Going On the Offensive Against Dementia

This article is re-posted from the Al Fin Longevity blog


Rather than fighting a rear-guard action against advancing dementia, some researchers are taking an offensive approach -- a "procognitive" approach. This means that instead of trying to slow down the inevitable decline of dementia, these researchers aim to rebuild brain tissues and brain function. They aim to push back against the decline and reverse it.

Scientists have developed a small peptide that they say can reverse some of the cognitive repercussions of neurodegenerative and potentially trauma-related brain disorders such as Alzheimer’s disease, by increasing synaptogenesis. The peptide, called dihexa, is a stabilized derivative of angiotensin IV (AngIV)...

...Washington State University’s Joseph W. Harding, Ph.D., Alene T. McCoy, Ph.D., and colleagues based their development on prior work demonstrating that the three terminal amino acids of AngIV and its analog Norleucine1-angiotensin IV (Nle1-AngIV) are central to the precognitive activities of the peptides. The team thus set out to develop much smaller, more stable derivatives of Nle1-AngIV that retained the active structure but could be administered orally and cross the blood-brain barrier.

The resulting lead compound, dihexia (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide) not only fulfilled these requirements, but proved to be active at picomolar concentrations, and led to dramatic improvements in the cognitive abilities of a scopolamine-treated rat model of learning deficits, and also aged Sprague-Dawley rats.

Importantly, the treatment was effective whether the animals received it directly into the brain, via injection, or orally. Further analyses indicated that dihexia’s precognitive activity was associated with a drug-induced stimulation of dendritic spinogenesis in the hippocampal brain region, and that the newly formed dendritic spins were creating functional synapses. Encouragingly, dihexia was even more potent than brain-derived neurotrophic factor (BDNF), a growth-promoting protein that is used to create neuronal connections, but which hasn’t yet been developed for therapeutic use.

“At its core dementia results from a combination of diminished synaptic connectivity among neurons and neuronal death in the entorhinal cortex, hippocampus, and neocortex,” the researchers note in their published paper in the Journal of Pharmacology and Experimental Therapeutics. However, previous attempts to develop protein neurotrophic factors as therapeutics has been limited by their inability to cross the blood-brain barrier, and the need to manufacture such agents by recombinant methods, which is costly. “The development of dihexa has seemingly overcome these impediments by virtue of its oral activity, demonstrated pro-cognitive/anti-dementia activity, and anticipated low manufacturing costs.” _Gen Engineering News

Another interesting candidate for procognitive therapy is ABT-288, an H3 receptor antagonist.

Another very interesting class of procognitive drugs is the Ampakines. Ampakine CX546 is a recent drug candidate undergoing study.

Here are two different approaches to procognition in the context of developing novel anti-psychotic drugs:

Egis 11150 which has broad spectrum adrenergic, serotenergic, and dopaminergic antagonist activity
New anti-psychotics with 5HT2C receptor agonist and 5HT6 receptor antagonist activity

It is important for neuropharmacologists to take this fateful step, of taking the offensive in the fight against dementia. Repairing and rebuilding the damaged tissues in the brain will likely get better results than a piecemeal promotion of this neurotransmitter, or combating this protein or another. A procognitive approach holds out the possibility of a return to normal function, rather than a mere slowing of inevitable decline.

The technology of the early diagnosis of future dementia is advancing on multiple fronts, from better brain scanners to genetic testing to two recent interesting developments:

Virtual Reality Functional Capacity Assessment Tool (VRFCAT). Not only does VRFCAT promise to provide early diagnosis of cognitive problems, but it should also prove useful for monitoring of different therapeutic regimens.

New mathematical approaches to model the brain as a complex network of interconnected processing nodes Such mathematical modeling approaches should provide new ways of diagnosing normal vs. impaired brain network activity, as well as new ways to monitor effects of therapies on brain network function.

Eventually, what we will want from procognitive treatments, is for all of us to be able to become capable of clearer and deeper thought. For now, we will be happy to watch dementia sufferers coming back into themselves.

But once we see that beginning to happen, we are likely to want to "spread the wealth around" to include more and more people, maybe even ourselves.

A Look at Cognitive Enhancers of Today and Tomorrow

Cognitive enhancer	Neuromodulatory mechanism	Cognitive functions improved	Known brain systems most affected	Currently recommended clinical use
Methylphenidate, amphetamine	Dopamine and noradrenaline reuptake inhibitors	Response inhibition, working memory, attention, vigilance	Frontoparietal attentional systems, striatum, default mode networks	ADHD, wake-promoting agent
Caffeine	Non-selective adenosine receptor antagonist	Vigilance, working memory, incidental learning	Frontal lobe attentional systems	–
Nicotine	Nicotinic cholinergic receptor agonist	Working memory, episodic memory, attention	Fronto-parietal attentional systems, medial temporal lobe, default mode networks	–
Modafinil	Unknown, but effects on dopamine, noradrenaline and orexin systems proposed	Working memory, episodic memory, attention	Frontal lobe attentional systems	Wake-promoting agent
Atomoxetine, reboxetine	Noradrenaline reuptake inhibitors	Response inhibition, working memory, attention	Frontoparietal attentional systems	ADHD, depression
Donepezil, galantamine, rivastigmine (AChEI)	Blocks enzymatic breakdown of acetylcholine	Episodic memory, attention	Frontal lobe attentional systems	Alzheimer's disease, PDD, DLB
Memantine	Noncompetitive, low-affinity, open channel blocker of the NMDA receptor	Episodic memory, attention	Frontal and parietal lobe	Alzheimer's disease

Table SourceThe ongoing process of ageing in all advanced societies around the world presents the unhappy prospect of a veritable global epidemic of Alzheimer's and other neurodegenerative conditions. Such an ominous prospect makes the quest for cognitive enhancers somewhat urgent, for all modern nations. We will look at the nature of current cognitive enhancers, and consider the prospects for future enhancers of cognition. The focus will be on long-term enhancement and neuroprotection, rather than the short-term performance enhancers which are popular on college campuses.

