Re: Adrafinil

"David Lui" <[EMAIL PROTECTED]> wrote in message
news:[EMAIL PROTECTED]
> No Way To Treat The Mind
>
> Steven Rose
> The idea of memory-boosting pills is appealing. But we should resist the
> claim that there is automatically a chemical fix for all our
> psychological fallings.
> Would you like to increase your mental energy, concentration and
> alertness? Perform better in school or at work? Improve your ability to
> solve problems? Who could fail to be tempted by these offers adorning
> the cover of Smart Drugs and Nutrients: How to Improve Your Memory and
> Increase Your Intelligence Using the Latest Discoveries in Neuroscience?
> And if you do answer yes, there are, so enthusiasts will tell you, some
> 140 or more different chemicals, food additives or drugs that will do
> the job for you.
>
> But the question remains: do any of the substances advertised as
> so-called ``smart drugs'' work? Moreover, if the pharmaceutical industry
> does come up with an effective treatment for Alzheimer's disease and
> other senile dementias, will it be of any value to healthy people?
> Britain's Consumers' Association recently asked me, as a neuroscientist
> specializing in the biochemical basis of memory, to review the evidence.
>
> It was not a cheering experience. In magazines, books and newsletters,
> smart drug enthusiasts cite an impressive string of scientific papers to
> support their claims. Using these and other papers reporting the results
> of experiments on prototype smart drugs, I examined well over 100
> studies, some on animals, some on people with dementia, some on healthy
> people. Most of these are either misleadingly quoted by advocates of
> smart drugs or describe experiments that are poorly controlled or
> extravagantly overinterpreted by the researchers. Worse, some studies
> use procedures that would not pass ethical scrutiny in Britain, and the
> most dramatic claims often appear in unrefereed conference proceedings
> or obscure journals.
>
> To assess the claims of the loudest advocates of smart drugs, it is
> vital to sort out what they mean by ``improving memory'' or ``enhancing
> cognition.'' Current psychological theory distinguishes between
> so-called ``procedural'' and ``declarative'' memory, or ``remembering
> how'' and ``remembering that''. Remembering how to ride a bicycle is
> procedural'; remembering that a two-wheeled vehicle with saddle and
> handlebar is called a bicycle is declarative. Declarative memory can be
> split into ``semantic'' and ``episodic'' memory. Remembering that 1
> January is New Year's Day is semantic; remembering the New Year party
> you went to last year is episodic. The most vulnerable form of memory is
> episodic.
>
> Only the most severe of memory disorders affect procedural memory; even
> profound amnesiacs can usually recall how to perform daily activities
> such as putting on clothes and cooking even when they cannot
> subsequently describe what they have done.
>
> Much of what we perceive is stored only for a short time before being
> discarded. Read a seven-figure set of numbers to a colleague, and the
> odds are he or she will be able to repeat them back without error. Ask
> again half an hour later, and the sequence will probably have been
> forgotten. Such observations have led to the idea that declarative
> memory passes through a short-term store into a long-term store.
> Persisting for periods of minutes to hours, short-term memory is one of
> the most susceptible to drugs: anæsthesia, concussion or electrical
> shock treatment will all obliterate it. By contrast, once a memory is in
> the long-term store, it is very hard to erase, though not always easy to
> retrieve without an appropriate cue. It is often hard to recall a
> person's name, for instance, even though one ``knows that one knows
> it''. Memory is often not so much lost as hard to find.
>
> This brings us to the first fundamental problem with smart drugs. Most
> people envision them as improving recall. Yet much of the evidence cited
> by smart drug enthusiasts comes from animal experiments which can, by
> virtue of their design, test only a drug's effects on learning, not
> recall. The animals are trained to perform highly specific tasks and the
> agents given within an hour or so of the training trials. On this basis,
> the best a smart drug could do would be to increase the likelihood of
> the transfer of information from the short-term to long-term memory
> store. There is little evidence than any of today's smart drugs can do
> even this much in humans.
>
> Indeed, the awesome complexity of human memory makes the smart drug
> creed look suspiciously simple. It is founded on two key assumptions.
> First, memory loss is not confined to patients with conditions such as
> Alzheimer's disease but happens to us all as we age. Second, this normal
> ``everyday'' deterioration is caused by a failure or weakening of the
> same kinds of biochemical mechanisms that break down in conditions such
> as Alzheimer's disease. To believers in the faith, the corollary is
> obvious: drugs developed for patients with senile dementia ought to be
> made available to the rest of us so that we can crank our memories up to
> maximum speed and capacity.
