October 09, 2003
Many Cognitive Enhancement Drugs Under Development

Businessweek has an article that highlights the development of drugs for memory and general cogntive enhancement.

HUMAN TRIALS. C.L. took nine capsules of CX516 daily for 12 weeks this spring. The impact was immediate. "At the start of the trial, I could remember less than five words out of a list of 20. By the second week, I could get 14 out of 20. There was a very, very appreciable enhancement." He has since finished his part in the study and says it was "heartbreaking" to go off the drug. "I've been thinking of some other way to get it, and I don't give a damn if it's legal or illegal."

If he waits a few years, C.L. should be able to solve his problem legally. At least 60 pharmaceutical and biotech companies around the world are working on novel memory pills. Some 40 are in human trials, and the first of these could be on the market within the next few years.

The aging of the baby boomers and their unwillingness to go quietly into the night provides a big incentive for drug developers to come out with compounds that will help boomers think more clearly. This would be especially helpful for the boomers who did too much bad LSD and other recreational drugs in the 60s and who haven't had a clear thought since then.

The compound CX516 is being developed by Cortex Pharmaceuticals as one of its Ampakine compounds.

The Companyís proprietary family of AMPAKINE compounds affects and enhances the activity of AMPA-type glutamate receptors, complexes of proteins that are involved in communication between cells in the human brain (neurons). Glutamatergic transmission between neurons is by far the brainís most abundant communication system. When a neuron releases glutamate and it binds to the AMPA receptor, AMPAKINE compounds increase or magnify the effect of glutamate, thereby amplifying normal brain signals.

The AMPAKINE compounds, which can be taken orally, rapidly enter the brain and increase the ability of neurons to communicate with each other. Data from pilot clinical trials have shown that the AMPAKINE CX516, a lead compound, is effective in improving memory in elderly volunteers and patients with schizophrenia.

Some of the drugs mentioned in the Businessweek article operate on neurotransmitter metabolism by enhancing neurotransmitter receptor sensitivity, preventing reuptake, stimulating release, or perhaps by preventing breakdown or stimulating production of neurotransmitters. One or more of these approaches will eventually result in useful drugs that provide real benefits for the middle aged, the elderly and perhaps even younger minds. Large numbers of people (including me!) would certainly jump at the opportunity to take a memory enhancing drug that operated by one of these mechanisms if the side effects didn't seem too onerous or risky. But the better longer term approach to the prevention of age-related decline in memory and processing speed is to develop treatments that reverse brain aging. What is worrying about any approach that does not target an actual aging or disease process is that turning up the functional level of the brain could conceivably increase mental functioning in the short term but, by speeding up brain metabolism, accelerate brain aging.

The article mentions of the Alzheimer's Disease experimental vaccine AN-1792 from Elan Pharmaceuticals that successfully cleared away beta amyloid plaque from many test subjects. In a clinical trial this vaccine AN-1792 prevented mental decline in two thirds of the subjects while causing fatal brain inflammation from immune T cell attack in a small number of them. The result provides evidence for the idea that plaque accumulation really does cause Alzheimer's and strongly suggests that a better vaccine (probably one designed to hit a different antigen section of the plaque that doesn't look like any surface protein on normal brain cells) could successfully target the plaque while avoiding brain inflammation. This result is causing Elan and others to pursue better Alzheimer's vaccines.

This vaccine approach for Alzheimer's is probably the easiest way to try to stop a disease process that comes with age. Send in antibodies to target the plaque and the immune system eats up the plaque and the plaque is no longer there to kill neurons. The problem, of course, is that there are plenty of disease processes and aging processes that are not amenable to treatment with vaccines. The other disease processes that come with aging will be much harder to target to stop and reverse. Accumulated damage in neurons will likely require gene therapy to send in instructions to repair them. But effective gene therapies for brain rejuvenation will take much longer to develop in comparison to vaccines.

Another useful approach will be to send in stem cells to replace aged neural stem cells in the hippocampus. The brain is constantly forming new neurons from stem cells in the brain but the reservoirs of stem cells age from repeated replication and accumulated damage and they need to be replaced in order to restore the ability to form new neurons back to youthful levels.

The classic chemical compound drug approach to disease treatment has real limits to what it can accomplish. To do the most complex manipulations of an organism requires many steps and fancier instructions than a single chemical compound can provide. In a nutshell, what is needed is the ability to send in the equivalent of computer programs. Cell therapies and gene therapies have a lot more potential than classical chemical compound drugs in the long run because cells and genes carry much more information and can therefore carry out more complex tasks.

