Will Drugs Make Us Smarter and Happier?

11:15 a.m. Five projects, 10 deadlines, an uncountable number of engineering calculations. And I´m on top of it all. Since I started taking a
cognitive enhancer, I don´t seem to forget a thing. And my mind runs so much faster. My boss doesn´t appreciate all I do, of course, but that doesn´t irritate me.
Emoticeuticals-gotta love ´em. Zen-like calm, but I still feel the important stuff. If I did somehow get ticked and reached for a cigarette-my crutch from way back when-it wouldn´t do any good. Nicotine vaccination. No point in ever taking a drag again.

The road to Naam´s pharma-utopia may begin here: on a slide, under a microscope, where two slices of rat hippocampus are being stimulated by electrodes. The neurons in slice one have been treated with a type of drug known as an ampakine, while those in slice two have not. A computer records the levels of electrochemical signaling within each slice. The experiment looks low-tech, like something out of my seventh-grade science class, but it has far-reaching implications: Ampakines may prove to be the world´s most powerful cognitive-enhancing, memory-boosting drugs.

I squint through the microscope for a few seconds, making out pale gray cell bodies surrounded by tangles of stringy dendrites, and then head down a hall to the office of Gary Lynch. A neuroscientist at the University of California at Irvine, Lynch made a series of discoveries in the late 1980s and early 1990s about memory and the ways in which it might be manipulated chemically. In 1987 he co-founded a biotech company called Cortex Pharmaceuticals, which has been working since 1993 to bring an ampakine drug to market.

Lynch is waiting for me behind his desk. Sixty-one years old, he looks like a curly-haired version of Martin Short, complete with broad upper lip, grin full of teeth, and eyes glinting with private mischief. After a few preliminaries, he launches into his favorite subject-memory-and quickly gains oratorical traction. "If these drugs do what I do expect them to do, which is to improve cognition, the social implications could be astounding," he says. "So much of our society is built around the idea of people thinking they´re smart or dumb-maybe you´d have people taking the pills and saying, ´I should be a professor at Harvard instead of doing this daily grind.´ "

Cortex isn´t alone in the quest to boost cranial capacity. About 40 other companies, including behemoths such as Eli Lilly and GlaxoSmithKline, are pursuing what many consider the holy grail of pharmacology, a pill to boost sagging memory-Viagra for the brain. The profit potential is enormous. Some 4.5 million Americans suffer from Alzheimer´s disease, which currently has only marginally helpful drug therapies; at least four million are afflicted with mild cognitive impairment, a precursor to Alzheimer´s; and more than 10 million have age-associated memory impairment, which means their memories are far below average for their age. And, as is the case with drugs like Provigil, there´s an off-label market as well. "Companies won´t tell you this, but they are really gunning for the market of
non-impaired people-the 44-year-old salesman trying to remember the names of his customers," James McGaugh, another U.C. Irvine neuroscientist, has said.

Cortex is attempting to improve cognition by tinkering with the brain´s intricate system of electrochemical communication. To convey information, neurons release various types of neurotransmitter molecules, which bind to complementary receptor sites on adjoining neurons. Successful "docking" signals the neuron to open
a channel that allows positive ions to flow inside, thus charging the cell. Ampakines crank up the volume of this neuronal conversation. They bond to the ampa receptor, which receives the neurotransmitter glutamate, causing the channel to stay open longer, allowing a stronger electrical charge to build.

"You can take a rat´s brain, stimulate one cortical region, and measure the electrical signal from another," Lynch says. "Wash in an ampakine, and the signal is bigger." Better signaling is thought to provide a cognitive boost, particularly in older brains with withering neurons. Aging baseball players have trouble hitting in part because they can´t process visual information as quickly, Lynch says. "Nothing is going to change that fact. But with an ampakine, maybe you could hit a curveball."

Also intriguing to Lynch is the effect of ampakines on memory. When one neuron signals another, the connection between them becomes stronger. The frequency and strength of signaling helps determine how long the connection-known as potentiation-will endure. A link lasting for days or years is called long-term potentiation (LTP), and LTP is the fundamental biological mechanism of memory. Ampakines enhance LTP. Extending the amount of time that glutamate bonds to the ampa receptors triggers the opening of the neighboring NMDA receptors (another docking site for glutamate). They, in turn, admit calcium into the neuron, which signals the cell to establish LTP.

Ampakines have an additional, related benefit: They trigger the production of brain-derived neurotrophic factor (BDNF), which many researchers suspect will lead to the creation of more receptor sites. In other words, the drug doesn´t just make the neurons listen longer, it also builds new ears. In rats, Lynch has been able to reverse memory decline using single injections of an ampakine, giving middle-aged animals memory abilities nearly equivalent to those of young ones. Maybe, Lynch speculates, ampakines will have the same regenerative effect in humans. "Can we make it go from the winter of the brain to the spring?" he asks.

Cortex has begun to gauge the efficacy of its drugs on people; earlier this year, the company tested CX717, its lead drug candidate, in a trial of 16 sleep-deprived British men. Fueled by ampakines, the impaired subjects showed improvements on a battery of cognitive tests. Three more trials, all in the U.S., are scheduled for this year: one for Alzheimer´s patients, one for adult sufferers of attention-deficit hyperactivity disorder, and another for sleep-deprived men, this one funded by the Defense Advanced Research Projects Agency. Soldiers and pilots are often sleep-deprived during missions, and the military is keenly interested in finding cognitive boosters that work better than today´s amphetamines.

Other companies, manipulating different neurochemical pathways, have also reported promising results in animals and are planning human trials. Both Memory Pharmaceuticals, co-founded by Nobel Prize"winning neuroscientist Eric Kandel, and Helicon Therapeutics, founded by neuroscientist Tim Tully, have developed drugs that improve the memories of rodents. "Memory enhancers could become ´lifestyle´ drugs," Tully says, "to be used by anyone interest

ed in learning a language, in playing a musical instrument, or in studying for an exam."But the drug researchers are cautious. The pharmaceutical industry is littered with would-be wonder drugs that didn´t make the leap from animals to people. Cortex has learned that some of its most potent ampakine formulations, those that best influence LTP formation, can also cause seizures in rats. Even if ampakines are safe, their primary benefit-making memory stronger-may also be a liability. Remembering is important, but so is forgetting; otherwise the brain would become swamped with trivia. "I´m not at all clear what is going to happen when you take a drug that makes it harder to get rid of the things you´ve encoded," Lynch says.

Overall, though, he is an optimist. Gazing at a poster of the brain on his office wall, Lynch remarks that a thought is essentially an ad hoc network of communicating neurons. Ampa- kines, by improving that communication, would allow a
larger network-and a larger thought?-to be formed. "I should say that the best implication of ampakines is that we make everybody go home happy when they´re 50-fully powered sexually, memory back, age slipping off like a cloak," he says. "But actually, personally, I wonder: Will you be able to think things that you can´t think right now? Ultimately we´d find out the limits of being human and go beyond them."