The Role of Natural Products in Pharmacotherapy of Alzheimer’s Disease
By Dr. Amrit Pal Singh, MD (Alternative Medicine), Medical Executive, Super Speciality Division, Ind Swift
Address for correspondence:
Dr Amrit Pal Singh
House No: 2101 Phase-7
Alzheimer’s disease is characterized by forgetfulness, disturbance in memory and loss of mental abilities. The final
outcome of the disease is loss of personality and intellectual functions. Alzheimer’s disease is common cause of
dementia particularly after the age of 70 years. Cholinesterase inhibitors are used for the treatment of Alzheimer’s
dementia, but due to unpleasant side effect; these groups of drugs can not be used for long term treatment. Phyto drugs
are being investigated for possible cure of Alzheimer’s disease. A number of constituents like Galanthamine,
Huperzine, Hyperforin, & Desoxy-peganine have shown promising result. Some Ayurvedic herbs like Bacopa
monneria (Bacosides) have recently gained attention because of memory enhancing activity. The article deals with
latest findings in phytotherapy of Alzheimer’s disease.
Keywords: Alzheimer’s disease, Dementia, Natural Products, Medicinal Herbs.
Alzheimer’s disease is a leading cause of dementia in developed countries. Alzheimer’s disease is a progressive,
degenerative disease characterized by memory loss, language deterioration, impaired visuospatial skills, poor judgment,
indifferent attitude, but preserved motor function (1). Alzheimer’s disease usually begins after age 65, however, its
onset may occur as early as age 40, appearing first as memory decline and, over several years, destroying cognition,
personality, and ability to function.
Confusion and restlessness may also occur. The type, severity, sequence, and progression of mental changes vary
widely. The early symptoms of Alzheimer’s disease, which include forgetfulness and loss of concentration, can be
missed easily because they resemble natural signs of aging (2). Similar symptoms can also result from fatigue, grief,
depression, illness, vision or hearing loss, the use of alcohol or certain medications, or simply the burden of too many
details to remember at once. The course of the disease varies from person to person (3).
There is no cure for Alzheimer’s disease and to slow the progression of the disease. Tacrine has shown positive results
in improving mental functions in patients in the early or middle stages of Alzheimer’s disease (4). Reversible
acetylcholinesterase inhibitors are used for the treatment of mild to moderate dementia of the Alzheimer’s disease (5).
Although acetylcholinesterase inhibitors have shown promising results, an effective therapeutic answer for Alzheimer’s
disease is still eluding the scientific research.
Natural products are significant source of synthetic and traditional herbal medicines (6). In rural areas natural products
are still the primary healthcare systems. The alternative systems of medicine include Ayurveda, Siddha, Homeopathy,
Unani and Traditional Chinese Medicine (TCM) and all have roots in natural products (7). The use of natural products
is limited not only to herbs but marine, animal and mineral preparations have been purified by the traditional healers
for medicinal use (8). Alternative medicine is becoming popular and increasing number of patients are visiting
alternative medicine healers (9).
The natural products are often crude in original state. Today standardised extracts are used in herbal practice and with
the help of procedures like chromatography it is possible to study the chemical composition of plants. Alzheimer’s
disease is the area, where natural products have not been exploited to their potential (10). Some institutions are
carrying out preclinical trials with isolated constituents like Huperzine, Bacosides, Hyperforin, & Desoxy-peganine.
Bacopa monniera (Nir-brahami) is a medicinal herb used in ancient system of medicine, Ayurveda. Recent clinical
research has highlighted the cognition enhancing activity of the herb. Saponins (Bacosides) are the active principles of
the herb and classified as Bacoside- A $ B. A standardised extract containing Bacosides content upto 2.5-3.0% is
recommended (11). In a double blind placebo-controlled study the herb (300-mg) was tested for cognition enhancing
activity. Neuropsychological testing was conducted pre- (baseline) and at 5 and 12 weeks post drug administration.
Bacopa monniera significantly improved speed of visual information processing measured by the IT task, learning rate
and memory consolidation measured by the AVLT (P<0.05), and state anxiety (P<0.001) compared to placebo, with
maximal effects evident after 12 weeks (12).
