting Patchouli alcohol 33%, alpha-patchoulene 22%, beta-caryophyllene 20%, beta-patchoulene 13%, beta-elemene 6%

    Rose (Egypt) Rosa damascena Antidepressant, aphrodisiac, relaxing, sedative, 2-Phenyl ethyl alcohol 38%, geraniol 16%, citronellolsoothing, uplifting 13%, farnesol 6%, nerol 4%

    Rosemary Rosmarinus officinalis Analgesic, anxiolytic, mentally stimulating, 1,8-Cineole 51%, camphor 11%, alpha-pinene 10%,(Tunisia, cineole) clarifying borneol 8%, alpha-terpineol 4%Sagec Salvia officinalis Nerve tonic Alpha-thujone 37%, beta-thujone 14%, camphor 12%,

    1,8-cineole 12%, alpha-pinene 4%Spearmint Mentha spica Analgesic, stimulating ()-Carvone 43%, dihydrocarvone 16%, 1,8-cineole 6%,

    perillyl alcohol 5%, alpha-terpinenyl acetate 5%Ylang-Ylang Cananga odourata Analgesic, aphrodisiac, relaxing Linalool 19%, beta-caryophyllene 11%, germacrene D

    10%, p-cresyl methyl ether 9%, benzyl benzoate 7%Vetiver Vetivera zizanoides Calming, nerve tonic, sedative, uplifting Vetiverol 50%, vetivenes 20%, alpha-vetivol 10%,

    vetivones 10%, khusimol 1%a Among hundreds of essential oils used in aromatherapy, only those referred to in the present review are included in this table. For reviews on subjective effects see Price

    and Price,[1] Tisserand and Balacs,[2] Lawless,[3] Buckle,[4] and Thomas;[5] for chemical compositions see Bowles.[6]b The principal chemical constituents are listed in order of concentration, with the highest first (note that proportions may vary according to the source and that many oils

    contain hundreds of terpenoids).c Not widely used in aromatherapy because of its high thujone content; Salvia lavandulaefolia is thujone-free.

  • 260 Perry & Perry

    function are summarised in table I; the list is not tion to psychiatric disorders, together with data fromexhaustive, focusing on the essential oils included in mechanistic, neuropharmacological studies of thethis review. With respect to safety, the evolution and effects of essential oils in relevant in vitro and inwidespread current use of aromatherapeutic prac- vivo models.tises, together with contemporary clinical trial evi- There is a vast literature on aromatherapy in non-dence, indicates that with due attention to the type, medical (including nursing and complementary) anddose and mode of application of essential oils (com- non-Western (reflecting the practices of Ayurvedicprehensively outlined by Tisserand and Balacs[2]) and traditional Chinese medicines, for example)aromatherapy can provide treatment for psychiatric journals. This review is based primarily on publica-disorders that is free of the adverse effects associat- tions in English language medical journals, with theed with conventional drugs. objective of assessing evidence that is both accessi-

    In a seminal report, Frey[11] described the rapid ble and acceptable to primary- and secondary-careintranasal delivery of therapeutic agents, such as medical practitioners within westernised nationalnerve growth factor to mouse brain, which allowed health services.the by-passing of the blood brain barrier. The olfac- The following databases and search terms weretory neural pathway provides both intraneuronal used to assess the literature: aromatherapy and the(via axonal transport, and taking hours) and ex- names of the specific essential oils and plant species,traneuronal (via bulk flow transport through per- the relevant chemical constituents and the variousineural channels, taking only minutes) access to the psychiatric disorders, in articles indexed inbrain. Born et al.[12] also described intranasal deliv- MEDLINE (1966October 2003), EMBASEery in humans of neuropeptides to the CSF. Tradi- (1980October 2003), EMB (Evidence Basedtional aromatherapeutic practices, dating back Medicine) Reviews (19912003) and CINAHL (Cu-thousands of years, are thus verified by 21st century mulative Index to Nursing And Allied Health)neuroscience. Equally fascinating is the evidence [1982October 2003].1that an odour-enriched environment increasesneurogenesis in adult mouse brain.[13] Since agents 2. Clinical Evidence of Efficacypromoting neurogenesis in adult human brain, in-cluding the hippocampus, are being investigated in a Amongst psychiatric disorders, significant num-variety of psychiatric disorders (e.g. depression, de- bers of controlled clinical trials of the use ofmentia and schizophrenia),[14,15] the possibility that aromatherapy have been conducted only in relationaromatherapy may have long-term protective poten- to dementia. This may reflect the lack of prescrip-tial in terms of regeneration is intriguing. tion medication specifically for dementia until re-

    In the US, aromatherapy is the fastest growing of cently, and/or the outstanding need for ameliorative,all complementary therapies amongst nurses,[16] and non-toxic therapeutic strategies for the advancedhas recently been recognised as a legitimate part of stages of dementia. With respect to psychiatric dis-holistic nursing.[17] However, judging by the litera- orders other than dementia, little or no evidenceture from controlled clinical trials, aromatherapy is from controlled trials of aromatherapy is available.only rarely considered by the medical profession. Instead, there exist reports of open-label studies,This article reviews the evidence of the clinical which may serve, as in dementia, to prompt con-efficacy and safety of psychoaromatherapy in rela- trolled trials.

    1 This review was submitted in May 2004 and accepted in March 2005.

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  • Aromatherapy for Psychiatric Disorders 261

    2.1 Behavioural Disorders Associated atypically, for 12 minutes via a cotton wool budwith Dementia attached to clothing). These studies highlight some

    of the issues to be resolved in the future.Controlled clinical trials of aromatherapy in de-

    Sage (Salvia) essential oils may be worth investi-mentia were originally prompted by open-label tri-

    gating as an aromatherapy for the treatment of de-als demonstrating beneficial effects, e.g. increased

    mentia since certain species possesses a number ofsleep with lavender vapourisation in patients with

    relevant bioactivities (cholinesterase inhibition,dementia who were in residential care,[18] reducedanti-inflammatory and oestrogenic properties[28])

    agitation in patients with severe dementia followingand in an open-label 4-week trial of ingested cap-lavender oil vapourisation,[19] and a range of thesesules of Salvia lavandulaefolia (Spanish sage) an

    and other improved outcomes using a mixture ofimprovement in attention and a reduction inlavender and other oils.[20] The results of the con-behavioural symptoms was noted in 11 patients with

    trolled trials are outlined in table II.Alzheimers disease.[29] The same oral preparation

    The most commonly used essential oils for de-enhanced memory in normal young volunteers.[30]

    mentia therapy in controlled trials have been laven- Although Salvia officinalis is not recommended forder (Lavandula angustifolia) and lemon balm (Me-aromatherapy due to its high thujone content, S.lissa officinalis), singly or in combination (table II). lavandulaefolia may be more applicable, although

    The trials have involved people with advanced de-this contains a substantial amount of camphor.

