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LETTER |
Western University of Health Sciences College of Osteopathic Medicine of the Pacific Pomona, Calif
To the Editor: Although memantine hydrochloride is currently known as the latest treatment for moderate-to-severe Alzheimer disease (AD),1 we entertain the idea that it might also come to be known as a memory enhancer among healthy high achievers.
The drug acts by noncompetitively binding to the N-methyl D-aspartate (NMDA) receptors of neurons in brain tissue to prevent overstimulation by glutamate.2 When this excitatory neurotransmitter overactivates NMDA receptors in a tonic manner, an excessive influx of neurotoxic calcium ions follows.2 The resultant excitotoxicity may play a role in the impairment of memory and cognition in AD.3 Because memantine has a low-to-moderate affinity for NMDA receptors, it does not seem to block normal glutamate transmission; rather, it reduces abnormal neurotransmitter-mediated activation of the receptors,4 thereby potentially reducing excitotoxic neuronal damage. This form of neuroprotection may explain the improved cognition in patients with AD reported in the literature.5–7
Can transient low-level, nonpathologic, glutamate-mediated neuronal damage occur in the brains of normal individuals? And, if so, could memantine's neuroprotective effect antagonize the damaging effects and enhance memory potential in these individuals? Future research should address these issues.
Memantine's suggested neuroprotective effect2,8 may also increase brain levels of the neuronal marker, N-acetyl aspartate (NAA). Because NAA is found primarily on neuronal axons in the brain,9 perhaps the neuroprotective effect of memantine can be measured by quantifying the change in NAA concentrations in brain tissue via magnetic resonance spectroscopy. Magnetic resonance spectroscopy has demonstrated that patients with AD show a decline in NAA relative to normal controls.10 The reduction in excitotoxicity via memantine's mechanism of action may allow affected neurons to regain some level of physiologic functioning, such as growth of neuronal processes and synaptogenesis, which is fundamental to learning and memory formation11—a process that is damaged in AD.2
Moreover, a direct relationship has been observed between NAA levels in the brain and intelligence. Healthy individuals with high levels of NAA appear to have higher scores on intelligence tests than healthy individuals with lower levels of this marker in brain tissue.12 It may be possible that the higher levels of NAA indicate an increased presence of neuronal processes and their synapses.
The effects of drugs that have cognitive-enhancing potential have been
studied in healthy individuals. Acetylcholinesterase inhibitors (some of which
are used to treat AD), such as donepezil, huperzine 
, and
physostigmine, have been shown to improve memory and cognitive tasks in normal
subjects.13–15
Another medication that enhances cognitive performance is methylphenidate, a
drug commonly prescribed for attention deficit hyperactivity disorder (ADHD)
but increasingly used by healthy university students nationwide as an academic
performance–enhancing
agent.16 A recent
national survey17
reported that ADHD medications have much higher rates of abuse in colleges
with higher admission standards.
In light of all of the mentioned factors and the recent reports regarding the misuse of anabolic-androgenic steroids for the enhancement of athletic performance,18,19 the misuse of memory-enhancing drugs to improve academic performance by some ambitious students may not be a far-fetched conjecture. The purpose of this letter is to raise a medically and ethically relevant question: If transient low-level, nonpathologic, glutamate-mediated neuronal damage can occur in normal brain tissue, and neuroprotection against this occurrence could promote neuroplastic processes such as synaptogenesis, could memantine be misused by students for academic performance-enhancement in the near future?
References 2. Danysz W, Parsons CG. The NMDA receptor antagonist memantine as a
symptomatological and neuroprotective treatment for Alzheimer's disease:
preclinical evidence. Int J Geriatr Psychiatry.2003; 18(suppl 1):S23
–S32.[Medline] 3. Ashford JW, Mattson M, Kumar V. Nerobiological systems disrupted by
Alzheimer's disease and molecular biological theories of vulnerability. In:
Kumar V, Eisdorer C, eds. Advances in the Diagnosis and Treatment
of Alzheimer's Disease. New York, NY: Springer Publishing
Co;1998: 53-89. 4. Lipton SA. Failures and successes of NMDA receptor antagonists:
molecular basis for the use of open-channel blockers like memantine in the
treatment of acute and chronic neurologic insults.
