Wadie Najm, MD

Dementia is defined as an acquired persistent impairment of intellectual function with compromise in at least three of the following spheres of mental activity: language, memory, visuospatial skills, emotion or personality, and cognition. 

Despite recent advances in our understanding of the pathophysiology of Alzheimer's disease (AD) and other dementing illnesses, current treatments for these disorders often fall short of expectation. Patients, family members and caregivers often find themselves unable to resist the lure of using so-called natural products to treat or prevent memory impairments and their behavioral and psychological symptoms. This article will focus on providing an overview of the current scientific evidence of commonly used supplements for memory impairment. 

Lecithin is found in many animal and vegetable sources (e.g., peanuts, cauliflower, oranges, eggs, steak and beef liver). Commercial sources can come from soybeans, eggs and other animal sources. Lecithin is a choline-containing phospholipid and a major dietary source of choline. It is postulated to accelerate the synthesis of acetylcholine in the brain (Higgins and Flicker, 2000). 

A review of 12 studies of dementia of the Alzheimer's type (DAT) to determine the efficacy of lecithin showed an overall relative deterioration of activities of daily living (ADLs) and no improvement of cognition or global impairment (Higgins and Flicker, 2000). In that same review, one trial of Parkinson's dementia showed a nonsignificant improvement in orientation and memory tests. There was no evidence of an effect on functional performance. However, the reviewers did find possible statistical improvement in one trial of subjective memory complaints.

The proposed lecithin dose is 1.2 g/day to 2.4 g/day. Possible adverse reactions include gastrointestinal (GI) pain, nausea or diarrhea. No adverse interactions have been reported.

Also known as tocopherol and tocotrienol, vitamin E occurs in oils, fats, nuts and other seeds, as well as a variety of animal foods. Alpha-tocopherol, the medical form used, is fat-soluble, and can therefore enter the brain. Vitamin E functions biologically as an antioxidant, inhibiting the process of lipid peroxidation. 

One study using 1000 international units (IU) bid of vitamin E over two years in subjects with moderate DAT found no difference in survival time. The combination of vitamin E (2000 IU/day) and selegiline (Eldepryl) (10 mg/day) was shown to reduce the rate of decline of functions in patients with AD. However, combined therapy was not superior to either agent alone (Sano et al., 1997). 

Data from the Honolulu-Asia Aging Study suggested that vitamins E and C have a protective effect for vascular and mixed dementias and may improve cognitive function in late life (Masaki et al., 2000). 

The proposed dose of vitamin E is 1000 IU bid. While possible adverse reactions are rarely reported, vitamin E may cause GI disturbances, blurred vision, headaches and fatigue. 

Theoretically, vitamin E might increase the risk of bleeding in people with vitamin K deficiency or bleeding tendencies. It may theoretically have an additive interaction with antiplatelet and anticoagulant medications. 

, which is present in cereal grains, nuts, meats and legumes, in treating alcoholic amnesia is well established. Animal studies both suggested that vitamin B

 might facilitate the presynaptic release of acetylcholine and bind to nicotinic receptors enhancing anticholinesterase activity. These may have a role in the management of AD. 

 as a treatment for AD are mostly small with fewer than 50 subjects. Most studies used subjects with mild-to-moderately severe AD and measured cognition and behavior as the primary outcomes. Overall results showed no improvement in cognition; however, results should be considered as inconclusive due to poor design and small number of subjects (Rodriguez-Martin et al., 2001). 

 may cause a hypersensitivity reaction or dermatitis. Loop diuretics may increase urinary B

 excretion resulting in a deficiency that can affect cardiac function. 

 is an Ayurvedic herbal used for mental illness, epilepsy and cognitive enhancement. 

Steroidal saponins derived from the leaves are the active principle ingredient thought to enhance nerve impulse transmission, and hence to improve memory and cognition. Animal and human studies conducted in India in the early 1980s reported memory enhancing effects with improved concentration and working memory (Singh and Dhawan, 1982; Singh and Singh, 1980). Further studies are needed to explore the pharmacology and clinical usefulness of this supplement.

The proposed dose of Bacopa monniera is 12 g/day of the dried plant in syrup. Possible adverse effects and interactions are unclear from the literature available.

