Smart drugs

Become Smarter Today - Eat the Right Foods

2007-11-17T14:26:00.000-08:00

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.

Acetylcholine

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

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

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.

http://www.becomingsmarter.com/eating-to-your-smartness-part-3

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DNA computers to fight diseases

2007-08-02T11:58:00.000-07:00

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?

2007-07-03T00:54:00.000-07:00

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

2007-07-03T00:51:00.000-07:00

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

2007-05-20T02:41:00.001-07:00

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.

RICK WEISS

Newly generated neurons help form new memories.

2007-05-20T02:39:00.001-07:00

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,

2007-04-07T10:37:00.001-07:00

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
cgianaro@uchospitals.edu
773-702-6241
University of Chicago Medical Center
8th October 2003

Sharper minds

2007-04-07T10:36:00.001-07:00

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

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

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

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

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

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

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

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

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

Developing research

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Ampakines

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

Mem compounds

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

HT-0712

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

Gene therapy

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

Source: LA Times
Date: 20 December 2004

By Melissa Healy, Times Staff Writer

Memory drugs create new ethical minefield

2007-04-07T10:35:00.001-07:00

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

SHARON BEGLEY

Viagra for the Brain

2007-03-16T20:04:00.001-07:00

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

2007-03-16T19:45:00.001-07:00

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

2007-03-16T19:43:00.001-07:00

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.

Hyperreal.org

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

2007-03-16T19:38:00.001-07:00

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

Seeking Smart Drugs

2007-03-16T19:37:00.001-07:00

Federal and biotech labs research a new generation of drug therapy that improves memory and concentration without side effects

By Eugene Russo

Cognition--memory, perception, and attention--is a prerequisite to success, an essential for a normal life. When it becomes impaired through illness or accident, a person's life is turned upside down. Existing memory enhancement drugs treat maladies that rob memory, but they are relatively ineffective and have significant side effects. Some researchers, realizing the huge market that an aging, memory-slipping population can generate, are working to modify some drugs currently on the market and to generate others that improve memory, sharpen perception, and focus attention. Goals include increasing hippocampal levels of cycle AMP, and targeting ion channels and intracellular cascades.

These hopeful cognition improvers are not household names. "The major pharmaceutical companies have been a little reluctant to venture into this arena," says Steven H. Ferris, executive director of New York University's Silberstein Aging and Dementia Research Center. "The small startup companies have nothing to lose. And frankly, whoever breaks through is going to be very successful. You can imagine what the market size is."

THE SCIENCE OF COGNITIVE ENHANCEMENT
For now, memory enhancement research is primarily geared toward neurodegenerative diseases. The few currently approved drugs are acetylcholinesterase inhibitors. Based on research in the 1960s and 1970s, these drugs work by boosting the effectiveness of the neurotransmitter acetylcholine. Oftentimes patients with Alzheimer disease have inadequate amounts of acetylcholine in the synapses between neurons. Acetylcholinesterase inhibitors increase the effectiveness of the neurotransmitters by inhibiting the enzyme that breaks down acetylcholine. Generally, however, these drugs have only modest effects in patients with Alzheimer disease. "The cholinergic approach is not sustained and not dramatic," says Rene A. Etcheberrigaray, laboratory director for NeuroLogic, in Rockville, Md. "The reason is very simple: It's not linked to an early pathophysiological event."

A new generation of enhancers is promising to be more specific and more powerful. Companies such as Memory Pharmaceuticals and NeuroLogic are seeking to uncover compounds that will alleviate an array of diseases by targeting the basic molecular underpinnings of memory formation. Researchers have shown that aged rodent models can demonstrate memory deficits, specifically within pathways involved in long-term memory consolidation, which may be akin to that in humans. Theoretically, the animals provide a good way to test compounds that restore the ability to form new memories. Nobel laureate Eric Kandel, who helped illustrate how changes in synaptic function underlie learning and memory, cofounded Memory Pharmaceuticals in 1998. Its mission: generate treatments for chronic learning and memory deficits associated with conditions like Parkinson disease, vascular dementia, and Alzheimer disease.

One major strategy is to increase hippocampal levels of cyclic AMP, a second messenger that carries signals from the cell surface to proteins within the cell. Memory president and chief scientific officer Axel Unterbeck calls cAMP the "cellular driver of gene expression associated with long-term memory consolidation." By inhibiting the intracellular enzyme phosphodiesterase, which is known to break down cAMP, he and his colleagues have boosted these cAMP levels in rodents and demonstrated memory improvement, he says. Other memory targets include G-protein-coupled receptors, neuron-governing ion channels, and mechanisms of neurotransmitter release. "Our strategy is to go upstream of nuclear events," explains Unterbeck. "We don't interfere with protein-DNA interactions, which is very difficult to do. But we go upstream on a second messenger level, and also [a] cell surface receptor level."

NeuroLogic focuses on somewhat different molecular cascades, based largely on the memory research of Daniel L. Alkon, scientific director of Johns Hopkins University's Blanchette Rockefeller Neurosciences Institute, a NeuroLogic collaborator. Targets include not only ion channels but intracellular cascades consisting of enzymes like protein kinase C or carbonic anhydrase, a synaptic plasticity mediator. Etcheberrigaray says that NeuroLogic is looking for targets that permit neurons to be either more receptive to stimuli or more susceptible to the associations that constitute memory. "This is a highly reductionist approach," says Etcheberrigaray, "and then we have to prove it back to the animal."

Lacking the super-screening power of Big Pharma, companies such as NeuroLogic and Memory are interested in using or modifying existing, approved drugs for their own needs--a cancer-treating compound, for example, may have many of the properties suitable for memory enhancement. "It's a very powerful way to eliminate lots of risk," says Unterbeck. As with all treatments targeting the brain, cognitive enhancers must somehow get past the blood-brain barrier to reach their targets. Optimizing drug delivery is a constant challenge.

Both companies claim to have strong preclinical results, and at least one drug manufacturer is paying attention: In late July, Memory Pharmaceuticals announced a potential $150 million deal with pharmaceutical giant F. Hoffmann-La Roche of Basel, Switzerland. If these companies successfully create a new generation of safe, effective enhancers, might healthy persons seek to reap the benefits as well?

ENHANCING NORMAL COGNITION
Thirty years ago, cholinesterase inhibitors were tested in normal individuals. But bad side effects, including nausea, vomiting, and diarrhea, made them acceptable only for patients with disease, though side effects have since lessened somewhat. One more recent study demonstrated the significant, positive effects of cholinesterase inhibitors, specifically one called donepezil, in normal, middle-aged private airplane pilots.1 This drug is frequently prescribed for patients with Alzheimer disease. In a randomized, double-blind, placebo-controlled study, investigators compared the flight simulator performance of nine normal pilots on placebo with that of nine normal pilots on donepezil. After 30 days of treatment, the latter group performed better on a set of complex simulator tasks. Senior investigator Peter J. Whitehouse, professor of neurology, Case Western Reserve University, says his group now plans to do tests with galantamine in normal persons; galantamine is the most recently approved drug for treating Alzheimer disease.

One group in particular is quite interested in finding ways to improve cognition: the US military. Research projects in drug enhancement are underway at the Defense Advance Research Projects Agency, the research and development organization for the Department of Defense. "Every uniform service, as far as I know back in history, has tried to do everything they could reasonably do to enhance performance to make our guys a little better than their guys or a lot better than their guys," says Dennis K. McBride, former head of the Navy's operational medicine research and development unit and the current president of the Potomac Institute for Policy Studies in Arlington, Va.

McBride cites three major reasons the military seeks to understand human performance: better selection techniques to get the best people for a given position; better ways of training to improve performance; and better ergonomics to make more efficient the interaction between humans and machinery. Pharmaceutical enhancement would be aimed at lengthy performance enhancement--perhaps to assist a special-operations soldier staking out an embassy for 48 sleepless hours. Says McBride: "It's not necessarily about improving his performance, but maintaining a level ... he wouldn't be able to maintain otherwise without the drugs."

Eugene Russo (erusso@the-scientist.com) is a contributing editor.

1. J.A. Yesavage et al., "Donepezil and flight simulator performance: Effects on retention of complex skills," Neurology, 59:123-5, July 9, 2002.

Source: The Scientist
Volume 16 | Issue 21 | 27 | Oct. 28, 2002

11 steps to a better brain

2007-03-16T19:35:00.001-07:00

You must remember thisIt doesn't matter how brainy you are or how much education you've had - you can still improve and expand your mind. Boosting your mental faculties doesn't have to mean studying hard or becoming a reclusive book worm. There are lots of tricks, techniques and habits, as well as changes to your lifestyle, diet and behaviour that can help you flex your grey matter and get the best out of your brain cells. And here are 11 of them.