Withania somnifera (Ashwagandha) is important medicinal plant of Ayurveda. Animal studies have shown that
Withania somnifera may alternate concentrations of neurotransmitters at brain levels. A methanolic extract of Withania
somnifera root inhibited the specific binding of [3H] GABA and [35S] TBPS, and enhanced the binding of [3H]
flunitrazepam to their putative receptor sites. The extract inhibited [3H] GABA binding by 20 +/- 6 per cent whereas a
concentration of 1 mg of the extract produced 100 per cent inhibition. The extract (5-100 micrograms) produced 20 +/-
4 to 91 +/- 16 per cent enhancement of [3H] flunitrazepam binding. In functional studies using 36Cl-influx assay in
mammalian spinal cord neurons, W. somnifera root extract increased 36Cl-influx in the absence of GABA. This effect
on 36Cl-influx was blocked by bicuculline and picrotoxin; and enhanced by diazepam. The results suggest that the
Withania somnifera extract contain an ingredient, which has a GABA-mimetic activity (13).
In another study, Sitoindosides VII-X, and Withaferin-A (Withanolide), isolated from aqueous methanol extract from
the roots of Withania somnifera induced increase in cortical muscarinic acetylcholine receptor capacity. This may be a
possible mechanism behind the cognition-enhancing and memory-improving effects of extracts from Withania
somnifera observed in animals and humans (14).
Latest research investigations have proved Ginkgo biloba to be effective in the treatment of cerebral insufficiency,
dementia (including Alzheimer’s disease), arteriosclerosis and depression. Ginkgo has shown to increase production of
adenosine triphosphate, resulting in increased cerebral glucose metabolism Ginkgo’s effect contains a group of
flavonoids called ginkgolides, which act by dilating micro-capillaries, thereby increasing oxygen levels in cerebral
tissue (15). A standardized extract containing 24% Ginkgo flavonglycosides of 40 mg three times daily is
recommended by many practitioners.
Hyperforin, the acylphloroglucinol derivative of Hypericum perforatum, commonly known as St.John’s wort, has
recently gained attention of researchers as a United States Patent has been filed by Chatterjee, et al for use of
Hyperforin and Hyperforin based extracts in the treatment of dementia (16). Although standardised extracts of
Hypericum perforatum are used in the treatment of mild to moderate depression, but Chatterjee, et al. have developed
a method for stabilization of Hyperforin, as it is a highly unstable compound (17). An international patent has also
been filed by Dr.Willmar Schwabe for the use of pure Hyperforin and Hyperforin containing salts for treatment of
Deoxypeganine (an alkaloid) present in Peganum harmala has been reported to be helpful in treating Alzheimer’s
dementia. Deoxypeganine has been investigated in detail in the former Soviet Union and its pharmacological actions
have been intensively researched. Pharmacological studies in America have revealed that Deoxypeganine has activity
similar to reversibly acting cholinesterase inhibitors. Deoxypeganine inhibits acetylcholinesterase and monoamine
oxidase, thereby preventing the degradation of acetylcholine and dopamine. Deoxypeganine is known to cross the
Huperzine, an alkaloid isolated from highly concentrated and purified extract of Huperzia serrata (previously known
as Lycopoduim serrata) has shown usefulness in Alzheimer’s disease. Huperzine A has been evaluated in placebocontrolled clinical trials in China both as a treatment for Alzheimer’s disease as well as a treatment for memory loss
(18). In these studies, the Huperzine was well-tolerated and significantly improved memory and cognitive performance
(19). Huperzine A readily crosses the blood-brain-barrier. Scientific studies have shown that Huperzine A inhibits
acetylcholinesterase activity in the brain and increases the acetylcholine levels for up to 6 hours (20).
Vinpocetine an alkaloid isolated from Madagascar periwinkle, Vinca alba, has demonstrated significant nootropic
activity (21). Vinpocetine, improves blood flow to the brain, makes it easier for the brain to use glucose and oxygen,
and allows the brain to survive longer and better after periods of oxygen deprivation. In another double-blind study
(22), elderly patients with central nervous system degenerative disorders were treated with Vinpocetine or placebo.
