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Advance Access Publication 23 October 2006 eCAM 2006;3(4)441–445
doi:10.1093/ecam/nel071
Review
The Use of Herbal Medicine in Alzheimer’s Disease—A Systematic
Review
Leopoldo Luiz dos Santos-Neto
1
, Maria Alice de Vilhena Toledo
2
, Patrı
´
cia Medeiros-Souza
3
and Gustavo Almeida de Souza
3
1
General Internal Medical Center, University Hospital of Brasilia, University of Brasilia,
2
General Internal Medical
Center, Department of Geriatrics, University Hospital of Brasilia, University of Brasilia and
3
School of Pharmacy,
Department of Health Sciences, University of Brasilia, Brazil
The treatments of choice in Alzheimer’s disease (AD) are cholinesterase inhibitors and NMDA-receptor
antagonists, although doubts remain about the therapeutic effectiveness of these drugs. Herbal medicine
products have been used in the treatment of Behavioral and Psychological Symptoms of Dementia
(BPSD) but with various responses. The objective of this article was to review evidences from controlled
studies in order to determine whether herbs can be useful in the treatment of cognitive disorders in the
elderly. Randomized controlled studies assessing AD in individuals older than 65 years were identified
through searches of MEDLINE, LILACS, Cochrane Library, dissertation Abstract (USA), ADEAR
(Alzheimer’s Disease Clinical Trials Database), National Research Register, Current Controlled trials,
Centerwatch Trials Database and PsychINFO Journal Articles. The search combined the terms
Alzheimer disease, dementia, cognition disorders, Herbal, Phytotherapy. The crossover results were
evaluated by the Jadad’s measurement scale. The systematic review identified two herbs and herbal
formulations with therapeutic effects for the treatment of AD: Melissa officinalis, Salvia officinalis and
Yi-Gan San and BDW (Ba Wei Di Huang Wan). Ginkgo biloba was identified in a meta-analysis study.
All five herbs are useful for cognitive impairment of AD. M. officinalis and Yi-Gan San are also useful
in agitation, for they have sedative effects. These herbs and formulations have demonstrated good
therapeutic effectiveness but these results need to be compared with those of traditional drugs. Further
large multicenter studies should be conducted in order to test the cost-effectiveness of these herbs for
AD and the impact in the control of cognitive deterioration.
Keywords: Alzheimer’s disease – cognitive impairment – dementia – elderly – herbs – randomized
clinical trial – systematic review
Introduction
Alzheimer’s disease (AD) is characterized as a progressive
neurodegenerative disorder and considered as prominent cause
of dementia in the elderly. The main characteristics of this
disease are difficulties in household handling routine and
cognitive and emotional disturbance in the elderly. The
treatment of AD is a clinical challenge. With the development
of cholinesterase inhibitors and a N-methyl-d-aspartate
antagonist (memantine), good perspectives have emerged in
controlling the symptoms of AD. Therapeutic decisions have
to be guided by clinical studies and should consider the
physiopathogenesis and epidemiology of the disease.
The main objective of these clinical trials is to reduce the
Behavioral and Psychological Symptoms of Dementia (BPSD)
and to improve cognition and the functional activity status,
thus reducing the impairment of instrumental activities of the
daily living (IADLs) and to lower the institutionalization rates
(nursing home placement). Unfortunately, only a limited
For reprints and all correspondence: Leopoldo Luiz dos Santos-Neto,
Centro de Clı
´
nica Me
´
dica, Hospital Universita
´
rio de Brası
´
lia (HUB)-UnB,
Caixa postal 04438, 70919-970 Brası
´
lia-DF, Brazil. Tel: þ61-81610333;
Fax: þ61-32451875; E-mail: leoneto@uninet.com.br
2006 The Author(s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/
by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
number of trials have dealt with this topic and with follow-up
periods shorter than two years. In spite of the absence of
sufficient therapeutic effectiveness in mild and moderate AD,
these drugs are still considered as the first line of treatment for
AD (1). Studies of cost-effectiveness suggest that memantine
(2,3) and donepezil (4) are useful in the reduction of
institutionalized care and/or cognitive impairment in patients
with AD. Recently, two clinical trials showed no improvement
of the cognitive deficit (5,6) or reduction in the institutiona-
lization rate (6).
Searching for alternatives, many herbal products have been
tested and employed in the treatment of AD, but with different
clinical responses (7). The assessment of these drugs through
randomized controlled trials should be useful to identify
effective products in the treatment of AD.