Smart drugs

Does getting old have to mean worsening memory, slower reactions and fuzzy thinking?

Around the age of 40, honest folks may already admit to noticing changes in their mental abilities. This is the beginning of a gradual decline that in all too many of us will culminate in full-blown dementia. If it were possible somehow to reverse it, slow it or mask it, wouldn't you?

A few drugs that might do the job, known as "cognitive enhancement", are already on the market, and a few dozen others are on the way. Perhaps the best-known is modafinil. Licensed to treat narcolepsy, the condition that causes people to suddenly fall asleep, it has notable effects in healthy people too. Modafinil can keep a person awake and alert for 90 hours straight, with none of the jitteriness and bad concentration that amphetamines or even coffee seem to produce.

In fact, with the help of modafinil, sleep-deprived people can perform even better than their well-rested, unmedicated selves. The forfeited rest doesn't even need to be made good. Military research is finding that people can stay awake for 40 hours, sleep the normal 8 hours, and then pull a few more all-nighters with no ill effects. It's an open secret that many, perhaps most, prescriptions for modafinil are written not for people who suffer from narcolepsy, but for those who simply want to stay awake. Similarly, many people are using Ritalin not because they suffer from attention deficit or any other disorder, but because they want superior concentration during exams or heavy-duty negotiations.

The pharmaceutical pipeline is clogged with promising compounds - drugs that act on the nicotinic receptors that smokers have long exploited, drugs that work on the cannabinoid system to block pot-smoking-type effects. Some drugs have also been specially designed to augment memory. Many of these look genuinely plausible: they seem to work, and without any major side effects.

So why aren't we all on cognitive enhancers already? "We need to be careful what we wish for," says Daniele Piomelli at the University of California at Irvine. He is studying the body's cannabinoid system with a view to making memories less emotionally charged in people suffering from post-traumatic stress disorder. Tinkering with memory may have unwanted effects, he warns. "Ultimately we may end up remembering things we don't want to."

Gary Lynch, also at UC Irvine, voices a similar concern. He is the inventor of ampakines, a class of drugs that changes the rules about how a memory is encoded and how strong a memory trace is - the essence of learning. But maybe the rules have already been optimised by evolution, he suggests. What looks to be an improvement could have hidden downsides.

Still, the opportunity may be too tempting to pass up. The drug acts only in the brain, claims Lynch. It has a short half-life of hours. Ampakines have been shown to restore function to severely sleep-deprived monkeys that would otherwise perform poorly. Preliminary studies in humans are just as exciting. You could make an elderly person perform like a much younger person, he says. And who doesn't wish for that?

Food for thought

You are what you eat, and that includes your brain. So what is the ultimate mastermind diet?

Your brain is the greediest organ in your body, with some quite specific dietary requirements. So it is hardly surprising that what you eat can affect how you think. If you believe the dietary supplement industry, you could become the next Einstein just by popping the right combination of pills. Look closer, however, and it isn't that simple. The savvy consumer should take talk of brain-boosting diets with a pinch of low-sodium salt. But if it is possible to eat your way to genius, it must surely be worth a try.

First, go to the top of the class by eating breakfast. The brain is best fuelled by a steady supply of glucose, and many studies have shown that skipping breakfast reduces people's performance at school and at work.

But it isn't simply a matter of getting some calories down. According to research published in 2003, kids breakfasting on fizzy drinks and sugary snacks performed at the level of an average 70-year-old in tests of memory and attention. Beans on toast is a far better combination, as Barbara Stewart from the University of Ulster, UK, discovered. Toast alone boosted children's scores on a variety of cognitive tests, but when the tests got tougher, the breakfast with the high-protein beans worked best. Beans are also a good source of fibre, and other research has shown a link between a high-fibre diet and improved cognition. If you can't stomach beans before midday, wholemeal toast with Marmite makes a great alternative. The yeast extract is packed with B vitamins, whose brain-boosting powers have been demonstrated in many studies.

A smart choice for lunch is omelette and salad. Eggs are rich in choline, which your body uses to produce the neurotransmitter acetylcholine. Researchers at Boston University found that when healthy young adults were given the drug scopolamine, which blocks acetylcholine receptors in the brain, it significantly reduced their ability to remember word pairs. Low levels of acetylcholine are also associated with Alzheimer's disease, and some studies suggest that boosting dietary intake may slow age-related memory loss.

A salad packed full of antioxidants, including beta-carotene and vitamins C and E, should also help keep an ageing brain in tip-top condition by helping to mop up damaging free radicals. Dwight Tapp and colleagues from the University of California at Irvine found that a diet high in antioxidants improved the cognitive skills of 39 ageing beagles - proving that you can teach an old dog new tricks.

Round off lunch with a yogurt dessert, and you should be alert and ready to face the stresses of the afternoon. That's because yogurt contains the amino acid tyrosine, needed for the production of the neurotransmitters dopamine and noradrenalin, among others. Studies by the US military indicate that tyrosine becomes depleted when we are under stress and that supplementing your intake can improve alertness and memory.

Don't forget to snaffle a snack mid-afternoon, to maintain your glucose levels. Just make sure you avoid junk food, and especially highly processed goodies such as cakes, pastries and biscuits, which contain trans-fatty acids. These not only pile on the pounds, but are implicated in a slew of serious mental disorders, from dyslexia and ADHD (attention deficit hyperactivity disorder) to autism. Hard evidence for this is still thin on the ground, but last year researchers at the annual Society for Neuroscience meeting in San Diego, California, reported that rats and mice raised on the rodent equivalent of junk food struggled to find their way around a maze, and took longer to remember solutions to problems they had already solved.

It seems that some of the damage may be mediated through triglyceride, a cholesterol-like substance found at high levels in rodents fed on trans-fats. When the researchers gave these rats a drug to bring triglyceride levels down again, the animals' performance on the memory tasks improved.

Brains are around 60 per cent fat, so if trans-fats clog up the system, what should you eat to keep it well oiled? Evidence is mounting in favour of omega-3 fatty acids, in particular docosahexaenoic acid or DHA. In other words, your granny was right: fish is the best brain food. Not only will it feed and lubricate a developing brain, DHA also seems to help stave off dementia. Studies published last year reveal that older mice from a strain genetically altered to develop Alzheimer's had 70 per cent less of the amyloid plaques associated with the disease when fed on a high-DHA diet.

Finally, you could do worse than finish off your evening meal with strawberries and blueberries. Rats fed on these fruits have shown improved coordination, concentration and short-term memory. And even if they don't work such wonders in people, they still taste fantastic. So what have you got to lose?

The Mozart effect

Music may tune up your thinking, but you can't just crank up the volume and expect to become a genius

A decade ago Frances Rauscher, a psychologist now at the University of Wisconsin at Oshkosh, and her colleagues made waves with the discovery that listening to Mozart improved people's mathematical and spatial reasoning. Even rats ran mazes faster and more accurately after hearing Mozart than after white noise or music by the minimalist composer Philip Glass. Last year, Rauscher reported that, for rats at least, a Mozart piano sonata seems to stimulate activity in three genes involved in nerve-cell signalling in the brain.

This sounds like the most harmonious way to tune up your mental faculties. But before you grab the CDs, hear this note of caution. Not everyone who has looked for the Mozart effect has found it. What's more, even its proponents tend to think that music boosts brain power simply because it makes listeners feel better - relaxed and stimulated at the same time - and that a comparable stimulus might do just as well. In fact, one study found that listening to a story gave a similar performance boost.

There is, however, one way in which music really does make you smarter, though unfortunately it requires a bit more effort than just selecting something mellow on your iPod. Music lessons are the key. Six-year-old children who were given music lessons, as opposed to drama lessons or no extra instruction, got a 2 to 3-point boost in IQ scores compared with the others. Similarly, Rauscher found that after two years of music lessons, pre-school children scored better on spatial reasoning tests than those who took computer lessons.

Maybe music lessons exercise a range of mental skills, with their requirement for delicate and precise finger movements, and listening for pitch and rhythm, all combined with an emotional dimension. Nobody knows for sure. Neither do they know whether adults can get the same mental boost as young children. But, surely, it can't hurt to try.

Bionic brains

If training and tricks seem too much like hard work, some technological short cuts can boost brain function

Gainful employment

Put your mind to work in the right way and it could repay you with an impressive bonus

Until recently, a person's IQ - a measure of all kinds of mental problem-solving abilities, including spatial skills, memory and verbal reasoning - was thought to be a fixed commodity largely determined by genetics. But recent hints suggest that a very basic brain function called working memory might underlie our general intelligence, opening up the intriguing possibility that if you improve your working memory, you could boost your IQ too.