    mentia in residential care and have generally as-In relation to memory function in normal individ-sessed behavioural symptoms, particularly agitation,

    uals, Degel and Koster[31] exposed 108 neurological-as outcome measures, although one trial did assessly normal adults to jasmine, lavender or odourlesscognitive parameters.[25] The trials divide equallyenvirons and found that jasmine had a positive andbetween inhalation or dermal application, with alavender a negative effect on memory test perform-duration of up to 4 weeks. What is remarkable, givenance. Since subjects were not aware of odour, it wasthe diversity of trial design and type of aromather-concluded that the effects were implicit. Similarly,apy, is that all treatments have resulted in significantLudvigson and Rottman[32] previously noted adversebenefit. The benefits include reductions in agitation,effects of lavender on arithmetic reasoning. In ainsomnia, wandering, difficult behaviour and socialcontrolled trial of the effects of rosemary and laven-withdrawal.der essential oils on cognition and mood in 144In a more recently published open-label trial, tenhealthy volunteers, Moss et al.[33] reported signifi-patients with dementia were treated for 6 monthscant enhancement of memory with rosemary, decre-with a range of essential oils (vaporised mixtures ofments with lavender, but significant increases inorange, ylang ylang, patchouli, basil, rosemary, pep-contentment with both oils. In contrast, Motomura etpermint, rosewood, geranium, bergamot, chamomileal.[34] found that lavender increased arousal rate inand jasmine). A marked decrease in disturbed beha-15 stressed healthy adults, indicating that aro-viour was observed in the majority of patients, lead-matherapeutic effects may be state-dependant.ing to reductions in psychotropic medications, with

    overall cost savings.[26] However, Gray and Clair[27] Encouragingly, in all the published trials ofnoted no reduction in combative, resistive aromatherapy in dementia a fragile aged popula-behaviours in 13 elderly people in residential care tion no adverse effects were reported, despite thetreated in an open-label manner with lavender, fact that they were on the outcome measure list. Thesweet orange or tea tree oil vapour (delivered, rather only possible exception to this is the trial by Bowles-

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    Table II. Controlled clinical trials of aromatherapy in patients with severe dementia

    Essential oil Study design Outcome Reference

    Lemon balm (Melissa) and lavender Placebo controlled; six patients received treatment Treatment oils increased functional abilities and 21aroma oils and six control oil; duration 1wk communication, and decreased difficult behaviours

    (no statistical analysis)

    Lavender aroma and massage Randomised, controlled; 21 patients; aromatherapy Aromatherapy with massage significantly reduced 22

    and massage compared with aroma or massage frequency of excessive motor behaviour (p = 0.05 vsalone; duration 2wk massage alone)

    Lavender aroma Placebo controlled; 15 patients; treatment with oil Aromatherapy significantly reduced agitated behaviour 23

    and placebo (water) on alternative days; duration (as assessed using the Pittsburgh Agitation Scale;10d p = 0.016 [one tailed] vs placebo)

    Melissa lotion applied to face and Randomised, controlled; 36 patients received Aromatherapy associated with highly significant 24

    arms Melissa and 36 sunflower oil; duration 4wk reductions in measures on the Cohen Mansfield

    Agitation Inventory and social withdrawal, together with

    an increase in constructive activities (dementia caremapping) [p = 0.01 to p = 0.0001 vs sunflower]

    Lavender, marjoram, patchouli and Placebo controlled; 36 patients; treatment vs Aromatherapy significantly increased MMSE score 25vetivert applied as a cream to body control cream; duration 4wk (>3 points, p = 0.015), but also increased resistanceand limbs to care (considered due to increase in alertness)

    Lavender, geranium and mandarin Open label: 39 patients; treatment over unspecified Aromatherapy increased alertness, contentment and 20

    essential oils in almond oil applied to period; patient, staff and carer interviews/rating sleeping at night, and reduced levels of agitation,

    skina withdrawal and wandering

    a This open-label trial is included here because the patient numbers are substantial and the multiple outcomes were measured.

    MMSE = Mini-Mental State Examination.

  • Aromatherapy for Psychiatric Disorders 263

    Dilys et al.,[25] in which improved cognitive function what essential oils were used or which particularwas associated with increased resistance to care. In symptoms were targeted.this study, the inclusion of oils such as marjoram, Sleep disorders and apathy are common symp-vetivert and patchouli in addition to lavender raises toms in Parkinsons disease and they are not readilythe question of how specific aromatic oils affect treated with orthodox pharmaceuticals without sig-individual cerebral functions. Aromatherapy may, nificant adverse effects. An aromatherapeutic ap-thus, be a much safer option than the use of conven- proach may be worth considering for such symp-tional drugs, such as antipsychotics or SSRIs for toms (see table I for relevant subjective effects ofexample. essential oils). The essential oils discussed in section

    According to the Cochrane Database Review,[35] 2.1 are likely to also be useful in the treatment ofaromatherapy demonstrated benefit for people with dementia and its associated behavioural problemsdementia in the only trial contributing original data that can occur in patients with Parkinsons disease.to this review (Ballard et al.[24]). Methodological

    2.3 Schizophreniaissues were identified highlighting the need for fur-ther large scale, randomised, controlled trials to Hicks[38] reported on the use of aromatherapy asestablish the effectiveness of aromatherapy in this

    an adjunct to care in a mental health day hospital ingroup. The following methodological issues, gener- London, UK. Staff and patients perceived aro-ally applicable to aromatherapy in other psychiatric

    matherapy to be a beneficial aid to sleep and relaxa-disorders, need to be addressed in future trials in tion, and agreed to the provision of one aromather-people with dementia: (i) maintaining blindness in

    apy session a week. The majority of those (n = 20)assessors (it is assumed that this issue is not so

    attending were diagnosed with schizophrenia. Basedrelevant for patients, anosomnia being prevalent in

    on user diaries and the aromatherapists assessment,people with dementia);[36] (ii) selecting the most 70% reported improvements in sleep and 80% ineffective essential oil(s) for symptom management

    well-being and stress management. The session hadand most effective mode of administration; (iii) the lowest drop-out and nonattendance rate of anystandardisation of the essential oil in terms of chem- group activity in the day hospital, and was reportedical composition, relevant bioactivities and dosage; to be subsequently over-subscribed.(iv) administering aromatherapy as an adjunct to What is missing from this report is any referenceor replacement for other medication such as antipsy- to the specific essential oil(s) employed, although itchotic or cholinergic drugs; and (v) inclusion of is likely these varied between individuals accordingphysiological, as well as behavioural, outcome mea- to the aromatherapeutic practice of tailoring applica-sures such as EEG or neuroimaging. tions to individual need and/or preference.

    2.2 Psychiatric Disorders Associated with 2.4 Sleep DisordersParkinsons Disease

    Disrupted sleep patterns, such as insomnia, sleepFerry et al.[37] conducted a survey of 80 cogni- apnoea and excessive daytime sleepiness, accompa-

    tively normal, non-institutionalised patients with ny many psychiatric diseases, and also affect gener-Parkinsons disease. Over half of the patients (54%) al, non-psychiatric populations. In folklore, linenreported using complimentary therapies, and bags were filled with lavender flowers and placedaromatherapy was one of the most commonly used, under the pillow to prevent problems in fallingalthough no information is provided in the report on asleep. The German Commission E monographs[39]