It would probably be fair to say that we are still in the first generation of studies to examine the potential for cognitive enhancement in humans. In both healthy individuals and many patient groups, the overall effects of drugs generally seem to be modest. However, there is evidence that there might be more significant effects in subgroups, such as those whose baseline performance is poorest or individuals with a particular genotype. Moreover, new drugs aimed at enhancing the phasic response of neurotransmitter systems, such as direct nicotinic agonists for the cholinergic system [34], might prove to have greater effects than existing modulators that globally increase levels of a neurotransmitter in a tonic fashion. The neurobiology underpinning the effects of cognitive enhancers and the mechanisms that determine responsiveness across individuals promise to be the focus of research in health and brain disorders in the future. _Source

The ongoing study of current cognitive enhancers such as those in the table above, have given us scattered hints as to what future therapies might offer. Here is a short list of possible future targets for cognitive therapies:

Among targets under investigation, cholinergic receptors have received much attention with several nicotinic agonists (α7 and α4β2) actively in clinical trials for the treatment of AD, CIAS and attention deficit hyperactivity disorder (ADHD). Both glutamatergic and serotonergic (5-HT) agonists and antagonists have profound effects on neurotransmission and improve cognitive function in preclinical experiments with animals; some of these compounds are now in proof-of-concept studies in humans. Several histamine H3 receptor antagonists are in clinical development not only for cognitive enhancement, but also for the treatment of narcolepsy and cognitive deficits due to sleep deprivation because of their expression in brain sleep centers. Compounds that dampen inhibitory tone (e.g., GABAA α5 inverse agonists) or elevate excitatory tone (e.g., glycine transporter inhibitors) offer novel approaches for treating diseases such as schizophrenia, AD and Down syndrome. In addition to cell surface receptors, intracellular drug targets such as the phosphodiesterases (PDEs) are known to impact signaling pathways that affect long-term memory formation and working memory. Overall, there is a genuine need to treat cognitive deficits associated with many neuropsychiatric conditions as well as an increasingly aging population. _Source

It is important for us, at the outset, to take as realistic a viewpoint toward the possibility of meaningful cognitive enhancement as possible. The Likelihood of Cognitive Enhancement (Lynch et al 2011 PDF) is a useful introduction to many of the practical issues that need to be faced from the very beginning of this enterprise. Cognitive Enhacement: Promises and Perils (Hyman 2011 PDF) is a less technical introduction to the topic, perhaps more accessible to most laymen.

Cognitive Enhancement as a Pharmacotherapy Target for Stimulant Addiction (Sofuoglu 2010) looks at the use of cognitive enhancers as possible treatments for cocaine and methamphetamine addictions. Long term and heavy use of these drugs leads to cognitive deficits which make it even more difficult for a person to stop using these drugs and lead a "normal" life. The restoration of cognitive function is likely to provide a certain amount of "mental fortification" to allow at least some addicts to turn away from the dead end lifestyle. Similarly, restoration of cognitive function in persons suffering from age-related neurodegeneration is more likely to allow the person to participate in normal social interaction, and to undertake some level of responsibility, and perhaps productive activity.

Emerging Pharmacotherapies for Neurodevelopmental Disorders (Wetmore et Garner 2010) looks at the use of cognitive enhancers for persons who suffer from neurodevelopmental disorders such as Down's Syndrome, Fragile X, autism, etc. Given the overlap of mechanisms between some of the cognitive deficits in developmental disorders and ageing-related cognitive deficits, some of the coming developments in this area of pharmacotherapy should also prove quite helpful for treating age-related dementias.

As more is learned about the time-course of dysfunction in NDDs [neurodevelopmental disorders], targeting of therapies to the existing brain state may be improved. Moreover, individuals with NDDs have multiple cognitive and behavioral disabilities, and a particular drug therapy may improve only a subset of cognitive functions. Thus, a combination of complementary drugs may offer the most benefit by addressing deficits in attention, arousal, information processing, or depression.
...
The NDDs discussed here are phenotypically diverse yet linked by common mechanisms of dysfunction, including abnormal gene dosage, imbalance among neurotransmitter systems, and local protein translation (Fig. 2). A particular NDD can be caused by mutations in multiple genes, underscoring the convergence of dysfunction in key biochemical pathways. _Source

Finally, I would like to append to this entry some material from an earlier Al Fin article, which provides a few hints of future drug targets, as well as links to related material:

AMPAkines
CREB
PDE Inhibitors(4,10)
Nicotinic Alpha-7 agonists
mGluR antagonists
5HT6 antagonists

Frontrunners in the pharmaceutical race for smarter, better memory drugs include Memory Pharmaceuticals, Cortex Pharmaceuticals, Saegis Pharmaceuticals, Helicon, Lilly, Pfizer, Wyeth, Merck, Sention and many others. The precedent of approving drugs for erectile dysfunction (ED)--a lifestyle drug--suggests that smart drugs will eventually be approved for drooping memories as well.