Working memory is the brain's short-term information storage system. It's a workbench for solving mental problems. For example if you calculate 73 - 6 + 7, your working memory will store the intermediate steps necessary to work out the answer. And the amount of information that the working memory can hold is strongly related to general intelligence.

A team led by Torkel Klingberg at the Karolinska Institute in Stockholm, Sweden, has found signs that the neural systems that underlie working memory may grow in response to training. Using functional magnetic resonance imaging (fMRI) brain scans, they measured the brain activity of adults before and after a working-memory training programme, which involved tasks such as memorising the positions of a series of dots on a grid. After five weeks of training, their brain activity had increased in the regions associated with this type of memory (Nature Neuroscience, vol 7, p 75). Perhaps more significantly, when the group studied children who had completed these types of mental workouts, they saw improvement in a range of cognitive abilities not related to the training, and a leap in IQ test scores of 8 per cent (Journal of the American Academy of Child and Adolescent Psychiatry, vol 44, p 177). It's early days yet, but Klingberg thinks working-memory training could be a key to unlocking brain power. "Genetics determines a lot and so does the early gestation period," he says. "On top of that, there is a few per cent - we don't know how much - that can be improved by training."

Memory marvels

Mind like a sieve? Don't worry. The difference between mere mortals and memory champs is more method than mental capacity

An auditorium is filled with 600 people. As they file out, they each tell you their name. An hour later, you are asked to recall them all. Can you do it? Most of us would balk at the idea. But in truth we're probably all up to the task. It just needs a little technique and dedication.

First, learn a trick from the "mnemonists" who routinely memorise strings of thousands of digits, entire epic poems, or hundreds of unrelated words. When Eleanor Maguire from University College London and her colleagues studied eight front runners in the annual World Memory Championships they did not find any evidence that these people have particularly high IQs or differently configured brains. But, while memorising, these people did show activity in three brain regions that become active during movements and navigation tasks but are not normally active during simple memory tests.

This may be connected to the fact that seven of them used a strategy in which they place items to be remembered along a visualised route (Nature Neuroscience, vol 6, p 90). To remember the sequence of an entire pack of playing cards for example, the champions assign each card an identity, perhaps an object or person, and as they flick through the cards they can make up a story based on a sequence of interactions between these characters and objects at sites along a well-trodden route.

Actors use a related technique: they attach emotional meaning to what they say. We always remember highly emotional moments better than less emotionally loaded ones. Professional actors also seem to link words with movement, remembering action-accompanied lines significantly better than those delivered while static, even months after a show has closed.

“We always remember highly emotional moments better”Helga Noice, a psychologist from Elmhurst College in Illinois, and Tony Noice, an actor, who together discovered this effect, found that non-thesps can benefit by adopting a similar technique. Students who paired their words with previously learned actions could reproduce 38 per cent of them after just 5 minutes, whereas rote learners only managed 14 per cent. The Noices believe that having two mental representations gives you a better shot at remembering what you are supposed to say.

Strategy is important in everyday life too, says Barry Gordon from Johns Hopkins University in Baltimore, Maryland. Simple things like always putting your car keys in the same place, writing things down to get them off your mind, or just deciding to pay attention, can make a big difference to how much information you retain. And if names are your downfall, try making some mental associations. Just remember to keep the derogatory ones to yourself.

Sleep on it

Never underestimate the power of a good night's rest

Skimping on sleep does awful things to your brain. Planning, problem-solving, learning, concentration,working memory and alertness all take a hit. IQ scores tumble. "If you have been awake for 21 hours straight, your abilities are equivalent to someone who is legally drunk," says Sean Drummond from the University of California, San Diego. And you don't need to pull an all-nighter to suffer the effects: two or three late nights and early mornings on the trot have the same effect.

Luckily, it's reversible - and more. If you let someone who isn't sleep-deprived have an extra hour or two of shut-eye, they perform much better than normal on tasks requiring sustained attention, such taking an exam. And being able to concentrate harder has knock-on benefits for overall mental performance. "Attention is the base of a mental pyramid," says Drummond. "If you boost that, you can't help boosting everything above it."

These are not the only benefits of a decent night's sleep. Sleep is when your brain processes new memories, practises and hones new skills - and even solves problems. Say you're trying to master a new video game. Instead of grinding away into the small hours, you would be better off playing for a couple of hours, then going to bed. While you are asleep your brain will reactivate the circuits it was using as you learned the game, rehearse them, and then shunt the new memories into long-term storage. When you wake up, hey presto! You will be a better player. The same applies to other skills such as playing the piano, driving a car and, some researchers claim, memorising facts and figures. Even taking a nap after training can help, says Carlyle Smith of Trent University in Peterborough, Ontario.

There is also some evidence that sleep can help produce moments of problem-solving insight. The famous story about the Russian chemist Dmitri Mendeleev suddenly "getting" the periodic table in a dream after a day spent struggling with the problem is probably true. It seems that sleep somehow allows the brain to juggle new memories to produce flashes of creative insight. So if you want to have a eureka moment, stop racking your brains and get your head down.

Body and mind

Physical exercise can boost brain as well as brawn

It's a dream come true for those who hate studying. Simply walking sedately for half an hour three times a week can improve abilities such as learning, concentration and abstract reasoning by 15 per cent. The effects are particularly noticeable in older people. Senior citizens who walk regularly perform better on memory tests than their sedentary peers. What's more, over several years their scores on a variety of cognitive tests show far less decline than those of non-walkers. Every extra mile a week has measurable benefits.

It's not only oldies who benefit, however. Angela Balding from the University of Exeter, UK, has found that schoolchildren who exercise three or four times a week get higher than average exam grades at age 10 or 11. The effect is strongest in boys, and while Balding admits that the link may not be causal, she suggests that aerobic exercise may boost mental powers by getting extra oxygen to your energy-guzzling brain.

There's another reason why your brain loves physical exercise: it promotes the growth of new brain cells. Until recently, received wisdom had it that we are born with a full complement of neurons and produce no new ones during our lifetime. Fred Gage from the Salk Institute in La Jolla, California, busted that myth in 2000 when he showed that even adults can grow new brain cells. He also found that exercise is one of the best ways to achieve this.

In mice, at least, the brain-building effects of exercise are strongest in the hippocampus, which is involved with learning and memory. This also happens to be the brain region that is damaged by elevated levels of the stress hormone cortisol. So if you are feeling frazzled, do your brain a favour and go for a run.

Even more gentle exercise, such as yoga, can do wonders for your brain. Last year, researchers at the University of California, Los Angeles, reported results from a pilot study in which they considered the mood-altering ability of different yoga poses. Comparing back bends, forward bends and standing poses, they concluded that the best way to get a mental lift is to bend over backwards.

“Get a mental lift by bending over backwards”And the effect works both ways. Just as physical exercise can boost the brain, mental exercise can boost the body. In 2001, researchers at the Cleveland Clinic Foundation in Ohio asked volunteers to spend just 15 minutes a day thinking about exercising their biceps. After 12 weeks, their arms were 13 per cent stronger.

Nuns on a run

If you don't want senility to interfere with your old age, perhaps you should seek some sisterly guidance

The convent of the School Sisters of Notre Dame on Good Counsel Hill in Mankato, Minnesota, might seem an unusual place for a pioneering brain-science experiment. But a study of its 75 to 107-year-old inhabitants is revealing more about keeping the brain alive and healthy than perhaps any other to date. The "Nun study" is a unique collaboration between 678 Catholic sisters recruited in 1991 and Alzheimer's expert David Snowdon of the Sanders-Brown Center on Aging and the University of Kentucky in Lexington.

The sisters' miraculous longevity - the group boasts seven centenarians and many others well on their way - is surely in no small part attributable to their impeccable lifestyle. They do not drink or smoke, they live quietly and communally, they are spiritual and calm and they eat healthily and in moderation. Nevertheless, small differences between individual nuns could reveal the key to a healthy mind in later life.

Some of the nuns have suffered from Alzheimer's disease, but many have avoided any kind of dementia or senility. They include Sister Matthia, who was mentally fit and active from her birth in 1894 to the day she died peacefully in her sleep, aged 104. She was happy and productive, knitting mittens for the poor every day until the end of her life. A post-mortem of Sister Matthia's brain revealed no signs of excessive ageing. But in some other, remarkable cases, Snowdon has found sisters who showed no outwards signs of senility in life, yet had brains that looked as if they were ravaged by dementia.

How did Sister Matthia and the others cheat time? Snowdon's study, which includes an annual barrage of mental agility tests and detailed medical exams, has found several common denominators. The right amount of vitamin folate is one. Verbal ability early in life is another, as are positive emotions early in life, which were revealed by Snowdon's analysis of the personal autobiographical essays each woman wrote in her 20s as she took her vows. Activities, crosswords, knitting and exercising also helped to prevent senility, showing that the old adage "use it or lose it" is pertinent. And spirituality, or the positive attitude that comes from it, can't be overlooked. But individual differences also matter. To avoid dementia, your general health may be vital: metabolic problems, small strokes and head injuries seem to be common triggers of Alzheimer's dementia.

