An alkaloid extracted from a moss, huperzine A (Huperzia serrata) 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(Drug information on 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.