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  • 264 Perry & Perry

    itemises states of unrest and difficulty in falling In a trial involving 122 patients in intensive care,asleep under indications for the use of lavender, massage aromatherapy using lavender essential oilincluding the volatilised oil. was compared with rest. The patients receiving

    aromatherapy reported a statistically significant im-In ten general hospital patients, improved sleepprovement in mood and reduction in anxiety com-quality (including reduced restlessness[40] and in-pared with patients receiving rest.[46] Vaporised or-creased sleep, together with a reduction in the re-ange oil compared to no aroma reduced anxiety inquirement for night sedation[41]) have been reported72 patients undergoing dental procedures.[47] Reduc-in open-label trials of aromatherapy. In one study,[41]tions in anxiety were reported in eight patients witha blend of basil, juniper, lavender and sweet marjo-brain tumour who were using lavender or chamo-ram was applied by hand massage; satisfactory sleepmile aromatherapy.[48] The use of lavenderincreased from 73% to 97% of patient nights, whilearomatherapy (60-minute exposure to vapourisedthe use of sedatives was reduced from 90% to 36%essential oil) was compared with no intervention orof patients nights (the study by Hardy et al.[40] usedhumidified water intervention in 17 patients withlavender alone). In a multiple crossover study of 23cancer in a hospice setting.[49] Applied scales fornon-psychiatric female subjects experiencing sleepanxiety and depression reflected reductions in thedisorders, lavender demonstrated CNS-depressantlavender compared to other sessions, although sta-activity via EEG recordings.[42] In a controlled,tistical analyses were not applied.crossover trial of chamomile (Roman) essential oil

    vapour versus no intervention in 58 elderly hospital- Graham et al.[50] reported that aromatherapy us-ised patients, there was significantly improved sleep ing lavender, bergamot and/or cedar wood oils ap-(fewer awakenings), more so in non-psychiatric than plied as drops on a paper bib had no benefit in apsychiatric (dementia or depression) cases.[43] controlled trial of 313 patients undergoing radio-

    therapy, as assessed using the Hospice Anxiety andAlthough no toxicity has been reported for laven-Depression scale. They noted that other oils or meth-der, it does potentiate the sleep-inducing activity ofods of administration might reduce anxiety.some other agents, such as alcohol, chloral hydrateWiebe[51] reported that inhalation of the essentialand hexobarbital.[44]oils vetivert, bergamot and geranium had no signifi-cant effect compared with placebo in reducing anxi-2.5 Anxietyety in 66 women awaiting surgical abortions. Cook

    In the only reported study (open label) of the use and Ernst,[52] in a meta-analysis of six randomised,of aromatherapy in patients with a primary diagnosis controlled trials of aromatherapy on anxiety or well-of anxiety and depression, Edge[45] reported that being in patients with cancer who were undergoingaromatherapy (individualised with respect to the cardiac surgery or in intensive care, concluded thatessential oils) reduced anxiety and improved mood aromatherapy massage has a small transient effectaccording to visual analogue rating scales in the on reducing anxiety immediately after administra-majority of patients when used over an 8-month tion.period.[45]

    Apart from the study by Edge,[45] there have been 2.6 Depressionno clinical trials of aromatherapy in psychiatric pa-tients with anxiety disorders published; however, a Many essential oils are associated with an im-number of studies in patients with other types of provement in mood (table I) indicative of potentialanxiety have been published. application for the treatment of depression. Anecdo-

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  • Aromatherapy for Psychiatric Disorders 265

    tal effects are intriguing; for example, Buckle[17] In patients with severe learning disability, nobenefit of lavender, lemongrass and orange flowerdescribes the following case:was reported by Lindsay et al.[58]

    Mrs H was an 85 year old woman with depres-Buckle[59] reviewed anecdotal evidence indicat-sion. Many of her friends were dead and she lived in

    ing that aromatherapy may be of value in the treat-a nursing home a long way from her family who didment of chronic pain.not visit her often. She did not sleep well and was

    Other unexplored clinical psychiatric applica-prone to hyperventilation and palpitations. Shetions of aromatherapy include: addiction; autismloved the smell of roses, which reminded her of aand other developmental disorders; bipolar affectiverose garden she had when her husband was alive.disorder; and, to judge by subjective effects of manyTwo drops of rose were inhaled on a facial tissueessential oils (table I), sexual disorders.four times a day. Within 1 week she was smiling,

    sleeping better, and discussing how she could be-come involved with looking after the houseplants in 3. Safety, Adverse Effectsthe facility. and Contraindications

    In 22 healthy adults exposed to chamomile oil orplacebo, chamomile significantly improved visual In the context of the modern clinical litigiousprocessing and subjective mood ratings.[53] In a pi- environment, one of the foremost concerns in thelot, controlled, randomised trial, the effect of citrus application of aromatherapy to clinical practice isfragrance was compared with no fragrance (n = 12 the issue of safety, particularly in view of the wide-

    spread availability of essential oils in health foodand 8, respectively) in men with depression. Thestores and other commercial outlets. The productsdose of antidepressant drugs was significantly re-are not licensed, and information on their safety orduced in the active treatment group.[54] Ratings ofchemical standardisation is generally not provided.anxiety were significantly reduced in 14 patientsThus, it is important to consider the use of anundergoing haemodialysis who were exposed to lav-essential oil in conjunction with the advice of aender aroma, compared with no fragrance.[55] In 40professional aromatherapist and with reference tohealthy adults, lavender aromatherapy was associat-standard texts on essential oil safety.ed with greater relaxation and less depressed

    One of the most comprehensive and widely usedmood.[56]texts in aromatherapeutic practice is Essential OilThere is a need for controlled trials of aromather-Safety: A Guide for Health Care Professionals by

    apy in patients with depression.Tisserand and Balacs.[60] This provides vital infor-mation for each essential oil used in aromather-

    2.7 Other Disorders apeutic practice, including hazards (e.g. dermal ormucous membrane irritation; phototoxicity; neuro-

    In 100 patients with intractable epilepsy who toxicity including, for example, convulsant activi-opted for treatment with aromatherapy, one-third ty), contraindications (e.g. pregnancy, breastfeed-were no longer taking conventional anticonvulsants ing, use in children), and toxicity based on relevantand were seizure free at a 2-year follow up.[57] These animal data (including LD50 values, which are usu-results, rather surprisingly, indicate efficacy for ally in the range of 25 g/kg; the clinical dose beingaromatherapy that is similar or superior to synthetic between 10 and 100mg per individual). Such safetydrugs. information from professional aromatherapeutic

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  • 266 Perry & Perry

    practice can be combined with that available from fatal in a child) are associated with hepatotoxicityclinical trials of the individual constituents. ranging from mild elevation of liver function test

    values to acute hepatic encephalopathy[62,63] andThe essential oils selected for common use indoses of 50150 mg/kg have led to status epilepticusaromatherapy are those with the least or no toxicitiesin children.[61] Camphor is often combined in coldor contraindications within the therapeutic range.remedies with eucalyptus oil (Eucalyptus globules),Thus, lavender (L. angustifolia) is considered to bewhich also contains 1,8-cineole (found to correlatethe safest amongst all oils and there are no contrain-with an increase in motor activity following inhala-dications to its use. Other oils without contraindica-tion in mice[64]). This combination has been reportedtions include basil, chamomile, clary sage, corian-to cause ataxia, slurred speech unconsciousness andder, frankincense, geranium, lemon, melissa, marjo-convulsions in high doses.[65] Myristicin andram, napeta, neroli, patchouli, tea tree, thyme andelemicin, two ethers found in nutmeg oil, are alsovetiver.[1]neurotoxic at doses suggested to be psychotropic.[2]Although there are very few reported contraindi-

    Individual sensitivity/allergic reactions may oc-cations to the aromatherapeutic use of many widelycur with any topically applied substance. In addi-used essential oils, some metabolic products of cer-tion, due to their high concentration, skin irritating,tain essential oil constituents have been reported tosensitising and allergic reactions can occur withbe more harmful than their parent constituents. Forrepeated exposure to certain essential oils that con-example, the ether safrole (and other phenyl methyltain specific constituents, such as certain phenolethers) has been found to lower the levels of gluta-(e.g. thymol in Thymus vulgaris), aldehyde (e.g.thione (a compound that removes free radicals andneral in Citrus limonene), monoterpene (e.g. alpha-other toxic substances) in the liver. Tisserand andpinene in Eucalyptus globules), lactone (occurringBalacs[2] caution against using essential oils contain-in small amounts in a few essential oils, e.g. ses-ing glutathione-depleting molecules in patients tak-quiterpenoid lactones present in chrysanthe-ing paracetamol (acetaminophen) or other drugs thatmums[66]) or ester (e.g. linalyl acetate in L. angus-many contain acetaminophen, and in patients withtifolia) compounds.[2] Although there are substantialliver disease. Certain essential oils, for examplereports of the beneficial effects of lavender (L.tansy, pennyroyal, rue, savin, juniper, sage andangustifolia) in the treatment of eczema, for exam-wormwood, are not recommended for use inple, there are conflicting reports on its sensitisingaromatherapy and have been shown to exhibit abor-and irritating effects (see review by Cavanagh andtifacient and/or neurotoxic effects at high doses.[2]Wilkinson[67]).Essential oils containing high quantities of ketones,

    for example thujone and camphor, should not be Essential oils should be treated with the sameused on individuals with epilepsy as these constitu- precautions as any synthetic drug and only usedents have been found to cause epileptiform activity under the advice of a qualified aromatherapist, me-in high doses.[2,60] dicinal herbalist or practicing physician as appropri-