Obviously, you don't have to become a nun to stay mentally agile. We can all aspire to these kinds of improvements. As one of the sisters put it, "Think no evil, do no evil, hear no evil, and you will never write a best-selling novel."

Attention seeking

You can be smart, well-read, creative and knowledgeable, but none of it is any use if your mind isn't on the job

Paying attention is a complex mental process, an interplay of zooming in on detail and stepping back to survey the big picture. So unfortunately there is no single remedy to enhance your concentration. But there are a few ways to improve it.

The first is to raise your arousal levels. The brain's attentional state is controlled by the neurotransmitters dopamine and noradrenalin. Dopamine encourages a persistent, goal-centred state of mind whereas noradrenalin produces an outward-looking, vigilant state. So not surprisingly, anything that raises dopamine levels can boost your powers of concentration.

One way to do this is with drugs such as amphetamines and the ADHD drug methylphenidate, better known as Ritalin. Caffeine also works. But if you prefer the drug-free approach, the best strategy is to sleep well, eat foods packed with slow-release sugars, and take lots of exercise. It also helps if you are trying to focus on something that you find interesting.

The second step is to cut down on distractions. Workplace studies have found that it takes up to 15 minutes to regain a deep state of concentration after a distraction such as a phone call. Just a few such interruptions and half the day is wasted.

Music can help as long as you listen to something familiar and soothing that serves primarily to drown out background noise. Psychologists also recommend that you avoid working near potential diversions, such as the fridge.

There are mental drills to deal with distractions. College counsellors routinely teach students to recognise when their thoughts are wandering, and catch themselves by saying "Stop! Be here now!" It sounds corny but can develop into a valuable habit. As any Zen meditator will tell you, concentration is as much a skill to be lovingly cultivated as it is a physiochemical state of the brain.

Positive feedback

Thought control is easier than you might imagine

It sounds a bit New Age, but there is a mysterious method of thought control you can learn that seems to boost brain power. No one quite knows how it works, and it is hard to describe exactly how to do it: it's not relaxation or concentration as such, more a state of mind. It's called neurofeedback. And it is slowly gaining scientific credibility.

Neurofeedback grew out of biofeedback therapy, popular in the 1960s. It works by showing people a real-time measure of some seemingly uncontrollable aspect of their physiology - heart rate, say - and encouraging them to try and change it. Astonishingly, many patients found that they could, though only rarely could they describe how they did it.

More recently, this technique has been applied to the brain - specifically to brain wave activity measured by an electroencephalogram, or EEG. The first attempts were aimed at boosting the size of the alpha wave, which crescendos when we are calm and focused. In one experiment, researchers linked the speed of a car in a computer game to the size of the alpha wave. They then asked subjects to make the car go faster using only their minds. Many managed to do so, and seemed to become more alert and focused as a result.

This early success encouraged others, and neurofeedback soon became a popular alternative therapy for ADHD. There is now good scientific evidence that it works, as well as some success in treating epilepsy, depression, tinnitus, anxiety, stroke and brain injuries.

And to keep up with the times, some experimenters have used brain scanners in place of EEGs. Scanners can allow people to see and control activity of specific parts of the brain. A team at Stanford University in California showed that people could learn to control pain by watching the activity of their pain centres (New Scientist, 1 May 2004, p 9).

But what about outside the clinic? Will neuro feedback ever allow ordinary people to boost their brain function? Possibly. John Gruzelier of Imperial College London has shown that it can improve medical students' memory and make them feel calmer before exams. He has also shown that it can improve musicians' and dancers' technique, and is testing it out on opera singers and surgeons.

Neils Birbaumer from the University of Tübingen in Germany wants to see whether neurofeedback can help psychopathic criminals control their impulsiveness. And there are hints that the method could boost creativity, enhance our orgasms, give shy people more confidence, lift low moods, alter the balance between left and right brain activity, and alter personality traits. All this by the power of thought.

Source: New Scientist
Date: 28 May 2005

REMEMBER MORE - THINK FASTER - BE WISER

2007-03-16T19:29:00.001-07:00

Wouldn't it be nice if you could swallow a pill rather than study for a test? Are there such "smart pills"? Perhaps you could take a pill and get a "mental tune-up" if you are feeling a bit dull.

Actually, researchers are studying substances that may improve mental abilities. These substances are called "cognitive enhancers" or "smart drugs" or "nootropics." ("Nootropic" comes from Greek - "noos" = mind and "tropos" = changed, toward, turn). The supposed effects of cognitive enhancement can be several things. For example, it could mean improvement of memory, learning, attention, concentration, problem solving, reasoning, social skills, decision making and planning.

In most cases, cognitive enhancers have been used to treat people with neurological or mental disorders, but there is a growing number of healthy, "normal" people who use these substances in hopes of getting smarter. Although there are many companies that make "smart" drinks, smart power bars and diet supplements containing certain "smart" chemicals, there is little evidence to suggest that these products really work. Results from different laboratories show mixed results; some labs show positive effects on memory and learning; other labs show no effects. There are very few well-designed studies using normal healthy people.

Let's look at the evidence regarding cognitive enhancing substances.

How might these substances work?

Increase brain metabolism
Increase cerebral circulation
Protection of brain from physical and chemical damage

What are the possible effects of these substances?

Increased mental "energy"
Increased alertness
Decreased depression
Improved memory
Improved learning ability

Specific Cognitive Enhancers

Hydergine - a "smart drug" that dilates the blood vessels of the brain.
Piracetam
Aniracetam
BMY-21502/BMs-181168
Minaprine
Oxiracetam
Pramiracetam

Drugs that Act on Neurotransmitters

Linopirdine (UP 996)
Physostigmine - an acetylcholinesterase (AChE) inhibitor - has short lasting effects and has been used to treat patients with Alzheimer's disease and traumatic brain injury
Sabeluzole (R58735)
Tacrine (tetrahydroaminoacridine) - an AChE inhibitor, but it may be toxic
Vasopressin - a neuropeptide released by the pituitary
Methylphenidate (Ritalin) and dextroamphetamine - stimulants used to treat attention deficit hyperactivity disorder. These drugs affect multiple neurotransmitter systems.
Amantadine - dopamine agonist
Nicotine and Caffeine - could be considered "smart drugs" by increasing alertness

Nutrients

Acetyl L Carnitine
Choline - precursor to acetylcholine; eggs, meat and milk are good sources of choline.
Cytidine-5'-diphosphate choline
L-alpha-glycerylphosphorylcholine
2-Dimethylaminoethanol (DMAE) - found in the brain and in anchovies and sardines; appears to increase acetylcholine production.
Phospatidylserine - found on the surface of neuronal membrane and synapse.

Other substances including herbs

BR-16A - a herb from India
Ginkgo Biloba - an extract from a tree that has been used as medicine in China and Europe. This herb increases cerebral circulation, increases glucose utilization by the brain and increases choline reuptake. It has been used to treat patients with Alzheimer's disease, but other studies show it has no effect on healthy males.
Ma-huang - a herb from China
Oxymethacil - reduces oxidation of molecules in the brain.
Pyritinol - similar to vitamin B6; also increases cerebral blood flow.

Some smart drugs can be found in health food stores; others are imported or are drugs that are intended for other disorders such as Alzheimer's disease and Parkinson's disease. There are many Internet web sites, books, magazines and newspaper articles detailing the supposed effects of smart drugs. There are also plenty of advertisements and mail-order businesses that try to sell "smart drugs" to the public. However, rarely do these businesses or the popular press report results that show the failure of smart drugs to improve memory or learning. Rather, they try to show that their products have miraculous effects on the brain and can improve mental functioning. Wouldn't it be easy to learn something by "popping a pill" or drinking a soda laced with a smart drug? This would be much easier than taking the time to study. Feeling dull? Take your brain in for a mental tune up by popping a pill!

Some data suggest that cognitive enhancers do improve some types of learning and memory, but many other data say these substances have no effect. The strongest evidence for these substances is for the improvement of cognitive function in people with brain injury or disease (for example, Alzheimer's disease and traumatic brain injury). Although "popular" books and companies that sell smart drugs will try to convince you that these drugs work, the evidence for any significant effects of these substances in normal people is weak. There are also important side-effects that must be considered. Many of these substances effect neurotransmitters systems in the central nervous system. The effects of these chemicals on neurological function and behavior is unknown. Moreover, the long-term safety of these substances has not been adequately tested. Also, the possibility that these substances will interact with other substances a person might take is untested. A substance such as the herb Ma-huang may be dangerous if a person stops taking it suddenly.

