Sharper minds

By Melissa Healy, Times Staff Writer

It would be hard to imagine improving on the intelligence of computer engineer Bjoern Stenger, a doctoral candidate at Cambridge University. Yet for several hours, a pill seemed to make him even brainier.

Participating in a research project, Stenger downed a green gelatin cap containing a drug called modafinil. Within an hour, his attention sharpened. So did his memory. He aced a series of mental-agility tests. If his brainpower would normally rate a 10, the drug raised it to 15, he said.

"I was quite focused," said Stenger. "It was also kind of fun."

The age of smart drugs is dawning. Modafinil is just one in an array of brain-boosting medications — some already on pharmacy shelves and others in development — that promise an era of sharper thinking through chemistry.

These drugs may change the way we think. And by doing so, they may change who we are.

Long-haul truckers and Air Force pilots have long popped amphetamines to ward off drowsiness. Generations of college students have swallowed over-the-counter caffeine tablets to get through all-nighters. But such stimulants provide only a temporary edge, and their effect is broad and blunt — they boost the brain by juicing the entire nervous system.

The new mind-enhancing drugs, in contrast, hold the potential for more powerful, more targeted and more lasting improvements in mental acuity. Some of the most promising have reached the stage of testing in human subjects and could become available in the next decade, brain scientists say.

"It's not a question of 'if' anymore. It's just a matter of time," said geneticist Tim Tully, a researcher at Cold Spring Harbor Laboratory on Long Island, N.Y., and developer of a compound called HT-0712, which has shown promise as a memory enhancer. The drug soon will be tested in human subjects.

The new brain boosters stem in part from research to develop treatments for Alzheimer's disease, spinal cord injuries, schizophrenia and other conditions. But they also reflect rapid advances in understanding the processes of learning and memory in healthy people.

Developing research

In the last two decades, scientists have made important discoveries about which regions of the brain perform specific functions and how those regions work together to absorb, store and retrieve information. Researchers also have begun to grasp how and where neurotransmitters are manufactured and which ones help perform which mental tasks.

"There are things cooking here that couldn't have been done one to two decades ago," said James L. McGaugh, director of UC Irvine's Center for the Neurobiology of Learning and Memory.

Research has gotten further stimulus from a deep-pocketed investor — the U.S. military, which is looking for ways to help pilots and soldiers stay sharp under the stress and exhaustion of combat.

The potential market for cognitive enhancers has never been bigger, or more receptive.

An estimated 77 million members of the baby boom generation will turn 50 in the next 10 years, joining 11 million who have already passed the half-century mark — a stage at which memory and speed of response show noticeable decline.

Modafinil, the drug that whetted Stenger's powers of concentration, is used to treat narcolepsy and other sleep disorders. It is one of three prescription medications on the market that have been shown to enhance certain mental powers.

The other two are methylphenidate, marketed under the name Ritalin as a remedy for attention deficit disorder, and donepezil, prescribed for patients with Alzheimer's.

Studies have shown that these drugs can produce significant mental gains in normal, healthy subjects. None of the three has been approved for that purpose. Nevertheless, a growing number of healthy Americans are taking them to get a mental edge.

Some obtain the medications from doctors who write prescriptions for "off-label" uses not approved by the Food and Drug Administration — a practice both legal and common. Others buy the drugs through unregulated Internet pharmacies.

Cambridge University psychologist Barbara Sahakian considers modafinil (marketed commercially under the name Provigil) especially intriguing. Its developers aren't sure exactly how it keeps drowsiness at bay. But even in healthy people, the medication appears to deliver measurable improvements with few side effects.

In a series of experiments in 2001, Sahakian and colleagues found that in games that test mental skill, subjects who took a 200-milligram dose of modafinil paid closer attention and used information more effectively than subjects given a sugar pill.

Confronted with conflicting demands, the people on modafinil moved more smoothly from one task to the next and adjusted their strategies of play with greater agility. In short, they worked smarter and were better at multi-tasking.

"In my mind, it may be the first real smart drug," Sahakian said. "A lot of people will probably take modafinil. I suspect they do already."

