Hindawi

Evidence-Based Complementary and Alternative Medicine

Volume 2017, Article ID 9416305, 8 pages
https://doi.org/10.1155/2017/9416305

Review Article
Aromatherapy and Aromatic Plants for the Treatment of
Behavioural and Psychological Symptoms of Dementia in
Patients with Alzheimer’s Disease: Clinical Evidence and
Possible Mechanisms

Damiana Scuteri,1 Luigi Antonio Morrone,1 Laura Rombolà,1

Pina Rosa Avato,2 Anna Rita Bilia,3 Maria Tiziana Corasaniti,4
Shinobu Sakurada,5 Tsukasa Sakurada,6 and Giacinto Bagetta1
1
Department of Pharmacy, Health Science and Nutrition, University of Calabria, 87036 Rende, Italy
2
Department of Pharmacy and Drug Science, University of Bari “Aldo Moro”, 70125 Bari, Italy
3
Department of Chemistry, University of Florence, Sesto Fiorentino, 50019 Florence, Italy
4
Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy
5
First Department of Pharmacology, Daiichi College of Pharmaceutical Sciences, Fukuoka, Japan
6
Department of Physiology and Anatomy, Tohoku Pharmaceutical University, Sendai, Japan

Correspondence should be addressed to Giacinto Bagetta; g.bagetta@unical.it

Received 22 January 2017; Accepted 2 March 2017; Published 30 March 2017

Academic Editor: Michele Navarra

Copyright © 2017 Damiana Scuteri et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.

The treatment of agitation and aggression, typical Behavioural and Psychological Symptoms of Dementia (BPSDs) of Alzheimer’s
Disease (AD), is one of the most complicated aspects of handling patients suffering from dementia. Currently, the management of
these symptoms often associated with an increased pain perception, which notably reduces the patients’ quality of life (QoL), relies
on the employment of antipsychotic drugs. Unfortunately, the use of these pharmacological agents has some limits: in the long term,
they do not result in being equally effective as in the first weeks of treatment and they present important side effects. Therefore,
there is growing interest, supported by clinical evidence, in aromatherapy for the control of agitation, aggression, and psychotic
symptoms. Some molecular mechanisms have been proposed to explain the behavioural effects of essential oils, as the whole
phytocomplex or the single components, but important basic research effort is still needed. For this reason, rigorous preclinical
studies are necessary in order to understand the pharmacological basis of aromatherapy in the treatment of BPSDs and to widen
the cluster of effective essential oils in pharmacotherapeutic practice.

1. Introduction: Characterization of social burden of AD worldwide. Other forms of dementia are

Alzheimer’s Disease Lewy body dementia, frontotemporal dementia, and vascular
dementia. AD is a progressive neurodegenerative disease
Alzheimer’s Disease (AD), originally described by Alzheimer characterized by cognitive and noncognitive dysfunctions
in 1907 [1], is the most common cause of dementia in the [3]. In particular, the WHO describes dementia as a clinical
elderly: 35 million people all over the world are affected syndrome due to disease of the brain, usually of a progres-
by dementia [2] and, according to the survey made by the sive nature, which leads to disturbances of multiple higher
World Health Organization (WHO) in 2012, 54% of all the cortical functions, including memory, thinking, orientation,
cases of dementia are AD-related. These data account for the comprehension, calculation, learning capacity, language, and
2 Evidence-Based Complementary and Alternative Medicine