>
> The first of these assumptions is by no means confined to smart drug
> advocates. In the US, a vociferous school of thought claims there is a
> clinically definable condition called Age Associated Memory Impairment
> (AAMI) - an inexorable loss of memory which, the argument goes, many of
> us suffer as we move through our fifties. It is true that after the age
> of 40 performance on standard intelligence tests steadily declines for
> most people - unless enough time si given to solve the problems. And if
> speed is taken as the main criterion of memory capacity, then it could
> be argued that memory grows weaker with age. Yet memory and learning are
> inextricably bound up with a whole range of other mental and physical
> abilities. As we age our attention spans, emotions and motivation levels
> all change. Such effects alone could explain why memory seems to falter
> and age, without there being any weakening of the molecular and cellular
> mechanisms of memory itself.
>
> Furthermore, decline is not inevitable. A recent Dutch study from the
> University of Limberg, Maastricht, has found that memory decline in
> otherwise healthy people as they age is associated with mild head
> injury, general anæsthesia or ``social drinking'' earlier in life. In
> people without such predisposing ``biological life events'', memory
> remained unimpaired even into extreme old age.
>
> It is extremely difficult to design experiments that test the direct
> effects of drugs on memory when there are so many indirect influences on
> mental performance. Elderly people living in institutions who cannot
> remember what they had for breakfast that morning may be able to recall
> childhood episodes with great clarity. Have they lost memory, or have
> they lost interest in institutional food, where one breakfast may be
> just like another? Recall is not some mechanical process like recovering
> files from a computer disk, but involves active and interested work on
> the part of the individual.
>
> Smart drugs are supposed to work in one of two main ways: either by
> increasing blood flow to the brain, or boosting the levels of one or
> other of the neurotransmitters thought to play a part in learning and
> memory. Such drugs are sometimes called ``nootropics'', a term coined by
> the pharmacologist Cornelius Giurgea in the 1970s from the Greek meaning
> acting on the mind. To qualify as a nootropic, Giurgea argued, a drug
> had to:
>
>
> Enhance learning and memory, especially under conditions of disturbed
> neural metabolism resulting from a lack of oxygen, electroshock or
> age-related changes
> Facilitate information flow between the cerebral hemispheres
> Enhance the general resistance of the brain to physical and chemical
> injuries
> Be devoid of any other psychological or physiological effects
> These criteria, though still quoted with zeal by smart drug enthusiasts
> today, seem absurdly vague by the standards of mainstream neuroscience.
> I am not sure, for instance, what is meant by ``facilitating information
> flow between the cerebral hemispheres'', or how to check that it was
> happening.
> The rationale to the belief that agents which affect blood flow or
> neurotransmitter levels could function as smart drugs came first from
> research into the effects of stroke. Stroke is one of the common causes
> of neurological damage in elderly people affecting many aspects of
> performance including memory and cognition. The damage is often cause by
> constriction of the arteries supplying blood, and hence oxygen and
> glucose, to the brain. Therefore, drugs which increase cerebral blood
> flow and diminish hypertension might be expected to ``improve the
> performance'' of otherwise energy-starved neurons. This is why
> propanolol, phenytoin or hydergine are used as smart drugs.
>
> The second reasoning came from work on the neurochemical deficits in
> Alzheimer's disease. One of the characteristic features of Alzheimer's
> is progressive loss of memory. Postmortem studies of the brains of
> Alzheimer's patients show a dramatic destruction of neurons, and
> particularly neurons which secrete or utilize the neurotransmitter
> acetylcholine. During the 1970s, research with animals also suggested
> that acetylcholine might be a key neurotransmitter in memory formation;
> for instance drugs such as scopolamine, which deplete brain
> acetylcholine also impair memory. In the early 1980s these observations
> gave birth to the ``colinergic hypothesis'' of memory loss. And if loss
> of acetylcholine was responsible for memory loss, why not attempt to
> increase the brain's supply of acetylcholine? In the wake of this
> argument came one of the first proposed smart drugs, piracetam, along
> with food additives which are potential metabolic precursors of
> acetylcholine, such as choline and acetlcarnosine.
>
> Despite the focus on the role of acetylcholine, nobody seriously
> believes that any one neurotransmitter dominates the complex processes
> that underpin cognition and memory. So the search for smart drugs has
> broadened to include agents that interact with other neurotransmitters,
> including glutamate, serotonin (5-HT) and dopamine.
>
> Another class of potential smart drugs are the calcium channel blockers.
> These, such as verapamil, diltiazem, nifedipine, nitrendipine and
> nimodipine are not only widely used to treat hypertension, and hence
> might affect cognition by increasing cerebral blood flow, but also block
> the entry of calcium ions into neurons. A key stage in the molecular
> cascade of memory formation appears to be the opening of membrane
> channels through which calcium ions flow. In old laboratory rodents, the
> mechanisms that open and close these calcium channels seem to become
> defective, and so calcium accumulates at dangerous levels inside the
> cells. The calcium channel blockers might improve memory by countering
> this effect. Ginseng, that all-purpose elixir of life, contains an agent
> that blocks calcium channels.
