Become Smarter Today - Eat the Right Foods

How You can become smarter by eating right
This is the longest section of the three parts on a single topic as it includes almost every single one of the other foods that hasn’t been mentioned yet. Our brain uses approximately 20% of all the energy our body uses at any given day. The amount of energy it consumes is tremendous, especially since it only takes up 2% of our total body mass. From this fact alone, you can see how much the food we eat can affect the brain.

The brain is picky about what it takes in, as it only uses certain nutrients. Brain cells, the primary component our brains are made out of, require what we call neurotransmitters to carry messages around. Proteins, vitamins and minerals are the building blocks needed to create new neurotransmitters. However, some can be consumed almost directly, and I will be talking about that just a little later in the post.

Eating enough of these foods will boost your ability to think faster, better and even raise your intelligence (IQ).

If you know what to eat, and what to not eat, your mental capabilities will skyrocket.

The 3 key neurotransmitters in our brain are Acetylcholine, Dopamine & Serotonin – each of which is responsible for certain functions.


Here is a list of foods that help boost Acetylcholine, the neurotransmitter responsible for memory, concentration and focus:
  • Egg Yolks
  • Peanuts
  • Meat – Chicken, Beef, Pork, Mutton
  • Fish
  • Liver
  • Dairy Products – Milk and Cheese
  • Vegetables – Broccoli, Cabbage and Cauliflower have higher amounts
Remember those clearly… and now for the next one neurotransmitter:


Dopamine is responsible for learning, a very important feature that helps boost intelligent memory, the memory that contributes to your overall intelligence. A list of foods that boost this particular neurotransmitter:
  • All proteins – Meat, Milk products, Fish, Nuts, Beans, Soy products, etc.
Basically, anything that contains protein and it’s really quite hard to find a meal where we Do Not eat meat – so you probably won’t have to worry about this too much!


Serotonin is also responsible for learning and memory. Carbohydrates are the primary foods that contain the building blocks for this neurotransmitter. Some foods to increase your serotonin levels are:
  • Pasta
  • Potatoes
  • Starchy Vegetables – Corn, Pumpkin, Peas, Yam, Sweet Potatoes
  • Breads
  • Cereals
Also to add, Serotonin is the key to a good sleep and it is responsible for making you sleepy, a very important factor for heightened intelligence and brain power – a topic for another day! Now back onto the subject…

The three main components

As you might have noticed, meat was present in two of the lists above and the reason is simple – they have complete proteins. Complete proteins contain essential quantities of all 8 essential amino acids that are needed for the body to create these neurotransmitters. Other foods such as vegetables, grains, seeds and nuts contain incomplete proteins and only have some of the 8 essential amino acids, but they contain the vitamins, which I will talk about soon enough.

If you find times where there’s hardly any meat on the dining table or if you are vegetarian, there is no need to worry. Combinations of foods with incomplete proteins will allow you to obtain ALL of the essential ones you can find in meats; the most popular combination being rice and beans.

You probably find it hard to remember what to eat with all these facts bombarding you, but only do it with the meals you can decide and plan. Simply, just remember that your meals should have at least one meat dish containing meat (chicken, beef, pork or mutton), at least one with carbohydrates (rice, bread, potatoes) and at least one with green, leafy vegetables. If any single one of them is missing, try to buy or find a dish that contains the missing one.

Alternatively, you could print this page out and put it in your kitchen as a reminder and checklist you can use whenever you go shopping for groceries.

DNA computers to fight diseases

Israeli scientists have developed tiny devices able to detect signs of cancer, and release drugs to treat the disease.

The work is still test-tube-based but it could lead to "nano-clinics" which remain in the body, sensing illnesses and then treating them automatically.
The devices are so small that roughly a trillion of them can fit into a microlitre (a millionth of a litre).
The research is led by Ehud Shapiro from the Weizmann Institute in Rehovot and is published in the journal Nature.
"The devices are made of biological molecules - DNA; synthetic DNA molecules which we produced to our design, and a naturally occurring enzyme which cuts DNA," Professor Shapiro told BBC News.
One algorithm which the team tested is intended to diagnose prostate cancer.
It says that if levels of two messenger RNA molecules (PPAP2B and GSTP1) are lower than usual, and levels of two others (PIM1 and HPN) are elevated, there must be prostate cancer cells in the vicinity.
If this analytical/computational segment "decides" that cancer is present, it tells the second segment to release the third segment, which is an anti-cancer drug - in this case, consisting of so-called anti-sense DNA.
This has the effect of suppressing gene activity involved in the cancer.
"We demonstrated one particular 'computer' for diagnosing prostate cancer and another 'computer' for diagnosing small-cell lung cancer," Professor Shapiro said.
"We mixed them together in solution with various disease conditions, and the right computer diagnosed the right disease in all conditions."

Smart medicine

So far these devices have only been trialled in test-tube solutions, and several decades of further work are needed before research could begin in humans.
But one day nano-scale devices like these could be used inside our bodies to protect against or treat cancers and other diseases.
"The best way to think about it is as a smart drug," suggested Professor Shapiro.
"Today, we bombard the body with drugs that go everywhere and operate everywhere and at any time.
"And what we designed is a smart drug that has some conditions encoded for its release; and it will be released and activated only at the right time and at the right location when a disease is diagnosed."
Dr Lesley Walker, director of cancer information at Cancer Research UK, said: "This work gives us some insight into the rapid progress being made in this field and the blurring of the divisions between the computer and natural sciences.
"They have moved the concept of the physician in the body - or more specifically here, an entire cancer team in the body - one whole step closer to reality.
"Inevitably, there's a huge amount of work to be done before molecular computers like this can be used to treat people.
"In the meantime, the global research effort to identify the perfect targets for treatment in different cancers will ensure that the biomolecular computers of the future have the best possible programmes."

By Richard Black
BBC science correspondent

Just who should get a boost in brainpower?

James McGaugh, director of the Center for the Neurobiology of Learning and Memory at the University of California-Irvine, bristles at the notion of people with normal brains taking medication to boost their brainpower. After all, he says, no one regards the slowing down of the body with age as a medical condition.

"Does Michael Jordan have age-related physical impairment?" McGaugh asks. Just as Jordan may not be as agile on the basketball court as he used to be, McGaugh says, there's strong evidence that memory processing slows with age. Any middle-aged person who has grasped for a word or a name can vouch for that. But "it's only critical if you want to appear on Jeopardy," McGaugh says.

Things get even more complicated if one considers the possibility of enhancing memory and learning in young people, McGaugh and others say.

For example, he says, if doctors took such a drug throughout their training, would they be required to continue taking it as a condition of their license to practice medicine? And what about children? McGaugh asks. "Are you going to put the pill in their lunchbox when they go off to school?" And, he asks, what if you can't afford to?

Nature Reviews Neuroscience published an article in May about the ethics of enhancing mental performance. The authors, a panel of neuroscientists and ethicists, suggest that "when we improve our productivity by taking a pill, we might also be undermining the value and dignity of hard work, medicalizing human effort" and labeling a normal attention span abnormal.

But memory researcher Mark Bear, a Massachusetts Institute of Technology neuroscientist, says it's unlikely that brain-boosting drugs will have much effect on young, healthy individuals whose brains have not yet begun to slow down.

"I think it's pretty clear in animal studies that treatments that will enhance memory in aged rats often will fail in young rats," says Bear, co-founder of Sention, a Providence, company that is testing two experimental drugs for Alzheimer's and other memory-robbing ailments in volunteers.

To Bear, taking a drug to counteract aging's effect on the brain isn't much different from wearing bifocals to compensate for aging's effect on vision.

Or maybe "smart drugs" are more analogous to Botox than to bifocals, another example of "the baby-boom generation wanting to maintain a youthful quality of life right into old age," says Bear, who, at 46, falls smack-dab in the middle of the boomer generation. "We really are not accepting age gracefully."

By Rita Rubin, USA TODAY

Smart pills' make headway

You can rub Rogaine into your scalp to try to regain the hairline of your youth. You can inject Botox into your forehead to smooth time's inroads, at least temporarily. And, some scientists predict, you'll eventually be able to pop a pill to freshen up the inside of your head as well.
Someday soon, if someone jokingly asks you if you remembered to take your smart pill, you can answer yes — seriously.
Thanks to recent strides in understanding how the brain works, it's only a matter of time before medications specifically designed to improve mental ability, or cognition, hit the market.
"The hallmark of these drugs is they don't create more memory," says John Tallman, CEO of Helicon Therapeutics of Farmingdale, N.Y., which plans to begin testing its most promising brain drug in humans later this year. "What these drugs really do is enhance the conversion process of short-term to long-term memories."
Besides Helicon (for the mountain in Greek mythology where Apollo played with the Muses), companies with such evocative names as Sention (apparently a play on sentient, which means conscious or aware) and Memory Pharmaceuticals are focusing on medications to treat patients whose brains are impaired by disease or injury.
But the real market for such drugs might be healthy people who would simply like to be a little quicker on the uptake.
Americans already spend $1 billion a year on dietary supplements claiming to boost brainpower, even though there's little evidence that they work, notes an article in the May issue of Nature Reviews Neuroscience. From vitamin B12 to ginkgo biloba to "BrainQUICKEN" capsules — "used by top students at every Ivy League institution," according to the product's Web site — health-food stores and the Internet are rife with products promising to enhance memory and learning.
Once the Food and Drug Administration allows a drug on the market to treat, say, Alzheimer's disease, doctors could prescribe it "off-label" for any purpose they like, including sharpening healthy minds dulled by age or fatigue. And Internet shoppers would have their pick of Web sites selling the drugs without even requiring a prescription.
To an extent, it's already happening. Though it's not clear how widespread the practice is, high school and college students who don't have attention deficit-hyperactivity disorder are taking Ritalin to help cram for exams. Scientists have been known to pop Provigil, approved only to treat narcolepsy, to increase alertness before speaking at professional meetings.
"People are already using a wide range of medical drugs to improve their own performance," says Sention CEO Randall Carpenter, citing Viagra's popularity with men who don't have erectile dysfunction as one example. "It's almost impossible to stop people if they want to do that."