    As with all substances used medicinally, there are ate. Essential oils should not be used undiluted andpotential adverse effects associated with the over- storage directions should be followed. With respectdose of essential oils. Camphor poisoning has been to the source of essential oil, the supplier should bedocumented for more than 100 years[61] and it pro- selected on the basis of the ability to guarantee theduces gastrointestinal and CNS irritation after toxic authenticity and purity of their product, togetheringestion. Large quantities (1g taken orally may be with information on whether the chemical profile of

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  • Aromatherapy for Psychiatric Disorders 267

    any particular plant oil conforms to international sleepiness and catatonia, which are present in manystandards. Information on typical chemical compo- psychiatric disorders.sitions is widely available and includes that outlined

    4.1 Pharmacology of Essential Oils within Tisserand and Balacs,[2] Price and Price[1] andSedative ActivityBowles-Dilys et al.,[25] amongst many other profes-

    sional aromatherapeutic texts. It may be advisable toThe pharmacological profile of lavender (L.have samples of oils for clinical use further tested

    angustifolia), the essential oil that has been the mostchemically, and services providing relevant analyseswidely investigated, provides a model for the phar-such as gas chromatography mass spectrometry aremacological activity of an essential oil and its indi-widely available.vidual constituents. The actions of lavender may beDespite potential adverse effects, it should besignificant in the quest for novel anxiolytic agents

    noted that no adverse effects have been reportedthat lack the dependency issues associated with cur-from the controlled clinical trials of aromatherapy inrent therapies such as benzodiazepines.[57]psychiatric disorders, such as lavender or melissa

    Inhalation of the essential oil of L. angustifoliaused for agitation in dementia (table II). These trials

    has been found to block pentetrazol-, nicotine- andindicate that treatment with these oils compareselectroshock-induced convulsions[79] and exhibit

    extremely favourably with the use of antipsychoticdose-dependent anti-conflict effects in mice similardrugs commonly prescribed for this condition; theseto those of diazepam.[78] Inhalation of L. angustifolia

    conventional drugs have only modest efficacy[68] (and its main constituents linalool and linalyl ace-and are associated with extrapyramidal symptoms

    tate) for 1 hour decreased the motility of normalincluding falls[69] and tardive dyskinesia,[70] seda-mice, and reversed caffeine-induced over-agitationtion[69] and even cognitive decline.[71]in mice.[72,73] This sedative and anxiolytic activitywas directly correlated with blood concentrations

    4. Mechanisms of Action (311 ng/mL of linalool and linalyl acetate).[73,75]However, L. angustifolia extracts exhibited no

    Pharmacological studies, combined with phyto- antidepressant effects in a forced swimming test inchemical analysis, have identified specific rats.[92] Such extracts protected neurons againstneuropharmacological actions for a variety of essen- glutamate toxicity in rat cerebellar granular celltial oils and their individual monoterpenoid (and culture.[81]other essential oil) constituents that relate to clinical The main constituent of lavender, the monoterpe-effects (tables III, IV and V). Individual constituents noid linalool, possessed anticonvulsant properties inreach the blood, cross the blood-brain barrier and glutamate-related seizure models and effects onenter the CNS following inhalation, dermal applica- NMDA receptor binding.[86,88,89] It also inhibitedtion, intraperitoneal or subcutaneous injection, and potassium-stimulated glutamate release and de-oral administration.[64,72-77] creased glutamate uptake in mice cortical

    synaptosomes,[90] and modified the kinetics of theIn vitro and in vivo studies in animals confirmnicotinic receptor ion channel at the mouse neuro-that particular essential oils have anxiolytic, seda-muscular junction.[91]tive and anticonvulsant actions or CNS-stimulant

    effects that are relevant to the respective treatment There is evidence for a distinction between theof symptoms such as anxiety, agitation, sleepless- pharmacology of the enantiomers of linalool. (R)-ness, epilepsy, apathy, lethargy, excessive daytime ()-Linalool (present in lavender oil) produced a

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    Table III. CNS effects of lavender speciesa essential oil and constituents

    Lavender species Main CNS effect In vitro and in vivo pharmacology References[% constituents]Lavandula angustifolia Mill. Anticonflict Dose-dependent (4001600 mg/kg, SC) anti-conflict effects in the Geller conflict test, 78(syn. Lavandula officinalis), with effects similar to diazepamFrench lavender [linalyl Anticonvulsant Inhalation of oil blocked pentetrazol-, nicotine- and electroshock- but not strychnine- 72,79acetate 45%, (R)-()-linalool induced convulsions in mice. A dose of 33mg decreased motility of normal mice and38%, (Z)--cis-ocimene 10%] reversed caffeine-induced over-agitation in mice; serum concentration of linalool

    correlated with effects on motilitySedative/anticonvulsant Increased pentobarbital-induced sleeping time. Sedative effects in certain tests in 80

    mice. Suppressed the population spike amplitude in the CA1 region of rathippocampal slice preparation following application of essential oil (IC50 65 g/mL);effects comparable to the GABAA agonist muscimol (Perry N et al., unpublished data)

    Neuroprotective Extract of flowers protected against glutamate-induced neurotoxicity in rats (100 mg/L) 81Spasmolytic Spasmolytic action on guinea-pig ileum smooth muscle (postsynaptic, not atropine 82

    like)Anaesthetic Concentrations of 0.0110 g/mL produced dose-dependent local anaesthetic activity 83,84

    in the rabbit conjunctival reflex test. Restorative effects on stress-inducedimmunosuppression

    Lavandula Anticonvulsant/sedative 600 mg/kg (aqueous-methanolic) extract of flowers reduced severity and increased 85stoechas L. latency of pentylenetetrazole-induced convulsions; prolonged pentobarbital-induced

    sleeping time in mice, with effects similar to diazepamLavandula vera D.C. Anticonvulsant Prevented metrazol-induced convulsions (200300 mg/kg, IP) in 6070% of mice and 44

    rats. 108164 mg/kg (IP) inhibited electroshock-induced convulsions in ratsSedative 10300 mg/kg potentiated narcotic effects of hexobatbital sodium, alcohol and chloral

    hydrate, and inhibited spontaneous motor activity in miceLinalool [3040%] Anticonvulsant Competitive antagonism of [3H]-glutamate and non-competitive antagonism of [3H]- 86-90

    dizocilpine (NMDA receptor antagonist) binding in rat cortical membranes. Evidencethat optically active linalools may have different CNS effects. Delayed NMDA-inducedconvulsions and blocked QUIN-induced convulsions; partial inhibition and significantdelay of behavioural expression of pentylenetetrazole-induced kindling in mice.Protection against pentylenetetrazol- and picrotoxin-induced convulsions and non-competitive inhibition of [3H]-dizocilpine binding (IC50 2.97 mmol/L) but no effect on[3H]-muscimol binding in mice. Significantly inhibited (at concentrations of 1 and 3mmol/L) potassium-stimulated [3H]-glutamate release and decreased its uptake inmice cortical synaptosomes

    Sedative Inhalation (of 27mg) decreased motility of normal mice and reversed caffeine-induced 72,73over-agitation in mice

    Anaesthetic Modified the kinetics of the nicotinic receptor ion channel at the mouse neuromuscular 86,91junction. Inhibited basal adenylate cyclase activity

    Linalyl acetate [1020%] Sedative Inhalation of 23mg caused a particular decrease in motility in normal mice and 72,73,92reversed caffeine-induced over-agitation in mice. No antidepressant effects in forcedswimming test in rats

    a The main lavender species used in aromatherapy is Lavandula angustifolia, although other species include L. latifolia, L. stoechas and L. x intermedia. These species donot have the same phytochemistry and may have differing biological activities.[67]

    IC50 = concentration that inhibited the effect by 50%; IP = intraperitoneal; QUIN = quinolinic acid; SC = subcutaneous.