judgment. The cognitive deficits include memory impair- 2. Strategy for the Management of BPSDs
ment, aphasia, apraxia, agnosia, and disturbances in executive
functioning [4, 5]. Although these are the fundamental goal Dementia is widespread among patients hosts of nursing care
in the long term, the most frequent issue for people with AD homes, since up to 80% of them suffer from it [13]. Lots of
remains the management of Behavioural and Psychological patients affected by dementia, in particular 40–60% of the
Symptoms of Dementia (BPSDs) [6] and pain [7]. The residents in care homes [14], develop BPSDs. These symptoms
pathogenesis of AD is explained by the amyloid hypothesis, include agitation, aggression, psychotic manifestations with
according to which deposition and accumulation of amyloid consequent stress, increased pain perception, and decreased
𝛽-peptide (A𝛽) are responsible for the neurodegeneration; quality of life (QoL). In order to establish the most suitable
thus the reduction of A𝛽 plaques should produce clini- treatment for each individual condition, a rigorous evaluation
cal improvement [8]. Other neuropathological markers of of the symptoms and assessment of pain is necessary; the
AD are the neurofibrillary tangles (NFTs), composed of latter is made much more complicated in AD patients due
hyperphosphorylated tau proteins. Available drugs for the to their difficulty to convey what they perceive. The atypical
pharmacological treatment of AD are acetylcholinesterase antipsychotic drugs have replaced the typical ones in the
inhibitors: Donepezil (Aricept, 1996), Rivastigmine (Exelon, treatment of BPSDs because of the improved safety shown in
1998), and Galantamine (Razadyne, 2001). A more recently the treatment of schizophrenic patients; indeed, the atypical
approved drug by Food and Drug Administration (FDA) is antipsychotics (Risperidone, Olanzapine, Aripiprazole, and
effective in AD-induced cognitive impairment, that is, the Quetiapine) were developed for schizophrenia therapy [15].
noncompetitive N-methyl-D-aspartate- (NMDA-) receptor Among these drugs, Risperidone is the safest antipsychotic
antagonist Memantine (Namenda, 2003). New strategies tar- drug for short-term therapy of BPSDs in patients with
geting A𝛽 have been tested in order to delay AD progression, dementia, even if it needs an accurate review of the treatment
but small molecules and immunotherapy both have failed [15]. Furthermore, since chronic pain affects mainly the
[9]. For this purpose, novel biological drugs have been population of the elderly, it often accompanies patients
studied as disease-modifying agents for AD. In particu- suffering from dementia, determining a reduction of the QoL
lar, two placebo-controlled multicenter, double-blind phase almost as remarkable as that provoked by memory loss. Pain
3 studies on mild-to-moderate AD, EXPEDITION 1 and takes on a pivotal importance in demented patients, because
EXPEDITION 2, unraveled that Solanezumab, a humanized it plays a fundamental role in the development of the BPSDs,
antiamyloid monoclonal antibody, which binds soluble A𝛽, in particular of agitation and aggression [16]. In AD pain
did not show significant results concerned with the primary perception is impaired because of neuropathological changes
outcomes, failed to improve cognition, and did not enhance of the pain systems, in particular in the locus coeruleus [17]
functional ability (funded by Eli Lilly; EXPEDITION 1 and
and in the periaqueductal gray [18]. For this reason, the
EXPEDITION 2 ClinicalTrials.gov numbers NCT00905372
effect of pain treatment on patients’ agitation has been tested.
and NCT00904683) [10]. Also Bapineuzumab, a human-
ized anti-amyloid-beta monoclonal antibody, was studied in During a multicenter cluster randomized controlled trial
two double-blind, randomized, placebo-controlled phase 3 (ClinicalTrials.gov NCT01021696 and Norwegian Medicines
trials on mild-to-moderate AD; the results demonstrated Agency EudraCTnr 2008-007490-20) [19], carried out in
that Bapineuzumab did not produce any improvements of Norway from October 2009 to June 2010 in 60 nursing
the set clinical outcomes (funded by Janssen Alzheimer homes, 65-year-old or older demented patients affected by
Immunotherapy and Pfizer; Bapineuzumab 301 and 302 Clin- BPSDs (apart from the patients belonging to the control
icalTrials.gov numbers NCT00575055 and NCT00574132 and group that were treated as they usually were) received
EudraCT number 2009-012748-17.) [11]. Interestingly, Adu- different analgesic drugs according to a standardized stepwise
canumab (BIIB037), a human monoclonal antibody able to protocol: oral paracetamol, oral morphine, buprenorphine
bind A𝛽 aggregates (soluble and insoluble form), was tested transdermal patch, or oral pregabalin. The primary out-
in a double-blind, placebo-controlled phase 1b randomized come was agitation, assessed through the Cohen-Mansfield
trial (PRIME; ClinicalTrials.gov identifier NCT01677572) agitation inventory, while the secondary outcomes were
involving patients showing prodromal or mild AD; Adu- aggression, pain, cognition, and daily activities. The results
canumab administration resulted in a reduction of brain A𝛽 demonstrated a significant average reduction in agitation
plaques in a dose- and time-dependent manner, as shown of 17% in the intervention group compared to the control
in Florbetapir PET imaging [12]. Moreover, Aducanumab
group; the former presented an increased agitation score
trial demonstrated an improvement of the Mini Mental State
when painkillers were withdrawn [19]. Therefore, this study
Examination (MMSE) at one year, mainly at the doses of
3 and 10 mg/Kg and of the Clinical Dementia Rating-Sum supports the importance of an adequate evaluation and treat-
of Boxes (CDR-SB) score at one year [12]. Therefore, the ment of pain for the management of agitation and aggression
studies on Aducanumab support the amyloid hypothesis in patients suffering from dementia. Indeed, an appropriate
and demonstrate that the use of Aducanumab could be an treatment strategy for BPSDs needs a complex evaluation of