Perhaps the most widely recognized plant in folk medicine, ginseng (

) refers to several different species originating in different countries. The root is considered the most valuable in traditional medicine and has been used in the treatment of a great number of symptoms and diseases. The contents of the particular root are dependent on the species, age, location of plant, and method and timing of harvest and processing. Over the last decades, laboratory and human studies have documented a range of pharmacological effects from the ginsenosides, the steroid-like compounds found in ginseng. Ginseng is known as an adaptogen. Animal studies report a reversal of scopolamine-induced memory deficits in rats, an increase in acetylcholine uptake and improved learning performance. In humans, two randomized, controlled trials reported some improvement in cognitive function over eight and 12 weeks of ginseng use. Another study, looking specifically at 50 elderly subjects, reported improvement over baseline measures (Vogler et al., 1999). 

The proposed ginseng dose is 400 mg/day. Possible adverse effects from taking ginseng include headache, hypoglycemia, tremor, sleep disorders and GI disorders. Ginseng may interact with warfarin (Coumadin), diabetic agents and insulin, diuretics, digoxin, phenelzine (Nardil), and alcohol.

An endogenous substance that participates in cellular energy production, acetyl-l-carnitine is structurally related to acetylcholine; hence it may enhance cholinergic neurotransmission. It may also promote mitochondrial membrane stabilization. 

Several animal and laboratory studies suggested a possible role in delaying cognitive decline. A large-scale study enrolled 229 subjects with probable AD between 45 years of age and 65 years of age. Subjects were randomized to 1 g tid or placebo. No differences in the rate of decline of cognitive function were noted (Thal et al., 2000). This finding is contrary to outcomes reported in previous smaller studies that indicated a slowing of cognitive decline. Further studies are needed to evaluate the possible role of acetyl-l-carnitine in the management of memory impairment.

The proposed dose of acetyl-l-carnitine is 1.5 g/day to 4 g/day divided in three doses. Possible adverse reactions may include confusion, depression, agitation or aggression in patients with AD. No adverse interactions have been reported.

 extracts are prepared from the green leaves of the maidenhair tree. More than 40 individual components of ginkgo have been identified so far. Actions of the components of ginkgo include antioxidant properties, vasodilation, antagonism of platelet-activating factor and an increase in density of muscarinic receptors. 

A recent review of nine randomized, double-blind, controlled studies suggested that ginkgo extract is more effective than placebo in delaying the deterioration of AD, vascular dementia and mixed types. A small effect was observed after six months in a meta-analysis looking at subjects with mild-to-moderate AD (Ernst and Pittler, 1999). Wettstein (2000) compared placebo-controlled studies of available cholinesterase inhibitors with studies of the standardized ginkgo extract EGb 761 and found similar periods of delay in disease progression, although  another well-designed study failed to find any benefit in elderly subjects with mild-to-moderate dementia (van Dongen et al., 2000). Large doses of ginkgo (>600 mg) resulted in subtle improvement in speed of information processing but not in other cognitive functions. Overall, studies looking at memory improvement in nondemented healthy adults have been inconclusive.

The proposed dose of ginkgo is 120 mg/day to 240 mg/day divided in three doses of the standardized extract containing 24% flavonoids and 6% terpenoids. Possible adverse reactions include headache, dizziness, palpitations, restlessness, weakness, central nervous system hemorrhage and seizures. Ginkgo should be used with caution with medications that inhibit clotting or enhance bleeding.

An alkaloid extracted from a moss, huperzine A (

) is used in Chinese medicine for a variety of conditions including memory problems. It is currently being sold in the United States as an over-the-counter dietary supplement to enhance cognition for people with memory loss. 

Research has shown huperzine A to be a selective and reversible inhibitor of acetylcholinesterase. It also has been shown to lessen neuronal toxicity caused by glutamate. Initial small investigations reported improvement in cognitive functions of subjects with AD (Xu et al., 1999; Xu et al.,1995). Further evaluations are warranted. 

The proposed dose of huperzine A is 30 mcg to 200 mcg bid. Possible adverse reactions include blurred vision, GI effects, hyperactivity, anorexia and bradycardia. Use of huperzine A might worsen overflow incontinence.	

Theoretically, huperzine A could have an additive effect on cholinergic and acetylcholinesterase inhibitors and interact adversely with anticholinergic drugs. 

Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S) are secreted by the adrenal glands and are the precursors of androgens. Their exact effect on cognition is unclear, but some authors attribute it to neurotransmission. Levels of DHEA peak at puberty and fall slowly as people get older (Schneider et al., 1992). Restoring low levels of DHEA has been reported to improve the overall well-being of older adults (Huppert et al., 2000). 

Two prospective studies of 833 community-dwelling men and a middle-class cohort of 270 men, respectively, found no association between levels of DHEA-S and cognitive decline (Barrett-Connor and Edelstein, 1994; Moffat et al., 2000). Other studies reported similar findings among men and women. A clinical observational study of patients with AD found no association between cognition and DHEA-S level. Huppert et al. (2000) concluded that the data offered no support for an improvement in memory or other aspects of cognitive function in normal older people.

Commercial products are manufactured from a wild yam extract. The proposed dose of DHEA or DHEA-S is 25 mg/day to 250 mg/day qid. Determination is based on measured blood levels. Possible adverse reactions include acne, hair loss, hirsutism, decreased high-density lipoproteins, insulin resistance, mania, hypertension, abdominal pain, liver dysfunction and menstrual irregularity. 

Since DHEA inhibits cytochrome P450 3A, it can potentially affect all drugs metabolized through this mechanism. Caution is required for people with diabetes as DHEA may increase insulin resistance. Individuals with hormone sensitive neoplasm, liver disease and bipolar disorder should avoid DHEA. Theoretically, soy may decrease the effect of DHEA. 

A broad-spectrum antibiotic previously used for the treatment of tuberculosis, D-cycloserine is a structural analogue of the amino acids glycine and D-alanine.

There is accumulating evidence that supports an important role for N-methyl-D-aspartate (NMDA) receptors in learning and memory through long-term potentiation. The activity of NMDA receptors can be modulated by the activity of glycine. These glycine receptors are also stimulated by the antibiotic D-cycloserine. Hence, it has been suggested that D-cycloserine might improve memory and other cognitive processes. An initial study using low doses of D-cycloserine reported a reversal of scopolamine-induced memory impairment in healthy young subjects (Laake and Oeksengaard, 2002). 

In a review of four studies (two large and two small) using varied doses in subjects with different levels of memory impairment, Laake and Oeksengaard (2002) found no evidence of differences with placebo in the measurement of Clinical Global Improvement Scale (CGI), mini-mental state exam (MMSE), and other cognitive and functional scales. The number of dropouts was much higher in the treatment group than in the placebo group. 

The proposed D-cycloserine dose is 10 mg to 200 mg divided into two doses per day. Adverse reactions are dose-related and include ankle clonus, confusion, dysarthria, headache, hyper-reflexia, irritability, nervousness, paranoid reactions, psychotic states with suicidal tendencies, vertigo, paresis, seizures and tremor. No adverse interactions have been reported.

An amino acid found in green tea, theanine is a glutamate analog. Theoretically it can provide neuroprotection by antagonizing the effect of glutamate and NMDA receptors. 

Animal studies indicate a possible protective effect of ischemic neuronal death (Kakuda et al., 2000). No human studies were located for this review.

No typical dose in humans has been proposed and the possible adverse reactions are unknown. Theanine can interact adversely with catecholamine and cause vasoconstriction, so it should be used with caution in people with hypertension.

Most studies of the phospholipid phosphatidylserine used bovine brain sources, but, due to concerns about mad cow disease, soy or cabbage sources are now available. Phosphatidylserine is active at cell membranes, including synaptic membrane zones. Partial improvement of learning and recall capacity was noted in subjects with age-related cognitive decline (Crook et al., 1991). 

The proposed dose is 100 mg/day to 300 mg/day. Possible adverse reactions include GI upset and insomnia at high doses. Phosphatidylserine may interact with uric acid and alanine aminotransferase (ALT/SGPT) lab tests. There have been no reported adverse interactions.

Among the many dietary supplements used for memory impairment, several have shown some evidence of effectiveness. Others are still awaiting proof through well-designed studies. Despite the great interest in and use of dietary supplements, the collection of scientific evidence on their efficacy is still in its infancy, and better-designed studies are needed to provide us with answers. For now, clinicians need to use caution in interpreting available information and in counseling their patients. 