  • Aromatherapy for Psychiatric Disorders 269

    decrease in beta wave activity (~13Hz) following 1,8-cineole (the major constituent of this oil).[64] 1,inhalation in healthy 20- to 26-year-old subjects that 8-Cineole has been shown to increase global cere-was similar to that of (RS)-()-linalool. However, bral blood flow after 20 minutes inhalation in human(S)-(+)-linalool had no effect on this parameter.[131] subjects; interestingly, and importantly in relation to

    physiological versus psychological mechanisms, theAvailable data suggest that the anticonvulsantsame effects were seen in an anosmic subject.[133]and CNS depressant effects of L. angustifolia and itsFurthermore, Kagawa et al.[98] showed that the ses-main constituent linalool (and its acetate) are likelyquiterpenoid cedrol (a component of pine essentialto occur via modulation of components of the gluta-oils) had sedative effects in normal and anosmicmatergic system (i.e. NMDA receptor subtype), al-(zinc sulphate treated) rats (table IV). This substan-though more direct cellular mechanisms such astiates the view that the effects of certain inhaledinhibition of adenylate cyclase (affecting cyclicessential oil constituents are independent of olfacto-adenosine monophosphate second messenger activi-ry function.[98] However, some essential oils mayty) and ion channel activity (affecting neurotrans-not affect those who are olfactory deprived, since amitter release) may also be relevant to clinical ef-chamomile and lavender oil mix reduced pentobar-fects.[82,86,90,91] Such physiological mechanisms arebital-induced sleep time in normal but not anosmicconsistent with the extensive use of lavender as amice and rats.[98]sedative/CNS depressant and anti-anxiety agent in

    aromatherapy and herbal medicine (for reviews see The effects of essential oils with stimulant activi-Cavanagh and Wilkinson,[67] Buchbauer et al.[73] and ty may occur through the modulation (antagonism)Kirk-Smith[132]). of GABAA receptor activity,[134] cholinergic (nico-

    tinic and muscarinic) receptors[110] or transmitter-Several essential oils have anxiolytic and seda-related enzymes (acetylcholinesterase, adenylatetive actions; the pharmacological action(s) of spe-cyclase).[124,127] Such stimulant effects may be rele-cies such as melissa (M. officinalis) and neroli (Cit-vant to the treatment of memory disorders and apa-rus aurantium), which are used in aromatherapythy common to a variety of psychiatric disordersmassage and inhalation for this purpose, are listed in(e.g. Parkinsons disease, frontotemporal dementia,table IV.progressive supranuclear palsy and catatonic schizo-phrenia).4.2 Pharmacology of Essential Oils with

    Stimulant Activity4.3 Pharmacokinetics

    Some essential oils are traditionally used as stim- and Pharmacodynamicsulants, although there are fewer of these than seda-tive oils (table V). Essential oils with stimulant From the data available, blood concentrations ofproperties include rosemary (Rosmarinus officinal- essential oil constituents following inhalation or oralis), sage (Salvia sp.) and jasmine (Jasminum administration are generally in the nL/mL bloodgrandiflora). Data (mainly from studies on locomo- range (tables III, IV and V). The therapeutic effectstor activity in animals) indicate that these oils have of oral versus inhalation/dermal application maypharmacological activity consistent with their thera- differ, since metabolism of the constituents maypeutic application (table I and table V). For exam- occur at differing rates before circulation in theple, inhalation and oral administration of rosemary body. An unexplored aspect of naturally occurringoil stimulated locomotor activity in mice and this terpenoids is the significance of their metabolites inwas correlated with blood concentrations of relation to neuropharmacological mechanisms and

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    Table IV. The main essential oils used in aromatherapy and their constituents that show pharmacological sedative activities

    Essential oil, common name if Main CNS effect In vitro effects and in vivo pharmacology Referencesknown (family) [mainconstituentsa]/constituent withactivity [essential oil/s found in]Acorus gramineus, Solander Anticonvulsant, Inhibited the binding of an NMDA receptor-ion channel blocker [3H]-dizocilpine, but 94,95(Araceae) [- and -asarone] neuroprotective, not a ligand selective for the glycine binding site. Rhizome essential oil 0.3 mg/mL

    sedative inhibited glutamate- (but not AMPA-) induced excitotoxicity in primary cultured ratcortical neurons. Rhizome essential oil inhalation in mice delayed appearance ofpentylenetetrazole-induced convulsions, prolonged pentobarbital-induced sleeping timeand inhibited activity of GABA transaminase

    Artemisia annua L. Sedative 470 mg/kg (IP) produced CNS depressant activity in rats 96(Asteraceae) [camphor 22.7%,1,8-cineole 20.4%, p-cymeme12.2%]Benzyl alcohol [in e.g. Tilia CNS depressant Decreased motility of mice following inhalation. Inhalation of its acetate produced no 72,97cordata] effect on pentobarbital-induced sleeping time in miceCedrol [in cypresses and Sedative Decreased spontaneous motor activity in normal, caffeine-treated and hypertensive rats 98pines, e.g. Juniperus and mice, and prolonged pentobarbital-induced sleeping time in normal and anosmicvirginiana L.] rats (408 g/mL in air 1.0 L/min)1,8-Cineole [in e.g. Sedative 30 mg/kg (IP) decreased motor activity in mice 99Rosmarinus officinalis]Citral [in e.g. Melissa Sedative, Increased duration of barbiturate-induced sleeping time and had motor relaxant effects 92,100officinalis] antidepressant (100200 mg/kg IP) in rats. 0.1 mL/h significantly reduced total immobility time and

    potentiated the imipramine-induced reduction of total immobility time in a forcedswimming test in rats

    Citronellol [in e.g. Rosa Anticonflict 400800 mg/kg (IP) possessed anticonflict effect similar to diazepam in Geller and 101,102centifolia] Vogel tests in miceCitrus aurantium L., neroli Anticonvulsant, 0.5 g/kg peel essential oil increased latency period of tonic seizures in 103(Rutaceae) [linalool 37.5%, anxiolytic, sedative pentylenetetrazole- and electroshock-induced convulsions in mice and 1 g/kg increasedlimonene 16.6%, -pinene the sleeping time induced by pentobarbital. Anxiolytic effect in the elevated plus maze11.8%] test. Inhalation of Subsp. aurantium reduced motility of mice by 65%. Inhalation

    decreased motility of normal but not caffeine-injected miceCitrus bergamia Risso, CNS depressant 1040 mg/kg (IP) nonvolatile extract of essential oil reduced spontaneous activity, 104bergamot (Rutaceae) potentiated sodium pentobarbital-induced sleeping time and protected against[limonene 38%, linalyl acetate pentylenetetrazole-induced convulsions in mice28%, linalool 8%]Eugenia caryophyllata, clove Anticonvulsant 0.0500.1 mL/kg (IP) suppressed tonic electroshock-induced convulsions and mortality 105(Myrtaceae) [eugenol 77%, - in micecaryophyllene 10%]Laurus nobilis Linn. Anticonvulsant, Protected mice against electroshock- and pentylenetetrazole-induced convulsions and 106(Lauraceae) [cineol, eugenol, sedative at 0.751 mL/kg (IP) produced sedation and motor impairment in mice, though LD50sabinene, 4-terpineol] value was 1.45 (1.221.71) mL/kg