'Normal' cognitive decline

On its Web site, Memory Pharmaceuticals of Montvale, N.J., acknowledges that the potential market for its compounds, one of which is being tested in humans, might extend far beyond patients with Alzheimer's and other memory-robbing ailments. Though 37 million people worldwide have Alzheimer's disease, the company says, more than 180 million — or half of all people over 65 — are experiencing "age-associated cognitive decline."
"This decline is not clearly linked to a definable disease condition and may be a 'normal' part of the process," the company says on its Web site.
Memory Pharmaceuticals raised $35.4 million in its initial public offering this year. President and chief science officer Axel Unterbeck says the medical need alone "would be worth the entire investment" in developing drugs to improve cognition. But he acknowledges that healthy people will seek them out. "This indeed will be a very interesting trend to look at," he says.
Tallman says older people are "very, very concerned about their memories, because their memories are what make them human. No honest person would ever say to you, 'I would never take the drugs.' "
Still, there's no guarantee drugs that work in people impaired by disease would also benefit healthy people who would simply like to recall names more quickly.
For example, first-generation Alzheimer's drugs Cognex and Arricept block the breakdown of acetylcholine, one type of neurotransmitter, a substance that enables nerve cells to communicate with each other. Alzheimer's patients have a shortage of acetylcholine, but people with normal brains do not, so it's not clear what effect the drugs would have on them, says Steven Rose, a director of the Brain and Behavioural Research Group at the Open University in England.
And even if such drugs did enhance cognition in average individuals, Tallman says, "highly functioning people would have probably limited benefit."
Duke University researchers have found that the nicotine patch, approved only to help smokers break the habit, boosts brain function in people with mild to moderate Alzheimer's disease and adults with ADHD and schizophrenia. But earlier tests in healthy volunteers found only a modest effect, says Edward Levin, a professor in Duke's psychiatry and behavioral science department.
Even in Alzheimer's patients, Levin cautions, the nicotine patch's benefits aren't worth the risks. Side effects include an elevated heart rate and blood pressure, sleep disturbances, nausea and dizziness.
The nicotine patch points out another obstacle toward developing "smart drugs" for normal brains. "It has to be as safe as water," Carpenter says. "That's a very daunting task that few people want to try to accomplish."
Perhaps somewhat surprisingly, Stanford University researchers found that nicotine gum as well as Aricept, used to treat patients with mild to moderate Alzheimer's, did improve healthy, middle-aged pilots' performance in flight simulators. However, Aricept also can cause side effects that would be pretty undesirable in a pilot, such as dizziness, fainting and vomiting, says pharmacologist Martin Mumenthaler, who led the study.
"The issue is: How do you specifically alter such a complex organ as the brain without affecting anything else?" asks biologist Robert Gerlai, a memory researcher at the University of Hawaii. "The brain doesn't just work on learning and memory. It has all kinds of other functions." In addition, Gerlai and others in the field point out, there is the potential risk that memory-enhancing drugs would work too well, preventing users' brains from distinguishing between important and trivial information.
Some scientists say Helicon's leading drug, aimed at activating a protein involved in the formation of long-term memories, might interfere with short-term memory, Tallman acknowledges.
Animal "memory models are pretty good, but it's hard to really get a total read on human memory without doing human trials," he says. Although Helicon has not yet begun testing its drug in people, Tallman says he suspects that any adverse effects on memory would be transient.

A mental 'jump-start'

Phase I trials, designed to assess the safety of experimental drugs, are conducted in healthy volunteers. So besides monitoring the volunteers for side effects, Sention, of Providence, and Memory Pharmaceuticals are administering tests to assess their drugs' effects on learning and memory.
Mark Bear, a Massachusetts Institute of Technology neuroscientist and Sention co-founder, emphasizes that the Phase I studies were too small to yield robust data about the drugs' effectiveness. Still, he says, "I would be willing to say that the results were very encouraging."
Though it would be unethical for Bear, 46, to test his company's drugs on himself, he does occasionally partake of a medication that might be the first safe and effective smart drug on the market.
Modafinil, sold as Provigil, was approved in 1999 for the treatment of daytime sleepiness in narcolepsy patients. It's not cheap. Web sites sell 30 100-milligram tablets for around $200.
In a small study of healthy men published last year, Barbara Sahakian of the University of Cambridge found that modafinil safely improved performance on tests of memory and attention.
Sahakian says she and her collaborators limited their study to men to eliminate the potentially confounding effect of women's menstrual cycles. But, she says, there's no reason to think that modafinil wouldn't work the same in women.
"It's probably the first smart drug that I've seen," says Sahakian, one of the co-authors of the Nature Reviews article on cognitive enhancers.
Bear says he takes modafinil "to jump-start myself across time zones," not to enhance his mental performance.
He first asked his doctor for a prescription before traveling to a scientific meeting in India. "I had to arrive and give a seminar in the same day. I said to my doctor, 'Look, I'm going halfway around the world. I simply would not be able to function' " without the drug.
Though Bear took modafinil to keep from nodding off in the middle of his presentation, he acknowledges that "anything that increases alertness will increase cognition."
And anyone who has downed a double espresso — or two or three — while studying for an exam or writing a report would probably drink to that.
By Rita Rubin, USA TODAY

Be smart

It hurts to be smart. That's one conclusion from the latest study of so-called Doogie mice - "smart" rodents that are genetically engineered to have enhanced memory and learning skills.

Along with those extra IQ points, researchers have found, comes an added sensitivity to pain. The new work offers a sobering lesson about the difficulty of enhancing certain brain functions without simultaneously taking a toll on others. It might temper any momentum to engineering genetic enhancements into people. Doogie mice, named after the main character in the television show Doogie Howser, MD, made a big splash when they were introduced to the world in September 1999.

Having been endowed with extra copies of a gene involved in memory formation, the animals outperformed their normal counterparts on a variety of tasks.

They were better at recognising objects they had seen before, remembered painful experiences longer and recalled with greater accuracy the location of submerged platforms in milky water.

Some scientists sniffed at the suggestion that the mice were brainy, noting intelligence was much more than a collection of four or five mental skills.

Nonetheless, the work was the first to show that, by adding a few extra copies of a single gene to an embryo, researchers improved an animal's performance on a range of memory and learning tasks.

Some suggested drugs designed to mimic the gene's effects might help Alzheimer's patients. The new work hints it won't be that easy.

Min Zhou and his colleagues at Washington University School of Medicine in St Louis assessed how Doogie mice responded to tissue damage and inflammation.

They suspected that pain caused by those types of injury might be controlled by the same "NR2B receptor" Doogie mice are overendowed with and that gives them their superior memories.

NR2B receptors are proteins that act as "coincidence detectors" in the brain. They recognise, for example, when a certain sound is linked to the arrival of food and help consolidate such coincidences into learnt associations.

The researchers subjected the mice to stimuli that caused either short-term or long-term pain.

They heated the animals' tails, poked their foot pads with stiff fibres and injected their paws with irritating solutions. Then they used neurological tests to see how the animals' brains responded and tracked their behavior.

Those tests indicated that, compared with normal mice, Doogie mice were equally sensitive to short-term pain. But chronic inflammatory pain, such as that caused by the injected irritants, lasted longer in Doogie mice.

"Our results suggest that a genetic manipulation conferring enhanced cognitive abilities may also provide unintended traits, such as increased susceptibility to persistent pain," the team reports in yesterday's issue of the journal Nature Neuroscience.

Joe Tsien, the Princeton scientist who led the creation of Doogie mice, said he wasn't convinced the mice felt more pain.

But several scientists said the new study offered strong substantiation that a Doogie mouse's pain was real.

"This is very convincing evidence" that the mice had prolonged chronic pain responses, said James L. McGaugh, a neuroscientist at the University of California at Irvine.

"Most of our brain regions are multipurpose. These things are all intertwined," he said.


Newly generated neurons help form new memories.

Contrary to long-held popular belief, our brains may not only produce new brain cells or neurons throughout life, but the newly generated neurons quickly become involved in the formation of new memories a fact that may have positive implications for the recuperative powers of our own brains when damaged by stroke or other disease or trauma.

In a study published today in the March 15 issue of the journal Nature, Rutgers psychology professor Tracey J. Shors and Princeton psychology professor Elizabeth Gould found that newly generated neurons in the hippocampus area of animal brains help form new memories.

Despite what is generally believed, scientists in recent years have learned that the brains of vertebrate animals, a category ranging from amphibians to humans, continue to produce new neurons throughout life. What was not known was whether the newly generated cells are actively involved in memory formation.