interesting disease-modifying approach for AD treatment in the several multiple symptoms manifested by the patients, so
the still ongoing long-term extension (LTE) phase of the that pharmacological agents are not administered if not or
PRIME and phase 3 studies [12]. until necessary.
Evidence-Based Complementary and Alternative Medicine 3

3. The Antipsychotics 10520

The typical antipsychotics have been the first off-label phar- 10000

Publications per decades

macological treatment of BPSDs. In order to study the effect
8000
of haloperidol in agitated demented patients, a search was
made on databases such as MEDLINE, EMBASE, PsycInfo, 6000
and CINAHL: five randomized, placebo-controlled trials
were included. The results yielded by the completed four 3125
4000
randomized controlled trials (RCTs) have proven evidence 1335
for the effectiveness of haloperidol on aggression, when 2000 106
compared to placebo, but not on other manifestations of
agitation [20, 21]. The relative effectiveness of these agents 0
1880–1950 1951–1975 1976–2000 2001–2016
was counterbalanced by their serious side effects especially
about the cardiac sphere and the parkinsonism. Indeed, a (Decades)
study on 495 psychiatric patients (with 101 healthy controls) Figure 1: PubMed search on essential oils. An exponential growth
demonstrated that these antipsychotic agents were predictors of scientific production about essential oils is displayed in the figure
of QTc lengthening in a dose-related manner [22]. Thus, soon from the 80s to 2016.
the novel atypical antipsychotics like Risperidone, Olanzap-
ine, and Quetiapine took the place of the older typical agents
in the management of aggression and agitation in dementia, use of atypical antipsychotic agents over 12 weeks is associated
thanks to their improved tolerability. Part of the amount with an accelerated cognitive decline assessed by MMSE
of data collected in placebo-controlled trials on atypical [24]. The FDA analyzed results of placebo-controlled trials
antipsychotic drugs in AD is not available; at variance with and outlined a 1,6-1,7-fold increased mortality in patients
the latter, all the results generated through meta-analyses on subjected to atypical antipsychotics rather than placebo over
Risperidone and Aripiprazole are available [21]. In particular, 12 weeks [21, 27]. Moreover, the mortality at 12 months
these drugs result effective in controlling aggression mainly in was evaluated in a randomized placebo-controlled, parallel,
a treatment period of 6–12 weeks, with larger evidence base two-group treatment discontinuation trial [28]: the results
for Risperidone [21, 23, 24]. Unfortunately, the randomized highlighted increased mortality both within the 12 months’
controlled trials lasting for a longer period have not high-
trial duration and during the 54 months of follow-up, thus
lighted efficacy of atypical antipsychotics in the long-term
outlining the persistence of the risk of mortality increase
and, even when some effectiveness occurred, the incidence
with the long-term treatment with antipsychotic drugs. By
of side effects made it irrelevant in terms of cost/effectiveness
contrast, another study to assess the antipsychotic-associated
[21, 25, 26]. For instance, a randomized double-blind placebo-
long-term mortality was conducted throughout a 75-month
controlled trial, conducted on 93 patients, guests of care
follow-up period in 4 Norwegian counties, but it did not show
facilities in Newcastle and who are affected by AD or demen-
an increased mortality [29].
tia, showed that Quetiapine did not produce significant
improvements in agitation score measured with Cohen-
Mansfield agitation inventory but was associated with a worse 4. Complementary Approach through
decline of cognition assessed by severe impairment battery Aromatherapy: Clinical Evidence and
at 6 and 26 weeks [25]. Another double-blind placebo- Possible Pharmacological Mechanisms
controlled trial (ClinicalTrials.gov number NCT00015548)
made on AD outpatients evaluated the effects of Olanzapine, Since the atypical antipsychotics should be used only in short-
Quetiapine, and Risperidone with respect to placebo [26]. term treatment and not over 12 weeks, there has been growing
The primary outcome of this trial, which made part of interest in the use of aromatherapy for BPSDs handling
the National Institute of Mental Health (NIMH) Clinical over the last years. Aromatherapy is a specialized segment
Antipsychotic Trials of Intervention Effectiveness, was the of phytotherapy that uses essential oils, extracted from the
time until discontinuation of treatment for any reason in different organs of aromatic plants, more often administered
phase 1: the median time to discontinuation of treatment via inhalation or topical application and massage for several,
for any reason resulted in being 5–8 weeks, without any sig- minor, clinical uses [30]. A PubMed search, conducted using
nificant differences among the three atypical antipsychotics “Essential oils” as key word, provided the graph shown in
and between them and the placebo [26]. Moreover, the time Figure 1.
to discontinuation of treatment for intolerance to the drug, The remarkable increase of the scientific production
adverse effects, or death was better for the placebo group dealing with essential oils, occurring from the 80s to 2016,
[26]. Some of the most important adverse events caused accounts for the intensity of the phenomenon “aromather-
by atypical antipsychotics are drowsiness, extrapyramidal apy.” Indeed, during the second half of the past century, since
symptoms, and, more importantly, cerebrovascular accidents: the first article published by Wood HC and Reichut ET in
according to the placebo-controlled trials, for Risperidone 1880 on the prestigious Journal of Physiology and entitled
this possibility is 3-fold higher than placebo [21]. Another “Note on the Action upon the Circulation of Certain Volatile
important matter to be dealt with is the cognitive decline: the Oils,” the interest in aromatherapy for the treatment of
4 Evidence-Based Complementary and Alternative Medicine