Many of the positive effects of cognitive enhancers have been seen in experiments using rats. For example, scientists can train rats on a specific test, such as maze running, and then see if the "smart drug" can improve the rats' performance. It is difficult to see how many of these data can be applied to human learning and memory. For example, what if the "smart drug" made the rat hungry? Wouldn't a hungry rat run faster in the maze to receive a food reward than a non-hungry rat? Maybe the rat did not get any "smarter" and did not have any improved memory. Perhaps the rat ran faster simply because it was hungrier. Therefore, it was the rat's motivation to run the maze, not its increased cognitive ability that affected the performance. Thus, it is important to be very careful when interpreting changes observed in these types of animal learning and memory experiments.

One symptom of Alzheimer's disease is a reduced brain level of the neurotransmitter called acetylcholine. It is thought that an effective treatment for Alzheimer's disease might be to increase brain levels of acetylcholine. Another possible treatment would be to slow the death of neurons that contain acetylcholine. Two drugs, Tacrine and Donepezil, are both inhibitors of the enzyme (acetylcholinesterase) that breaks down acetylcholine. These drugs are approved in the US for treatment of Alzheimer's disease.

Moral and Ethical Questions about the Use of Smart Drugs

2007-03-16T19:28:00.001-07:00

Here are some questions for you to think about IF and WHEN smart drugs are developed:

What would happen if people got smarter? Is this a good thing or a bad thing?
What are the possible advantages and disadvantages of short-term and long-term "smartness"?
If such drugs existed, should they be manufactured, distributed and used?
If they can be used, who should get them?
Should they be banned like some drugs in athletics (e.g., stimulants, steroids)?
Is going to a special school or class or getting a tutor different from taking a "smart drug"? What about learning a trick to solve a math problem? Isn't this like taking a special drug? What about getting a computer to help with homework? Isn't this like using technology to help you get smarter and learn more?
Should it be illegal to pop a smart pill before a spelling test or before you take the SAT? Would this be like taking a stimulant before a track meet or swimming race? Would this be cheating?
As people got smarter, would their personality change?
What would happen to people's emotional and social behavior?
We have drugs to improve our mood (antidepressants) and to look better (weight loss drugs). We even have a drug to increase the height of children (growth factor).
What is wrong with a drug that makes us smarter?
What about the benefits of such drugs? Couldn't these substances make people better drivers, workers and teachers?
Could important new discoveries and cures for diseases be made faster if we were smarter? ?

"Smart Drugs" & the Aging Brain:

2007-03-16T19:22:00.001-07:00

A Superficial Review

by Ben Best

A life-extensionist is concerned with survival -- of the body, of the self -- and, in particular, of the brain. But beyond resisting the destruction & degeneration of the brain there looms also the possibility of regeneration & perhaps even augmentation. The "Smart Drug Movement" implies that this is possible -- and possible now.

I have several personal problems with "Smart Drug" people. Many of these individuals are the same people with whom I was arguing 20 years ago over the value of LSD, marijuana and other "recreational drugs" for enhanced creativity. I have seen several individuals devolve into intellectual dysfunction from brain-dissolving neurochemical pleasures. Even alcohol can promote a sense of one's own capabilities which is unrelated to reality. People who attempt to take a substance and try to judge it's effects must be aware that the substance may not only be influencing the experienced effects, but the very judgement of those experienced effects.

Here I review the subject of "Smart Drugs", referring to the most popular (to my knowledge) books on the subject: MIND FOOD & SMART PILLS by Ross Pelton (1989), SMART DRUGS & NUTRIENTS by Ward Dean & John Morgenthaler (1990) and SMART DRUGS II by Dean, Morgenthaler and Fowkes (1993) -- all paperback editions. What is presented here is mostly based on my remembered information and what is in these books, so readers should take what I say with a "grain of salt". I may write a more scientific analysis once I know more about neurochemistry.

The science of "Smart Drugs" is in an even more difficult position than that of anti-aging research. The brain is perhaps the most distinctive feature of human anatomy, and the results of animal studies may be more difficult to extrapolate. The anti-parkinsonian (and anti-aging) drug Deprenyl, for example, acts primarily in the brain, but has been studied in rats -- a species which does not demonstrate Parkinson's Disease. Many, if not most, of the experiments on human subjects using "Smart Drugs" have been performed on patients with Alzheimer's Disease and other forms of senile dementia. The applicability of these results to normal humans is questionable. Many of the so-called "Smart Drugs" are indeed valuable as anti-aging agents of specific value for the brain -- but to include these substances in a category of compounds intended to increase the intelligence of normal subjects is questionable.

The book by Pelton is the worst of the series. Samplings of the author's ignorance include statements like "acetylcholine is the major chemical transmitter for thoughts and memories" and "the hippocampus is involved in working memory" . He expresses the belief that glutathione is part of glutathione peroxidase (the enzyme that accepts glutathione as its substrate). On page 69 he tells readers that he will use the word "lecithin" to refer to phosphatidyl choline, but by the bottom of page 71 he has forgotten his convention (short-term memory loss?). As a role-model for "Smart Drugs" Pelton is a wash-out.

It does make intuitive sense that brains require certain neurochemicals to function in an optimum manner, and that diets don't always include optimum nutrients. In such a case, diet or supplements could rectify the situation. But the brain is an intricate signalling device, and flooding brains with neurotransmitter -- or even neurotransmitter precursors -- has the potential of disrupting communications. Page 30 of SMART DRUGS & NUTRIENTS shows an inverted "U" curve of improvement of short term memory in rats with increasing dosage levels of pramiracetam. The authors seem to support the view that such a relationship holds for all "Smart Drugs", suggesting that the use of these substances requires careful experimentation and self-assessment by each individual to determine the optimum dose.

SMART DRUGS II carries this principle even further with a remarkable study quoted on pages 114-117. School children given a multivitamin/mineral supplement of 100% RDA showed IQ improvement greater than those given 50% or 200% RDA. Even if megavitamins promote health and have anti-aging effects, if these results are true then those who take megavitamins may be gaining benefits at an IQ cost. The implications for "Orthomolecular Psychiatry" must also be re-examined in this light. At a recent conference I asked one of the authors about this (Ward Dean) and he seemed dumbfounded. He suggested that I subscribe to SMART DRUG NEWS and write a letter to the editor.

Hydergine is a mixture of alkaloids that come from a fungus (ergot) that grows on rye. Hydergine may have antioxidant and nerve growth factor (NGF)-like properties, but it's prime benefit is through increased blood circulation in the brain, possibly acting on the major vessels (since it is touted as opposing the vasoconstriction of nicotine). Hydergine is used medically to treat senile dementia, much of which is related to brain circulatory decline (and mini-strokes). Vincamine, Nimodipine and Vinpocetine (from periwinkle) can also promote brain blood circulation. Ginko biloba (from the oldest known species of tree) reputedly increases brain blood circulation, but by increased flow in the capillaries, rather than the arterioles.

L-Deprenyl has also been called a "Smart Drug", but again because it may protect against the effects of aging in the brain. The Japanese researcher Kenichi Kitani has shown that deprenyl can greatly increase the activity of SuperOxide Dismutase and Catalase in the striatum of rat brains, but above a certain dose level, deprenyl reduces the activity of these antioxidant enzymes. Deprenyl also binds to MonoAmine Oxidase B (MAO-B), opposing the increasing activity of that enzyme in aging brains & hearts. Deprenyl particularly reduces neuron loss in the rat frontal cortex and hippocampus.

Centrophenoxine (Lucidril) & DMAE (DiMethylAminoEthanol) function to protect against free-radical oxidation. DMAE (which is found in high concentrations in sardines & anchovies) is claimed to facilitate production of the neurotransmitter acetylcholine (as is phosphatidyl choline). Since acetylcholine (primarily from the nucleus of Meynert in the basal forebrain) acts as a neurotransmitter to stimulate the hippocampus, memory function can be improved somewhat by substances that facilitate acetylcholine production -- particularly in Alzheimer's patients. No cholinergic agonists have been successful in simulating this effect, but some acetylcholinesterase (acetylcholine-destroying enzyme) antagonists like tacrine have been.

DMAE is metabolized in the brain to form phosphatidyl-DMAE which becomes incorporated in nerve cell membranes where it is highly protective against hydroxyl (OH ) free-radical damage. Loss of permeability of cell membranes with aging is correlated with dehydration, declining enzyme activity and increasing lipofuscin accumulation. This is most serious in the brain & heart because the cells in these tissues are non-dividing.