 Barrett-Connor E, Edelstein SL (1994), A prospective study of dehydroepiandrosterone sulfate and cognitive function in an older population: the Rancho Bernardo study. J Am Geriatr Soc 42(4):420-423.
 

 Crook TH, Tinklenberg J, Yesavage J et al. (1991), Effects of phosphatidylserine in age-associated memory impairment. Neurology 41(5):644-649.
 

 Ernst E, Pittler MH (1999), Ginkgo biloba for dementia: a systematic review of double-blind, placebo-controlled trials. Clinical Drug Investigation 17(4):301-308.
 

 Higgins JP, Flicker L (2000), Lecithin for dementia and cognitive impairment. Cochrane Database Syst Rev (2):CD001015.
 

 Huppert FA, Van Niekerk JK, Herbert J (2000), Dehydroepiandrosterone (DHEA) supplementation for cognition and well-being. Cochrane Database Syst Rev (2):CD000304.
 

 Kakuda T, Yanase H, Utsunomiya K et al. (2000), Protective effect of gamma-glutamylethylamide (theanine) on ischemic delayed neuronal death in gerbils. Neurosci Lett 289(3):189-192.
 

 Laake K, Oeksengaard AR (2002), D-cycloserine for Alzheimer's disease. Cochrane Database Syst Rev (2):CD003153.
 

 Masaki KH, Losonczy KG, Izmirlian G et al. (2000), Association of vitamin E and C supplement use with cognitive function and dementia in elderly men. Neurology 54(6):1265-1272 [see comment].
 

 Moffat SD, Zonderman AB, Harman SM et al. (2000), The relationship between longitudinal declines in dehydroepiandrosterone sulfate concentrations and cognitive performance in older men. Arch Intern Med 160(14):2193-2198.
 

 Rodriguez-Martin JL, Qizilbash N, Lopez-Arrieta JM (2001), Thiamine for Alzheimer's disease. Cochrane Database Syst Rev (2):CD001498.
 

 Sano M, Ernesto C, Thomas RG et al. (1997), A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med 336(17):1216-1222 [see comments].
 

 Schneider LS, Hinsey M, Lyness S (1992), Plasma dehydroepiandrosterone sulfate in Alzheimer's disease. Biol Psychiatry 31(2):205-208.
 

 Singh HK, Dhawan BN (1982), Effect of Bacopa monniera Linn. (brahmi) extract on avoidance responses in rat. J Ethnopharmacol 5(2):205-214.
 

 Singh RH, Singh L (1980), Studies on the anti-anxiety effect of the medyha rasayana drug, Brahmi (Bacopa monniera Wettst.). J Res Ayur Siddha 1:133-148.
 

 Thal LJ, Calvani M, Amato A, Carta A (2000), A 1-year controlled trial of acetyl-l-carnitine in early-onset AD. Neurology 55(6):805-810 [see comment].
 

 van Dongen MC, van Rossum E, Kessels AG et al. (2000), The efficacy of gingko for elderly people with dementia and age-associated memory impairment: new results of a randomized clinical trial. J Am Geriatr Soc 48(10):1183-1194.
 

 Vogler BK, Pittler MH, Ernst E (1999), The efficacy of ginseng. A systematic review of randomised clinical trials. Eur J Clin Pharmacol 55(8):567-575.
 

 Wettstein A (2000), Cholinesterase inhibitors and Gingko extracts-are they comparable in the treatment of dementia? Comparison of published placebo-controlled efficacy studies of at least six months' duration. Phytomedicine 6(6):393-401.
 

 Xu SS, Cai ZY, Qu ZW et al. (1999), Huperzine-A in capsules and tablets for treating patients with Alzheimer disease. Acta Pharmacologica Sinica 20(6):486-490.
 

 Xu SS, Gao ZX, Weng Z et al. (1995), Efficacy of tablet huperzine-A on memory, cognition, and behavior in Alzheimer's disease. Acta Pharmacologica Sinica 16:391-395.

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The promise of natural products as possible sources of new treatments for Alzheimer's disease and other dementing illnesses is on the rise. Scientific evidence for the 13 dietary supplements most commonly used for memory impairment is analyzed and evaluated.

Wadie Najm, MD

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