several disorders such as anxiety, mood disorders, and certain or a matching placebo, at 7-day intervals. Cognitive perfor-
forms of pain registered a great growth [30]. Furthermore, mance and mood were assessed before dose and at 1, 3, and 6 h
aromatherapy has provided the best evidence, together with after dose, using the Cognitive Drug Research computerized
psychological treatment, for the management of agitation assessment battery and the Bond–Lader visual analog scales,
in dementia [21]. In particular, the essential oils of two respectively. The obtained data supported the cholinergic
species of Lamiaceae family, Melissa officinalis L. (lemon receptor-binding properties of M. officinalis and the fact that
balm) and Lavandula officinalis L. (lavender), are the most it acts on mood and cognition in a dose- and time-dependent
used aromatherapeutic treatments for BPSDs in dementia manner [43]. It is noteworthy that M. officinalis has shown
[31–33]. Melissa officinalis L. (Lemon balm) belongs to the some effects also on nociceptive behaviour in animal pain
Lamiaceae family and is a traditional medicinal plant native models and this could contribute to its effectiveness in the
of East Mediterranean region and West Asia and widespread reduction of agitation. In fact, the mechanisms involved
in Teheran, where it is named Badranjbooye [34]. in the antinociceptive effects of a hydroalcoholic extract
A placebo-controlled trial, conducted on patients affected of M. officinalis and of rosmarinic acid have been recently
by severe dementia guests of care facilities in the UK, reported investigated in mice [44]. In the formalin test, the extract
the effect of Melissa officinalis (M. officinalis) essential oil, provided a significant inhibition of both phases and inhibited
applied as massage twice a day for 4 weeks, on agita- in a dose-dependent manner the glutamate-induced pain.
tion measured by the Cohen-Mansfield agitation inventory The antinociceptive effect elicited by this extract in the
(CMAI) [31]: seventy-one out of the seventy-two participants glutamate test was significantly attenuated by intraperitoneal
completed the trial and results demonstrated an improve- (i.p.) treatment of mice with atropine, mecamylamine, or L-
ment of agitation without the occurrence of significant side arginine but not with naloxone or D-arginine [44], thus sup-
effects. The efficacy of lemon balm hydroalcoholic extracts porting the involvement of the cholinergic system and of the
rather than the essential oil is also well documented. In a L-arginine-nitric oxide pathway. In addition, the rosmarinic
study (a parallel group, double-blind, randomized, placebo- acid contained in this extract appeared to contribute to the
controlled trial), involving aged patients (from 65 to 80 years antinociceptive features of M. officinalis extract [44]. Table 1
of age) suffering from mild-moderate AD, 60 drops/day of summarizes the main studies supporting the use of Melissa
lemon balm extract were administered. Lemon balm exerted officinalis in aromatherapy.
positive effects both on cognition, as measured through the Lavender belongs to the family Labiatae (Lamiaceae).
11-item cognitive subscale of the Alzheimer’s Disease Assess- Lavender essential oil is obtained by distillation of diverse
ment Scale (ADAS-cog) and the CDR-SB, and on agitation as members of the genus Lavandula and it has been used for
side effect at 4 months [35]. The effectiveness of M. officinalis centuries. Some of the enumerated most commonly used
in AD could be explained by some cholinergic activities that species are L. officinalis (syn. L. angustifolia), L. latifolia, and
have been detected in its extracts; this feature is shared also by L. stoechas. L. angustifolia has been used for centuries in folk
Salvia officinalis (sage) and Ginkgo biloba [36, 37]. In a further medicine to treat anxiety and agitation: this is the reason
study [38], the crude lemon balm hydroalcoholic extract has of the growing investigation of lavender aromatherapy for
shown anticholinesterase activity. After fractionation, most the control of BPSDs. Lavender essential oil is composed of
of its fractions resulted in being more active than the whole over 100 constituents, among which the principal are linalool
extract. The constituents of the most active fractions are (51%), linalyl acetate (35%), 𝛼-pinene, limonene, 1,8-cineole,
represented by cis- and trans-rosmarinic acid isomers and a cis- and trans-ocimene, 3-octanone, camphor, caryophyl-
rosmarinic acid derivative [38]. The high anticholinesterase lene, terpinen-4-olandlavendulyl acetate, and cineole [45].
activity and free radical scavenger properties of rosmarinic According to the existing literature, lavender essential oil is
acid have been previously investigated by other authors able to inhibit glutamate and GABA receptor binding [46–
[39]. Moreover, it is reported that a similar extract of M. 48] and to improve behavioural conflict between mice [48,
officinalis contains compounds with acetylcholine receptor 49]. Furthermore, lavender has been shown to lower plasma
affinities being higher for the nicotinic subtype of receptors cortisol levels [48, 50, 51] and reduce the need for analgesia
[40]. Therefore, the effects of M. officinalis could be due during the postoperative period in humans [48, 52]; a possible
to the content of rosmarinic acid mainly [41–43] and also action of lavender essential oil on tryptophan has also been
to the monoterpenoid constituents of the essential oil [41, hypothesized [53, 54]. Lavender oil revealed also an interest-
43]. Because of this hypothesis, a two-phase study was per- ing analgesic activity relevant after inhalation mainly, at doses
formed using lemon balm dried leaves [43]. Preliminarily, the devoid of sedative side effects [55]. In the hot plate test the oil
inhibition of acetylcholinesterase (AChE) and nicotinic and inhalation induced an analgesic activity which was inhibited
muscarinic receptor-binding properties were evaluated for by naloxone, atropine, and mecamylamine before treatment,
eight samples of dried leaves in human postmortem occipital thus supporting the involvement of both opioidergic and
cortex tissue. Subsequently, the sample of M. officinalis which cholinergic pathways [55]. A placebo-controlled trial includ-
resulted to have the highest cholinergic activity was adminis- ing 15 demented patients affected by agitation, according to
tered to healthy young volunteers and the effects on cognition the Pittsburgh Agitation Scale (PAS), reported some effective-
and mood were examined in a multiple-dose, multiple time- ness of 2% lavender oil aromatherapy stream [32]. The efficacy
point, double-blind, placebo-controlled, balanced crossover of aromatherapy could be partly due to the terpenes content
study [43]. Twenty healthy young participants received single of the used essential oils, since these molecules undergo quick
doses of 600, 1000, and 1600 mg of encapsulated dried leaf, lung absorption and are able to cross the blood-brain barrier
Evidence-Based Complementary and Alternative Medicine 5