NeuroRx. 2004;1:101
–110.[Medline] 5. Rossom R, Adityanjee, Dysken M. Efficacy and tolerability of
memantine in the treatment of dementia. Am J Geriatr
Pharmacother. 2004;2:303
–312.[Medline] 6. Rogawski MA. What is the rationale for new treatment strategies in
Alzheimer's disease? CNS Spectr.2004; 9(7 suppl 5):6
–12.[Medline] 7. Robles-Bayon A. The action of memantine on the cognitive disorders
of patients with dementia: reflections following 2 years' experience in Spain
[in Spanish]. Rev Neurol.2006; 42:288
–296.[Medline] 8. Rao VL, Dogan A, Todd KG, Bowen KK, Dempsey RJ. Neuroprotection by
memantine, a non-competitive NMDA receptor antagonist after traumatic brain
injury in rats. Brain Res.2001; 911:96
–100.[Medline] 9. Barker PB. N-acetyl aspartate—a neuronal marker?
Ann Neurol.2001; 49:423
–424.[Medline] 10. Adalsteinsson E, Sullivan EV, Kleinhans N, Spielman DM, Pfefferbaum
A. Longitudinal decline of the neuronal marker N-acetyl aspartate in
Alzheimer's disease. Lancet.2000; 355:1696
–1697.[Medline] 11. Waites CL, Craig AM, Garner CC. Mechanisms of vertebrate
synaptogenesis. Annu Rev Neurosci.2005; 28:251
–274.[Medline] 12. Jung RE, Brooks WM, Yeo RA, Chiulli SJ, Weers DC, Sibbitt WL Jr.
Biochemical markers of intelligence: a proton MR spectroscopy study of normal
human brain. Proc Biol Sci.1999; 266:1375
–1379.[Medline] 13. Davis KL, Mohs RC, Tinklenberg JR, Pfefferbaum A, Hollister LE,
Kopell BS. Physostigmine: improvement of long-term memory processes in normal
humans. Science.1978; 201:272
–274. 14. Zhang Z, Wang X, Chen Q, Shu L, Wang J, Shan G. Clinical efficacy
and safety of huperzine alpha in treatment of mild to moderate Alzheimer
disease, a placebo-controlled, double-blind, randomized trial [in Chinese].
Zhonghua Yi Xue Za Zhi.2002; 82:941
–944.[Medline] 15. Mumenthaler MS, Yesavage JA, Taylor JL, O'Hara R, Friedman L, Lee
H, et al. Psychoactive drugs and pilot performance: a comparison of nicotine,
donepezil, and alcohol effects.
Neuropsychopharmacology.2003; 28:1366
–73.[Medline] 16. Butcher J. Cognitive enhancement raises ethical concerns: academics
urge pre-emptive debate on neurotechnologies. Lancet.2003; 362:132
–133.[Medline] 17. McCabe SE, Knight JR, Teter CJ, Wechsler H. Non-medical use of
prescription stimulants among US college students: prevalence and correlates
from a national survey [published correction appears in Addiction.
2005;100:573]. Addiction.2005; 100:96
–106.[Medline] 18. Maravelias C, Dona A, Stefanidou N, Spiliopoulou C. Adverse effects
of anabolic steroids in athletes: a constant threat. Toxicol
Lett. 2005;158:167
–175.[Medline] 19. Calfee R, Fadale P. Popular ergogenic drugs and supplements in
young athletes. Pediatrics. 2006;117:e577–589. Available at:
http://pediatrics.aappublications.org/cgi/content/full/117/3/e577.
Accessed April 20, 2006.
1. Ellis JM. Cholinesterase inhibitors in the treatment of dementia
[review]. J Am Osteopath Assoc. 2005;105: 145–158. Available
at:
http://www.jaoa.org/cgi/content/full/105/3/145.
Accessed May 10, 2006.
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