To find out, Shors and Gould studied the thousands of neurons produced daily in the hippocampus area of rat brains, an area that controls a form of memory known as trace conditioning, in which the animal must learn to associate stimuli that are separated in time. The researchers discovered that when they reduced the production of new hippocampus cells via a drug inhibitor, the rats were no longer able to form certain types of new memories.

This occurred even though mature hippocampus neurons remained functionally intact. On the other hand, when the researchers stopped administering the drug inhibitor, thus restoring the hippocampus area's ability to generate new cells, the ability to acquire trace memories was also restored.

"It appears that the new neurons become involved in memory about a week to two weeks after they are generated and they are involved in memories normally handled by the hippocampus," says Shors.

The team also noted that the reduction of new hippocampal cells had no apparent effect on memory that depends on other parts of the brain.

Although the researchers studied only the hippocampus, their research implies that the brain's recuperative powers may be far greater than previously thought. "We've known for some time that the brain generates new cells throughout life," says Shors. "These results suggest that one of the functions of these new cells is related to the process of memory formation."

In an earlier study, the two researchers demonstrated the nostrum, "use it or lose it." In the earlier study of rat brains, they found that while most new brain cells die within weeks of their generation, putting them to work through hippocampal-related learning improved their survival rate.

Rutgers, The State University Of New Jersey

Sleep boosts ability to learn language,

Scientists at the University of Chicago have demonstrated that sleeping has an important and previously unrecognized impact on improving people's ability to learn language.

Researchers find that ability of students to retain knowledge about words is improved by sleep, even when the students seemed to forget some of what they learned during the day before the next night's sleep. This paper, "Consolidation During Sleep of Perceptual Learning of Spoken Language," is being published in the Thursday, Oct. 9 issue of the journal Nature. The paper was prepared by researcher Kimberly Fenn, Howard Nusbaum, Professor of Psychology, and Daniel Margoliash, Professor in Organismal Biology and Anatomy.

"Sleep has at least two separate effects on learning," the authors write. "Sleep consolidates memories, protecting them against subsequent interference or decay. Sleep also appears to 'recover' or restore memories."

Scientists have long hypothesized that sleep has an impact on learning, but the new study is the first to provide scientific evidence that brain activity promotes higher-level types of learning while we sleep.

Although the study dealt specifically with word learning, the findings may be relevant to other learning, Nusbaum said. "We have known that people learn better if they learn smaller bits of information over a period of days rather than all at once. This research could show how sleep helps us retain what we learn."

In fact, the idea for the study arose from discussions Nusbaum and Fenn had with Margoliash, who studies vocal (song) learning in birds. "We were surprised several years ago to discover that birds apparently 'dream of singing' and this might be important for song learning," Margoliash said.

"Ultimately, our discussions stimulated a research design first proposed by Kim Fenn. The interdisciplinary nature of the research and the free exchange of ideas between animal and human work is also very exciting for us," Margoliash added.

For their study, the team tested college student understanding of a series of common words produced in a mechanical, robotic way by a voice synthesizer that made the words difficult to understand. They first measured the students' ability to recognize the words. They then trained them to recognize the words and then tested them again to see how effective the training was.

None of the students heard the same word more than once, so they had to learn how to figure out the pattern of sounds the synthesizer was making. "It is something like learning how to understand someone speaking with a foreign accent." Nusbaum said.

The team tested three groups of students. The control group was tested one hour after they were trained and recognized 54 percent of the words, as opposed to the 21 percent they recognized before training.

The scientists next trained students at 9 a.m. and tested them at 9 p.m., 12 hours later. During that time, the students had lost much of their learning and only made a 10 percentage point gain over their pre-test scores.

A third group was tested at 9 a.m. after having been trained at 9 p.m. After a night's sleep, those students improved their performance by 19 percentage points over their pre-test scores.

The students who were trained at 9 a.m. were tested again after a night's sleep, and their scores improved to the same level as the other students who had had a night's sleep.

"We were shocked by what we found," Nusbaum said. "We were particularly intrigued by the loss of learning the students experienced during the day and then recovered."

Researchers could not determine if the reduction in performance during the day was due to students forgetting what they'd learned, their listening to other speech or their thinking about unrelated issues during the day.

"If performance is reduced by interference, sleep might strengthen relevant associations and weaken irrelevant associations, improving access to relevant memories," the authors write. If information was forgotten, sleep might help people restore a memory.

Margoliash said, "Although these initial results cannot explain what is lost during the day, the question is very amenable to follow-up experiments."

Fenn added, "We are currently considering an FMRI study to investigate brain activity at the end of a day's learning compared with activity patterns after a night's sleep."

Contact: Catherine Gianaro
University of Chicago Medical Center
8th October 2003

Sharper minds

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:


  • 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.



  • 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.


Source: LA Times
Date: 20 December 2004

By Melissa Healy, Times Staff Writer

Memory drugs create new ethical minefield

Move over, botox. Although injections of the most potent natural toxin known to science are marketed as knife-free plastic surgery to reduce wrinkles, Botox treatment is actually a neurological intervention. The toxin blocks the release of a neurochemical, acetylcholine, from neurons. That makes it the opening act in what promises -- or threatens -- to be a significant new drama. Welcome to "cosmetic neurology."

Sure, there have been reports over the years of, shall we say, recreational use of prescription pharmaceuticals. Some musicians and nervous public speakers take beta blockers (a heart drug) to vanquish stage fright. Modafinil (aka Provigil) is a stimulant approved for narcolepsy, but it has an underground following among those who want to feel as alert and rested after five hours of sleep as after eight. Ritalin, for attention-deficit hyperactivity disorder, improves concentration and the ability to plan, making it popular among healthy adults who simply want an edge in multitasking.

A string of recent discoveries, many of them from small studies that have flown under the radar, suggest that this is only the beginning. Ritalin, for instance, specifically boosts spatial working memory, or the ability to remember layouts and locations. Just the thing for back-country hikers, perhaps, or architects mentally juggling blueprints?

Compounds called cholinesterase inhibitors boost levels of the neurotransmitter acetylcholine, which lets neurons communicate with each other. One, donepezil (sold as Aricept), is approved for Alzheimer's disease. But that may be only one of its talents. In a 2002 study, scientists gave donepezil to one group of healthy, middle-age pilots and dummy pills to another. The donepezil group did markedly better learning maneuvers in a Cessna 172 simulator, particularly those used in flight emergencies.

Some drugs that affect memory work very selectively. So-called CREB inhibitors (CREB is a protein essential for incising memories in the brain) "seem to selectively erase only disturbing memories," says neurologist Anjan Chatterjee of the University of Pennsylvania, Philadelphia. And propanolol, a beta blocker, enhances the memory of events that are emotionally charged and that the brain otherwise suppresses. It also seems to erase the negative emotions associated with bad memories. Healthy people given the drug recall disturbing stories as if they were no more emotionally charged than a grocery list.

It's not that neuroscientists are deliberately looking for drugs that might be used for cosmetic neurology. Rather, these more frivolous uses are being discovered serendipitously, often in research on serious neurological diseases such as stroke. For instance, scientists find that small doses of amphetamines help stroke patients undergoing physical therapy relearn motor skills, such as tying shoes and using utensils, better and more quickly than with therapy alone. Taken half an hour before a therapy session, amphetamines seem to promote what's called neuroplasticity, the ability of the brain to form new connections or strengthen existing ones between its neurons. Those connections underlie both simple and complex sequences of movement.

"With amphetamines, the effects of therapy are more pronounced," says Dr. Chatterjee. "And animal studies suggest that pairing amphetamines with motor training leads to greater brain plasticity."

The day may be coming when perfectly healthy people will pop speed before a tennis lesson or piano instruction, knowing it may stimulate the brain rewiring that underlies a perfect backhand or a flawless "Fur Elise." Botox, after all, originally received government approval to treat two serious eye-muscle disorders, and now aging boomers regard a quick fix as no more momentous than a swipe of mascara. Cosmetic neurology could well follow the same arc, which means that the time for neurologists to weigh in on the ethical implications of all this is now.

Those implications are profound. If drugs can improve learning, make painful memories fade and sharpen attention, should physicians prescribe them? Must physicians prescribe them? Must patients -- perhaps pilots compelled by an employer -- take them? Might one airline distinguish itself from competitors by advertising its donepezil-taking crews?

Dr. Chatterjee captures the dilemma in a paper he wrote for the current issue of Neurology: "The distinction between therapy and enhancement can be vague, particularly when the notion of 'disease' lacks clear boundaries. ... If one purpose of medicine is to improve the quality of life of individuals who happen to be sick, then should medical knowledge be applied to those who happen to be healthy," lifting patients from normal functioning to enhanced functioning?

We can wring our hands all we want about pills that make learning more effective without greater effort, offending the belief that gains should be hard-earned, or about drugs that selectively erase painful memories, evoking a Brave New World of the happily drugged -- and less-than-fully human. I have a feeling it won't make much difference. "Patient" has become synonymous with "consumer," someone unlikely to take kindly to physicians, let alone ethicists, blocking his or her pursuit of self-improvement and happiness.