Further Reading:

Molecules for Memory

Nootropics

Smart Drugs: What Are the Prospects?

Shaping the Brain with Smart Drugs PDF (Gazzaniga)

CREB and Memory PDF (basic neuroscience)

CREB, Synapses, and Memory Disorders PDF

Hat tip Advanced Nano and Kurzweilai.net

Cross-posted from an earlier article at Al Fin Longevity

Check back for updated information on coming cognitive enhancers in the not-too-distant future.

Al Fin cognitivists have always believed that true, lasting cognitive enhancement will require genetic modification in conjunction with cell replacement and in situ cell rejuvenation. But there will be a wide range of stopgap measures between here and there.

In the meantime, use it or lose.

A Race Against the Idiocracy

“I think we’re getting closer to harnessing neurogenesis to improve cognition and mood in humans. This research may also help explain a bit of a mystery in the field, which we still don’t understand, regarding how the hippocampus can be involved with both cognition – which is its classic function – and in mood and anxiety-related functions. Perhaps the fact that pattern separation affects both the cognitive and mood domains is the beginning of an answer to that paradox,” said Dr. Hen. _StemCells

René Hen, PhD, professor of Neuroscience and Pharmacology, in the Departments of Neuroscience and Psychiatry at Columbia University and the New York State Psychiatric Institute, has discovered a possible escape hatch by which some members of society might escape the Idiocracy. It involves the use of chemicals called "BAX inhibitors." Particular members of that class of drugs have the potential to preserve newborn stem cells in the brain's hippocampus. And doing that could make all the difference in the course of a person's life success and happiness.

After boosting the number of neurons in the hippocampus, an area of the brain involved in memory and mood, the researchers tested the mice in both learning and mood-related tasks and looked for changes in behavior. The researchers found specific effects on learning tasks that involve a process called pattern separation, which is the ability to distinguish between similar places, events and experiences.

“This process is crucial for learning because it enables us to know whether something is familiar or novel,” said Dr. Hen. “If it is familiar, you move on to the next bit of information; if it’s novel, you want to be able to recognize that it’s new and give it meaning. These mice, with just more adult-born neurons, and no other changes in the brain, basically learn better in tasks where they have to discriminate between similar contexts.”

Earlier strategies for manipulating neurogenesis, according to the investigators, were broader and less specific. “In addition to stimulating neurogenesis, these earlier methods exerted many other effects on the brain. As a result, you never knew with these older manipulations what’s due to neurogenesis, or what’s due to the other effects that these manipulations cause, and, indeed, what we find is that when you stimulate just adult neurogenesis, you actually get a subtle effect. Unlike broader manipulations, it does not affect all forms of learning, it’s very specific to tasks that require pattern separation,” said Dr. Hen.

Pattern separation is not only important for learning; it may also be important for anxiety disorders, including post traumatic stress disorder (PTSD) and panic disorder. People with PTSD, say the researchers, have a more generalized fear response, so that when they are placed in a situation that reminds them of even one aspect of their trauma, they frequently have a full fear response.

...The researchers say that the genetic strategy used to stimulate neurogenesis in their experiments can be mimicked pharmacologically, potentially leading to the development of new drugs to reverse pattern separation deficits. One such class of drugs the investigators are currently testing – BAX inhibitors – works by blocking cell death.

“These drugs are basically doing the same thing that we did with our genetic manipulation-namely, increasing the survival of the young neurons which normally undergo a process of cell death that eliminates at least half of these neurons. Now instead of dying, the neurons will go on to survive,” said Dr. Sahay.

Some BAX inhibitors have been developed for stroke research, where the goal has also been to prevent neurons from dying. The Columbia researchers plan to begin testing the BAX inhibitors in mice shortly. And if they produce cognitive benefits, the testing will be extended to clinical trials to determine if there’s also a beneficial effect in humans. _StemCells

This is all related to the length of time required before antidepressants are able to bring about a full "antidepressive response." The full effect of modern antidepressants requires new stem cell production in the hippocampus -- but that takes time to achieve. Drugs capable of rapid and prolonged increases of hippocampal stem cells could conceivably keep anxiety and depression at bay, while improving a person's cognitive capacity.

No, this is not NZT. As mentioned here previously, a drug that could achieve the effect of the fictional NZT would have to stimulate changes in gene expression on multiple levels, and across a wide range of brain centers.

Smart drugs alone will not achieve the goal of smarter, better-rounded, and happier humans. Educational and environmental interventions would also be necessary, to blunt the Idiocratic brainwashing effect of modern media, modern academia, and modern popular culture, while allowing the brain to develop newer, more functional pathways.

Realistically, it will take 15 years at the earliest to see the early promise of this type of medication come to fulfillment. But a single ray of hope in the distance is worth a lot to a person immersed in the modern rush to Idiocracy.

More 5April2001: An example of rapid brain plasticity in human adults
The PNAS Abstract from the actual study

The Limits of Smart Drugs

The Clear Pill
Why Smart Drugs Don't Work Like NZT

What are smart drugs? Pills that are supposed to enhance a person's cognitive abilities in some way. Anything from Ritalin to Amphetamines to Provigil might qualify, as well as a wide range of lesser known "nootropics."