Table 1: Main studies supporting the use of Melissa officinalis in aromatherapy.

Study Main characteristics

Placebo-controlled trial, conducted on seventy-two demented resident in care facilities in the
UK (seventy-one out of whom completed the trial), demonstrating that M. officinalis essential
Ballard et al., 2002.
oil, applied as massage twice a day for 4 weeks, produced an improvement of agitation
(according to the CMAI), without the occurrence of significant side effects.
Parallel group, double-blind, randomized, placebo-controlled trial, involving aged patients
(from 65 to 80 years of age) suffering from mild-moderate AD, who were given 60 drops/day of
Akhondzadeh et al., 2003.
lemon balm extract. Lemon balm exerted positive effects both on cognition (according to the
ADAS-cog and the CDR-SB) and on agitation as side effect at 4 months.
Fractionation of the crude lemon balm hydroalcoholic extract, demonstrating
anticholinesterase activity of most of the fractions, that resulted in being more active than the
Dastmalchi et al., 2009.
whole extract. The constituents of the most active fractions are cis- and trans-rosmarinic acid
isomers and a rosmarinic acid derivative.
Two-phase study: preliminary evaluation of the AChE inhibition and of nicotinic and
muscarinic receptor-binding properties for eight samples of lemon balm dried leaves in human
postmortem occipital cortex tissue and subsequent administration to 20 healthy young
participants of the sample that resulted to have the highest cholinergic activity. The effects on
Kennedy et al., 2003.
cognition and mood were examined in a multiple-dose, multiple time-point, double-blind,
placebo-controlled, balanced crossover study. The obtained data supported the cholinergic
receptor-binding properties of M. officinalis and the fact that it acts on mood and cognition in
a dose- and time-dependent manner.
Study performed using the formalin test in mice, in which the M. officinalis extract provided a
significant inhibition of both phases and inhibited in a dose-dependent manner the
glutamate-induced pain. The antinociceptive effect elicited by this extract in the glutamate test
Guginski et al., 2009. was significantly attenuated by i.p. administered atropine, mecamylamine, or L-arginine but
not naloxone or D-arginine, thus supporting the involvement of the cholinergic system and of
the L-arginine-nitric oxide pathway. The rosmarinic acid contained in this extract appeared to
contribute to its antinociceptive features.

Table 2: Studies supporting the use of Lavandula officinalis in aromatherapy.

Study Main characteristics

In the hot plate test the lavender oil inhalation induced analgesic activity, which was inhibited
Barocelli et al., 2004. by naloxone, atropine, and mecamylamine before treatment, thus supporting the involvement
of both opioidergic and cholinergic pathways.
A placebo-controlled trial including 15 demented patients affected with agitation, as assessed
Holmes et al., 2002.
by the PAS, which reported some effectiveness of 2% lavender oil aromatherapy stream.
A cross-over randomized trial, conducted on 70 Chinese aged demented patients, which
Lin et al., 2007. suggested the efficacy of lavender administered by inhalatory route as adjunctive therapy for
the management of agitation.
A group of 28 demented old patients, 17 of whom suffering from AD, was exposed to the aroma
of 0.04 mL lemon and 0.08 mL rosemary essential oil in the morning and to the aroma of
0.08 mL lavender and 0.04 mL orange essential oils in the evening, in order to improve
Jimbo et al., 2009.
concentration and memory in the morning and to make the patients quiet in the evening. The
results obtained so far support the clinical use of aromatherapy in AD patients, also when
performed using more than one single essential oil.