Source: The Wall Street Journal
Date: 1 October 2004


Viagra for the Brain

Biotech firms are tantalizingly close to unraveling the mysteries of memory. On the way are drugs to help fading minds remember and let haunted ones forget. Inside a small lab in an anonymous office park off the Garden State Parkway in northern New Jersey, researchers probe the molecular intricacies of memory. Tiny metal electrodes zap minute jolts of electricity at precise intervals into slices of rat brain suspended in nutrient broth in plastic lab dishes. This simulates the electrochemical changes that occur in brain cells when a new memory is created. A robotic pump drips experimental drugs through plastic tubes onto the brain cells, while other electrodes measure how each drug alters their activity. Six such setups chart the mind-altering effects of dozens of compounds a month. Most have little effect, but a few drugs fit a cherished profile: helping the disembodied neurons form stronger, longer-lasting connections.

Memory Pharmaceuticals, the closely held biotech firm doing this work, is at the forefront of an intense scientific race to devise the first effective memory-enhancing drug. The idea has long been the stuff of science fiction, but now researchers are decoding the molecular details of how memories are formed and how they are lost. They have taken a crucial first step: identifying the genes and proteins inside brain cells that regulate memory formation. They are tantalizingly close to creating a kind of Viagra for the brain: a chemical that reinvigorates an organ that has faded with age. This new generation of drugs could mend memory loss in the seriously ill or the merely absentminded.

"My friends keep asking when the little red pill is coming," says Eric Kandel, 72, the elder statesman of the field, a Columbia University researcher who founded Memory Pharmaceuticals in 1998 and won the Nobel Prize in 2000. He began his work in the 1950s, when most researchers viewed it as futile. "If we continue making the kind of progress we are now, we will have drugs for age-related memory loss in five or ten years," he says.

At his lab chemists have concocted prototypes that counteract age-related memory loss, making grizzled mice race through mazes as quickly as younger ones. Human trials could begin next year.

Kandel's archrival in this race is 25 years younger and a bit more brazen: Timothy Tully, 47, a researcher at Cold Spring Harbor Laboratory and a founder of privately held Helicon Therapeutics in Farmingdale, N.Y. He hopes to begin human trials in two years.

Other small biotechs and big drug firms, including Merck, Johnson & Johnson and GlaxoSmithKline, also are in pursuit. The prize is a stake in what will be one of the next huge global drug markets.

The first users will be the four million Americans with Alzheimer's disease, but ultimately the market may be far larger. Several million people have so-called mild cognitive impairment, and Pfizer and J&J now are testing whether this can be treated by their already-approved Alzheimer's drugs, Aricept and Reminyl.

The market ratchets up quickly from there. Depending on their mechanism of action, memory drugs might work in the treatment of millions of people with head trauma, Down's syndrome or mental retardation. Patients recovering from severe strokes may one day ingest memory drugs while getting cognitive therapy to relearn basic motor skills and speech. Some new drugs may even block bad memories

The big score: treating 76 million middle-aged folks who aren't demented but may welcome a way to reverse the frustrating forgetfulness that comes with age. "People in the industry are thinking about it. It would be a huge market, but the drugs would have to be very safe," says Novartis research chief Paul Herrling. Adds James McGaugh, a neuroscientist at the University of California, Irvine: "Drug companies won't tell you this, but they are really gunning for the market of nonimpaired people--the 44-year-old salesman trying to remember the names of his customers."

But a pill popped by millions of healthy people looking for a mental edge could pose serious risks. Forgetfulness is an important part of proper mental function. A too-potent drug might wreak havoc on emotions or fill the brain with useless clutter. The pill would have to be free of side effects before it could be used for mild deficits. Regulators would balk at clearing a lifestyle drug that has any risk associated with it. The big question, of course, is whether these drugs will in fact do what is expected of them. Some scientists are skeptical about that.

But if Kandel and Tully succeed, they will forever alter medicine and how we view the world. Ever since 17th-century French philosopher René Descartes famously divided the world into two parts-"extended things" (the physical world) and "thinking things" (the mind)-philosophers and scientists have debated whether the human mind is so elusive as to be unknowable. A memory drug would knock out the few pillars still supporting the view that the mind exists apart from the gray, cellular mush of the brain. Says Tully: "Memory is a biological process that can be manipulated by modern biology like anything else. Not only can you disrupt it, you can improve it. Descartes was wrong."

Should a bottle of memory pills appear on your nightstand one day, a heap of credit will go to Tully and Kandel, with an assist from two of God's lowliest creatures: the fruit fly and the sea slug. Kandel, a forceful, Brooklyn-bred and Harvard-trained polymath, was born in Vienna in 1929 and fled to the U.S. with his parents in 1939, months before World War II began. The vivid memory of Nazi horrors, in part, drove him to study the mind. As a promising young psychiatrist, he gambled his career on a hunch that studying sea slugs could yield insights into human memory. In the decades since, his lab at Columbia University's Howard Hughes Medical Institute has dominated the field. But even after winning the Nobel, he still hasn't persuaded all his peers that his sea-slug studies explain human memory. An effective drug would vindicate a lifetime of scientific pursuit.

Tim Tully, a down-to-earth Irish Catholic with blue-collar roots in Peoria, Ill., studied genetics at the University of Illinois at Urbana-Champaign. His ten-person team of researchers at Cold Spring Harbor Laboratory has battled Kandel to a draw by producing, in a dramatic series of experiments, fruit flies with photographic memory.

At the heart of both men's research is a startling fact: The basic mechanics of memory formation in humans aren't much different from those of snails, flies and other simple creatures. Brain cells seem to be similar in all animals; the difference is in the complexity of the wiring that links them. "Humans are like laptop computers, and flies are like Philco radios," says Tully.

This wasn't at all obvious when Kandel got started in the late 1950s, when most scientists assumed the human brain was far more advanced. Early on, after graduating from Harvard with plans to become a psychoanalyst, he detoured into research after becoming fascinated with new methods for probing the electrical activity of brain neurons.

About this time, scientists got their first serious clue to how and where memories are formed. A 27-year-old patient, known in medical literature only as H.M., had severe epilepsy. In an attempt to cure it, surgeons in 1953 removed his hippocampus, a small ridge in the center of the brain. His seizures went away and his reasoning capacity was intact, but he could no longer recall any new facts for longer than a few seconds. Oddly, though, H.M. had no trouble remembering his childhood. That hinted the hippocampus was crucial for converting immediate perceptions into memories yet wasn't the storage site.

Inspired, Kandel focused on the cellular workings behind memory. He chose an animal that would be easy to study: the lowly sea slug, Aplysia. It has 20,000 central nervous system cells so big they can be seen without a microscope. (Humans have 100 billion brain cells.) Kandel turned down an offer to run the psychiatry department at Harvard's Beth Israel Hospital and bet his career on the slugs.

In a series of landmark studies, Kandel began to show how simple memories are formed by gauging one of the slug's basic reflexes: the withdrawal of its gill at a perceived threat. He learned that a slug's nerve cells (and, by implication, human brain cells), perform a subtle electrochemical mating dance that reinforces links between them. A short-term memory is like a one-night stand, held together by fleeting but intense surges in chemicals that bind cells together. The effect fades away minutes or hours later. Long-term memories are more like marriages, cemented in place for weeks or years with new proteins that reinforce the synapses connecting the cells. Even these, however, erode with time. By the mid-1970s Kandel was a star. Though prone to brutal candor in describing the work of lesser scientists, he mesmerized colleagues with sweeping lectures, encyclopedic knowledge and charming wit. "He is just about the smartest guy I know," says Johns Hopkins neuroscientist Solomon Snyder.

The advent of biotech in the late 1970s allowed Kandel and others to explore memory on a molecular level. That was crucial: Once the molecular workings are understood, drug targets become easier to find.

Kandel helped show that a messenger called cyclic-AMP (adenosine monophosphate) played a central role in memory formation. It sits inside the surface of a cell and springs into action when signaled by other cells, activating proteins that temporarily boost the connection between two nerve cells. But cyclic-AMP is just a messenger; it doesn't churn out the new proteins essential for building long-term memories. In 1990 Kandel found an intriguing molecule, CREB (c-AMP response element binding protein), that appeared to be involved. His team showed that blocking CREB in sea slug nerve cells also blocked new long-term memory, without affecting short-term memory.

Kandel had the first clues, but the most dramatic proof in understanding just how much CREB influences memory came from Tim Tully and his Cold Spring colleague Jerry Yin. Tully's fruit flies had advantages over sea slugs: a wider range of behavior, easy genetic engineering and an ability to be bred by the millions in test tubes. In 1994 Tully and Yin created fruit flies with photographic memories by engineering them with the CREB protein switched into the "on" position. Normal flies took ten tries to learn to avoid a scented chamber where they would get an electric shock. Tully's superflies learned after just one try. Since then, other researchers have shown CREB plays a similar role in mice.