Donepezil, sold under the name Aricept, also has been found to boost the brain function of healthy people. The drug increases the concentration of a neurotransmitter called acetylcholine, boosting the power of certain electrical transmissions between brain cells.

In a 2002 study, 18 pilots with an average age of 52 were put through seven training flights in a simulator and taught a complex set of piloting skills over 30 days. Half took a low dose of donepezil; the other half took a placebo. At month's end, all were tested on the skills they had learned.

The pilots on donepezil retained more of the skills than those who took the placebo. On the most challenging parts of the test, an emergency drill and a landing sequence, their performance was notably superior, according to results of the study published in the journal Neurology.

Botox for the mind?

Some scientists predict that the development of even more-effective brain-enhancing drugs will usher in an age of "cosmetic neurology."

"If people can gain a millimeter, they're going to want to take it," said Jerome Yesavage, director of Stanford University's Aging Clinical Research Center and an author of the donepezil study.

Judy Illes, a psychologist at Stanford's Center for Biomedical Ethics, said mind-enhancing medicine could become "as ordinary as a cup of coffee." This could be good for society, helping people learn faster and retain more, she said.

But it also raises questions: Will the rich get smarter while the poor fall further behind? (Drugs such as modafinil can cost as much as $6 per dose.)

Will people feel compelled to use the medications to keep up in school or in the workplace? In a world where mental function can be tweaked with a pill, will our notion of "normal intelligence" be changed forever?

Mirk Mirkin of Sherman Oaks, 77, a retired marketing manager, would like to regain a bit of his old intellectual nimbleness. A member of Mensa, a society for people with IQs in the top two percentile of the nation, Mirkin is bothered by what he laughingly calls "senior moments," such as when a name stubbornly eludes him.

If a pill could halt the march of forgetfulness without uncomfortable side effects, he would probably take it, Mirkin said.

Mirkin, who proctors tests for admission into Mensa, said he would not object if younger people took such pills to pump up their mental muscle for the test. "If they physically can handle it and want it bad enough, why not?"

Many college and graduate students want an edge bad enough to take Ritalin, even if they do not suffer from attention deficit disorder.

At campuses, test sites and, increasingly, workplaces across the country, people are popping "vitamin R." Some users persuade a doctor to prescribe it; others get it from friends who have been diagnosed with attention deficit disorder.

The growing demand for Ritalin, which can be addictive, has prompted the U.S. Drug Enforcement Administration to classify it as a "drug of concern."

On the Internet chat board of the Student Doctor Network, college students preparing for medical school admission tests frequently discuss the benefits of taking Ritalin or similar drugs on exam day.

Some students think they have no choice. "You figure you're being compared to people who are on Ritalin," said one Los Angeles student who frequents the site and recently asked a relative to supply the drug. "I just figured it would be more fair if you're on the same level."

Eventually, ambitious parents will start giving mind-enhancing pills to their children, said McGaugh, the UC Irvine neurobiologist.

"If there is a drug which is safe and effective and not too expensive for enhancing memory in normal adults, why not normal children?" he said. "After all, they're going to school, and what's more important than education of the young? And what would be more important than giving them a little chemical edge?"

Defense Department scientists are pursuing just such an advantage for U.S. combat forces. The Pentagon spends $20 million per year exploring ways to "expand available memory" and build "sleep-resistant circuitry" in the brain.

Among its aims: to develop stimulants capable of keeping soldiers awake, alert and effective for as long as seven days straight. The armed forces have taken leading roles in testing modafinil and donepezil as performance enhancers for pilots and soldiers.

On the horizon are other potential smart drugs, each operating on different systems in the brain. If they progress through tests of safety and effectiveness, the first of them could be available as early as 2008. (See "What's on the horizon?").

Three companies are among the leading contenders in the race to develop drugs for memory and cognitive performance: Memory Pharmaceuticals Corp. of Montvale, N.J.; Cortex Pharmaceuticals Inc. of Irvine; and Helicon Therapeutics Inc., founded by Tully, the geneticist at Cold Spring Harbor Laboratory.