Methods
Searching at MEDLINE (during April 2006, PubMed),
LILACS (Latin American and Caribbean Health Science
Literature: 40th edition, May 2001, the last research was
performed in April 2006); Cochrane Library (issue 1, 2006);
Dissertation Abstract (USA, during April 2006); ADEAR
(Alzheimer’s Disease Clinical Trials Database, until April
2006); National Research Register (1/2006); Current Con-
trolled trials (the last research was performed in October
2005); PsychINFO Journal Articles (during the year of 2006);
relevant web sites; and scanning of reference list of relevant
articles. There were no language or publication restrictions.
Search for keywords in MeSH (medical subject heading
(MeSH) with the words ‘Alzheimer disease, dementia,
cognition disorders’ was performed first. In the second part,
the keywords were ‘Herbal’ and ‘Phytotherapy’. The crossover
results of the two searches were evaluated by the Jadad’s
measurement scale (8).
Inclusion criteria: Three investigators independently
reviewed all of the articles found. The articles were selected
using the criteria listed below:
i. The studies should be randomized; double-blind and
controlled (with a control group and a treatment
group).
ii. Studies should establish methodological procedures
in the crossover or be conducted at the same time.
iii. In the case of being crossover, a washout period of at
least 7 days was required.
iv. Patients included in the researches had their diagnosis
rated into three degrees as follows: mild, moderate
and severe forms of AD, according to the criteria from
the National Institute of Neurological and Commu-
nicative Disorders and Stroke—AD and Related
Disorders Association (NINCDS-ADRDA) (9). The
models used were as follows: Mini-mental beginning
values between 10 and 26 (initial and mild group) or
<10 (initial group).
v. Clinical trials should last for at least 1 month
(4 weeks).
vi. Detailed description of the herbal product used.
vii. Neuropsychiatry symptoms progression should be
measured with numerical score using the Assessment
Scale (ADAS-noncog, range of score, 0–70), NPI
(Neuropsychiatric Inventory, range of score 0–120),
Clinical Global impression of change or Behavioral
rating scale for Geriatric patients.
viii. The final score should be quantified using a
combination of ADL and IADL methodological
procedures.
Exclusion criteria: The herbal product has already been
target of a quantified systematic review study. In this case,
only the results of the studies will be considered.
Jadad’s measurement scale: Methodological quality was
assessed using a scale developed and validated by Jadad et al.
(8). This scale assesses the completeness of reporting using
three items with a five points maximum score. If the allocation
into groups is explicitly randomized, item 1 is scored. A bonus
point is given if an adequate method to generate the random
sequence is described. If there is an explicit statement that the
study is double-blind Item 2 is scored. A bonus point is given if
the method is described and adequate. Item 3 is scored if there
is either an explicit statement that all patients included were
also analyzed or if the number and reasons for dropouts in all
groups are given separately. For being classified as adequately
reported a trial should score at least three of five points, a
cut-off point is recommended by the author of the scale (10).
All extraction and quality assessments were performed by at
least two independent reviewers using standard forms
developed for each review. Disagreements were documented
and discussed with final decisions made by the principal
reviewer.
Results
Two herbs and two herbal formulations were identified to have
effectiveness in the treatment of cognitive disturbance of AD
in the systematic review: Salvia officinalis (11), Melissa
officinalis (12), and Yi-Gan San (13) and Ba Wei Di Huang
Wan (BDW) (14). The main characteristics of the study are
described in Table 1.
Gingko biloba was previously identified in one meta-
analysis (15), and only the conclusions of the study will be
considered. Another study will be conducted with huperzine A,
a product derived from a Chinese herb Huperzia serrata,to
evaluate the safety and efficacy in the treatment of AD in a
multicenter randomized controlled trial of its effect on
cognitive function (16).
The studies of Salvia (11), Melissa (12), Yi-Gan San (13)
and BDW (14) have reached Jadad’s measurement scale of
3. The researches had a follow up of 1 month (Yi-Gan San)
(13), 2 months (BDW) (14) and 4 months (Salvia and Melissa)
(11,12). All samples studied were composed of patients with
initial mild symptoms judged as AD. Two studies compared
herbal medicines and control samples, using intention to treat
[Salvia (11) and Melissa (12)].