Centrophenoxine is an ester (carboxyl-linked dimer, ie, two molecules linked to a C=O group by a -O- connection) of p-chlorophenoxyacetic acid and DMAE. Centrophenoxine crosses the blood-brain barrier (BBB) much more effectively than DMAE alone, and once across the BBB the DMAE can be released by hydrolysis. Centrophenoxine has actually been shown to reverse lipofuscin concentration in the frontal cortex and hippocampus in treated mice (lipofuscin concentration normally increases particularly dramatically in the CA3 cells of the hippocampus). Procaine (an ingredient of Gerovital, GH-3) is broken-down in the body into para-aminobenzoic acid (PABA, sometimes called a B-vitamin) and DEAE (DiEthylAminoEthanol), which may function similarly to DMAE. Acetyl-L-carnitine (an ester of the amino acid L-carnitine) has also been shown to reduce lipofuscin accumulation in neurons.

Diphenylhydantoin (Dilantin) decreases spontaneous electrical activity in neuronal cell membranes, and is therefore used in the treatment of epilepsy. It has also been touted as a "Smart Drug" that can improve concentration by reducing "distracting thoughts". But "distracting thoughts" may be the product of a more active mind and, indeed, epileptics taking excessive doses of Dilantin show decreased intelligence & reaction times. Dilantin also has an anti-thyroid effect and can result in gum overgrowth.

So far, most of the reputed "Smart Drugs" I have mentioned either oppose brain aging or serve to eliminate what I would call a nutrient deficiency. A few drugs remain which may increase intellectual performance in normal people. Vasopressin (Diapid) has some role as a neurotransmitter in the brain and it has been shown to improve learning ability. Piracetam in optimal concentrations can enhance memory & learning also, but the exact mechanism of its action is unknown. Piracetam is derived from Gamma-Amino Butyric Acid (GABA). GABA may have an inhibitory effect on memory & learning. Milacemide crosses the blood-brain barrier where it is converted to the amino acid glycine, a co-agonist with glutamic acid at NMDA receptors.

Although I am normally on the side of those who believe that everything in nature can ultimately be re-engineered, in such an exceedingly natural system as the human brain I am wary of tampering with the "ecology" when so little is known about it. I have even avoided the so-called "Smart Drug" caffeine, and I note with irony that SMART DRUGS & NUTRIENTS cites examples on page 83 of caffeine impairing intellectual performance.

So while I am skeptical of the ability of so-called "Smart Drugs" cause a long-term increase in intelligence (the current ones, anyway), I do believe that many of these substances are of value in an anti-aging plan with specific focus on reduction of the aging of the brain.

nootropics.com

SMART DRUGS THE NEXT GENERATION

2007-03-16T19:20:00.001-07:00

by Ward Dean, John Morgenthaler and Steven Fowkes
(ISBN 0 9627418 7 6)
Sceptics about nootropics ("smart drugs") are unwitting victims of the so-called Panglossian paradigm of evolution. They believe that our cognitive architecture has been so fine-honed by natural selection that any tinkering with such a wonderfully all-adaptive suite of mechanisms is bound to do more harm than good. Certainly the notion that merely popping a pill could make you brighter sounds implausible. It sounds like the sort of journalistic excess that sits more comfortably in the pages of Fortean Times than any scholarly journal of repute.

Yet as Dean, Morgenthaler and Fowkes' (hereafter "DMF") book attests, the debunkers are wrong. On the one hand, numerous agents with anticholinergic properties are essentially dumb drugs. They impair memory, alertness, verbal facility and creative thought. Conversely, a variety of cholinergic drugs and nutrients, which form a large part of the smart-chemist's arsenal, can subtly but significantly enhance cognitive performance on a whole range of tests. This holds true for victims of Alzheimer's Disease, who suffer in particular from a progressive and disproportionate loss of cholinergic neurons. Yet, potentially at least, cognitive enhancers can aid non-demented people too. Members of the "normally" ageing population can benefit from an increased availability of acetylcholine, improved blood-flow to the brain, increased ATP production and enhanced oxygen and glucose uptake. Most recently, research with ampakines, modulators of neurotrophin-regulating AMPA-type glutamate receptors, suggests that designer nootropics will soon deliver sharper intellectual performance even to healthy young adults.

DMF provide updates from Smart Drugs (1) on piracetam, acetyl-l-carnitine, vasopressin, and several vitamin therapies. Smart Drugs II offers profiles of agents such as selegiline (l-deprenyl), melatonin, pregnenolone, DHEA and ondansetron (Zofran). There is also a provocative question-and-answer section; a discussion of product sources; and a guide to further reading.

So what's the catch? One problem, to which not all authorities on nootropics give enough emphasis, is the complex interplay between cognition and mood. Thus great care should be taken before tampering with the noradrenaline/acetylcholine axis. Thought-frenzied hypercholinergic states, for instance, are characteristic of one "noradrenergic" sub-type of depression. A predominance of forebrain cholinergic activity, frequently triggered by chronic uncontrolled stress, can lead to a reduced sensitivity to reward, an inability to sustain effort, and behavioural suppression.

This mood-modulating effect does make some sort of cruel genetic sense. Extreme intensity of reflective thought may function as an evolutionarily adaptive response when things go wrong. When they're going right, as in optimal states of "flow experience", we don't need to bother. Hence boosting cholinergic function, alone and in the absence of further pharmacologic intervention, can subdue mood. It can even induce depression in susceptible subjects. Likewise, beta-adrenergic antagonists (e.g. propranolol (Inderal)) can induce depression and fatigue. Conversely, "dumb-drug" anticholinergics may sometimes have mood-brightening - progressing to deliriant - effects. Indeed antimuscarinic agents acting in the nucleus accumbens may even induce a "mindless" euphoria.

Now it might seem axiomatic that helping everyone think more deeply is just what the doctor ordered. Yet our education system is already pervaded by an intellectual snobbery that exalts academic excellence over emotional well-being. In the modern era, examination rituals bordering on institutionalised child-abuse take a heavy toll on young lives. Depression and anxiety-disorders among young teens are endemic - and still rising. It's worth recalling that research laboratories routinely subject non-human animals to a regimen of "chronic mild uncontrolled stress" to induce depression in their captive animal population; investigators then test putative new antidepressants on the depressed animals to see if their despair can be experimentally reversed by patentable drugs. The "chronic mild stressors" that we standardly inflict on adolescent humans can have no less harmful effects on the mental health of captive school-students; but in this case, no organised effort is made to reverse it. Instead its victims often go on to self-medicate with ethyl alcohol, tobacco and street drugs. So arguably at least, the deformed and emotionally pre-literate minds churned out by our schools stand in need of safe, high-octane mood-brighteners more urgently than cognitive-tweakers.

One possible solution to this dilemma involves taking a cholinergic agent such as piracetam (Nootropil) or aniracetam (Draganon, Ampamet) that also enhances dopamine function. Some researchers tentatively believe that the mesolimbic dopamine system acts as the final common pathway for pleasure in the brain. This hypothesis may well prove simplistic. There are certainly complications: it is not the neurotransmitter dopamine itself, but the post-synaptic metabolic cascades it triggers, that underlies motivated bliss. Other research suggests that it is the endogenous opioid system, and in particular activation of the mu opioid receptors, that mediates pure pleasure. Mesolimbic dopamine amplifies "incentive-motivation": "wanting" and "liking" may have different substrates, albeit intimately linked. Moreover there are mood-elevating memory-enhancers such as phosphodiesterase inhibitors (e.g. the selective PDE4 inhibitor rolipram) that act on different neural pathways - speeding and strengthening memory-formation by prolonging the availability of CREB. In any event, several of the most popular smart drugs discussed by DMF do indeed act on both the cholinergic and dopaminergic systems. In addition, agents like aniracetam and its analogs increase hippocampal glutaminergic activity. Hippocampal function is critical to memory - and mood. Thus newly developed ampakines, agents promoting long-term potentiation of AMPA-type glutamate receptors, are powerful memory-enhancers and future nootropics.

Another approach to enhancing mood and intellect alike involves swapping or combining a choline agonist with a different, primarily dopaminergic drug. Here admittedly there are methodological problems. The improved test score performances reported on so-called smart dopaminergics may have other explanations. Not all studies adequately exclude the confounding variables of increased alertness, sharper sensory acuity, greater motor activity or improved motivation - as distinct from any "pure" nootropic action. Yet the selective dopamine reuptake blocker amineptine (Survector) is both a mood-brightener and a possible smart-drug. Likewise selegiline, popularly known as l-deprenyl, has potentially life-enhancing properties. Selegiline is a selective, irreversible MAO-b inhibitor with antioxidant, immune-system-boosting and anti-neurodegenerative effects. It retards the metabolism not just of dopamine but also of phenylethylamine, a trace amine also found in chocolate and released when we're in love. Selegiline also stimulates the release of superoxide dismutase (SOD); SOD is a key enzyme which helps to quench damaging free-radicals. Taken consistently in low doses, selegiline extends the life-expectancy of rats by some 20%; enhances drive, libido and endurance; and independently improves cognitive performance in Alzheimer's patients and in some healthy normals. It is used successfully to treat canine cognitive dysfunction syndrome (CDS) in dogs. In 2006, higher dose (i.e. less MAO-b selective) selegiline was licensed as the antidepressant EMSAM, a transdermal patch. Selegiline also protects the brain's dopamine cells from oxidative stress. The brain has only about 30-40 thousand dopaminergic neurons in all. It tends to lose perhaps 13% a decade in adult life. An eventual 70%-80% loss leads to the dopamine-deficiency disorder Parkinson's disease and frequently depression. Clearly anything that spares so precious a resource might prove a valuable tool for life-enrichment.