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    Table IV. ContdEssential oil, common name if Main CNS effect In vitro effects and in vivo pharmacology Referencesknown (family) [mainconstituentsa]/constituent withactivity [essential oil/s found in]Lavandula species See table III See table III See table IIId-Limonene [in e.g. C. Sedative 50200 mg/kg (IP) increased duration of barbiturate-induced sleeping time and had 100bergamia] motor relaxant effectsMatricaria chamomilla L., Anxiolytic Inhalation decreased restriction stress-induced increases in plasma ACTH level in 107Roman chamomile normal and ovariectomised rats in the same manner as diazepam. Effect was blocked(Asteraceae) [see below] by pretreatment with the benzodiazepine receptor antagonist flumazenil. 200800

    mg/kg (SC) exhibited no anticonflict effects in the Vogel or Geller conflict tests in miceMatricaria recutita L., German Anticonvulsant Extracts of chamomile reduced the latency in the onset of picrotoxin-induced 108,109chamomile (Asteraceae) convulsions and decreased mortality rate. Flavonoids present in herb (e.g. apigenin)[farnesene 27%, chamazulene demonstrated a low affinity for the benzodiazepine receptor, with no effects at17%, ()--bisabolol 14%, muscarinic or 1-adrenergic receptors, or the GABA binding site of the GABAA channel()--bisabololoxides A and B11%]Melissa officinalis, lemon balm CNS depressant, Suppression of the population spike amplitude in the CA1 region of rat hippocampal 110-115(Labiatae) [geranial 31.9%, anticonflict, slice preparation following application of essential oil (IC50 128 g/mL), comparable toneral 22.3%, -caryophyllene analgesic, sedative, the GABAA agonist muscimol. 3100 L/kg did not influence behavioural parameters in9.7] cholinergic, the staircase test in mice and inhalation produced no effect on the motility of mice.

    antioxidative 12800 mg/kg extract decreased behavioural parameters measured in a non-familiarenvironment test (staircase test) and familiar environment test (two compartment test).4001600 mg/kg extract produced peripheral analgesia by reducing acetic acid-inducedpain; 36 mg/kg extract (and not 100 L/kg essential oil) induced sleep in mice aftertreatment with an infrahypnotic dose of pentobarbital; 6 and 50 mg/kg potentialisedsleep induced by pentobarbital. 25 and 50 mg/kg extract produced sedative andhypnotic effects and potentiated barbiturate-induced sleep time. Extracts (ethanolic)displaced [3H]-(N)-nicotine and [3H]-(N)-scopolamine in receptor binding studies usinghuman cerebral cortical cell membranes. Leaves contain compounds with 10-foldgreater radical scavenging ability than ascorbic acid and -tocopherol (Perry N et al.,unpublished data)

    Mentha rotundifolia, L. mint Sedative CNS depressant effect (100400 mg/kg) in spontaneous activity and curiosity test, 116(Labiatae) [rotundifolone potentiation of pentobarbital-induced sleep (50 mg/kg) in mice and rats10.4%, piperitol 57.6%],Mentha longifolia, mint(Labiatae) [rotundifolone33.2%, diosphenol 47.7%]Menthone Sedative 30 mg/kg (IP) decreased motor activity in mice 99[in e.g. Calamintha sylvatica]Passiflora incarnate L., Sedative Decreased motility of caffeine-induced over-agitated mice but not normal mice following 73passiflora (Passifloraceae) inhalation[matol, 2-phenylethanol]

    Continued next page

  • 272 Perry & Perry

    to psychological and clinical psychiatric effects. Inaddition, chiral differences influence the pharma-cokinetic behaviour, as well as affecting the biologi-cal activity, of constituents.[10,64,131,135,136]

    The pharmacokinetic profile of monoterpeniodsso far studied indicate a two-phase elimination rapid and slow rate with accumulation in adiposetissue.[64,73,137] The cytochrome P450 enzymesmetabolise certain essential oil constituents by addi-tion of a sulphate or glucuronate group (e.g. linaloolshows part conjugation to glucuronic acid) and,thus, some contraindications associated withhepatotoxicity are evident (see section 3).

    5. Conclusions and Challenges

    The essential oils with reputed sedative actionssuch as lavender, lemon balm and neroli have phar-macological actions consistent with reducing CNSactivity (tables III and IV) and, likewise, those witha stimulant reputation, for example rosemary, sageand jasmine, have comparable CNS stimulant-likein vitro and in vivo activities (table V). Thus, thereare no apparent contradictions between the anecdo-tal and scientific literature, or clinical effects andpharmacological profiles. There is, however, a needto establish a phytochemical and pharmacologicalprofile (database) of specific putative clinical essen-tial oil agents in order to establish phytochemicalstandardisation, mechanism of action and anyclinical contraindications.

    Relevant psychoaromatherapeutic effects of es-sential oils so far studied occur through a directaction of chemical constituents on: CNS receptors,including cholinergic,[110,138] GABAergic[128,134] andglutamatergic subtypes;[88,89,94] ion channels, includ-ing potassium and calcium;[85,90,91,124,139,140] and en-zymes, for example adenylate cyclase andacetylcholinesterase.[13,76,84,86,126,127,141-145] However,to date, all of the pharmacological studies of terpe-noids have involved established bioassays generallybased on receptor targets of established neurotrans-

    2006 Adis Data Information BV. All rights reserved. CNS Drugs 2006; 20 (4)

    Tabl

    e IV

    . Con

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    cetat

    ese

    dativ

    era

    t sci

    atic

    ner

    ve, s

    ugge

    sted

    to b

    e cl

    inica

    lly r

    elev

    ant (

    i.e. c

    once

    ntrati

    on re

    ache

    d in

    derm

    al ti

    ssue

    s du

    ring

    mas

    sage

    s wi

    th e

    ssen

    tial o

    ils).

    Inhala

    tion i

    ncrea

    sed p

    entob

    arbita

    l-in

    duce

    d sle

    ep ti

    me

    in m

    icea

    Take

    n fro

    m th

    e in

    divid

    ual r

    efer

    ence

    s de

    taile

    d or

    from

    Bow

    les.

    [93] T

    he p

    rincip

    al c

    hem

    ical c

    onst

    ituen

    ts a

    re li

    sted

    in o

    rder

    of c

    once

    ntra

    tion,

    hig

    hest

    firs

    t; no

    te th

    at p

    ropo

    rtion

    sm

    ay

    vary

    acc

    ordi

    ng to

    sou

    rce

    and

    that

    man

    y oi

    ls co

    ntai

    n hu

    ndre

    ds o

    f ter

    peno

    ids.

    ACT

    H =

    adr

    enoc

    ortic

    otro

    pic

    horm

    one;

    IC50

    =

    co

    nce

    ntra

    tion

    that

    cau

    sed

    50%

    inhi

    bitio

    n; IP

    =

    in

    trape

    riton

    eal;

    LD50

    =

    do

    se le

    thal

    to 5

    0% o

    f ani

    mal

    s; S

    C =

    su

    bcut

    aneo

    us.