These pills are not only popular among university students, but also among workers from truck drivers to pilots to fast-paced professionals who are pushing every synapse to its limit. They can enhance attention, prolong attention span, help keep the mind on topic. All very important when facing a deadline for a research paper, a big work project, or when cramming for an exam.

In one sense, advanced societies run on smart drugs. Western societies embraced coffee, tea, and chocolate as quickly as they could -- and significant battles were fought over the rights to market these early smart drugs.

Fast forward to today, and the "stimulant smart drugs" are being pumped onto the markets -- both legal and illegal -- at prodigious rates. But newer, more advanced generations of smart drugs may be on the horizon.

This Al Fin posting from 2007 is still one of the best summaries of the smart drug research pipeline I have found. Here is a more recent survey of the field from Gizmodo. Some of the newer drugs enhance attention, some enhance memory, some may enhance creativity.

But what about other approaches to getting smarter, besides drugs?

Instead of drugs, the first brain boosters to channel creativity could be electromagnetic devices designed to enhance cognitive skills. One fascinating proposal comes from Allan Snyder, director of the Centre for the Mind at the University of Sydney in Australia. He theorizes that autistic savants derive their skills from an ability to access “privileged, less processed sensory information normally inhibited from conscious awareness.” For normal people, tapping that sensory well might lead to deeply buried creative riches. To test the idea, Snyder and colleagues exposed subjects to low-frequency magnetic pulses (the technology is called transcranial magnetic brain stimulation, or TMS) that suppressed part of their brain function. The researchers found that the subjects acquired savantlike skills, including the ability to render more detailed, naturalistic art. _Discover

Electromagnetic stimulation of the brain probably has a great future ahead of it. But caution is always wise, when working in and around the brain.

All of these drugs -- past, present, and future generation -- are relative sledge-hammers compared to the intricate workings of the human brain. But the real reason smart drugs won't work like "NZT" (from the movie "Limitless") is because none of them can make the necessary changes in both function and structure, to turn mediocrity into brilliance. To do that it is necessary to tweak gene expression at multiple levels.

NZT is an idea whose time has come. But ideas can only take you so far. Converting this idea into a dynamic reality will take more than a little thought.

From an earlier posting at Al Fin, the Next Level

The Ultimate High?

Have you ever wondered why governments spend many $billions every year to restrict the mental states it allows its citizens to experience, while it spends nothing at all to develop ways for its people to get truly, safely high, and reach their ultimate potential?

The ultimate high is to be the perfect version of yourself. Smarter, stronger, faster, wiser, healthier, wealthier, more mobile, with an unlimited future, a great family, and a circle of smart devoted friends that just won't quit.

There is a reason why the mind-altering drug is such a huge blockbuster business worldwide. Most people don't like who they are enough to be able to resist the opportunity for a bit of chemical (external or internal) alteration. To take a hit of this or that -- anything to boost, to blunt, to make you forget, to help you remember.

Something most people may not think about often -- being too busy getting stoned, drunk, high, or wasted. But the new movie "Limitless" may bring the idea to light for at least a few weeks.

Bradley Cooper is Eddie, a struggling writer who takes a mysterious smart drug, and unsurprisingly gets smart. Name the mental power - Analytical, memory, strategic, creative - it's suddenly all there. _SMH

But strip away all the Hollywood glitz, drama, and titillation, and the underlying reality remains inside the brain of most people you know: people want something different, something more.

The smart thing for governments would not be to restrict chemical use, but rather to develop safe, enabling recreational drugs that don't give you a hangover, or otherwise leave you less capable in the aftermath. A better drug that you can drive under the influence of, copulate in the brilliant light of, socialise at the height of your untapped wit and wisdom all night long, then sleep soundly and wake refreshed and alert.

We are not talking about the next level here, just a more rational approach to a deep-seated need of humans to explore, experiment, and go further into the mystery and potential of their own selves. Up until now, that instinct has necessarily been diverted and perverted to mostly destructive and wasteful uses. But that would not be necessary under a wiser regime. (For example, there was no DEA or FDA in the original US Constitution....)

This is certainly not about something like Soma, the drug of choice for the alpha, beta...zetas of Huxley's Brave New World. Better drugs make you better...more, not less of who you could be.

Of course there are a lot of foolish, dystopic aspects to the world we inhabit -- far beyond idiotic drug laws and policies. It is even worse if you travel to the hinterlands of China, or -- heavens forbid -- North Korea. It is the belief of Al Fin sociohistorians that a better society grows from a better substrate of inhabitants. And a better substrate of inhabitants grows from an attitude and ethic of enhancing the potential of members of society. Bottom up, and top down at the same time. But wiser all around. And smarter.

More on this topic later.

17 Healthy Young Men Spent the Night in the Lab . . .

.... In the morning when they awoke, they were "smarter". The young men were experimental subjects in a University of Lubeck experiment to test the effects of interleukin 6 (IL-6) on memory.

In a research report featured as the cover story of the October 2009 print issue of The FASEB Journal, these scientists show that a molecule from the body's immune system (interleukin-6) when administered through the nose helps the brain retain emotional and procedural memories during REM sleep.