Chemical compound drug therapies still have a long life ahead of them. One reason is that cell therapy and gene therapy development are both (unfortunately) still in their infancy. Also, the same kinds of advances in DNA sequencing and gene activity assays that are pointing the way toward useful gene therapies are also pointing the way toward targets in the cell for chemical compounds. Since cells already have tens of thousands of genes one way that drug therapies will improve is by the development of compounds that can turn individual genes on and off by binding to regulatory proteins. Fairly complex transformations of cells will eventually be carried out by sending in series of compounds that sequentially turn on and off various genes. One area where this will be used first is in cancer therapy. The way forward for anti-angiogenesis compound usage is probably going to be to use multiple compounds in concert to cut off different pathways that cause the angiogenesis (the growth of new blood vessels) that helps keep growing tumors fed. Also, anti-angiogenesis compounds will be used in combination with other compounds that regulate other steps involved in cell proliferation.

Update: A team led by Canadian researcher Dr. William Molloy of McMaster University and of St. Peter's Centre for Studies in Aging in Hamilton, Ontario have discovered antibiotics slow the rate of advance of Alzheimer's Disease.

Alzheimer's patients who took the drugs - doxycycline and rifampin - in combination for three months showed significantly slower cognitive decline at six months out from the start of the trial than patients who received a placebo, they will report at the annual meeting of the Infectious Disease Society of America in San Diego on Saturday.

The researchers thought that chlamydia pneumoniae found more in brains of Alzheimer's patients might be involved in beta amyloid plaque formation.

Armed with the knowledge that plaques formed in the brain have been associated with jumbled memories, and the fact that researchers have also found the chlamydia pneumoniae bacterium in the brains of people with Alzheimer's disease, Molloy came up with a novel hypothesis.

The antibiotics did not, however, lower the level of chlamydia by all that much (which itself is bad news). So did they knock out a different bacteria or block some action that chlamydia takes or did they work in some manner unrelated to bacteria? Also, would other antibiotics have a more beneficial effect? Expect a lot of research groups to jump to repeat this result. Heck, expect doctors to be deluged by requests for antibiotics prescriptions for Alzheimer's patients. Is the best antibiotic against chlamydia still under patent? What drug company makes it and how much do they make in profit from that antiobiotic?

This is obviously going to be a simple enough study to repeat.

The research lends credence to the notion that common bacterial infections might play a role in determining who is stricken with the debilitating neurological disorder. It also offers hope of a cheap, simple treatment for Alzheimer's, a condition for which there is virtually no effective treatment.

There is a hypothesis that bacteria play a role in the formation of plaques in arteries and this study was an attempt to discover whether the same might be going on with Alzheimer's plaques. This suggests another target for vaccine development: the bacteria that might be involved in Alzheimer's. Also, the development of better antibiotics would be another approach. Given that Alzheimer's plaque formation probably starts for people in their 40s or 50s it also brings up the question of whether we should all go get dosed with a heavy antibiotic regimen before our brains start accumulating damage. It may also be an argument for less sexual promiscuity if chlamydia is mostly getting spread by that route. (anyone know?)

Share |      Randall Parker, 2003 October 09 12:48 PM  Brain Enhancement

Eye Opener said at October 10, 2003 6:42 AM:

Instapundit sent me over... Wow! You're MY kinda guy...

Chlamydial plaques and meta-reprogramming at the cellular
level... where's my blotter? (To dab the ink, d'accords...)

Ah'll be bokk. (That's GOVERNOR T to you, Bwah!)

rob said at October 10, 2003 11:13 AM:

Results like this and the t. gondii infection provide yet more evidence for the new germ theory. When are medical researches going to try antibiotics and antivirals as a matter of course when looking at disease?

Vineet Bhardwaz said at July 25, 2005 8:53 AM:

i want to know that wether i can participate in the human trials or the CX516 drug which i think can help me in the development of the cognitive abilities.If at any point of time u people that u need any one who is to be tested for the human trials for any type of human cognitive enhancer molecule or drug please drop me a mail and i will go ahead and do it for u.


atj said at March 19, 2010 10:26 AM:

I will be glad if you could respond to my message...I am planning on how to get some drugs to improve my memory because i easily forget information and that is not making me happy with my academics...I read about ritalin,modafinil,piracetam etc when i am browsing and i will like to know if it will be good for me or not or if there is other safe drug and readily available i can use. ..please i will be grateful if i can get a reply very soon

Daniel Willis said at October 5, 2010 5:00 PM:

Im also interested in these trials as well,more on the fact of exspanding the reaches of my mind. Im curious on how much or how far do you want to go with this.I know people are going to argue over this statement but I have a bright mind that i sqanderd away by joining the military and it feels as if my mind has a blockage that i cant pass.id be more then welcome to help in anyway i can offer.

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