Viagra for the Brain

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

* * *

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

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

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

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

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

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

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

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

Source: Forbes
Date: February 2002

Robert Langreth

Messing with our minds

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

A memory drug might cause subjects to remember too much detail, cluttering the mind, for example. Martha Farah, a psychologist at the University of Pennsylvania, says: "The brain was designed by evolution over millennia to be well adapted because of the lives we lead. We are better served by being able to focus on the essential information than being able to remember every little detail. We meddle with these designs at our peril."

Source: Independent
Date: 18 January 2005

Smart Drinks

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

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

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

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


Hyperreal.org

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

 

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

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

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

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

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

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

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

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

11:15 a.m. Five projects, 10 deadlines, an uncountable number of engineering calculations. And I’m on top of it all. Since I started taking a cognitive enhancer, I don’t seem to forget a thing. And my mind runs so much faster. My boss doesn’t appreciate all I do, of course, but that doesn’t irritate me. Emoticeuticals—gotta love ’em. Zen-like calm, but I still feel the important stuff. If I did somehow get ticked and reached for a cigarette—my crutch from way back when—it wouldn’t do any good. Nicotine vaccination. No point in ever taking a drag again.

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

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

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

Cortex isn’t alone in the quest to boost cranial capacity. About 40 other companies, including behemoths such as Eli Lilly and GlaxoSmithKline, are pursuing what many consider the holy grail of pharmacology, a pill to boost sagging memory—Viagra for the brain. The profit potential is enormous. Some 4.5 million Americans suffer from Alzheimer’s disease, which currently has only marginally helpful drug therapies; at least four million are afflicted with mild cognitive impairment, a precursor to Alzheimer’s; and more than 10 million have age-associated memory impairment, which means their memories are far below average for their age. And, as is the case with drugs like Provigil, there’s an off-label market as well. “Companies won’t tell you this, but they are really gunning for the market of non-impaired people—the 44-year-old salesman trying to remember the names of his customers,” James McGaugh, another U.C. Irvine neuroscientist, has said.

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

“You can take a rat’s brain, stimulate one cortical region, and measure the electrical signal from another,” Lynch says. “Wash in an ampakine, and the signal is bigger.” Better signaling is thought to provide a cognitive boost, particularly in older brains with withering neurons. Aging baseball players have trouble hitting in part because they can’t process visual information as quickly, Lynch says. “Nothing is going to change that fact. But with an ampakine, maybe you could hit a curveball.”

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

Ampakines have an additional, related benefit: They trigger the production of brain-derived neurotrophic factor (BDNF), which many researchers suspect will lead to the creation of more receptor sites. In other words, the drug doesn’t just make the neurons listen longer, it also builds new ears. In rats, Lynch has been able to reverse memory decline using single injections of an ampakine, giving middle-aged animals memory abilities nearly equivalent to those of young ones. Maybe, Lynch speculates, ampakines will have the same regenerative effect in humans. “Can we make it go from the winter of the brain to the spring?” he asks.

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

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

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

Overall, though, he is an optimist. Gazing at a poster of the brain on his office wall, Lynch remarks that a thought is essentially an ad hoc network of communicating neurons. Ampa- kines, by improving that communication, would allow a larger network—and a larger thought?—to be formed. “I should say that the best implication of ampakines is that we make everybody go home happy when they’re 50—fully powered sexually, memory back, age slipping off like a cloak,” he says. “But actually, personally, I wonder: Will you be able to think things that you can’t think right now? Ultimately we’d find out the limits of being human and go beyond them.” 5:50 p.m. I’m driving home, and Senator Davidson is on the radio. I support this psychopharm-disclosure bill she’s pushing. Shouldn’t we have the right to know if our elected leaders are taking empathogens and avarice-reducers like they’re supposed to? My wife is working late tonight; I’m with the kids. I love them, but sometimes my patience wears thin. With the advanced beta-blocker I take, though, a tantrum doesn’t set me off. Before bed, we say prayers. Truthfully, I never used to believe. But one little white entheogen pill and I feel—I don’t know, a presence. It’s comforting.

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

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

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

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

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

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

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

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

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

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

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

Source: Popular Science
Date: September 2005

Seeking Smart Drugs

 

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

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