"Sleep to remember, a dream or reality?" said Lisa Marshall, co-author of the study, from the Department of Neuroendocrinology at the University of Lubeck in Germany. "Here, we provide the first evidence that the immunoregulatory signal interleukin-6 plays a beneficial role in sleep-dependent formation of long-term memory in humans."

To make this discovery, Marshall and colleagues had 17 healthy young men spend two nights in the laboratory. On each night after reading either an emotional or neutral short story, they sprayed a fluid into their nostrils which contained either interleukin-6 or a placebo fluid. The subsequent sleep and brain electric activity was monitored throughout the night. The next morning subjects wrote down as many words as they could remember from each of the two stories. Those who received the dose of IL-6 could remember more words. __MachinesLikeUs

Augmented reality means a lot more than electronic gadgetry. True reality augmentation goes to the heart of how we invent the world.

If the US Drug Enforcement Administration thinks it has its hands full controlling the marketing of marijuana, cocaine, heroin, and crystal meth, just wait until true smart drugs hit the black market. That will be the beginning of an all-pervading revolution.

Believers in Kurzweil's Singularity expect the world to change once machines become smart enough. A much better approach is to help humans to become smarter and wiser simultaneously. Then you can worry about machines.

Cognitive Enhancement: Smart Drugs Fast Track

We all know university students who are taking Ritalin, Provigil, or other cognitive enhancers in order to compete better on the academic battleground. Professionals from many backgrounds also try to give themselves a career advantage with such smart drugs. Using fMRI on healthy volunteers taking Provigil (modafinil), neuroscientists are beginning to zero in on one likely mechanism of action for cognitive enhancers, which will allow for the faster and more targeted development of nootropics.

The drug modafinil is approved by the Food and Drug Administration (FDA) for treating narcolepsy, shift-work related sleep disorders and obstructive sleep apnea, and indicated for conditions including ADHD, Parkinson's disease and depression. But how it works has not been well understood until now.

"We have shown that the way modafinil works is by quieting activity in the LC and increasing its connections with the frontal cortex," said Cameron Carter, a UC Davis professor of psychiatry and behavioral sciences and senior author of the study.

"Now that we know how it works, we can develop better cognitive enhancers that can treat more people suffering from a wider variety of neurodevelopmental disorders, like ADHD, autism and schizophrenia," he said. _ScienceDaily

The demand for cognitive enhancers goes far beyond the competition for better grades and job performance for healthy young adults. A significant proportion of middle aged and older persons suffer from cognitive disorders which lead to confusion, forgetfulness, and a loss of ability to perform everyday normal activities of work and home life. The treatment of such acquired and debilitating cognitive disorders will drive the financing and research goals of neuro-cognitive science labs. But the competition for better grades and better career performance will provide a secondary motivation researchers and bystanders alike.

The use of smart drugs amounts to a type of "bootstrapping" of human consciousness, when used by neurocognitive researchers themselves to develop better means of achieving heightened cognition for impaired and healthy humans. For the long term, smart drugs will not be enough. Augmentation and modification of genetic and epigenetic mechanisms will be necessary in order for between-levels humans to step up to the next level.

Underlying the applied research into smart drugs and cognitive enhancement, is a massive ongoing research into systems biology, synthetic biology, bioinformatics, development of new research tools of all types, and a slow but steady transformation of popular expectation of what science can and should provide in the way of life enhancement.

Update: Here is a short but intriguing GNXP.com piece suggesting that part of the blame for the ongoing financials crash is due to the competitive use of amphetamines by financial analysts and traders. "A man's got to know his limitations." The abuse of amphetamines has certainly become a blight across many parts of the western world. A significant part of the abuse may begin as performance enhancement, which progresses to abject dependency and personal ruin in many cases.

It makes you wonder: how many ultra-aggressive politicians and celebrities owe some of their success to pharmaceuticals? A dependency upon caffeine is expected in high achievers. Addiction to nicotine is common as well. No reason to believe it stops there.

Brain Boost: Neural Wave "Surfer's Helper"

In a recent commentary in the journal Nature, two Cambridge University researchers reported that about a dozen of their colleagues had admitted to regular use of prescription drugs like Adderall, a stimulant, and Provigil, which promotes wakefulness, to improve their academic performance. The former is approved to treat attention deficit disorder, the latter narcolepsy, and both are considered more effective, and more widely available, than the drugs circulating in dorms a generation ago.

NYTimesThese are competitive times for top brains. The person who can best keep up with trends while developing his own competitive approach to his field, has the best chance of success. One must ride the wave of discovery--and inject unique input into the wave at the same time. Brains strain to stay "on" all the time. An assist is often needed.

One person who posted anonymously on the Chronicle of Higher Education Web site said that a daily regimen of three 20-milligram doses of Adderall transformed his career: “I’m not talking about being able to work longer hours without sleep (although that helps),” the posting said. “I’m talking about being able to take on twice the responsibility, work twice as fast, write more effectively, manage better, be more attentive, devise better and more creative strategies.”___NYTimes

Cognitive enhancers are being used in many areas where focus and alertness are valued, beyond the academic and research setting.

Cognitive-enhancing drugs are increasingly being used in non-medical situations such as shift work and by active military personnel....There are also situations in which many would agree that the use of drugs to improve concentration or planning may be tolerated, if not encouraged, such as by air-traffic controllers, surgeons and nurses who work long shifts. One can even imagine situations where such enhancing-drug-taking would be recommended, such as for airport-security screeners, or by soldiers in active combat.