* * *
Who's Who in the Race for Recall

  • Cortex Pharmaceuticals
    Irvine, Calif.
    Drug: CX516
    How it works: Acts as hearing aid for aging neurons, magnifying signals from other brain cells .
    When: Human trials under way.
  • GlaxoSmithKline
    Middlesex, U.K.
    Drug: SB271046
    How it works: Blocks a serotonin receptor that is prevalent in the hippocampus.
    When: Human trials in Alzheimer's patients starting.
  • Johnson & Johnson
    New Brunswick, N.J.
    Drug: H3-blocker
    How it works: Blocks histamine-3 receptor, which may be involved in alertness, attention and memory.
    When: Entering human trials for jet lag or memory loss.
  • Memory Pharmaceuticals
    Montvale, N.J.
    Drug: Phosphodiesterase-4 inhibitors; other approaches
    How it works: Indirectly boosts memory by preventing the breakdown of cyclic-AMP, a key cellular messenger.
    When: Human trials in 12 to 18 months.
  • Helicon Therapeutics
    Farmingdale, N.Y.
    Drug: PDE-4 inhibitors and others
    How it works: Indirectly boosts CREB memory protein.
    When: Human trials within two years.
  • Merck & Co.
    Whitehouse Station, N.J.
    Drug: GABA inverse agonists
    How it works: Modulates GABA receptors to increase alertness in brain regions central to learning and memory.
    When: In lab testing; plans for human tests undisclosed.
  • Axonyx
    New York, N.Y.
    Drug: Gilatide
    How it works: Activates various memory genes.
    When: Human tests 12 to 18 months away.
  • Pfizer/Natl. Inst. on Aging
    New York, N.Y.
    Drug: Aricept
    What and when: NIA now testing whether Pfizer's Alzheimer's drug Aricept can protect people with mild memory loss from Alzheimer's.

* * *

The snail and fly experiments showed that CREB, which hangs out near the nucleus of a brain cell, is a molecular "general contractor" for memory formation. CREB helps turn on the genes needed to produce new proteins that etch permanent connections between nerve cells; it is in these links that long-term memories are stored. The Tully and Kandel teams also found a second factor: CREB repressor. Yin and Tully engineered flies with excess CREB repressor, and they failed to form memories even after many tries. CREB repressor apparently stops the brain from bogging down in random details.

The superfly results were so astonishing that Tully kept them secret while he prepared to publish them. But Kandel got an early peek at Tully's work, because at the time he was on a panel reviewing Tully's grant application. Tully contends Kandel conducted similar tests on sea slugs and tried to pass off his results as a first. This sparked a spat, and Tully retaliated a few years later by taking a jab at Kandel in an article he wrote for a prominent medical journal. Asked about the rift, Kandel dismisses it as a distraction from the science and says of his younger rival: "Tully is very good. He is a worthy competitor."

Cyclic-AMP and CREB are now targets for drugs. In 1998 Kandel's team injected aging mice with a failed antidepressant called Rolipram, which prevents the breakdown of cyclic-AMP by blocking an enzyme called phosphodiesterase-4. The hope was the drug would boost old, tiring brain cells. Rolipram, though developed in the late 1980s, never made it because it did not work well and caused nausea and vomiting. But, sure enough, old mice on Rolipram began navigating mazes faster.

Kandel shared the amazing results with his friend, Walter Gilbert, a Nobel laureate at Harvard who founded Biogen. Gilbert contacted venture capitalist Jonathan Fleming of Oxford Bioscience Partners, who helped raise $38 million to form Memory Pharmaceuticals. Axel Unterbeck, then head of dementia research at Bayer, signed on as president. "I was stunned. Never had I seen data like this," says Unterbeck, now Memory's chief science officer.

Now Kandel is devising a Rolipram-like drug that targets the brain's memory centers but avoids regions that control the vomiting reflex. It turns out some 20 variants of phosphodiesterase-4 play different roles. Memory Pharmaceuticals researchers carefully mapped the regions in the brain where each variant is found. It is testing prototype drugs that block those present only in the hippocampus. In animal tests, the compounds duplicate Rolipram's success without the nasty side effects. The first human trials are about 18 months away, most likely first in Alzheimer's. Says Unterbeck, "If it is safe, the market is incalculable."

Tully's Helicon Therapeutics is keeping pace. Under the direction of veteran biotech executive John Tallman, Helicon has screened 200,000 compounds for ones that boost CREB and cyclic-AMP, producing several drug candidates. So far Helicon's compounds have enabled mice to learn events associated with mild electric shocks twice as fast as normal. A legal showdown between Helicon and Memory may be in the cards. Helicon chief John Tallman says its CREB patent may prevent other companies from marketing memory drugs that target CREB pathways.

Numerous other brain molecules are involved in memory, and some may offer even better drug targets than CREB and cyclic-AMP. Cortex Pharmaceuticals in Irvine, Calif. has designed molecules, called ampakines, that amplify incoming signals from other neurons by targeting so-called AMPA receptors on brain cells. With a partner, it is beginning a second-stage trial with 160 patients with mild cognitive impairment. Another firm, Axonyx in New York City, hopes to begin human trials next year of a drug derived from the saliva of the gila monster.

Tully and Kandel also are looking for additional genes and proteins beyond CREB. Both are using DNA chips to scan thousands of genes at once. Success, says Tim Tully, is only a matter of time: "It's not an 'if'--it's a 'when.'"

Source: Forbes
Date: February 2002

Robert Langreth

Messing with our minds

Want to improve your mental ability, boost concentration and even neutralise painful memories? There's a new generation of drugs to help you, says Jeremy Laurance

To err is human. But for the pilot of a commercial airliner, it is unacceptable. As holidaymakers jet off on winter breaks or plan next summer's long-haul adventure, the one thing that they will demand above all is safety. Airlines have spent millions devising elaborate systems to guarantee maximum safety. Pilot error can never be ruled out, but researchers now believe that it might be reduced - by careful tweaking of brain chemistry. Drugs are becoming available that increase alertness and improve concentration. Should all pilots take them?

This question has begun to tax scientists in the US involved in the development of so-called "smart" drugs - chemical enhancements for the mind. A range of compounds are being tested - some are already available and being traded over the internet - that may change not only the way we perform, but what we think of as "normal" performance.

The drugs being examined have applications far beyond air travel. Three areas that are attracting attention are movement and endurance, attention and learning, and moods. Medicines such as anabolic steroids can already make people stronger, swifter and more enduring. Though life-giving to victims of muscle disorders, they are widely abused in sport. Long- distance lorry drivers and Air Force pilots have used amphetamines to ward off drowsiness. Generations of students have sustained themselves through exams with over-the-counter caffeine tablets. But the new "cognitive enhancers" may offer more powerful, better targeted and longer lasting improvements in mental acuity. And some are already being tested on human volunteers.

One such drug is donepezil, a cholinesterase inhibitor developed for the treatment of dementia. This drug slows the progress of Alzheimer's disease and is being used as a treatment for age-associated memory impairment. But what is causing excitement among researchers is the possibility that donepezil may boost highly skilled performance, where concentration and alertness are prerequisites. A study published in the journal Neurology found that commercial pilots who took 5mg of donepezil for one month performed better than pilots on a placebo when asked to fly a Cessna 172 on a flight simulator. There was a marked difference between the groups when dealing with emergencies.

Modafinil, a drug used to treat the sleep disorder narcolepsy, has also been tested on pilots. A trial reported in the Psychopharmacology journal found that it boosted the performance of helicopter pilots flying on simulators who had been deprived of sleep.

Anyone who has gone two nights without sleep will know what it is like to suffer from extreme tiredness. Nothing can defeat the desire to sleep. Nothing except, apparently, modafinil. While commercial pilots have strict rules governing flying time and rest periods, fighter pilots may be called to action at a moment's notice. Modafinil is under investigation by the military for its ability to keep pilots and other members of the armed forces awake for long periods without the "rebound" effect associated with stimulants such as amphetamines.

Barbara Sahakian, Professor of Neuropsychology at the University of Cambridge, who tested modafinil in a series of experiments on volunteers found that they showed greater concentration, faster learning and increased mental agility. "It may be the first real smart drug," she says. "A lot of people will probably take modafinil. I suspect they do already."

"If people can gain a millimetre, they'll want to take it," says Jerome Yesavage, director of Stanford University's Ageing Clinical Research Center, and an author of the donepezil study. That view was backed by Judy Illes, a psychologist at Stanford's Centre for Biomedical Ethics. Mind-enhancing medicine could become as "ordinary as a cup of coffee", she says.

If drugs such as donepezil and modafinil were proved to raise performance, and hence safety, the implications could be far-reaching. Airline executives might require pilots to take the drugs, or offer financial incentives for doing so. They might market their airline as the one whose pilots took the safety-enhancing drug. Would people pay more to fly on such an airline?

The question is raised in a review of the new science, dubbed "cosmetic neurology", by Dr Anjan Chatterjee, a neurologist at the University of Pennsylvania. As the rich turn to cosmetic surgery to refine what nature gave them, cosmetic neurology offers a different kind of personal improvement. It is the "nip and tuck" for the mind. The conventional aids of caffeine, alcohol and tobacco are already used to boost mood and performance, and neurologists argue that the use of other drugs is a logical extension of this self-medication. Writing in Annals of Neurology, Dr Chatterjee says that amphetamine drugs that help stroke patients who have suffered partial paralysis to relearn motor skills might assist healthy individuals to learn to swim or play the piano. A new class of drugs called ampakines are being investigated as memory enhancers, and have already been shown to boost recall in early studies in humans.

Trials of the heart drug propranolol, a beta-blocker, have shown that it can neutralise emotionally charged memories so that they do not cause distress when recalled. In one experiment, reported in Biological Psychiatry, patients injured in accidents were given propranolol in the A&E department and were found to suffer fewer post-traumatic stress disorder symptoms when assessed one month later.