Patients receiving 10 mg of Vinpocetine three times a day for 30 days, then 5 mg three times a day for 60 days scored
consistently better in all evaluations. CGI Vinpocetine group at day 30; 77% at day 90; improvement seen in 77% at
day 30 and 87% at day 90. The improvement in 59% Vinpocetine-treated patients was rated good to excellent. No
serious side effects were reported (22).
An acetone extract of Lawsonia inermis has shown nootropic effect in animal models. The active constituent of
Lawsonia inermis has not been studied (23). Salvia officinalis has been reported to have cholinergic activities (10).
Melissa officnalis has been reported to have interaction with nicotinic receptors in the Central nervous system (24).
Nicotinic receptor activation is associated with protection against beta-amyloid- and glutamate- induced cytotoxicity.
Cholinergic activity in the GI tract might explain the use of lemon balm to treat functional GI complaints; however, the
actions of lemon balm on the GI tract are unclear.
Galantamine is an alkaloid, which was isolated from Galanthus nivalis L by D. Paskov and L. Ivanova in 1956 (25).
Now a day’s synthetic version of Galantamine is available for the treatment of Alzheimer’s dementia. Several
multicenter clinical trials have shown usefulness of Galantamine in the treatment of dementia. Studies have revealed
that Galantamine interacts with nicotinic cholinergic receptors. In a 6-month double-blind phase, 1289 patients were
randomized to treatment with 24 or 32 mg/day of Galantamine vs. placebo, followed by a 6 month open-label phase, in
which all patients received 24 mg/day. The group on Galantamine was benefited more than placebo in terms of
Dementia scale (26). So far seven studies have been done and it has been concluded that the pharmacological activity
of Galantamine is similar to acetylcholinesterase inhibitors.
The efficacy of certain herbal products is beyond doubt, common examples being Vincristine, Vinblastine, and
Morphine & Digoxin. Artemesinin, Taxol & Silymarin have been recently developed from plant source and are
reputed drugs in their respective segments. Scientists are exploring natural products for effective answer for
Alzheimer’s disease and isolated fractions of some medicinal herbs have shown promising results. Ethical
phytochemical screening and large-scale trials are required for further scientific validation of these remedies.
1. Daly MP. Diagnosis and management of Alzheimer disease. J Am Board Fam Pract 1999; 12(5): 375-384.
2. Brinton RD A women’s health issue: Alzheimer’s disease and strategies for maintaining cognitive health. Int J Fertil
Womens Med 1999; 44: 174-85.
3. Plassman BL, Havlik RJ, Steffens DC, Helms MJ, Newman TN, Drosdick D, Phillips C, Gau BA, Welsh-Bohmer
KA, Burke JR, Guralnik JM, Breitner JC. Documented head injury in early adulthood and risk of Alzheimer’s disease
and other dementias. Neurology 2000; 55: 1158-66.
4. Qizilbash N, Whitehead A, Higgins J, Wilcock G, et al. Cholinesterase inhibition for Alzheimer disease. JAMA.
5. Knapp MJ, Knopman DS, Solomon PR, Pendlebury WW, Davis CS, Gracon SI, for the Tacrine Study Group. A 30-
week randomized controlled trial of high-dose tacrine in patients with Alzheimer’s disease. JAMA. 1994; 271:985-991.
6. Wasik J. The truth about herbal supplements. Consumer’s Digest. July/August 1999; 75-76, 78-79.
7. Eisenberg DM, Kessler RC, Foster C, Norlock FE, Calkins DR, Delbanco TL. Unconventional medicine in the
United States – Prevalence, costs and patterns of use. NEJM 1993,328-246-252.
8. Malhotra S, Bhatia GS, Pandhi P. Patterns of use of unconventional therapies in the medical outpatient department
of a tertiary care hospital in India. J Ethnopharmacol 2001, 75: 71-75.
9. Quid PM. A review of nutrients and botanicals in the integrative management of cognitive dysfunction. Alternative
Medicine Review 1999; 4: 144-161.
10. Perry EK, Pickering AT, Wang WW, Houghton PJ, Perry NS Medicinal plants and Alzheimer’s disease: from
ethnobotany to phytotherapy. Medical Research Council, Newcastle General Hospital, Newcastle upon Tyne. J Pharm
Pharmacol 1999 May; 51(5):527-34.