...In future, drug treatment may be better tailored to individuals through a better understanding of how genes influence the body's response to drugs. Because domain-specific effects vary between individuals depending on their genetic make-up, drug efficacy may ultimately be enhanced and side effects reduced. Many believe that with increasingly sophisticated and targeted treatments, truly smart drugs with moderate-to-large effects on cognition, will become feasible in the future.___Nature

Investment analysts, stock brokerages, venture firms, commodities traders, and the like certainly support the manufacturers of methylphenidate, adderall, and modafenil. The military is another big customer. And we all know medical students or grad students who swear by the stuff--insist it keeps them going.

The tradeoff is the main consideration. What do you gain, what do you lose? A few drinks of alcohol can make it harder to refuse the next drink. Perhaps once on the mental enhancers, coming off of them becomes doubly or triply hard?

Never forget the evolutionary origins of life. Life is competition. Competition entails risk. For modern humans, making sense of information can be craved more desperately than food or drink.

Better Memories, Smarter Minds, Larger Horizons

Drug makers trying to create smart drugs and better memory drugs are approaching the goal from several directions. First of all, the need for an effective anti-Alzheimer's drug is growing critical--with the aging of the western world, Russia, and China. Next, competition in schools and the workplace (including the casino) makes a better memory worth its weight in gold. Effective drug treatments to mitigate disability from mental retardation are also being sought. Finally, society itself is in need of a more intelligent population--to maximise solutions to problems, and to minimise crime and delinquency.

Beyond traditional treatment approaches to Alzheimer's, ADHD, and abnormal drowsiness, some genuinely novel approaches to smart drugs are being tested in several research labs.

AMPAkines
CREB
PDE Inhibitors(4,10)
Nicotinic Alpha-7 agonists
mGluR antagonists
5HT6 antagonists

Frontrunners in the pharmaceutical race for smarter, better memory drugs include Memory Pharmaceuticals, Cortex Pharmaceuticals, Saegis Pharmaceuticals, Helicon, Lilly, Pfizer, Wyeth, Merck, Sention and many others. The precedent of approving drugs for erectile dysfunction (ED)--a lifestyle drug--suggests that smart drugs will eventually be approved for drooping memories as well.

Further Reading:

Molecules for Memory

Future Directions in Neuroscience

Nootropics

Smart Drugs: What Are the Prospects?

Shaping the Brain with Smart Drugs (Gazzaniga)

CREB and Memory (basic neuroscience)

CREB, Synapses, and Memory Disorders

Hat tip Advanced Nano and Kurzweilai.net

Getting to Ampakines--How Much Longer?

Brain boosting drugs in the new Ampakine class are back in the news--this time in connection with the problem of respiratory depression from sedative/hypnotic drugs.

Researchers at the University of Alberta (Edmonton, AB) and Cortex Pharmaceuticals (Irvine, CA) believe that AMPAKINE drugs may provide protection from drug-induced respiratory depression, while simultaneously allowing the sedative or analgesic to continue working as it was intended.

The drug tested in this study belongs to a novel class of molecules known as AMPAKINE compounds being developed by Cortex Pharmaceuticals, Inc. located in Irvine, California. AMPAKINE compounds act on the most common excitatory receptor in the brain, the AMPA "Glutamate type receptor," which has been shown in rodent models to boost the brain's own protein for improving age-related deficits in memory mechanisms. In primate models AMPAKINE compounds have replicated the studies in rodents and in adults patients suffering from Attention Deficit Hyperactivity Disorder, significant clinical and statistical improvement in increase attention and decrease hyperactivity have been observed. The U. Alberta research provide evidence that another important AMPAKINE indication is to stimulate primitive areas of the brain called the pre-Botzinger Complex responsible for breathing, without causing side effects. The pre-Botzinger Complex generated respiratory-related oscillations similar to those generated by the whole brainstem in vitro, and neurons with voltage-dependent pacemaker-like properties that have been identified in this brain region.

In a study published in 2006, Dr. John J. Greer of U. Alberta demonstrated that certain AMPAKINE compounds enhance the respiratory drive and breathing rhythm at the brain-stem level containing the pre-Botzinger Complex in laboratory rats whose respiration rates were purposely suppressed by administration of central nervous system depressants.

Dr. Greer found that respiratory depression induced by these agents can be reversed or prevented in test animals with an experimental AMPAKINE drug, without a reduction of pain relief or sedation.

Greer and coworkers treated rats with the opioids analgesic fentanyl or the barbiturate sedative Phenobarbital, both commonly prescribed in the United States. Greer used a technique known as plethysmography, which measures blood flow throughout the body, to determine the level of respiratory distressed caused by the drugs. When drugged rats were treated with the AMPAKINE , the respiratory distress quickly resolved. The drug worked in both newborn and adult rats. Interestingly, the drug on its own did not affect blood flow in animals not treated with the sedative drugs, nor did administration of the drug cause noticeable arousal in the animals.

Greer concluded, in a study published in the September 20, 2006 issue of the American Journal of Respiratory Critical Care Medicine, that CX546, "effectively reverses opioid- and barbiturate-induced respiratory depression without reversing the analgesic response."