The new science is creating problems for neurologists, who are used to treating the sick, not enhancing the healthy. Dr Chatterjee writes: "One plausible scenario is that neurologists will become quality-of-life consultants. Following the model of financial consultants, we could offer a menu of options with the likely outcomes and risks." The advent of cosmetic neurology is inevitable, he says, and warns: "Prospecting for better brains may be the new gold rush."

Signs that it has already arrived can be seen on college campuses in the US. Faced with the pressure of exams and essay deadlines, students have been abandoning the traditional crutches of coffee and cigarettes for Ritalin, a stimulant best known as a treatment for hyperactive children. It has found a ready black market among students who are desperate to succeed. Users say that it helps them to concentrate.

Anecdotal reports from drug agencies in Britain suggest that the problem is just emerging here. It has already spread to Canada and Australia, and university authorities have been warned to be vigilant. The search for a short cut in learning has worried teachers. But doctors have confirmed the potential benefits of the drugs, unwittingly encouraging the trend. For example, Eric Heiligenstein, the director of clinical psychiatry at Wisconsin University, says: "Caffeine is fine. This [Ritalin] is better. Students are able to accumulate more information in a shorter time. They minimise fatigue and help maintain a high performance level." A study of 2,200 students at an unnamed university in North America, published in Pharmacotherapy last year, found that 66 of them (3 per cent) admitted abusing Ritalin in the previous year. "Illicit use of prescription-only stimulants on college campuses is a potentially serious public health issue," it said.

If "natural" performance or responses can be boosted in these areas, it may challenge our concept of what it is to be human. In one view, medicine should be about healing the sick, not turning people into gods. But the boundary between therapy and enhancement can be hard to define. Short people can be treated with growth hormone - but is that cosmetic or therapeutic? In an ageing society, treatments to boost attention, learning and memory will be increasingly relevant - but should they be applied to people who are healthy but merely old?

In the field of athletics, drug use is rife but it is referred to disparagingly as "doping". The underlying assumption is that boosting performance without doing the work is cheating and undermines human endeavour. Yet no one feels the same way about putting up with a headache or indigestion. We reach for tablets without hesitation. The ethical dilemma may prove to be academic, however, if the drugs now being tested fail to deliver on performance, or their side-effects prove to be troublesome.

A memory drug might cause subjects to remember too much detail, cluttering the mind, for example. Martha Farah, a psychologist at the University of Pennsylvania, says: "The brain was designed by evolution over millennia to be well adapted because of the lives we lead. We 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."

Source: Independent
Date: 18 January 2005

Smart Drinks

The term 'Smart Drinks' was originally coined to describe drinks that improved cognition under typical conditions often found in our lives: mental and chemical stress, as caused by environmental toxins, sustained mental effort, as when involved in late-night computer hacking, and the physical stress that can frequently be caused by lots of work, or all night dancing to high BPM's. Since I've been lucky enough to read a bit and apply this knowledge to finding out about nutrition and the brain, I'll describe here what I consider to be Smart Drinks - drinks that use nutritive elements of a natural diet to positively effect brain function. I don't look as Smart Drinks as drugs, but they frequently can have therapeutic (and druglike) effect. And this is not through reliance on adding stimulants or sedatives, but instead, through application of a savvy knowledge of the way our bodies assimilate and use nutrients- foods-...

Using these techniques, you can use foods to attain the results you might not be able to get reliably with drugs. I'm not talking about a druglike effect, I'm talking about much more subtle, but still noticeable, positive effects on alertness, stress resistance and energy level. I first got an inkling of what these formulas could do when I was still in high school, when I first became fascinated with somewhat psychoactive compounds, many of them technically classified as foods, that did not cause perceptoral distortion, but instead, subtly seemed to release creative energy blocks within the body. After gaining an understanding of what these compounds were doing, I realized that a lot of these mental changes were basically changes in neurotransmitter levels, and I began experimenting with taking measured doses of tryptophan, tyrosine, phenylalanine and choline at various times of the day. You have probably also experienced a lot of these changes, but just didn't realize that these subtle effects were psychoactive.

Remember the last time you got sleepy after a big dinner of turkey or pasta? Didn't you feel a lot more rested the next day? We all remember feeling energetic after a big high-protein meal in the morning. Over time, and after getting a *lot* of help from friends, I realized that a lot can be discovered by listening to your body's natural "neurotransmitter signals"... and that a well thought out vitamin/neurotransmitter precursor/augmentation recipe can improve your quality of life tremendously. Athletes can get tangible benefits in performance too, particularly at high altitudes. I settled on a regimen of 3 to 6 grams of tyrosine in the morning and niacin/B6 based serotonin support in the early evening. Of course nobody's neurochemistry is typical. You may need something completely different. I'll try to explain my approach.. Basically, these amino acids are the cofactors and "precursors" of very important brain chemicals "neurotransmitters" the messengers of the brain.