[33]. A crossover randomized trial conducted on seventy 0.08 mL lavender and 0.04 mL orange essential oils in the
Chinese aged demented patients suggested the efficacy of evening [57]. The rationale underneath this scheme relies on
lavender administered by inhalatory route as an adjunctive the possibility that the mixed lemon and rosemary aromas
therapy for the management of agitation [56]. Moreover, the activate the sympathetic nervous system in order to improve
effect of aromatherapy performed using more than one single concentration and memory in the morning and the mixed
essential oil on dementia and AD was tested. A group of lavender and orange aromas activate the parasympathetic
28 demented old patients, 17 of whom suffering from AD, nervous system, thus making the patients quiet in the evening
was exposed to the aroma of 0.04 mL lemon and 0.08 mL [57]. The results obtained so far support the clinical use of
rosemary essential oil in the morning and to the aroma of aromatherapy in AD patients [57]. Table 2 summarizes the
6 Evidence-Based Complementary and Alternative Medicine

main studies supporting the use of Lavandula officinalis in minimize the role of the psychological action [30]. The most
aromatherapy. used aromatherapeutic treatments for BPSDs in dementia are
represented by Melissa officinalis and Lavandula officinalis
5. Conclusions and Future Perspectives [31–33]. Both of them have been used in traditional medicine
for centuries: for example, the documented historical uses
Dementia, of which AD represents the most prevalent eti- of M. officinalis date back to the “Materia Medica” in
ological factor, is a very complex social problem and it has approximately 50–80 BC [43]. In addition, essential oils from
an even more remarkable burden in a future view, since both plants are included in the European Pharmacopoeia.
it is expected to affect more than 115 million people all Another fundamental facet is the increase of pain states in
over the world by 2050 [58]. Apart from the urgent need demented patients that are particularly related to agitation
of disease-modifying drugs able to delay the progression and aggression [16]. There is promising evidence for the
of the neurocognitive decline, another important aspect to effectiveness of aromatherapy for managing chronic pain:
deal with is the management of aggression, agitation, and it was demonstrated that the intraplantar administration
psychotic symptoms, clustered under the acronym BPSDs, of Bergamot Essential Oil (BEO), a citrus fruit belonging
which contribute to reduce the QoL and, in particular, the to the Rutaceae family, significantly attenuates capsaicin-
health-related quality of life (HRQL) of patients suffering induced nociceptive behaviour [63] and both the first and
from dementia. The pharmacological treatment of BPSDs the second phase of formalin-induced nocifensive response,
is represented by the atypical antipsychotics (Risperidone, thus confirming the previous observation that BEO reduces
Olanzapine, Aripiprazole, and Quetiapine), among which mechanical allodynia in neuropathic pain models [64–66].
Risperidone is the safest drug for short-term therapy, with Therefore, more rigorous RCTs assessing the effectiveness of
necessary review of the treatment [15]. The employed treat- aromatherapy on BPSDs, with recruitment of larger samples
ments, especially for BPSDs, affect the HRQL; the influence of patients and longer duration, are needed [21]. Additional
of person-centred care (PCC), antipsychotic review, social basic research effort is necessary to understand the pharma-
interaction, and exercise interventions on HRQL was studied cological mechanisms underlying aromatherapy. Finally, it is
in the Improving Wellbeing and Health for People with fundamental to carry out pharmacovigilance for ensuring a
Dementia (WHELD) factorial cluster RCT in nursing home correct and safe application of aromatherapy.
residents [59]. The obtained results support the importance
of an adequate review of the antipsychotics use and of the Conflicts of Interest
use of evidence-based nonpharmacological approaches as
combination therapy [59]. The atypical antipsychotic agents The authors declare that there are no conflicts of interest
for the management of BPSDs in patients suffering from regarding the publication of this paper.
dementia should be used in the short term (6–12 weeks),
since they result in being safer and effective in this treatment References
option (although almost exclusively on aggression rather than [1] A. Alzheimer, R. A. Stelzmann, H. N. Schnitzlein, and F. R.
on agitation), under rigorous review and in combination Murtagh, “An English translation of Alzheimer’s 1907 paper,
with nonpharmacological interventions. Among the alter- ‘Uber eine eigenartige Erkankung der Hirnrinde’,” Clinical
native treatments, aromatherapy has provided substantial Anatomy, vol. 8, no. 6, pp. 429–431, 1995.
evidence for agitation handling in AD [21]. The mechanism [2] C. Ballard, M. Orrell, S. Y. Zhong et al., “Impact of antipsychotic
of action of constituents of aromatic plants has yet to be review and nonpharmacological interventionon antipsychotic
discovered. Detailed information on psychological effects use, neuropsychiatric symptoms, and mortality in people
of aromatic plants, their essential oils, and hydroalcoholic with dementia living in nursing homes: a factorial cluster-
extracts has been reported. The aromatic molecules bind randomized controlled trial by the well-being and health for
to olfactory epithelium acceptors that are specific for each people with dementia (WHELD) program,” American Journal
different smell. The olfactory nerve system is responsible for of Psychiatry, vol. 173, no. 3, pp. 252–262, 2016.
the transmission of this stimulus to hippocampus, limbic [3] S. H. Barage and K. D. Sonawane, “Amyloid cascade hypothesis:
system, and amygdala and then to the hypothalamus with pathogenesis and therapeutic strategies in Alzheimer’s disease,”
Neuropeptides, vol. 52, pp. 1–18, 2015.
consequent release of neuromediators [57]. The involvement
of hippocampus and amygdala in the cognitive impairment [4] American Psychiatric Association, Diagnostic and Statistical
Manual of Mental Disorders, Third Edition-Revised (DSM-III-
characterizing dementia and the presence of neurofibrillary
R), American Psychiatric Association, Washington, DC, USA,
tangles (NFTs) in the entorhinal cortex, already in the early 1987.
stages of AD [57, 60, 61], suggest an interesting link between [5] American Psychiatric Association, Diagnostic and Statistical
olfaction and AD, furtherly confirmed by the dysfunctional Manual of Mental Disorders, (DSM-IV), American Psychiatric
olfaction by which demented patients are often affected [57]. Association, Washington, DC, USA, 4th edition, 1994.
It has been hypothesized that aromatherapy may promote [6] C. G. Ballard, S. Gauthier, J. L. Cummings et al., “Management
neurogenesis in dentate gyrus of hippocampus [57, 62]. of agitation and aggression associated with Alzheimer disease,”
Accordingly, systemic absorption (following direct inhalation Nature Reviews Neurology, vol. 5, no. 5, pp. 245–255, 2009.
or inhalation after topical application) and distribution of [7] W. Achterberg, M. J. Pieper, A. H. van Dalen-Kok et al., “Pain
pharmacologically active components of the phytocomplex management in patients with dementia,” Clinical Interventions
are needed for aromatherapy to control BPSDs, and this may in Aging, vol. 8, pp. 1471–1482, 2013.
Evidence-Based Complementary and Alternative Medicine 7