"These results open up the real possibility of combining an ampakine compound with commonly prescribed barbiturates or opiates to reduce the likelihood that life-threatening respiratory depression will occur," noted explained Roger G. Stoll, Ph.D., Chairman, President, and CEO of Cortex.

Source

Ampakines hold out a promise for effective palliative treatments for Alzheimer's and other neurodegenerative disease. Currently, the Cortex drug CX717 is being held up by the FDA over toxicity concerns. Consequently the stock price of Cortex is currently quite low--trading below US $3 a share for over a year.

It is easy to see that should Cortex navigate through the labyrinthine bureaucracy of the FDA and reach approval for any of its Ampakines in development, that the stock price could rise rapidly.

Frankly, it is the potential for cognitive enhancement in normal people that fascinates me the most about the Ampakines. But the potential to make a substantial profit on a fairly small investment is also attractive. But do your own research before investing.

Here is more about Cortex' attempt to satisfy the FDA's concerns about possible toxicity of CX717 in animal studies.

Here is a recent report on a study that suggests that Ampakines might benefit Huntington's Disease patients, through their role in releasing BDNF in the brain.

Beyond Smart Drugs: Getting Smarter

Aubrey de Grey's SENS approach to gerontology may very well help us to live longer, perhaps much longer. Then what? Humans really do need to become smarter. Present levels of human intelligence are just about good enough to get us all killed. To go beyond what was discussed in the posting Smart Drugs, I would like to look toward longer term prospects for boosting intelligence--permanently.

Returning briefly to neuroscientist Michael Gazzaniga in his Oct 2005 SCIAM articleSmarter On Drugs, we see the real essence of the problem. Smart drugs temporarily augment the brains we have, but they do not make them better. To do that, we have to go further:

We have isolated one gene involved in intelligence, and others will follow. We know which parts of the brain are influenced by particular genes and which parts correlate with high IQ. We also know some of the neurochemicals involved in learning and memory. With such knowledge, we will gain understanding of what needs to be manipulated to increase intelligence in people who were not blessed with brilliance in their genomes or further increase the intelligence of those who were. Gene therapy could insert, delete, turn on or turn off genes that we find to be associated with intelligence.

We know about the Human Genome Project, and we understand that it is the foundation for much bigger things. We have heard about the International Hapmap Project, and we may have a vague idea of the possibilities that will be generated because of it. Diseases and other human attributes possess significant genetic components. We need to know what they are.

But we must think more broadly than mere genes. Genes are only part of the story. The better understanding of proteins, or proteomics, holds many of the keys we are looking for. In addition, non-coding RNA is a critical piece of the puzzle. The entire control structure of each cell is a highly complex internetwork of feedback systems. If you add the feedback systems of neighboring cells and tissues, then take into account signals coming to the cell from the blood, lymph, nerve terminals, and other meta-control systems--and you begin to see the problem.

We were talking about how to become more intelligent, using the genes. But now we understand that it can never be just the genes. It has to include the entire biological environment of the nervous system, and the entire organism.

But, wait. The organism is not hermetically sealed. The organism has inputs from the outside, and outputs to the outside. We know that growing organisms have to be given adequate nutrition, physical exercise, and mental stimuli to develop normally. They also need emotional nurturing. From Intelligence Testing Blog, we learn from Kevin that even video games may contribute to cognitive enhancement in young children. But what about the mature, developed organism--human? Assuming he is getting optimal nutrition, exercise, mental challenge, and emotional support? What else can be done?

OK, I talked about ampakines, donezepil, and modafinil here. If you are living on the edge of your mental capacity, it might be worth it to you, to try to get your hands on some donezepil. Modafinil should be treated gently, since everyone needs ample sleep, and with modafinil the temptation is to skimp on sleep to get more done, potentially abusing the body in the process. Ampakines are not available yet, but will be relatively soon. These are temporary approaches.

While we are waiting for researchers to understand the genetics, proteomics, and epigenetics of intelligence, there may be more permanent actions we can take to augment our mental capacity.

Assuming your nutrition is indeed optimal, your physical activity regular, your mental stimulation productive, and your emotional supports satisfying--what else can you do?

Neurofeedback is a technology that has been largely ignored by the public and news media, but is an approach that holds enormous potential for mental growth, even for mature and normal human mind/brains. It is still experimental in terms of stimulating mental growth for normal brains, but it is safe and non-invasive.

People with phobias, such as math phobia, are preventing themselves from progressing in the direction of their phobia. Such persons can certainly be helped by neurofeedback and other behavioural approaches.

There are many commercial programs, such as this one, that tries to capitalise on the human desire to improve oneself. This is another group that seems to be taking an even more advanced approach to developing mind improving technology. And while Daniel Amen may be rightly criticised by his peers for jumping too quickly into imaging technology to diagnose common everyday conditions, there is no doubt that Amen is at the leading edge of the curve, and may have the last laugh after all.

Taking nutritional supplements may not be a bad idea, either. In addition to the multivitamins, the extra vitamin C and E, and the minerals, taking curcumin, lipoic acid, and precursors for neurotransmitters might be helpful for many, particulary those with depression, fatigue, or ADD. This is not medical advice, but merely a suggestion for something that might be looked into.

Long life and increased intelligence are not the final goal. To reach the final goal, you must also include enlightenment, and wisdom. Using both sides of the brain to the fullest extent. Mysticism and holism are only part of wisdom. Wisdom also includes the ability to look at the details with exquisite clarity, and being able to place them into dynamic context.