442 The use of herbal medicine in Alzheimer’s disease
Table 1. Phytotherapic interventions in the Alzheiemer’s disease—selected RCT
Reference
number
No. of
patients
Study and
duration
Herbal medicinal
product name
Composition Dosage regimen and
quantitative
description
Qualitative
testing
Placebo/
control
group
Cognitive
outcome
measurements
Inclusion/exclusion
criteria
Adverse
effects
11 30 Single blind,
4 months
Salvia officinalis
extract manufactured
by the Medicinal
Plants Institute
(Tehran)
Leaf extract
containing essential
oil: aldehydes,
monoterpene,
flavonoids, polyphe-
nol (rosmarinic acid)
and monoterpene
glycosides
3000 mg of alcoholic
solution (45%) per
day, corresponding to
100 mg per ml per day
in a dosage of 3 ml per
day or 60 drops per
day. There is no
information on
interval
There is no
reference on
the article
There is no
reference
on the pla-
cebo used
ADAS-cog
CDR-SB
Cognitive deficit in
the past 6 months.
Mild to moderate
dementia. Patients
under ChE-I treatment
were excluded
Not significant
12 30 Single blind,
4 months
Melissa officinalis
extract, manufactured
by the Department of
Cultivation and
Development of the
Plants Institute
(Tehran)
Hydroalcoholic leaf
extract the containing
500 mg citral per ml
1500 mg of an
alcoholic solution
(45%) per day,
corresponding to
500 mg per ml per day
in a dosage of 3 ml
per day or 60 drops
per day
There is no
reference on
the article
There is no
reference
on the pla-
cebo used
ADAS-cog
CDR-SB
Cognitive deficit in
the past 6 months.
Mild to moderate
dementia. Patients
under ChE-I treatment
were excluded
Agitation
occurred to
40% of indi-
viduals from
placebo group
versus 5%
from the study
group
(P ¼ 00.3)
13 52 Single-blind,
1 month
Yi-Gan-San formula* Rootstock and
branches lyophilized
dry extract
2.5 g of YGS powder,
corresponding to 1.5 g
of the TID extract
before meals
3D-HPLC There is no
reference
on the pla-
cebo used
NPI Barthel
Index MMSE
Dementia with over
than 12 month of
diagnosis. 17.3% (9)
presented some type
of associated cerebral-
vascular disease.
Patients under ChE-I
treatment were
excluded
Not significant
14 50 Double-blind,
2 months
Ba Wei Di Huang
Wan
†
. Product
approved for use in
Japan, manufactured
by Uchida
Wakanyaku Co. Ltd
Powder containing
medicinal plants
mixed with honey
20 cpr (2 g) of BDW
or TID placebo after
meals
There is no
reference on
the article
Black face
powder
with
Sepia sp.
MMSE
Barthel Index
Dementia with over
than 12 month of
diagnosis. 17.3% (9)
presented some type
of associated cerebral-
vascular disease.
Patients under ChE-I
treatment were
excluded
Not significant
ADAS-cog, Alzheimer’s disease assessment scale; CDR-SB, clinical dementia rating-sum of the boxes; ChE-I, acetyl cholinestarase inhibitor; MMSE, mini-mental state examination; NPI, neuropsychiatric
inventory; HPLC, high-performance liquid chromatography.
*Formula containing 4 g de Atractylodis Lanceaea rootstock; 4.0 g of Poria cocos Wolf; 3.0 g of Cnidium monnieri rootstock; 3.0 g of Urticaria and Angelica sinensis root; 2.0 g of Bupleuri radix; 1.5 g of
Glycyrrhizae uralensis rhizoma; and 3.0 g of Uncariae ramulus et Uncus.
†
Formula containing 8 g of Rehmannia glutinosa Libosh. var. purpurea Makino (Scrophulariaceae); 4 g of Cornus officinalis Sieb et zucc (Cornaceae); 4 g of Dioscorea batatas Decne root (Dioscoreaceae); 3 g od
Alisma orientale Juzep rhizome (Alimataccae); 3 g of Poria cocos Wolf (Poriacea); 3 g of Paeonia suffruticosa Andr. (Paeoniaceae); 1 g of Cinnamomum cassia Blume (Lauraceae); and 1 g of Aconitum
carmichaeli Debx. (Ranunculaceae).
eCAM 2006;3(4) 443
None of the studies evaluated the institutionalization rate or
compared the active principle with the current therapies with
Acetyl Cholinesterase Inhibitor or memantine.