These "Smart Drinks" are highly targeted micronutrient foods.. foods for the brain. Nutrients can affect brain function, and the biological effect of consuming them at different times of the day is also highly significant. Your body has evolved mechanisms which we can take advantage of. "Tryptophan is converted in the terminals of certain neurons into the neurotransmitter serotonin. In other cells choline is converted into the transmitter acetylcholine. In still another population of cells tyrosine acts as the precursor of dopamine, norepinephrine and epinephrine, which are collectively called the catecholamine transmitters. An increase in the brain blood level of a precursor nutrient subtly enhances the synthesis of the corresponding neurotransmitter. The enhanced synthesis can in turn cause the neuron to release more transmitter molecules when it fires, amplifying the transmission of signals from the neuron to the cells it innervates. "These days, drugs are popular in psychotherapy, etc. but these drugs are often too strong, and too broad in their effects. (they have unwanted side effects.) They can also be expensive way out of proportion to their cost. (My main beef is with the way that this limits access to often-neccesary drug therapy. Recent research on environmental toxins, inadequate nutrition, and their effect on the developing brain make the implications of this particularly cruel in the developing world, where a nightmare of environmental toxins must have substantial effects on pediatric brain development.) But enough of a tangent, Whenever you have a problem, it is best to approach the problem with the less intrusive and most natural methods (which I would say are nutrients) first. If those methods fail to completely address the problem, then you might be able to bring in the power tools..
When I was approached by friends and asked to create my interpretation of what Smart Drinks should be for one of the first Bay Area cyberclubs, ToonTown, I drew upon a host of papers I had read on depression, stimulant use and abuse, nutrients that effect brain function, military research I had read about the use of amino acid supplements to protect the mental function of soldiers under battlefield stress, material I had read about defective dopamine transport mechanisms in many people because of genetic abnormalities, and what I knew about the conditions and the drugs commonly consumed at raves. The picture painted by this research seemed to me to lead me to what I ended up with. Basically, two products based on expensive stimulant and alcohol recovery formulas that I had seen used by physicians in the drug recovery industry, and the first-generation brain-drink products like the MLM, etc. products...(also without their high expense and my perceived shortcomings) Smart Drink Recipies Some background: Tyrosine's ability to reduce the negative effects of the dopaminergic stimulants had certainly been known in the quasi-underground neuroscience interest community since the mid to late 80's. The need certainly wasn't being met by the vitamin industry, largely because of their immense greed. The products that were out there at the time, mostly the caffeine/sugar products that we were/are all are so familiar with .. just weren't doing it for us, so we had to make our own. That's still largely the situation, (although the economics of Internet distribution might make a more evolutionary product more economically feasable now..) so that's still what I suggest.
Perhaps by understanding these neurotransmitter deficits, and making formulas to reduce them, I thought, we could reduce some of the negative effects of the rave environment.
Computer programmers also would use them, and initially they were our best customers. And also perhaps some of these formulas might be useful for people under less stressful conditions as well. Even the people with dopamine system based neurological problems, like people in recovery.. and also the people who have ADD/ADHD who are being treated with dopaminergic stimulants..which can have negative side effects.. I ended up with several formulas that worked for me, but people should experiment with what is available to them. The most valid approach to making nootropic drinks would be to apply these principles to your daytime and evening diet 'with a gourmet flair'. With a little imagination, these recipies can be adapted into cybercafe drinks.. as I did with Nutrient Cafe in the early 90's As I said earlier, in the morning, I supplement with catecholamine precursors..(tyrosine and/or phenylalanine) and maybye a bit of DMAE... (Precursors of acetylcholine serve far better as catalyzers of the initial rise in catecholamine turnover than caffeine, because they don't let you down later on, It has been shown that DMAE or choline initiates a "cascade" effect on catecholamines. When I combined DMAE with tyrosine in a citrus (and initially spirulina, which we later dropped..) based drink in 1990 it eventually led to the wildly popular "Renew-You(TM)". (no longer available)
Here is a simplification of it's recipe: Renew-You is based on a heaping teaspoon of L-Tyrosine, (you might want to 'melt' the tyrosine in some hot water..) DMAE and orange juice.. ) and of course lots of other co-factors and other nutrients, but tyrosine and DMAE is the essense.. Don't scrimp on the tyrosine.. I have found large amounts of tyrosine to be much more effective as a catecholamine precursor than phenylalanine. One study I've seen suggests 'frequent feedings throughout the early part of the day', as the best way to use tyrosine. Also: Don't consume tyrosine or phenylalanine in the late afternoon or evening unless you are planning on getting involved in some serious exercise. (in other words, unless your neurons are aroused..) They compete with tryptophan- blocking off the production of serotonin.. which you need for good rest. So, that's it for the morning formula, what about lunch? A midday "business lunch" recipe might consist of precursors of acetylcholine.... (choline or DMAE..) along with the cofactor vitamin B5.I also like to add a dollop of ginkgo extract, but here, let the buyer beware.. Ginkgo is so expensive that most vitamin preparations are worthless.
Choline or DMAE taste very bitter, so here, you'll need a strong tart flavor to cover up the taste. For example, I used to use grapefruit and cranberry juice with choline and other nutrients in a drink I called 'Intellex (TM)' Everyone's neurochemistry is different, and so it is worthwile to experiment with different combinations of nutrients, and as importantly, different times of consumption. But, unless you are turning your day upside down. (like dopaminergic stimulant-takers, who can experiment with disregarding this advice..) you should, in general, avoid phenylalanine or tyrosine in the latter part of the day.. Low serotonin causes irratibility and agression, and prevents you from getting restful sleep..(This is why L-Tryptophan, serotonin's precursor, was so good at helping people sleep well when it was available.) I can't buy L-Tryptophan at my vitamin store anymore, but in the evening I try to increase serotonergicity of dietary tryptophan. This is done by supplementation with niacin and B6, consumption of carbohydrates to stimulate insulin, and/or tryptophan-laden foods like turkey or soy... Or L-Tryptophan itself, if you can get it and trust the evidence against it's removal from the market. (coincidentally, just as the SSRI market began to take off..) So the best advice I can give you is to read and carefully experiment. Effective amounts of nutrients must be consumed, but especially if you are consuming atypically large amounts of a substance, again, read up, so you can be aware of the risks. It's also wise to inform your doctor if you are taking large amounts of any substance. So, watch your step...if you don't - you could get burned..
Please send me your experiences. I am still doing research on food-based neuronutrition. A particular interest is the use of neuronutrients in stimulant recovery. Quite bluntly, I believe precursor loading is a valuable potential therapy for drug addiction that is being overlooked. Watch for a web page giving references here soon. (time permitting) Some nutrients used in 'Smart Drinks' include: L-Tyrosine - an amino acid and the most direct precursor of norepinephrine and dopamine. This is the nutrient most used in recovery. First used in a drink by Nutrient Cafe in 1990. Shows promise in many areas, particularly for people under stress or with abnormal brain function. Choline (trimethylaminoethanol) - A B-complex vitamin that your body uses to manufacture acetylcholine, a neurotransmitter involved in the formation and recall of memories. Take this with vitamin B5. Available in many forms, choline chloride and bitartrate being the cheapest. Can increase acid stomach problems markedly.
Synergizes (as does DMAE) with the pyrrilidones. (piracetam/pyroglutamate family) Good in alcohol recovery. Pyroglutamic acid, arginine pyroglutamate - Natural pyrrilidones, found naturally in high quantities in fruits and beer. Enhancing effect on some cognitive function, especially in people with brain disfunction. Some studies have indicated that pyroglutamate may help improve cognition in aging alcoholics. Many people with ADD have also found help from a close relative, piracetam (Glaxo 'Nootropil' is best, available cheaply in Mexico.) Effect may seem to diminish with daily use. DMAE (dimethylaminoethanol) - A B-complex nutrient that is used,like choline, to manufacture acetylcholine in the body. DMAE is found in large quantities in fish, and this is thought to be why people have always thought of fish as "brain food".
Also somewhat useful in alcohol recovery. DL- or L-Phenylalanine - An amino acid that is the precursor of tyrosine and hence dopamine and norepinephrine, the main alerting neurotransmitters and those most depleted by stress,stimulant drugs etc. L-Phenylalanine is also the precursor of phenethylamine,a alerting amine thought to modulate libido and agressive behavior. DLPA may also have some use in treating depression. In addition to fish,other natural foods that are high in "smart nutrients" include soy products,almonds and other nuts,brewers yeast,some fruits,and raw chocolate. Two herbs that also have been associated with smart nutrition are Ginkgo biloba (very useful, but quite expensive...
Check the label of ginkgo products carefully.) and Siberian (eluthero) ginseng. Other herbs and vitamins that may have cognitive-enhancement properties are St. John's wort (hypericin is a interesting site-specific MAO inhibitor, but it must be taken for a month before it's effects can be measured.) Beta-carbolines -like the alkaloids in Syrian Rue and passionflower may also be nootropic in small doses. There are many others. Many vitamins enhance or inhibit various metabolic pathways, sometimes with nootropic effect. Read up on toxicity before overdosing ones- self with vitamins, though. For example, when taken in the evening, vitamin B6 (never more than 50 mg. / day) can help improve serotonin metabolism.
A different, but synergistic effect can be derived from non-time-release niacin. Although it's useful to promote sleep, I have not seen any evidence that melatonin has any nootropic properties. Good sleep is highly nootropic, as well as a potent GH releaser. For this reason it is extremely regrettable that after the tryptophan debacle L-Tryptophan was never researched with an eye to discovering the real story. Despite many unanswered questions about the series of incidents that caused it's removal, and very real evidence that it helped in many neurotransmitter -related medical conditions, including many kinds of drug addiction, L-Tryptophan was never returned to the US market. If you _really_ found benefit from tryptophan and can't replace it, 5-hydroxytryptophan, (5-HT) the immediate precursor of serotonin, is available, although hard-to-find, in the nutritional supplement market. Insomnia may also be a symptom of diseases like sleep apnea, ADD, or depression, so check with your doctor. Small amounts of gammahydroxybutyrate (GHB) when used to assist sleep are nootropic - mostly by dramatically improving the quality of sleep in some people. The improvement in mood can be measured. (I've seen it help friends with depression that wasn't helped by other drugs) Researchers in Illinois have published some amazing reports of older people actually feeling much younger due to the increased GH release during deep sleep, something many people rarely get. Note that the amounts of GHB used to improve sleep in this way are MUCH lower than "recreational" doses. Research on nontoxic sleep aids should be promoted, but unfortunately some deaths (due to overdoses by uninformed people) the war on drugs has made GHB controversial. (Note: GHB can depress breathing, so it should not be used casually. Especially when combined with other drugs, such as alcohol, or taken in high doses, it has caused deaths and irreversable brain damage due to suppression of the breathing reflex!) For those with sleeping problems, GHB should be available by prescription, but again, since it is unpatentable, there is no route in the current medical system for research to be done. (funded) even though the number of people with sleep problems is huge. (UPDATE: GHB is now illegal, with all that implies, in California, due to several deaths.) DHEA, a hormone/hormone precursor, has also shown a lot of evidence that it improves cognition in some, particularly aging people. (possibly by increasing estrogen, a hormone that women produce until menopause, and men manufacture from testosterone, both of which DHEA is a precursor to) In response to many questions, in my (and many others) opinion, caffeine or Ephedra - i.e.: 'Ma Huang' are _not_ appropriate ingredients for Smart Drinks. Ephedra can be dangerous if combined with some drugs, and it isn't a clear-headed stimulant. It's primary use is as a decongestant. Caffeine is a lot better consumed as coffee.. These ephedra products are ludicrously expensive and sometimes dangerous. Note: Please dont email me asking for information on nootropic nutrients or drugs, unless you are actually doing research in this area... What you see is what you get for the time-being. Most nootropic drugs are officially unavailable in the US- but if you need one be activist in asking your doctor about it. They can prescribe them, and even if you cant get them that way, you can (with slight difficulty) sometimes order them direct for personal use. Almost all nootropics are remarkably safe.

The Quest for A Smart Pill Will Drugs Make Us Smarter and Happier?


June 6, 2025, 7:30 a.m. The alarm is going off, and I feel great. Thanks to Reposinex, I’ve had a full four hours of deep, restorative sleep. My head hit the pillow, and boom! I was right into slow-wave delta sleep. In the car, driving to work, I sip an Achieve latte. I love these things—they sensitize my dopamine receptors, shift my MAO levels, and send my noradrenaline levels soaring. I have no jitters, and my concentration is tack-sharp. Driving used to freak me out, actually. I was involved in a bad accident a few years back. Good thing the doctor prescribed that trauma blunter. I still remember the accident; it just doesn’t bug me anymore. I’m no longer one of those Human 1.0s—I’m a human with complete control of his brain chemistry.

June 6, 2005, 7:30 p.m. Ramez Naam has a queen and a six face-up on the green felt of the blackjack table. The dealer shows a six. The obviously correct strategy is for Naam to stay, but this is his first time gambling at a casino, and nothing is obvious to him. Naam is 32, with dark hair and a neatly trimmed goatee. He peers uncertainly at his hand through blue-rimmed glasses, then taps the table with his fingertips. The dealer flips a card: a jack. Naam is out. He’s blown through his $40 stack of chips in less than 10 minutes.