11. Singh HK, Dhawan BN. Neuropsychopharmacological effects of the Ayurvedic nootropic Bacopa monniera Linn.
(Brahmi). Indian Journal of Pharmacology 1997; 29: S359-S365.
12. Stough C, Lloyd J, Clarke J, Downey LA, Hutchison CW, Rodgers T, Nathan PJ. The chronic effects of an extract
of Bacopa monniera on cognitive function in healthy human subjects. Neuropsychology Laboratory, School of
Biophysical Science and Electrical Engineering, Victoria, Australia.
13. Mehta K Binkley P Gandhi S S Ticku MK Pharmacological effects of Withania somnifera root extract on GABAA
receptor complex. In: Indian J Med Res (1991 Aug) 94:312-5.
14. Schliebs R.; Liebmann A.; Bhattacharya S.K.; Kumar A.; Ghosal S.; Bigl V.R. Schliebs, Paul Flechsig Systemic
administration of defined extracts from Withania somnifera (Indian Ginseng) and Shilajit differentially affects
cholinergic but not glutamatergic and gabaergic markers in rat brain. Institute Brain Res., Department of
Neurochemistry, University of Leipzig, D-04109 Leipzig Germany. Neurochemistry International (United Kingdom),
1997, 30/2 (181-190).
15. Kanowski S, Herrmann W M, Stephen K, Wierich W, Horr R, (1995). Proof of efficacy of the Ginkgo biloba
special extract Egb 761 in outpatients suffering from primary degenerative dementia of the Alzheimer’s type and multi
infract dementia Pharmacopsychiatry 4- 149- 158.
16. Chatterjee SS, Noldner M, Koch M, Erdelmeier C. Antidepressant activity of Hypericum perforatum L. and
hyperforin, the neglected possibility. Pharmacopsychiatry. 1998; 31(1): 7-15.
17. Sparenberg B, Demisch L, Holzl J. Investigations of the antidepressive effects of St. John’s wort. Pz Wissenschaft.
1993; 138(2): 50-54.
18. Zhang RW, et al. Drug evaluation of Huperzine A in the treatment of senile memory disorders (in Chinese). Chung
Kuo Yao Li Hsueh Pao 12: 250–252, 1991.
19. Cheng DH and Tang XC. Comparative studies of Huperzine A, E2020, and tacrine on behavior and cholinesterase
activities. Pharmacol Biochem Behav 60: 377-386, 1998.
20. Cheng DH et al. Huperzine A, a novel promising acetylcholinesterase inhibitor. Neuroreport 8: 97–101, 1996.
21. Tamaki, N., Kusunoki, T., Matsumoto, S., The effect of Vinpocetine on cerebral blood flow in patients with
cerebrovascular disease. Ther Hung, 33: 13-21. 1985.
22. Balestreri, R., Fontana, L., and Astengo, F., A double-blind placebo controlled evaluation of the safety and efficacy
of vinpocetine in the treatment of patients with chronic vascular senile cerebral dysfunction. J Am Geriatr Soc 35: 425-
23. Iyer MR, Pal SC, Kasture VS, Kasture SB. Effect of Lawsonia inermis on memory and behavior mediated via
monoamine neurotransmitters. Indian J Pharmacol 1998:30:181-5.
24. Wake G, Court J, Pickering A, et al. CNS acetylcholine receptor actvity: Ethnopharmacol 2000; 69: 105—14.
25. Olin J, Schneider L. Galantamine of Alzheimer’s disease. Cochrane Database Syst Rev 2001; 1: CD001747.
26. Olin J, Schneider L. Galantamine for Alzheimer’s disease. Adult and Geriatric Treatment and Preventative
Interventions Branch, National Institute of Mental Health, NIMH, Room 7160, MSC 9635, 6001 Executive Blvd.,
Bethesda, Maryland, USA, 20892-9635. Cochrane Database Syst Rev 2001; 4: CD001747.
Return to Home Page
SIUC / Ethnobotanical Leaflets /
Last updated: 08-July-2003 / du
The Role of Natural Products in Pharmacotherapy of Alzheimer’s Disease