All the new smart drugs are being developed as treatments for recognized illnesses such as Alzheimer's — a requirement for FDA approval. But the drug that will make a company and its stockholders rich will be the one that treats a disorder that until recently was not seen as an illness at all — "age-associated memory impairment," the mild but progressive forgetfulness that afflicts us all as we get older.

The risks involved

Neuroscientists say two factors could prevent Americans from succumbing completely to the seductions of smart pills. First, their performance may not live up to expectations. Second, they could have side effects, some of them difficult to predict.

"There's no free lunch," said Tully. Consumers will have to consider what level of discomfort or risk they're willing to accept in exchange for sharper recall or enhanced powers of concentration.

The side effect that most neuroscientists fear is not physical discomfort, but subtle mental change. Over time, a memory-enhancing drug might cause people to remember too much detail, cluttering the brain.

Similarly, a drug that sharpens attention might cause users to focus too intently on a particular task, failing to shift their attention in response to new developments.

In short, someone who notices or remembers everything may end up understanding nothing.

"The brain was designed by evolution over the millennia to be well-adapted because of the lives we lead," said Martha Farah, a psychologist at the University of Pennsylvania. "Our lives are better served by being able to focus on the essential information than being able to remember every little detail…. We meddle with these designs at our peril."

Despite such qualms, Farah is drawn to the idea that a mind enriched by a life of experience might not have to lose the speed of recall it enjoyed in its youth.

"To have the wisdom of age and the memory of a young person? That'd be a very good combination."

What's on the horizon?

Smart drugs will probably emerge from among medications developed for impairments of the brain and nervous system, including depression and schizophrenia, Alzheimer's disease and multiple sclerosis, stroke and spinal cord injury. Here are a few under development:

Ampakines

• Are designed to amplify the strength of electrical signals between brain cells.
• Could be the first of the new generation of cognitive enhancers to come to market; developed by Cortex Pharmaceuticals Inc., which has launched human trials.
• One is being tested by the Pentagon as an antidote for sleep deprivation.
• Boosted cognitive function of healthy Swedish medical students in a 1997 study.

Mem compounds

• Are designed to strengthen consolidation of long-term memory — key to learning new skills.
• Are under development by Memory Pharmaceuticals Corp., which has begun human testing on three separate Mem compounds as treatment for Alzheimer's disease, mild cognitive impairment and depression.
• In early animal studies, one Mem compound appeared to restore the maze recall of middle-aged rats to youthful levels.
• Could come to market by 2008.

HT-0712

• Is designed to speed and strengthen the process by which short-term memories are committed to long-term storage.
• Is under development by Helicon Therapeutics Inc., which plans to move from animal testing to trials on humans soon.
• Shows particular promise as a drug to aid in the rehabilitation of stroke victims and to counter the effects of age-associated memory impairment.

Gene therapy

• Genetically engineered cells are implanted deep inside the cortex, acting as a miniature biological pump that secretes nerve growth factor (NGF), a naturally occurring protein in all vertebrates.
• Nerve growth factor revitalizes brain cells that atrophy and shrink as their host's age advances.
• Biotechnology company Ceregene Inc. has launched early tests of the gene therapy on human subjects suffering from the early stages of Alzheimer's disease, in hopes of slowing its progress.
• UC San Diego neuroscientist Mark Tuszynski, who designed the NGF-secreting pump, reported in 2000 that aged monkeys who got the implanted cells showed an almost complete restoration of normal cell function and size.

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HOME
Brainfood
Urine tests?
Smarter brains?
Smart and happy?
Modafinil (Provigil)
Denepezil (Aricept)
Cosmetic neurology?
Growing new brain cells
Methylphenidate (Ritalin)
Does it hurt to be smart?
Rasagiline (Agilect, Azilect)
New smart drugs/nootropics
Smart drugs and aging brains
Parkinson's Disease: hotlinks
Smart drugs and mind control
Scepticism about smart drugs
Mood and cognitive performance
Sleep boosts ability to learn language
Alzheimer's Disease: resources and hotlinks

Refs
SMART DRUGS 2: REVIEW