In mid-2005, a second selective MAO-b inhibitor, rasagiline (Azilect) gained an EC product license. Its introduction was followed a year later in the USA. Unlike selegiline, rasagiline doesn't have amphetamine trace metabolites - a distinct if modest therapeutic advantage.

Looking further ahead, the bifunctional cholinesterase inhibitor and MAO-b inhibitor ladostigil acts both as a cognitive enhancer and a mood brightener. Ladostigil has neuroprotective and potential antiaging properties too. Its product-license is several years away at best.
Does it hurt to be smart?
So what could be the pitfalls here? One snag illustrates a more general problem with the DMF strategy. Unless it is applied with extreme caution, a virtue not associated with all self-experimenters, taking self-designed cocktails of "smart-pills" may carry significant but unknown risks.

Consider, for instance, the plight of genetically engineered "smart mice" endowed with an extra copy of the NR2B subtype of NMDA receptor. It is now known that such brainy "Doogie" mice suffer from a chronically increased sensitivity to pain. Memory-enhancing drugs and potential gene-therapies targeting the same receptor subtype might cause equally disturbing side-effects in humans. Conversely, NMDA antagonists like the dissociative anaesthetic drug ketamine exert amnestic, antidepressant and analgesic effects in humans and non-humans alike.

Amplified memory can itself be a mixed blessing. Even among the drug-naïve and chronically forgetful, all kinds of embarrassing, intrusive and traumatic memories may haunt our lives. Such memories sometimes persist for months, years or even decades afterwards. Unpleasant memories can sour the well-being even of people who don't suffer from clinical PTSD. The effects of using all-round memory enhancers might do something worse than merely fill our heads with clutter. Such agents could etch traumatic experiences more indelibly into our memories. Or worse, such all-round enhancers might promote the involuntary recall of our nastiest memories with truly nightmarish intensity.

By contrast, the design of chemical tools that empower us selectively to forget unpleasant memories may prove to be at least as life-enriching as agents that help us remember more effectively. Unlike the software of digital computers, human memories can't be specifically deleted to order. But this design-limitation may soon be overcome. The synthesis of enhanced versions of protease inhibitors such as anisomycin may enable us selectively to erase horrible memories. If such agents can be refined for our personal medicine cabinets, then we'll potentially be able to rid ourselves of nasty or unwanted memories at will - as distinct from drowning our sorrows with alcohol or indiscriminately dulling our wits with tranquillisers. In future, the twin availability of 1] technologies to amplify desirable memories, and 2] selective amnestics to extinguish undesirable memories, promises to improve our quality of life far more dramatically than use of today's lame smart drugs.

Such a utopian pharmaceutical toolkit is still some way off. Given our current primitive state of knowledge, it's hard to boost the function of one neurotransmitter signalling system or receptor sub-type without eliciting compensatory and often unwanted responses from others. Life's successful, dopamine-driven go-getters, for instance, whether naturally propelled or otherwise, may be highly productive individuals. Yet they are rarely warm, relaxed and socially empathetic. This is because, crudely, dopamine overdrive tends to impair "civilising serotonin" function. Unfortunately, tests of putative smart drugs typically reflect an impoverished and culture-bound conception of intelligence. Indeed today's "high IQ" alpha males may strike posterity as more akin to idiot savants than imposing intellectual giants. IQ tests, and all conventional scholastic examinations, neglect creative and practical intelligence. They simply ignore social cognition. Social intelligence, and its cognate notion of "emotional IQ", isn't some second-rate substitute for people who can't do IQ tests. On the contrary, according to the Machiavellian ape hypothesis, the evolution of human intelligence has been driven by our superior "mind-reading" skills. Higher-order intentionality [e.g. "you believe that I hope that she thinks that I want...", etc] is central to the lives of advanced social beings. The unique development of human mind is an adaptation to social problem-solving and the selective advantages it brings. Yet pharmaceuticals that enhance our capacity for empathy, enrich our social skills, expand our "state-space" of experience, or deepen our introspective self-knowledge are not conventional candidates for smart drugs. For such faculties don't reflect our traditional [male] scientific value-judgements on what qualifies as "intelligence". Thus in academia, for instance, competitive dominance behavior among "alpha" male human primates often masquerades as the pursuit of scholarship. Emotional literacy is certainly harder to quantify scientifically than mathematical puzzle-solving ability or performance in verbal memory-tests. But to misquote Robert McNamara, we need to stop making what is measurable important, and find ways to make the important measurable. By some criteria, contemporary IQ tests are better measures of high-grade autism than mature intelligence. So before chemically manipulating one's mind, it's worth critically examining which capacities one wants to enhance; and to what end?

In practice, the first and most boring advice is often the most important. Many potential users of smart pills would be better and more simply advised to stop taking tranquillisers, sleeping tablets or toxic recreational drugs; eat omega-3 rich foods, more vegetables and generally improve their diet; and try more mentally challenging tasks. One of the easiest ways of improving memory, for instance, is to increase the flow of oxygenated blood to the brain. This can be achieved by running, swimming, dancing, brisk walking, and more sex. Regular vigorous exercise also promotes nerve cell growth in the hippocampus. Hippocampal brain cell growth potentially enhances mood, memory and cognitive vitality alike. Intellectuals are prone to echo J.S. Mill: "Better to be an unhappy Socrates than a happy pig". But happiness is typically good for the hippocampus; by contrast, the reduced hippocampal volume anatomically characteristic of depressives correlates with the length of their depression.

In our current state of ignorance, homely remedies are still sometimes best. Thus moderate consumption of adenosine-inhibiting, common-or-garden caffeine improves concentration, mood and alertness; enhances acetylcholine release in the hippocampus; and statistically reduces the risk of suicide. Regular coffee drinking induces competitive and reversible inhibition of MAO enzymes type A and B owing to coffee's neuroactive beta-carbolines. Coffee is also rich in antioxidants. Non-coffee drinkers are around three times more likely to contract Parkinson's disease. A Michigan study found caffeine use was correlated with enhanced male virility in later life.

Before resorting to pills, aspiring intellectual heavyweights might do well to start the day with a low-fat/high carbohydrate breakfast: muesli rather than tasty well-buttered croissants. This will enhance memory, energy and blood glucose levels. An omega-3 rich diet will enhance all-round emotional and intellectual health too. A large greasy fry-up, on the other hand, can easily leave one feeling muddle-headed, drowsy and lethargic. If one wants to stay sharp, and to blunt the normal mid-afternoon dip, then eating big fatty lunches isn't a good idea either. Fat releases cholecystokinin (CCK) from the duodenum. Modest intravenous infusions of CCK make one demonstrably dopey and subdued.

To urge such caveats is not to throw up one's hands in defeatist resignation. Creative psychopharmacology can often in principle circumvent such problems, even today. Complementary and sometimes effective combinations such as sustained-release methylphenidate (Ritalin) and SSRIs such as fluoxetine (Prozac), for instance, are arguably still under-used. They could be more widely applied both in clinical psychiatry and, at least in the context of a general harm-reduction strategy, on the street. There may indeed be no safe drugs but just safe dosages. Yet some smart drugs, such as piracetam, really do seem to be at worst pretty innocuous. Agents such as the alpha-1 adrenergic agonist adrafinil (Olmifron) typically do have both mood-brightening and intellectually invigorating effects. Adrafinil, like its chemical cousin modafinil (Provigil), promotes alertness, vigilance and mental focus; and its more-or-less pure CNS action ensures it doesn't cause unwanted peripheral sympathetic stimulation.

Unfortunately the lay public is currently ill-served, a few shining exceptions aside, by the professionals. A condition of ignorance and dependence is actively fostered where it isn't just connived at in the wider population. So there's often relatively little point in advising anyone contemplating acting on DMF's book to consult their physician first. For it's likely their physician won't want to know, or want them to know, in the first instance.