We have some distance yet to travel, many things to learn. There is no reason not to use the footstools, ladders, and knotted ropes dangling above us.

Smart Drugs: What are the Prospects?

We begin with an article from Sciam Mind, by Michael Gazzaniga.
Enhancing intelligence is not science fiction. Many "smart" drugs are in clinical trials and could be on the market in less than five years. Some medications currently available to patients with memory disorders may also increase intelligence in the healthy population. Likewise, few people would lament the use of such aids to ameliorate the forgetfulness that aging brings. Drugs that counter these deficits would be adopted gratefully by millions of people.

Drugs designed for psychotherapy can also be used to enhance certain regular mental functions. Just as Ritalin can improve the academic performance of hyperactive children, it can do the same for normal children. It is commonly thought to boost SAT scores by more than 100 points, for both the hyperactive and the normal user. Many healthy young people now use it that way for that purpose, and quite frankly, there is no stopping this abuse.

... consider the following. In July 2002 Jerome Yesavage and his colleagues at Stanford University discovered that donepezil, a drug approved by the FDA to slow the memory loss of Alzheimer's patients, improves the memory of the normal population. The researchers trained pilots in a flight simulator to perform specific maneuvers and to respond to emergencies that developed during their mock flight, after giving half the pilots donepezil and half a placebo. One month later they retested the pilots and found that those who had taken the donepezil remembered their training better, as shown by improved performance. The possibility exists that donepezil could become a Ritalin for college students. I believe nothing can stop this trend, either.

...Recently geneticists have discovered that even such abstract qualities as personality and intelligence are coded for in our genetic blueprint. Studies of the genetic basis of g are just beginning, and because g most likely arises from the influence of many genes, the hunt will be a long one. Yet one study has already found that a gene on chromosome 6 is linked to intelligence.

So-called genetic brain mapping could help the search. Scientists are looking at the structural features (size, volume, and so on) of the brains of many individuals, including twins, familial relatives and unrelated individuals. By scanning all these brains in magnetic resonance imaging machines and looking at the differences, researchers have been able to determine which areas of the brain are most under the control of genes. These studies have emerged only in the past three to four years. Geneticists hope that once they know which brain areas are most affected by heredity, they can figure out which genes are responsible for those regions. With this kind of reverse mapping, the experts should be able to learn more about the genetics of intelligence.

...Whatever happens, we can be sure that cognitive enhancement drugs will be developed and that they will be used and misused. But just as most people do not choose to alter their mood with Prozac and just as we all reorient our lives in the face of unending opportunities to change our sense of normal, our society will absorb new memory drugs according to each individual's underlying philosophy and sense of self. Self-regulation will occur. The few people who desire altered states will find the means, and those who do not want to alter their sense of who they are will ignore the drug potions. The government should stay out of it, letting our own ethical and moral sense guide us through the new enhancement landscape. by Michael Gazzaniga

Next we go to Nootropics.com, a Hedweb site. This review of "Smart Drugs 2" by John Morgenthaler and Steven Fowkes, links to discussions of several potential smart drugs, as well as discussions about the underlying neuroscience and pharmacology involved. Here, we are introduced to modafinil, an increasingly prescribed drug that seems to do what it is supposed to do, with few serious side effects.

Modafinil, or Provigil, is a new stimulant with several different indications, and many more off label uses. Modafinil.org lists 45 uses of modafinil, cognitive enhancement being number 45. Modafinil.com is another Hedweb site, full of links to other pages describing the neuropharmacology of provigil, and the underlying neuroscience involved. Modafinil is becoming very popular with young professionals who never seem to have enough time to get everything done. Militaries use it for special ops troops, helicopter pilots, and pilots on long bombing missions. It works for ADD/ADHD, as an adjunct for depression, for cerebral palsy, and many more dysfunctions. Cephalon is coming out with a single isomer formulation of modafinil called "Nuvigil."

Both donazepil and modafinil are available from physicians, and over the internet. The ethics of internet prescribing are a bit shaky, but expect these drugs to become more available, rather than less, with time.

The last stop on today's smart drug train is the Ampakine station. Ampakines have the potential to not only help normal people think more clearly, as Donazepil and Modafinil seem to do, but to also make them "smarter." Ampakines directly affect the basic learning system of the brain.

New Scientist presented an article last May titled "11 Steps to a Better Brain." Gary Lynch, the inventor of ampakines, was cautious but optimistic:
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.

While donazepil works on the acetylcholine system, and modafinil works on dopamine receptors, ampakines in contrast affect the glutamate receptors, specifically AMPA receptors. From neurotrasmitter.net, here are a few dozen scientific abstracts dealing with potential ampakines and mechanisms of ampakines--if the wikipedia article did not give you enough information.

That is a lot of information to digest, although if you take these drugs it may not be as difficult as you might think. Perhaps a joke, perhaps not? In time, people who choose not to boost their cognition may be less common than those who choose to do so.

The long term goal is to adjust the genes themselves, to do a better job of improving cognition than any one drug, or symphony of drugs, could possibly do. In the meantime, expect smart drugs to be delivered by pill, injection, skin patch, long term implant, and even injector pumps. The intelligence of a population is serious business, more serious than most people understand. For now.