Designing software for Microsoft is Naam’s job; envisioning the future—one in which biotechnology would allow us to shatter natural evolutionary limits—is his calling. A senior member of futurist think tanks such as the Acceleration Studies Foundation and the Foresight Institute, he speaks regularly at technology trade shows and is the author of the provocative new book More Than Human: Embracing the Promise of Biological Enhancement. Like most overachievers, Naam doesn’t like to lose. In blackjack and in life, of course, many factors are beyond our control—we can’t choose what we’re dealt, from the card deck or the genetic one—and Naam argues that we should change the restrictive rules of the biological game. He asks: What if you could pop a pill to make you remember more, think faster, or become happier or higher-achieving? What if there were safe steroids for the brain? You could effectively stack the deck, and the payoff could be huge.

The prospect of drug-enabled superminds is not just a futurist’s fantasy. In the past 20 years, scientists—aided by advances in computing, brain imaging and genetic engineering—have made significant progress toward understanding the biochemical systems that regulate cognition and emotion. This knowledge has raised the possibility of manipulating those systems more powerfully and precisely than ever before. One prominent neuroscientist, Anjan Chatterjee, calls what’s coming the era of cosmetic neurology. “Prospecting for better brains may be the new gold rush,” he says.

Roman Casino, where I’ve met Naam, is Caesars Palace on a serious budget, located in a strip mall near Seattle rather than on the Strip in Vegas. Coming here was my idea. A casino—where quick thinking, a good memory and control of your emotions can pay—seemed like a fitting backdrop for getting an overview of the possibilities of enhancement drugs. After a fruitless go at the tables, Naam and I retreat to the bar and order rum-and-Cokes.

“We’ve been enhancing ourselves since the dawn of civilization,” he says. The latest drugs are, to be sure, considerably more complex than the caffeine and alcohol we’re sending toward our bloodstream at the moment. And the way new enhancement pills reach us is complex as well: A pharmaceutical company develops a medication to treat a recognized physical or mental illness; people gradually realize that the drug can help healthy users too; doctors prescribe the substance to patients “off label,” meaning for purposes other than the ones recognized by the Food and Drug Administration; and other people obtain it illegally. Thus, college students end up popping Ritalin to help them ace exams. Concert pianists take propranolol, a hypertension and angina medication, to ease preperformance jitters. And coffee addicts switch to Provigil, a sleep-disorder medication, for powerful, enduring, jitter-free stimulation.

Naam argues that we shouldn’t be limited to using bootlegs of therapeutic drugs (FDA rules prohibit the development of drugs just for enhancement). If companies could turn their attention directly to the task, he says, “in the next few decades, we could create new drugs to sculpt or alter any aspect of human behavior: infatuation, pair-bonding, empathy, appetite, spirituality, thrill-seeking, arousal, even sexual orientation.”

These drugs wouldn’t simply be nice to have, he and other enhancement advocates believe—they would enable a societal transformation every bit as significant as the one wrought by computers. To true believers like Naam, the issue with drugs of the future is about cognitive liberty, the right to do what we want with our minds. It is about a capitalistic fight for the neurocompetitive advantage: The country with the most drug-enhanced citizens wins. And it is an ideological war against bio-Luddites. Past technological revolutions have allowed us to master the world around us. The pharmaceutical one, he believes, will allow us to master the world within.

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.” 5:50 p.m. I’m driving home, and Senator Davidson is on the radio. I support this psychopharm-disclosure bill she’s pushing. Shouldn’t we have the right to know if our elected leaders are taking empathogens and avarice-reducers like they’re supposed to? My wife is working late tonight; I’m with the kids. I love them, but sometimes my patience wears thin. With the advanced beta-blocker I take, though, a tantrum doesn’t set me off. Before bed, we say prayers. Truthfully, I never used to believe. But one little white entheogen pill and I feel—I don’t know, a presence. It’s comforting.

Smarts, of course, don’t guarantee happiness. In the pro- enhancement manifesto The Hedonistic Imperative, transhumanist philosopher David Pearce calls for liberation from our natural biochemistry—the “sick psycho-chemical ghetto bequeathed by our genetic past”—and the beginning of an era of “paradise engineering.” With the help of drugs, he writes, we’ll be able to chemically crank our dopaminergic systems so that “undiluted existential happiness will infuse every second of waking and dreaming existence.”

Sounds great. Sounds familiar, too. Similar if slightly more modest claims circulated two decades ago about Prozac, Paxil and other selective serotonin reuptake inhibitor (SSRI) antidepressants. The drugs are indeed effective and popular. Still, most Americans don’t use them. Their side effects—jitteriness, fuzzy thinking and diminished sex drive—are one reason they haven’t been widely adopted as enhancers, says Samuel Barondes, a psychiatrist at the University of California at San Francisco and author of Better Than Prozac: Creating the Next Generation of Psychiatric Drugs. “The public’s desire for a pure, selective-acting wonder drug remains.”

For much of the 20th century, drug development relied on luck—usually in the form of a serendipitous discovery that a known substance had additional positive effects. Miltown, the first blockbuster psychiatric drug, launched in the 1950s, was originally an antibiotic; Prozac, created in 1972, was a descendant of a common over-the-counter antihistamine.

Going forward, drug development will become less depen-dent on chance. Studies of genetically modified lab animals are revealing valuable information about the genetic and biochemical mechanisms underlying mood. At the University of Colorado, behavioral geneticist John DeFries selectively bred dozens of generations of mice until he had a dark-haired strain that was 30 times as brave as an albino one, as mea-sured by fearfulness tests. The gene variants governing mouse anxiety may turn out to be different than the human ones, but DeFries’s discoveries will probably shed light on genetic contributions to human fear—and may lead to new drug targets.

The completion of the Human Genome Project in 2003 and the rapidly decreasing cost of tools to collect and analyze DNA samples are also aiding drug development. By examining the gene variants that distinguish a depressed man from his happy brother, for instance, researchers may be able to create a more effective mood-elevating drug. Maybe. This burgeoning field, known as psychiatric genetics, is controversial. Any given aspect of personality, behavior or mood is influenced by the interplay of multiple genes—often a dozen or more—as well as environmental factors.

Nevertheless, futurists hail these genetic advances; some drug developers do as well, though more cautiously. In 2001 Emory University neurobiologist Larry Young genetically engineered a line of male prairie voles to have extra receptors for the hormone vasopressin. The manipulated voles formed bonds with females more quickly than normal voles and didn’t need to have sex before doing so. Futurists wonder: Will this knowledge pave the way for a drug to domesticate wayward men? Dean Hamer, chief of gene structure and regulation at the National Cancer Institute, has found that people with a variation of the VMAT2 gene, which affects the transport of the neurochemical monoamine, are more likely to report having transcendent spiritual experiences. Futurists wonder: A pill to make you believe in God?

And finally, happiness itself. Studies of twins have indicated that our fundamental dispositions may be 40 to 50 percent rooted in genetics. Futurist James Hughes writes in Citizen Cyborg: Why Democratic Societies Must Respond to the Redesigned Human of the Future that “the heritability of happiness . . . suggests that there could be future drugs and gene therapies that jack our happiness set-point to its maximum without negative side effects.”

June 7, 2025, 8 p.m. I’m out at dinner with my wife, and things couldn’t be better. Hard to believe we were so close to divorce. All that tiresome couples counseling. Then, simple oxytocin therapy. In a few sessions, it was as if we were dating again—such great chemistry. Right now, we’re on our third bottle of Connect—serotonin levels up, corticosteroid levels down. Sure, you can have an intimate conversation without this stuff, but it’s so much easier with it. We’ll go dancing later. Not naturally my thing, but I can pop some Steppinex—it makes me feel ecstatic. Before driving home, I’ll take an AntiStep and instantly be sober. Let’s say the optimists are right, and we’re able to create powerful new enhancement drugs. Should we? To many people, the answer is clear: absolutely not. Social critic Francis Fukuyama, author of Our Posthuman Future, presents a disquieting vision of a pharma-enhanced population. “Stolid people can become vivacious; introspective ones extroverted; you can adopt one personality on Wednesday and another for the weekend,” he writes. Fukuyama worries that the qualities that make us essen-tially human would be lost.

Biomedical philosopher Leon Kass, who recently chaired President Bush’s Council on Bioethics, writes that “in those areas of human life in which excellence has until now been achieved only by discipline and effort, the attainment of those achievements by means of drugs . . . looks to be ’cheating.’” Enhancement, in his view, is wrong because it is unfair. And unnatural: “All of our encounters with the world . . . would be mediated, filtered, and altered.” More than human, in his view, is no longer human at all. Back at the casino, Naam and I decide to have another go at the tables. He watches closely, soaking up information from the dealer and other players. Soon he’s hitting when he should hit, staying when he should stay, and doubling down. He goes up $120 before pushing back from the table, smiling and flipping the dealer a tip. Seldom is learning so rapid. Still, if Naam had been on a cognitive enhancer, maybe he would have learned even faster and lost less money up-front. Would that be unnatural? Unfair?

“I think it’s unfair that Michael Jordan was born with better basketball genes than me,” he says. “If somebody has a disposition toward being smarter or having a better memory than me, then maybe drugs could help even that out.” Naam also disagrees that enhancement drugs are unnatural. “The urge to better ourselves has been a force in history as far back as we can see,” he says as we head for the door. “Embracing the quest to improve ourselves doesn’t call our hu-manity into question—it reaffirms it.”

James Vlahos wrote about the riskiness of everyday life in July’s Popular Science.

Source: Popular Science
Date: September 2005