[8] J. A. Hardy and G. A. Higgins, “Alzheimer’s disease: the amyloid [25] C. Ballard, M. Margallo-Lana, E. Juszczak et al., “Quetiapine
cascade hypothesis,” Science, vol. 256, no. 5054, pp. 184–185, and rivastigmine and cognitive decline in Alzheimer’s disease:
1992. randomised double blind placebo controlled trial,” British
[9] J. L. Cummings, T. Morstorf, and K. Zhong, “Alzheimer’s disease Medical Journal, vol. 330, no. 7496, pp. 874–877, 2005.
drug-development pipeline: few candidates, frequent failures,” [26] L. S. Schneider, P. N. Tariot, K. S. Dagerman et al., “Effectiveness
Alzheimer’s Research and Therapy, vol. 6, no. 4, article 37, 2014. of atypical antipsychotic drugs in patients with Alzheimer’s
[10] R. S. Doody, R. G. Thomas, M. Farlow et al., “Phase 3 trials disease,” The New England Journal of Medicine, vol. 355, no. 15,
of solanezumab for mild-to-moderate Alzheimer’s disease,” The pp. 1525–1538, 2006.
New England Journal of Medicine, vol. 370, no. 4, pp. 311–321, [27] FDA Public Health Advisory, “Deaths with antipsychotics in
2014. elderly patients with behavioral disturbances,” 2005, https://
[11] S. Salloway, R. Sperling, N. C. Fox et al., “Two phase 3 trials of www.fda.gov/Drugs/DrugSafety/ucm053171.htm.
Bapineuzumab in mild-to-moderate Alzheimer’s disease,” The [28] C. Ballard, M. L. Hanney, M. Theodoulou et al., “The dementia
New England Journal of Medicine, vol. 370, no. 4, pp. 322–333, antipsychotic withdrawal trial (DART-AD): long-term follow-
2014. up of a randomised placebo-controlled trial,” The Lancet Neu-
[12] J. Sevigny, P. Chiao, T. Bussière et al., “The antibody adu- rology, vol. 8, no. 2, pp. 151–157, 2009.
canumab reduces A𝛽 plaques in Alzheimer’s disease,” Nature, [29] G. Selbæk, D. Aarsland, C. Ballard et al., “Antipsychotic drug
vol. 537, no. 7618, pp. 50–56, 2016. use is not associated with long-term mortality risk in Norwe-
[13] A. Corbett, K. Nunez, and A. Thomas, “Coping with dementia gian nursing home patients,” Journal of the American Medical
in care homes,” Maturitas, vol. 76, no. 1, pp. 3–4, 2013. Directors Association, vol. 17, no. 5, pp. 464.e1–464.e7, 2016.
[14] M. Margallo-Lana, A. Swann, J. O’Brien et al., “Prevalence [30] G. Bagetta, M. Cosentino, and T. Sakurada, Eds., Preface in
and pharmacological management of behavioural and psycho- Aromatherapy: Basic Mechanisms and Evidence Based Clinical
logical symptoms amongst dementia sufferers living in care Use, Oxfordshire, UK, Taylor & Francis, 2016.
environments,” International Journal of Geriatric Psychiatry, vol. [31] C. G. Ballard, J. T. O’Brien, K. Reichelt, and E. K. Perry,
16, no. 1, pp. 39–44, 2001. “Aromatherapy as a safe and effective treatment for the man-
[15] C. Ballard and A. Corbett, “Agitation and aggression in people agement of agitation in severe dementia: the results of a double-
with Alzheimer’s disease,” Current Opinion in Psychiatry, vol. 26, blind, placebo-controlled trial with Melissa,” Journal of Clinical
no. 3, pp. 252–259, 2013. Psychiatry, vol. 63, no. 7, pp. 553–558, 2002.
[16] A. Corbett, B. Husebo, M. Malcangio et al., “Assessment and [32] C. Holmes, V. Hopkins, C. Hensford, V. MacLaughlin, D.
treatment of pain in people with dementia,” Nature Reviews Wilkinson, and H. Rosenvinge, “Lavender oil as a treatment
Neurology, vol. 8, no. 5, pp. 264–274, 2012. for agitated behaviour in severe dementia: a placebo controlled
[17] C. Zarow, S. A. Lyness, J. A. Mortimer, and H. C. Chui, “Neu- study,” International Journal of Geriatric Psychiatry, vol. 17, no.
ronal loss is greater in the locus coeruleus than nucleus basalis 4, pp. 305–308, 2002.
and substantia nigra in Alzheimer and Parkinson diseases,” [33] A. Burns, J. Byrne, C. Ballard, and C. Holmes, “Sensory
Archives of Neurology, vol. 60, no. 3, pp. 337–341, 2003. stimulation in dementia,” British Medical Journal, vol. 325, no.
[18] J. Parvizi, G. W. Van Hoesen, and A. Damasio, “Selective 7376, pp. 1312–1313, 2002.
pathological changes of the periaqueductal gray matter in [34] A. Zarei, S. Changizi Ashtiyani, S. Taheri, and F. Rasekh,
Alzheimer’s disease,” Annals of Neurology, vol. 48, no. 3, pp. “Comparison between effects of different doses of Melissa
344–353, 2000. officinalis and atorvastatin on the activity of liver enzymes in
[19] B. S. Husebo, C. Ballard, R. Sandvik, O. B. Nilsen, and D. hypercholesterolemia rats,” Avicenna Journal of Phytomedicine,
Aarsland, “Efficacy of treating pain to reduce behavioural vol. 4, no. 1, pp. 15–23, 2014.
disturbances in residents of nursing homes with dementia: [35] S. Akhondzadeh, M. Noroozian, M. Mohammadi, S. Ohadinia,
cluster randomised clinical trial,” BMJ, vol. 343, no. 7816, Article A. H. Jamshidi, and M. Khani, “Melissa officinalis extract in
ID d4065, 2011. the treatment of patients with mild to moderate Alzheimer’s
[20] E. Lonergan, J. Luxenberg, and J. Colford, “Haloperidol for disease: a double blind, randomised, placebo controlled trial,”
agitation in dementia,” The Cochrane Database of Systematic Journal of Neurology, Neurosurgery, and Psychiatry, vol. 74, no.
Reviews, no. 2, Article ID CD002852, 2002. 7, pp. 863–866, 2003.
[21] C. G. Ballard, S. Gauthier, J. L. Cummings et al., “Management [36] E. K. Perry, A. T. Pickering, W. W. Wang, P. Houghton, and N. S.
of agitation and aggression associated with alzheimer disease,” L. Perry, “Medicinal plants and Alzheimer’s disease: integrating
Nature Reviews Neurology, vol. 5, no. 5, pp. 245–255, 2009. ethnobotanical and contemporary scientific evidence,” Journal
[22] J. G. Reilly, S. A. Ayis, I. N. Ferrier, S. J. Jones, and S. H. L. of Alternative and Complementary Medicine, vol. 4, no. 4, pp.
Thomas, “QTc-interval abnormalities and psychotropic drug 419–428, 1998.
therapy in psychiatric patients,” The Lancet, vol. 355, no. 9209, [37] E. K. Perry, A. T. Pickering, W. W. Wang, P. J. Houghton,
pp. 1048–1052, 2000. and N. S. L. Perry, “Medicinal plants and Alzheimer’s disease:
[23] C. Ballard and R. Howard, “Neuroleptic drugs in dementia: from ethnobotany to phytotherapy,” Journal of Pharmacy and
benefits and harm,” Nature Reviews Neuroscience, vol. 7, no. 6, Pharmacology, vol. 51, no. 5, pp. 527–534, 1999.
pp. 492–500, 2006. [38] K. Dastmalchi, V. Ollilainen, P. Lackman et al., “Acetyl-
[24] L. S. Schneider, K. Dagerman, and P. S. Insel, “Efficacy and cholinesterase inhibitory guided fractionation of Melissa offic-
adverse effects of atypical antipsychotics for dementia: meta- inalis L.,” Bioorganic and Medicinal Chemistry, vol. 17, no. 2, pp.
analysis of randomized, placebo-controlled trials,” The Amer- 867–871, 2009.
ican Journal of Geriatric Psychiatry, vol. 14, no. 3, pp. 191–210, [39] M. Petersen and M. S. J. Simmonds, “Rosmarinic acid,” Phyto-
2006. chemistry, vol. 62, no. 2, pp. 121–125, 2003.
8 Evidence-Based Complementary and Alternative Medicine