  • Arom

    atherapy for Psychiatric Disord

    ers273

    2006 A

    dis D

    ata

    Info

    rma

    tion

    BV. A

    ll righ

    ts rese

    rved

    .C

    NS D

    rug

    s 2006; 20 (4)

    Table V. The main essential oils used in aromatherapy that show pharmacological stimulant activities

    Essential oil, common name Main effect In vitro and in vivo pharmacology References(family) [main chemicalconstituentsa]/singleconstituents (% in oil)Citrus limonum, lemon Antidepressant, stimulant, 0.1 mL/h vapour reduced total immobility time and potentiated the imipramine- 92,117,118,121-123(Rutaceae) [citral, geranyl neuroimmunomodulatory induced reduction of total immobility time in a forced swimming test in rats.acetate] Shortened pentobarbital-induced sleep time in normal but not anosmic (via zinc

    sulphate) mice. Long-term inhalation of lemon fragrance in mice inducedsuppression of plaque-forming cells in blood (immune response) induced by high-pressure stress. Inhalation modulated the behavioural and neuronal (acetylcholinerelease) responses related to nociception and pain differently in male and femalerats. Restorative effects on stress-induced immunosuppression in mice

    Isoborneol and isoeugenol Stimulant in normal, Inhalation increased locomotor activity of mice under normal conditions, though 73anxiolytic in stressed decreased it in over-agitated mice pretreated with caffeine

    Jasminum grandiflora L., Stimulant, spasmolytic Stimulant on inhalation in animals and humans. Shortened pentobarbital-induced 7,8,10,78,97,117,124Jasmine [benzyl acetate sleep time in normal but not anosmic mice. 200800 mg/kg (IP) exhibited no22%, benzyl benzoate anticonflict effect using the Geller-type conflict test in mice or antidepressant14.5%, phytyl acetate effects in forced swimming test in rats. Spasmolytic activity on guinea-pig ileum10.2%) and rat uterus, suggested mediation via (rise in) cAMPMentha piperita L., 400 and 800 mg/kg (IP and IV) increased ambulatory activity of mice. Note other 116,125peppermint (Labiatae) Mentha species with distinct photochemistry (e.g. Mentha longifolia) may have[menthol 43%, menthone CNS depressant activity (table IV)19%)Rosmarinus officinalis L., Stimulatory Increase in locomotor activity observed after inhalation and oral administration. 64,108,126rosemary (Labiatae) Following 0.5mL rosemary oil per cage for 1 hour, the concentration of 1,8-cineole[-pinene 22%, camphor in the blood was 11.15 nL/mL (approaching that in the breathing air, 13.65 nL/mL).17%, 1,8-cineole 17%] Inhalation and oral administration produced dose-related increase in blood levels of

    1,8-cineole. There was rapid elimination after 10 min (t1/2 6 min) and slowerelimination after 45 min. Extracts delayed the onset of picrotoxin-induced seizuresand decreased the mortality rate in mice

    Salvia officinalis L., French Cholinergic, stimulatory, 0.1 mg/mL and certain constituent monoterpenoids inhibited erythrocyte 29,76,110,127sage (Labiatae) [-thujone GABAergic, antioxidant acetylcholinesterase. Extracts (ethanolic) of certain Salvia sp. displaced [3H]-(N)-37%, -thujone 14%, nicotine and [3H]-(N)-scopolamine in receptor binding studies using humancamphor 12%, 1,8-cineole cerebral cortical cell membranes. 0.07 mg/mL initially increased population spike12%] amplitude and within minutes caused epileptiform activity, followed by suppression

    in population spike amplitude in the CA1 region of rat hippocampal slicepreparation. -Thujone (neurotoxic in high doses) is believed to modulate GABAAreceptor. Plant diterpenes (e.g. carnosol and carnosic acid) inhibited TBPS bindingto the chloride channel of the GABA receptor complex, but not muscimol ordiazepam binding in rat brain membranes. Monoterpenoids, extracts and phenoliccomponents exhibited antioxidant activity on lipid peroxidation (Perry N et al.,unpublished data)

    Continued next page

  • 274 Perry & Perry

    mitters, which are almost all amines or nitrogen-containing. Terpenoids, in contrast, generally beinghydrocarbons, may interact with the CNS in as yetundiscovered ways, raising the exciting prospect ofuncovering novel receptors, molecular targets orendogenous chemical signals in the CNS. This par-allels the discovery of the endogenous cannabinoidsand their receptors, which were identified originallybased on the interaction of plant-based terpenoidsfrom Cannabis sativa with CNS receptors.

    Some of the challenges for further research thatcan presently be identified are summarised in tableVI. As well as considering potential contraindica-tions and/or adverse effects of certain essential oils(including skin sensitivities and toxicities and abor-tifacient effects), in the event that clinical efficacy isestablished for particular oils and this efficacy isattributable to specific terpenoids, the question thenarises as to whether future treatment should involvethe use of single chemical constituents or combina-tions of these. This would satisfy those that seeksimple, standardised formulations as medicines butmost probably not the vast majority of aromather-apeutic practitioners who believe in the value of thewhole essential oil.

    The linking of subjective or objective be-havioural evaluations to potential objective assess-ments, such as neuroimaging or EEG, when assess-ing essential oils would help establish aromatherapyin clinical practice. Several studies have reportedresults from such assessments. In healthy individu-als, 810Hz EEG reductions in parietal and tempo-ral regions were reported after lavender oil inhala-tion, associated with subjective ratings of feelingcomfortable.[146] In 15 healthy adults exposed tolavender or single aromatic chemicals (e.g. ethylaceto acetate and camphor), autonomic measuresincluding skin potential and respiratory and heartrates altered in conjunction with hedonic effects.[147]Other potential physiological measures that are af-fected by lavender include auditory reaction time

    2006 Adis Data Information BV. All rights reserved. CNS Drugs 2006; 20 (4)

    Tabl

    e V.

    Con

    tdEs

    sent

    ial o

    il, c

    omm

    on n

    ame

    Mai

    n ef

    fect

    In v

    itro

    and

    in v

    ivo

    phar

    mac

    olog

    yR

    efer

    ence

    s(fa

    mily)

    [main

    chem

    ical

    const

    ituen

    tsa]/s

    ingle

    const

    ituen

    ts (%

    in oi

    l)Sa

    lvia

    lava

    ndul

    aefo

    lia Va

    hl.,

    Neu

    roch

    emic

    al/p

    utat

    iveEs

    sent

    ial o

    il (IC

    50 0.

    03 m

    g/m

    L) an

    d cert

    ain co

    nstitu

    ent m

    onote

    rpeno

    ids in

    hibite

    d28

    ,29,

    76,1

    27Sp

    anish

    sag

    e (La

    biatae

    )m

    em

    ory

    -enh

    ancin

    g,ery

    thro

    cyte

    ace

    tylch

    olin

    este

    rase

    . 20

    and

    50L

    ess

    entia

    l oil

    inhi

    bite

    d ra

    t stri

    atal

    and

    [camp

    hor 2

    2%, 1

    ,8-cin

    eole

    stim

    ulat

    ory,

    ant

    ioxid

    ant,

    hipp

    ocam

    pal a

    cety

    lchol

    ines

    tera

    se fo

    llowi

    ng o

    ral a

    dmin

    istra

    tion.

