\\ smart pill - further proof of occident imbecility.

[integer at www.god-emil.dk]

smart pill - further proof of occident imbecility.


ost.europa version:

stress hormones smack memory storage++
kompetition + alienation increase stress and efficiency
oxytocin lowers stress hormones and efficiency
touching. love. sex. conviviality increase oxytocin
konkluzie - komrade lovers for your healthz sake - ....freel!

after all any bovine knows:

1. art arrived when humans secured their food supplies
   + began tasting boredom

2. childhood




Arrival of the smart pill     - the occident likes chasing its mirror
1 December 2003

by Laura Spinney 
While pharmaceutical companies race to develop memory-enhancing drugs for patients with clinical memory impairment, other researchers are finding that existing, approved drugs have the potential to be "smart" - that is, to enhance cognitive function in healthy people without side effects. 

A clutch of US companies is chasing the same dream: to increase the ease with which short-term memories are converted into long-term memories, and hence ameliorate the natural decline in memory that is associated with aging, as well as more severe causes of memory impairment such as Alzheimer's disease.

It's a secretive business, but one company that has so far kept a low profile, Sention Pharmaceuticals of Providence, Rhode Island, could well be ahead of the field. Mark Bear, a neuroscientist at the Massachusetts Institute of Technology's Picower Center for Learning and Memory and co-founder of Sention, won't go into details, but he says his company already has two drugs in clinical trials, and is expecting to have generated useful data from them by next summer.

Bear says that Sention's experimental drugs exploit the brain's natural modulation of the memory consolidation process. Two of Sention's better known competitors, Helicon Therapeutics of Farmingdale, New York and Memory Pharmaceuticals of Montvale, New Jersey, which extrapolates the work of Nobel laureate Eric Kandel, have homed in on one particular signaling pathway known to be involved in memory consolidation, with the aim of intervening in it.

The pathway involves the second messenger cyclic AMP (cAMP). A protein called cAMP response element binding protein (CREB) that is activated by cAMP plays a key role in strengthening synapses, which are widely thought to be the neural basis of memory formation. By inhibiting enzymes called phosphodiestereases that break down cAMP, it is possible to prolong the activity of CREB at a synapse. Inhibitors of one such enzyme, PDE-4, have performed well in animal trials of memory enhancement. But they have also been shown to cause more or less severe side effects, and neither company's product has yet entered human trials.

Memory has since expanded its remit, and is looking at other potentially memory-enhancing molecules such as nicotine receptor agonists. But side effects, Kandel admits, are a major hurdle to be overcome. While that remains the case, he thinks that the use of memory-enhancing drugs will only be feasible for those suffering from severe memory loss, for whom tolerating the nausea and other side effects is still worthwhile because of the benefits the drugs bring.

"There's no question that some of these drugs that work in age-related memory loss enhance memory in normal mice," he says. "If one could develop drugs that are absolutely safe, that have no down side, then I think that these would be used as memory enhancers for people who are middle-aged or younger."

At the University of Cambridge, clinical neuropsychologist Barbara Sahakian thinks her team has demonstrated what could potentially be the first such smart pill. The drug in question, modafinil or Provigil as it is marketed, has actually been around for a long time and is routinely prescribed for narcolepsy or excessive daytime sleepiness. Anecdotal evidence suggests that healthy people also take it, when they can get hold of it, to keep them alert and to allow them to work more efficiently.

In a study published earlier this year in the journal Psychopharmacology, Sahakian's group gave 60 healthy young men either 100mg or 200mg doses of modafinil, and compared their performance on a battery of neuropsychological tests to that of a control group who received a placebo. Those who took the drug showed improved performances on tests that required them to think before acting - that is, tasks involving planning and working memory, functions associated with the brain's frontal cortex.

"I don't think the significance of this [Psychopharmacology] paper has fully been realized," said Sahakian. "The drug improves cognition in healthy volunteers, and it doesn't seem to make anything worse, so you're getting enhancement without impairment." There has been some debate over whether modafinil has anything over caffeine in terms of the cognitive benefits it brings, but Sahakian says that no-one has yet ruled out that caffeine-users have a cognitive price to pay for any enhancing effect.

Meanwhile, in a study yet to be published, her team has found that modafinil improves performance on planning tasks in adults diagnosed with attention deficit hyperactivity disorder (ADHD). It also seems to dampen their impulsivity, as measured by how fast they break from a task in response to a stop signal.

Methylphenidate, better known by its brand name Ritalin, is the drug most commonly prescribed for ADHD today. But as Sahakian points out, there are different forms of ADHD depending on whether the patient's symptoms lean more to the hyperactive or the inattentive. "It may well be that people are going to get benefit from modafinil who haven't necessarily got benefit from methylphenidate," she said, adding that teasing apart these subtle cognitive distinctions will allow doctors to tailor drug treatments to different sub-groups of patients.

Although Ritalin's mode of action at the neurotransmitter level is well-known - it increases the availability of noradrenaline and dopamine - how that molecular action translates into cognitive effects is not well understood. Sahakian's husband and collaborator Trevor Robbins, also at Cambridge, has found that Ritalin produces the greatest improvement in performance on working memory tasks in 'normal' people with relatively poor working memory spans, and in patients with mild ADHD. But the benefits diminish as the ADHD symptoms grow more severe.

Robbins believes that brain circuits obey a tuning function the shape of an inverted U: if a system is working mildly below par, a dose of the right brain chemical could shift it up to the peak of the curve, thereby optimizing performance. But if that same system is operating poorly - at a low point on the curve - the equivalent dose won't bring it significantly nearer the peak, so the behavioral difference will be small. By the same token, if the system is already operating at its peak, that dose could shift it to the descending limb of the U, resulting in impairment.

In other words, Robbins thinks that tinkering with the brain's neurotransmitters inevitably involves a trade-off. To illustrate his theory he gives the example of Parkinson's disease (PD) and the drug most commonly prescribed for it, levodopa (L-dopa), which is a precursor of dopamine. PD patients suffer from the loss of dopaminergic neurons, which results in both cognitive as well as motor problems. But the evidence as to the cognitive benefits of L-dopa is ambiguous.

Robbins and co-workers have now shown that, in healthy people, L-dopa improves planning and working memory but impairs other aspects of cognition that involve emotional decisions based on expectations of reward. The same turns out to be true for PD patients, and it fits with what's known about the underlying brain circuits. Planning and other so-called executive functions involve the dorsolateral prefrontal cortex, which is connected to the movement circuits of the basal ganglia that are damaged by the disease. But emotion-reward systems are separate, and remain relatively unaffected by dopamine depletion.

"You are titrating dopamine up to an optimal level for movement and some aspects of cognition," says Robbins. "But by the same token you're overdosing the part of the system which is relatively normal, and making it perform aberrantly." That, he believes, is why some PD patients react psychotically to L-dopa. Knowing the neural bases of these differential effects will, he says, enable clinicians to modify the drug dose, or combine L-dopa with other drugs, to produce the best outcome for individual patients and avoid such reactions. It will also lead to the development of drugs that produce only benefits for normal people - that is, smart drugs.

According to Sahakian, many groups including hers are now moving towards incorporating genetics into their studies, to investigate how a person's genetic make-up interacts with a neurochemical intervention. That will, in turn, lead to even smarter and more tailored drugs. Whether the use of such drugs in normal people should be considered ethical or not is, of course, another question.