[40] G. Wake, J. Court, A. Pickering, R. Lewis, R. Wilkins, and disruptive behaviour in people with dementia,” BMC Comple-
E. Perry, “CNS acetylcholine receptor activity in European mentary and Alternative Medicine, vol. 13, article 165, 2013.
medicinal plants traditionally used to improve failing memory,” [55] E. Barocelli, F. Calcina, M. Chiavarini et al., “Antinociceptive
Journal of Ethnopharmacology, vol. 69, no. 2, pp. 105–114, 2000. and gastroprotective effects of inhaled and orally administered
[41] A. P. Carnat, A. Carnat, D. Fraisse, and J. L. Lamaison, “The Lavandula hybrida Reverchon ‘grosso’ essential oil,” Life Sciences,
aromatic and polyphenolic composition of lemon balm (Melissa vol. 76, no. 2, pp. 213–223, 2004.
officinalis L. subsp. officinalis) tea,” Pharmaceutica Acta Helve- [56] P. W.-K. Lin, W.-C. Chan, B. F.-L. Ng, and L. C.-W. Lam,
tiae, vol. 72, no. 5, pp. 301–305, 1998. “Efficacy of aromatherapy (Lavandula angustifolia) as an inter-
[42] J. Hohmann, I. Zupkó, D. Rédei et al., “Protective effects of vention for agitated behaviours in Chinese older persons with
the aerial parts of Salvia officinalis, Melissa officinalis and dementia: a cross-over randomized trial,” International Journal
Lavandula angustifolia and their constituents against enzyme- of Geriatric Psychiatry, vol. 22, no. 5, pp. 405–410, 2007.
dependent and enzyme-independent lipid peroxidation,” Planta [57] D. Jimbo, Y. Kimura, M. Taniguchi, M. Inoue, and K. Urakami,
Medica, vol. 65, no. 6, pp. 576–578, 1999. “Effect of aromatherapy on patients with Alzheimer’s disease,”
[43] D. O. Kennedy, G. Wake, S. Savelev et al., “Modulation of mood Psychogeriatrics, vol. 9, no. 4, pp. 173–179, 2009.
and cognitive performance following acute administration of [58] World Health Organization and Alzheimer’s Disease Inter-
single doses of Melissa officinalis (Lemon balm) with human national, Dementia: A Public Health Priority, World Health
CNS nicotinic and muscarinic receptor-binding properties,” Organization, Geneva, Switzerland, 2012.
Neuropsychopharmacology, vol. 28, no. 10, pp. 1871–1881, 2003. [59] C. Ballard, M. Orrell, Y. Sun et al., “Impact of antipsychotic
[44] G. Guginski, A. P. Luiz, M. D. Silva et al., “Mechanisms involved review and nonpharmacological intervention on antipsychotic
in the antinociception caused by ethanolic extract obtained use, neuropsychiatric symptoms, and mortality in people
from the leaves of Melissa officinalis (lemon balm) in mice,” with dementia living in nursing homes: a factorial cluster-
Pharmacology Biochemistry and Behavior, vol. 93, no. 1, pp. 10– randomized controlled trial by the Well-Being and Health for
16, 2009. People With Dementia (WHELD) program,” The American
[45] H. M. A. Cavanagh and J. M. Wilkinson, “Biological activities Journal of Psychiatry, vol. 173, no. 3, pp. 252–262, 2016.
of lavender essential oil,” Phytotherapy Research, vol. 16, no. 4, [60] H. Braak and E. Braak, “Neuropathological stageing of
pp. 301–308, 2002. Alzheimer-related changes,” Acta Neuropathologica, vol. 82, no.
[46] E. Elisabetsky, J. Marschner, and D. Onofre Souza, “Effects of 4, pp. 239–259, 1991.
linalool on glutamatergic system in the rat cerebral cortex,” [61] G. Gold, C. Bouras, E. Kövari et al., “Clinical validity of Braak
Neurochemical Research, vol. 20, no. 4, pp. 461–465, 1995. neuropathological staging in the oldest-old,” Acta Neuropatho-
[47] L. Huang, S. Abuhamdah, M.-J. R. Howes et al., “Pharmacolog- logica, vol. 99, no. 5, pp. 579–584, 2000.
ical profile of essential oils derived from Lavandula angustifolia [62] P. S. Eriksson, E. Perfilieva, T. Björk-Eriksson et al., “Neurogen-
and Melissa officinalis with anti-agitation properties: focus on esis in the adult human hippocampus,” Nature Medicine, vol. 4,
ligand-gated channels,” Journal of Pharmacy and Pharmacology, no. 11, pp. 1313–1317, 1998.
vol. 60, no. 11, pp. 1515–1522, 2008. [63] T. Sakurada, H. Kuwahata, S. Katsuyama et al., “Chapter 18
[48] D. W. O’Connor, B. Eppingstall, J. Taffe, and E. S. Van Der Ploeg, intraplantar injection of bergamot essential oil into the mouse
“A randomized, controlled cross-over trial of dermally-applied hindpaw. Effects on capsaicin-induced nociceptive behaviors,”
lavender (Lavandula angustifolia) oil as a treatment of agitated International Review of Neurobiology, vol. 85, pp. 237–248, 2009.
behaviour in dementia,” BMC Complementary and Alternative [64] G. Bagetta, L. A. Morrone, L. Rombolà et al., “Neuropharma-
Medicine, vol. 13, article 315, 2013. cology of the essential oil of bergamot,” Fitoterapia, vol. 81, no.
[49] T. Umezu, “Behavioral effects of plant-derived essential oils 6, pp. 453–461, 2010.
in the geller type conflict test in mice,” Japanese Journal of [65] H. Kuwahata, T. Komatsu, S. Katsuyama et al., “Peripherally
Pharmacology, vol. 83, no. 2, pp. 150–153, 2000. injected linalool and bergamot essential oil attenuate mechan-
[50] Y. Shiina, N. Funabashi, K. Lee et al., “Relaxation effects of ical allodynia via inhibiting spinal ERK phosphorylation,”
lavender aromatherapy improve coronary flow velocity reserve Pharmacology Biochemistry and Behavior, vol. 103, no. 4, pp.
in healthy men evaluated by transthoracic Doppler echocardio- 735–741, 2013.
graphy,” International Journal of Cardiology, vol. 129, no. 2, pp. [66] S. Katsuyama, A. Otowa, S. Kamio et al., “Effect of plantar
193–197, 2008. subcutaneous administration of bergamot essential oil and
[51] T. Field, T. Field, C. Cullen et al., “Lavender bath oil reduces linalool on formalin-induced nociceptive behavior in mice,”
stress and crying and enhances sleep in very young infants,” Biomedical Research, vol. 36, no. 1, pp. 47–54, 2015.
Early Human Development, vol. 84, no. 6, pp. 399–401, 2008.
[52] J. T. Kim, C. J. Ren, G. A. Fielding et al., “Treatment with
lavender aromatherapy in the post-anesthesia care unit reduces
opioid requirements of morbidly obese patients undergoing
laparoscopic adjustable gastric banding,” Obesity Surgery, vol.
17, no. 7, pp. 920–925, 2007.
[53] C. A. Zeilmann, E. J. Dole, B. J. Skipper, M. McCabe, T. Low
Dog, and R. L. Rhyne, “Use of herbal medicine by elderly
Hispanic and non-Hispanic white patients,” Pharmacotherapy,
vol. 23, no. 4, pp. 526–532, 2003.
[54] C.-Y. Fu, W. Moyle, and M. Cooke, “A randomised controlled
trial of the use of aromatherapy and hand massage to reduce
 MEDIATORS of

INFLAMMATION

The Scientific Gastroenterology Journal of

World Journal
Hindawi Publishing Corporation
Research and Practice
Hindawi Publishing Corporation
Hindawi Publishing Corporation
Diabetes Research
Hindawi Publishing Corporation
Disease Markers
Hindawi Publishing Corporation
http://www.hindawi.com Volume 2014
http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Journal of International Journal of

Immunology Research
Hindawi Publishing Corporation
Endocrinology
Hindawi Publishing Corporation
http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Submit your manuscripts at

https://www.hindawi.com

BioMed
PPAR Research
Hindawi Publishing Corporation
Research International
Hindawi Publishing Corporation
http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Journal of
Obesity

Evidence-Based
Journal of Stem Cells Complementary and Journal of
Ophthalmology
Hindawi Publishing Corporation
International
Hindawi Publishing Corporation
Alternative Medicine
Hindawi Publishing Corporation Hindawi Publishing Corporation
Oncology
Hindawi Publishing Corporation
http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Parkinson’s
Disease

Computational and
Mathematical Methods
in Medicine
Behavioural
Neurology
AIDS
Research and Treatment
Oxidative Medicine and
Cellular Longevity
Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation
http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014