    0.0

    7 m

    g/m

    L21

    %, b

    orne

    ol 1

    3%,

    anti-

    infla

    mm

    ator

    yin

    crea

    sed

    popu

    latio

    n sp

    ike a

    mpl

    itude

    with

    no

    epile

    ptifo

    rm a

    ctivi

    ty in

    the

    CA1

    regi

    on

    -th

    ujone

    1%]

    of r

    at h

    ippo

    cam

    pal s

    lice

    prep

    arat

    ion.

    Ess

    entia

    l oil

    and

    certa

    in m

    onot

    erpe

    noid

    const

    ituen

    ts e

    xhib

    it in

    vitr

    o antio

    xida

    nt a

    nd a

    nti-i

    nfla

    mm

    ator

    y ac

    tivity

    (Perr

    y N et

    al.,

    unp

    ublis

    hed

    data

    )Ta

    gete

    s m

    inut

    a L.

    ,An

    xiog

    enic

    45

    g/m

    L in

    hibi

    ted

    bind

    ing

    of th

    e be

    nzod

    iaze

    pine

    [3H

    ]-flun

    itraze

    pam

    to rat

    and

    128-

    130

    chi

    nchi

    lla (A

    sterac

    eae)

    chic

    k br

    ain

    mem

    bran

    es. 0

    .3 m

    g/kg

    (SC)

    disp

    layed

    anxio

    genic

    and a

    ntide

    press

    ant-

    [c-oci

    men

    e, t-

    oci

    men

    e,lik

    e ef

    fect

    s in

    rats

    in e

    leva

    ted

    plus

    maz

    e an

    d fo

    rced

    swi

    mm

    ing

    test

    s. 0

    .04

    0.45

    dihy

    drot

    aget

    one]

    mg/

    kg e

    xhib

    ited

    anxio

    geni

    c ef

    fect

    s on

    chi

    ck b

    ehav

    iour

    in T

    -maz

    e an

    d to

    nic

    imm

    obilit

    y te

    sts

    Thym

    olSt

    imul

    ant i

    n no

    rmal

    ,In

    hala

    tion

    incr

    ease

    d lo

    com

    otor

    act

    ivity

    of m

    ice u

    nder

    nor

    mal

    con

    ditio

    ns, t

    houg

    h73

    anxi

    olyt

    ic in

    stre

    ssed

    decr

    ease

    d it

    in o

    ver-a

    gita

    ted

    mice

    pre

    treat

    ed w

    ith c

    affe

    ine

    aTa

    ken

    from

    the

    indi

    vidua

    l ref

    eren

    ces

    or fr

    om B

    oele

    ns B

    ACIS

    ESO

    dat

    abas

    e;[6]

    pr

    incip

    al c

    hem

    ical c

    onst

    ituen

    ts li

    sted

    in o

    rder

    of c

    once

    ntra

    tion,

    hig

    hest

    firs

    t; no

    te th

    atpr

    opor

    tions

    may

    var

    y ac

    cord

    ing

    to s

    ourc

    e an

    d th

    at m

    any

    oils

    cont

    ain

    hund

    reds

    of t

    erpe

    noid

    s.cA

    MP

    = cy

    clic

    aden

    osin

    e m

    onop

    hosp

    hate

    ; IC 5

    0 =

    co

    nce

    ntra

    tion

    that

    cau

    sed

    50%

    inhi

    bitio

    n; IP

    =

    in

    trape

    riton

    eal;

    IV =

    in

    trave

    nous

    ; SC

    = su

    bcut

    aneo

    us; t

    1 /2 =

    e

    limin

    atio

    n ha

    lf-life

    ;TB

    PS =

    t-b

    utylb

    icyclo

    phos

    phor

    othi

    onat

    e.

  • Aromatherapy for Psychiatric Disorders 275

    Table VI. Challenges for further research into the use of aromatherapeutic agents for psychiatric disordersClinical trials Conducting suitably powered, controlled trials, fulfilling the rigid criteria for blinded, randomised, controlled

    trials, or developing other criteria for establishing clinical efficacySelection and Selecting appropriate aromatic oil(s), based on relevant bioactivities and chemical composition as well asstandardisation of oils traditional use, together with standardisation of commercial preparations, application procedure and dose

    deliveryChemical constituents Establishing the active constituent(s) in order to understand the pharmacology, toxicology and interactions

    that may occur between constituentsAnosmic issues Identifying and separating the psychological and pharmacological effects and relevance to anosmic

    patientsAdverse reactions, Developing awareness of which essential oils do or no not have contraindications, potential interactionsinteractions and with other medications, and individual dermal or other adverse reactionscontraindicationsIndividuality Aromatherapeutic practice tailors the application to the individual as opposed to standardised symptomatic

    treatment; this poses obvious challengesAcceptance Bridging the gap between preferences and practices between nursing and medical practitioners;

    accumulating scientific evidence, clinical trial data and relevant pharmacology to enable, e.g. generalpractitioners, to consider prescribing the use of specific essential oils as an adjunct to conventionalmedicine in psychiatric disorders; availability of standardised aromaceuticals with information on clinicaland pharmacological effects; including such information in medical student education; acceptance ofcomplex, synergistic effects of a therapeutic agent

    Research support Identifying research support the absence of economic incentives for the pharmaceutical industry and theinsufficient resources of commercial suppliers of essential oils indicate the need for government andcharity support

    and critical flicker fusion frequency.[146] Preliminary Since aromatherapy, like any pharmacotherapy,evaluations to select the most appropriate aromatic potentially affects all systems, the indirect effects ofoil for individual symptoms could, thus, include essential oil therapy on cerebral function, such asstandardised physiological and perhaps also psycho- those on the cardiovascular system and autonomiclogical assessment measures. function, may need to be considered. Heuberger et

    al.[10] reported that inhalation of (+)-limonene in-One of the major challenges in conducting con-creased systolic blood pressure, together with sub-trolled trials of aromatherapy is the issue of individ- jective alertness and restlessness, whereas ()-limo-

    uality, not only in terms of treatment response butnene had only effects on blood pressure (also inci-also the selection of the essential oil on the basis ofdentally indicating that molecular chirality issubjective preference and context. Sugawara etrelevant in terms of mechanisms). Similar peripheralal.[87] evaluated the perception of a range of oilschanges affected by lavender inhalation were noted(ylang ylang, orange, geranium, cypress, bergamot,in healthy volunteers who liked, as opposed to didspearmint and juniper) in 24 healthy young adults,not like, the fragrance.[148] Nagai et al.[149] observedbased on a range of responses including soothing,that odours of choice, including rose, jasmine or

    pleasant and comfortable, while performing dif-lavender, reduced an increase in diastolic bloodferent types of work. They reported various results,pressure induced by exercise in healthy adults, andincluding that juniper was found to be more favour-Komori et al.[54] showed that citrus odours restoredable during mental work, whereas geranium andstress-induced immunosuppression.orange were unfavourable under this condition. This

    and other reports[84,131] raise the issue of whether Thus, it may not be possible to fully assess thesuch subjective sensory tests should be incorporated clinical value of aromatherapy in psychiatry withoutinto preliminary clinical trials of essential oils. taking into account the additional pharmacology of

    2006 Adis Data Information BV. All rights reserved. CNS Drugs 2006; 20 (4)

  • 276 Perry & Perry

    interest that are directly relevant to the contents of thisessential oils that contributes to general physicalreview.well-being. Essential oil constituents that penetrate

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    Perry was supported by the Newcastle Medicinal Research 20. Kilstoff K, Chenoweth L. New approaches to health and well-Centre and Dr Elaine Perry was supported by the Medical being for dementia day-care clients, family carers and day-care

    staff. Int J Nurs Pract 1998; 4: 70-83Research Council. The authors have no potential conflicts of

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