Discussion
The results of this systematic review identified four studies
with methodological quality assessing S. officinalis (11),
M. officinalis (12), Yi-Gan San (13) and BDW (14). The last
two are composed of formulations with different phytoactive
agents. These herbs and formulations presented efficiency in
reducing the mild and moderate symptoms of AD.
Gingko biloba presented statistically significant mild
effectiveness in the treatment of cognitive deficit in AD. The
meta-analysis study of Cochrane (13) concluded that addi-
tional controlled studies would be necessary in order to
recognize cognitive improvement with the use of gingko.
There is still need of a prospective study with an appropriate
duration and representative sample to identify if G. biloba
reduces the development of AD (17). Another plant with a
large application perspective is H. serrata, after multicenter
trial confirmation underway (16).
Melissa and Yi-Gan San showed reduction in the cognitive
deficits and a good sedative effect in patients with AD (12,13).
Previous clinical studies showed that the extract of
M. officinalis reduces laboratory-induced stress (18) and might
have benefits in mood improvement (19–21). The use of these
herbs and formulations should be well tolerated, (22) and
adverse effects have not yet been reported (23). Further studies
should be conducted to compare the current therapies for
AD and the use of these herbal remedies in controlling the
symptoms of AD.
The action mechanisms of these herbs and formulations are
not well known. It has been suggested that the chemical
composition of the essential oil of the Melissa and Salvia leaf
extracts are monoterpene aldehydes, polyphenol flavonoids
(including rosmarinic acid) (24) and monoterpene glycosides
(25). All of these components have many observable effects
in vitro, which include powerful anti-oxidative activity (26,27)
and an affinity to nicotinic and muscarinic receptor in the
human cerebral cortex (28). This last mechanism is of special
interest, as modulation of cholinergic systems should play a
role in improving the cognitive function, especially in AD.
Yi-Gan San and BDW are mixes of many herbal ingredients.
Yi-Gan San is a mixture of 7 different dried plants, many of
them (Unticariae sinensis and Angelicae root) with possible
actions in the serotoninergic and gaba system. BDW consists
of 8 herbs: Rehmannia glutinosa Libosh. var purpurea Makino,
Cornus officinalis Sieb et Zucc (Cornaceae), Dioscorea
batatas Decne root (Dioscoreaceae), Alisma orientale Juzep
rhizome (Alimataccae), Poria cocos Wolf, Paeonia suffruti-
cosa Andr. (Paeoniaceae), Cinnamomum cassia Blume (Laur-
aceae) and Aconitum carmichaeli Debx. (Ranunculaceae).
Studies have suggested that BDW enhances the choline
acetyltransferase activity and increases the acetylcholine
content of the frontal cortex in a murine model (29,30).
Major methodological limitations of the four studies are
small size of samples and short-term duration. There is no
description of the chemical composition and/or possible active
principles of the different products employed in studies
Involving Yi-Gan San (13) and BDW (14) formulation
(Table 1). In the study with BDW (13), Sepia sp. and face
powder were used as placebo; however, the way that the
shellfish formulation was performed was not described. In the
control group of the study using the Yi-Gan-San (14)
formulation, 25 mg per day of tiapride hydrochloride were
introduced. This drug is a substituted derivative with selective
dopamine D2-receptor antagonist properties. This intervention
(contamination) occurred in 44% of the individuals and was
responsible for the symptoms, among them dizziness.
Generally, crude herbal drugs are natural products and their
chemical composition depends on several factors such as
geographic source of the plant material, climate in which it
was grown, and time of harvest. Commercially available
herbal medicinal products also vary in their content and
concentration of chemical constituents from batch to batch and
when products containing the same herbal ingredient are
compared between manufacturers. Even when herbal products
are standardized for content of known active or marker
compounds to achieve more consistent pharmaceutical quality,
variations in the concentrations of other constituents can be
observed. The use of a protocol such as the Consolidated
Standards of Reporting Trials (CONSORT), composed of
22 items, will probably minimize the limitations of RTC with
phytotherapic agents (31).
The use of herbal medicines in the treatment of AD should
be compared with the pharmacological treatment currently in
use. Such studies should include the identification of the active
principle in order to improve the validation of the clinical
trial. Further large-scale, multicenter studies are necessary to
determine the effectiveness of these substances in the
cognitive deterioration of AD. Until then, this review provides
some evidence of the benefit of Melissa, Salvia, Yi-Gan San
and BDW in the treatment of AD.
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Received November 26, 2005; accepted September 15, 2006
eCAM 2006;3(4) 445