As traditional forms of censorship, news-management and governmental information-control break down, however, and the Net insinuates itself into ever more areas of daily life, more and more people are stumbling upon - initially - and then exploring, the variety of drugs and combination therapies which leading-edge pharmaceutical research puts on offer. They are increasingly doing so as customers, and not as patronisingly labelled role-bound "patients". Those outside the charmed circle have previously been cast in the obligatory role of humble supplicants. The more jaundiced or libertarian among the excluded may have felt themselves at the mercy of prescription-wielding, or -withholding, agents of one arm of the licensed drug cartels. So when the control of the cartels and their agents falters, there is an especially urgent need for incisive and high-quality information to be made readily accessible. Do DMF fulfil it?

Smart Drugs 2 lays itself wide open to criticism; but then it takes on an impossible task. In the perennial trade-off between accessibility and scholarly rigour, compromises are made on both sides. Ritual disclaimers aside, DMF's tone can at times seem too uncritically gung-ho. Their drug-profiles and cited studies don't always give due weight to the variations in sample size and the quality of controls. Nor do they highlight the uncertain calibre of the scholarly journals in which some of the most interesting results are published. DMFs inclusion of anecdote-studded personal testimonials is almost calculated to inflame medical orthodoxy. Moreover it should be stressed that the scientific gold-standard of large, placebo-controlled, double-blind cross-over prospective trials are still quite rare in this field as a whole.

Looking ahead, this century's mood-boosting, intellect-sharpening, empathy-enhancing and personality-enriching drugs are themselves likely to prove only stopgaps. This is because invincible, life-long happiness and supergenius intellect may one day be genetically pre-programmed and possibly ubiquitous in our transhuman successors. Taking drugs to repair Nature's deficiencies may eventually become redundant. Memory- and intelligence-boosting gene therapies are already imminent. But in repairing the deficiencies of an educational system geared to producing dysthymic pharmacological illiterates, Smart Drugs 1 and 2 offers a warmly welcome start.

nootropics.com

“Brain-specific” nutrients: a memory cure?

2007-03-16T14:54:00.001-07:00

“Brain-specific” nutrients: a memory cure?

Objective

We review the experimental evaluations of several widely marketed nonprescription compounds claimed to be memory enhancers and treatments for age-related memory decline. We generally limit our review to double-blind placebo-controlled studies. The compounds examined are phosphatidylserine (PS), phosphatidylcholine (PC), citicoline, piracetam, vinpocetine, acetyl-L-carnitine (ALC), and antioxidants (particularly vitamin E).

Results

In animals, PS has been shown to attenuate many neuronal effects of aging, and to restore normal memory on a variety of tasks. Preliminary findings with humans, though, are limited. For older adults with probable Alzheimer’s disease, a single study failed to demonstrate positive effects of PS on memory performance. For older adults with moderate cognitive impairment, PS has produced consistently modest increases in recall of word lists. Positive effects have not been as consistently reported for other memory tests. There is one report of consistent benefits across a number of memory tests for a subset of normal adults who performed more poorly than their peers at baseline.

The choline compounds PC and citicoline are thought to promote synthesis and transmission of neurotransmitters important to memory. PC has not proven effective for improving memory in patients with probable Alzheimer’s disease. The issue remains open for older adults without serious degenerative neural disease. Research on citicoline is practically nonexistent, but one study reported a robust improvement in story recall for a small sample of normally aging older adults who scored lower than their peers in baseline testing.

Animal studies suggest that piracetam may improve neuronal efficiency, facilitate activity in neurotransmitter systems, and combat the age-related decrease in receptors on the neuronal membrane. However, for patients with probable Alzheimer’s disease, as well as for adults with age-associated memory impairment, there is no clear-cut support for a mnemonic benefit of piracetam.

Vinpocetine increases blood circulation and metabolism in the brain. Animal studies have shown that vinpocetine can reduce the loss of neurons due to decreased blood flow. In three studies of older adults with memory problems associated with poor brain circulation or dementia-related disease, vinpocetine produced significantly more improvement than a placebo in performance on global cognitive tests reflecting attention, concentration, and memory. Effects on episodic memory per se have been tested minimally, if at all.

ALC participates in cellular energy production, a process especially important in neurons, and in removal of toxic accumulation of fatty acids. Animal studies show that ALC reverses the age-related decline in the number of neuron membrane receptors. Studies of patients with probable Alzheimer’s disease have reported nominal advantages over a range of memory tests for ALC-treated patients relative to placebo groups. Significant differences have been reported rarely, however. Whether ALC would have mnemonic benefits for aging adults without brain disease is untested as far as we know.

Antioxidants help neutralize tissue-damaging free radicals, which become more prevalent as organisms age. It is hypothesized that increasing antioxidant levels in the organism might retard or reverse the damaging effects of free radicals on neurons. Thus far, however, studies have found that vitamin E does not significantly slow down memory decline for Alzheimer’s patients and does not produce significant memory benefits among early Parkinson’s patients. Neither did a combination of vitamins E and C significantly improve college students’ performance on several cognitive tasks.

Conclusions

In sum, for most of the “brain-specific” nutrients we review, some mildly suggestive effects have been found in preliminary controlled studies using standard psychometric memory assessments or more general tests designed to reveal cognitive impairment. We suggest that future evaluations of the possible memory benefits of these supplements might fruitfully focus on memory processes rather than on memory tests per se.

Replenishing and increasing neurotransmitters

2007-03-16T13:57:00.001-07:00

Thinking is a biologically demanding task. It involves the firing of neurons which requires plenty of neurotransmitters, and even though these are reuseable to some extent, they do get depleted. Depletion of neurotransmitters generally results in reduced mental performance, which may include difficulty concentrating, slowed reasoning, decreased learning efficiency, impaired recall, reduced coordination, lowered moods, inability to cope, increased response times, and mental fatigue. This also generally increases the likelihood of human error on tasks and activities performed. Stress causes neurotransmitters to be depleted even faster. The brain's neurotransmitters need to be replenished frequently, made by the body from substances ingested in the diet. Maintaining neurochemicals at optimal levels has a corresponding effect on brain performance, supporting improved mental agility and stamina, even beyond the individual's normal limits.

As the brain ages, its ability to produce and maintain youthful levels of neurotransmitters declines. Thus, the theory is that by providing the brain with ample raw materials to make the neurotransmitters it needs can restore them to more youthful levels to help maintain cognitive function at vigorous youthful levels as well.

Dopaminergics

Dopaminergics are substances which affect the neurotransmitter dopamine or the components of the nervous system which utilize dopamine. Dopamine is produced in the synthesis of all catecholamine neurotransmitters, and is the rate limiting step for this synthesis. Dopaminergic nootropics include dopamine precursors and cofactors, and dopamine reuptake inhibitors:

L-dopa - Precursor to the neurotransmitter dopamine, general nootropic, anti-depressant.
Phenylalanine - Precursor to dopamine, general nootropic, anti-depressant, sleep reducer.
Tyrosine - Precursor to dopamine, general nootropic, anti-depressant, sleep reducer.
Theanine - Found in tea. Increases serotonin, GABA and dopamine levels in the brain. Increases alpha wave-based alert relaxation.
Deprenyl - Inhibits MAO B (an enzyme that breaks down dopamine) thus raising dopamine by partially inhibiting its breakdown.

Neurotransmitter Serotonin

In order to increase the levels of the neurotransmitter serotonin the most effective way is taking serotonin reuptake inhibitors, which are also called antidepressants.

Anti-depression, adaptogenic and mood stabilization

Depression and depressed mood negatively affect cognitive performance. Feelings of sadness, guilt, helplessness, hopelessness, anxiety, and fear caused by depression detract from productive thought, while apathy (which is also induced by depression) is the lack of motivation and driving moods (like curiosity, interest, determination, etc.) Other symptoms include disturbed sleep patterns, mental fatigue and loss of energy, trouble concentrating or making decisions, and a generalized slowing and obtunding of cognition, including memory. Obviously, removing these effects improves intelligence and mental performance, and therefore, counteracting and preventing depression are effective nootropic strategies. There is a high correlation between depression and a reduction or depletion of neurotransmitters (dopamine, norepinephrine, and serotonin) in the brain, therefore it is no surprise that increasing the brain's supply of neurotransmitters alleviates (or at least reduces the symptoms of) most depressions. Stress is another major factor in neurotransmitter depletion, being both a cause and effect of it (creating a vicious downward spiral), therefore stress management and anti-stress substances are also very useful nootropic strategies.

All of the "nergics" listed above have been found to increase stress tolerance and alleviate depression (by replenishing or increasing the brain's supply of specific neurotransmitters), especially when used in precursor/co-factor combinations.

Here are some more nootropics which affect mood and stress:

Vasopressin - Drug. Memory hormone produced by the pituitary gland which improves both memory encoding and recall. Rapidly counters chronic apathy syndrome and drug-induced vasopressin depletion.