Drug Development for Cognitive Enhancement

AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate)

Cognitive enhancement seeks to improve cognitive function in healthy adults.  Although medicine typically focuses on treatment of medical disorders, a significant effort is underway to explore the mechanism of human attention, concentration, memory and other cognitive functions.  


Cognitive enhancement does not replace other methods of cognitive performance.  There is no substitute for repetitive practice and learning content through reading, writing, speaking and physical activity.  Cognitive enhancement looks to maximize performance without serious adverse effects risk.  The development of drugs and model molecules related to basic brain is expanding.  


This is really not a new area as man has been using dietary aids to enhance cognition for thousands of years.  Perhaps the best, but not the only, example of this is use of caffeine.  Caffeine can increase performance on a number of tests of cognitive function as well as extend the duration of time for productive activity.


Cognitive enhancement candidate drugs include extension of drug used in attention-deficit hyperactivity disorder (ADHD) as well as drugs designed to reduce the rate of cognitive decline in Alzheimer's disease and other dementias.  This class of pharmacology has been label the nootropic drugs.  de Jongh and colleagues from Utrecht University in the Netherlands recently summarized current and future targets for enhancing cognition.   Here is the listing of drugs from their review:


Currently available enhancers
Donepezil-an anticholinesterase inhibitor indicated for Alzheimer's disease with evidence of improved flight simulator performance after training older pilots
Modafanil-seen as a wakefulness enhancer with FDA approval for those shift work sleep disorder.  Effective at extending helicopter pilot performance effectiveness up to 36 continuous hours.
Dopamine agonists (d-amphetamine, bromocriptine, pergolide)-appears to improve working memory, particularly for those with memory problems or the COMT genotype val/val associated with reduced prefrontal dopamine levels
Guanfacine- Alpha 2 adrenergic receptor agonist approved for ADHD in the U.S. Inconsistent findings of improved memory and executive function 
Methylphenidate--Improves prefrontal cortical function in rodents but ineffective for age related cognitive decline found in older human research volunteers


Future targets
AMPA receptors-Ampakines are drugs that enhance fast excitatory neurotransmission by modulating AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate see diagram above)-type glutamate receptors--effective in improving memory and performance after sleep deprivation in monkeys.  Also effective improving memory in healthy elderly (65-75 years of age) human study.
NMDA receptors-D-cycloserine, a partial agonist at the NMDA receptor enhances memory and has been effective in increasing the speed of response to psychotherapy as noted in previous Brain Post commentary here.
CREB (cAMP response element binding protein)-cAMP response element protein a crucial compound in long-term memory formation.  Has problems with adverse effects (anxiety and depression) outside of brain amygdala. 


Mood and pro-social behavior
Antidepressants-may have some ability to increase social behaviors in those without depression, also felt to improve "hassle tolerance"
Oxytocin-increases pro-social behaviors such as pair bonding and maternal care.  Leads to increased trust in others in social game simulations.


Research in this area carriers some significant ethical challenges that will need discussion and consideration.  Nevertheless, look for additional research into "nootropic" drug development.


DEJONGH, R., BOLT, I., SCHERMER, M., & OLIVIER, B. (2008). Botox for the brain: enhancement of cognition, mood and pro-social behavior and blunting of unwanted memories Neuroscience & Biobehavioral Reviews, 32 (4), 760-776 DOI: 10.1016/j.neubiorev.2007.12.001