>
> There is some evidence that calcium channel blockers, glutamate
> agonists, 5-HT antagonists and certain piracetam derivatives can help
> laboratory animals learn highly specific tasks if the agent is injected
> around the time of training. Yet in many cases, it is clear [sic; not?]
> how the drugs act in animal tests. Some may work by interfering with the
> molecular events leading to memory; others by affecting the animal's
> general level of physical activity. Testing memory in non-humans
> presents nearly as many ambiguities as studying it in humans.
>
> A popular approach is to measure how effective a drug is in helping rats
> and mice their way around mazes. In some of these mazes, the animals
> must run down a series of ``arms'' fanning out from a central area in
> search of food. Other mazes consist of a large tank of water with a
> submerged platform, which animals must learn to swim towards and clamber
> on to to ensure safety. A different kind of test relies on ``passive
> avoidance.'' If a rat is placed on a narrow shelf above the floor of its
> cage, its normal tendency is to step down; if the animal is given a mild
> electric shock every time it does so, however, it will learn to stay put.
>
> Alleviating amnesia
>
> Clearly, such tasks involve many other aspects of performance than
> merely learning and memory. Drugs that alter sensations of hunger or
> thirst, or reduce sensitivity to pain, or simply make an animal more
> active could all improve performance. In some cases animals are trained
> on tasks and then made amnesiac either by electric shock, or, in one
> popular test, by administering scopolamine to deplete acetylcholine.
> Something may be considered a potential smart drug if it can alleviate
> this kind of amnesia in animals. But there is an obvious flaw: the drug
> may not necessarily work on less artificially induced amnesia.
>
> There are many other problems with animal studies of smart drugs. The
> drugs are usually administered by injection, sometimes into the brain,
> and often at very high doses. In some studies reporting a positive
> effect on learning, drugs were injected at doses equivalent to inject a
> human with about 8 grams of the drug. Taken orally, as all smart drugs
> are, this might scale up to as much as 40 grams - scarcely a realistic
> proposition. Although it is standard practise in reputable
> pharmacological papers to publish dose-response curves for any proposed
> agent, the smart drug literature is remarkably coy on this point. At
> best two or three concentrations of the drug are tested, often without
> discernible dose-related effects.
>
> Studies of smart drugs on human patients are much rarer but no less
> contentious. Most involve patients in hospitals or other institutions,
> frequently diagnosed as suffering from Alzheimer's or cerebrovascular
> disease. Many of the trials are based on small samples of patients, less
> than 10 in each of the drug and placebo groups. A sizeable number of the
> human studies come from trials carried out in the south of Italy where
> the ethical controls and statistical procedures require in British and
> American trials are often lacking, or at least unspecified. What is
> more, effects on the patients are often evaluated using subjective
> criteria. One paper, reporting a study of aniracetam in elderly
> patients, simply states that doctors and nurses evaluated the drug
> according to its ``resocialising and revitalizing effects''.
>
> The better research papers supplement such observations with IQ and
> memory tests, in which subjects try to recall or recognize names or
> dates associated with past public episodes. Yet often researchers find a
> drug improves performance in only one or two of a battery of tests. The
> proper way to avoid error is to then repeat the trial with a different
> group of patients using only the tests which were found to be
> significant the first time. I have seen no such reports.
>
> But even if an experimental drug does help patients with Alzheimer's
> disease, it may not necessarily be of value to healthy people. In
> addition to suffering memory loss, elderly patients in hospital,
> especially those with Alzheimer's disease, are often angry, suspicious,
> anxious or depressed. A drug that reduced such feelings could easily
> result in an apparent improvement in memory while having no effect on
> the actual mechanisms of memory.
>
> Clinical trials have yielded some drugs which may be of help in the
> early stages of Alzheimer's disease. But the claims made by smart drug
> advocates go far beyond offering treatments for devastating diseases;
> they offer instant cognitive enhancement to us all. True, at best the
> research papers on which the claims are based imply that for most of the
> smart drugs to work, a person should self-administer a massive dose,
> preferably by intravenous injection, either just before or after
> learning a particular problem or revising for an examination. Not the
> most likely of scenarios.
>
> But, of course, in addition to claims based on research papers,
> advocates of smart drugs, such as Dean Morgenthaler, offer personal
> testimonials as evidence. I am not trying to challenge individual
> experience and testimony. It is well known that the experience of
> consuming psychotropic agents varies between individuals, is intensely
> subjective, depends on mood and expectation, and is often hard to verify
> by objective scientific criteria. What is abundantly clear, however, is
> that the primary scientific literature does not justify the claim that
> smart drugs can be of any therapeutic or ``memory-boosting'' value to
> healthy humans.
>
> Nor should this surprise us. There is no reason to assume that, for most
> of us at most time, our enzyme and neurotransmitter systems are not
> working at more or less optimal levels. The brain is well buffered
> against the effect of arbitrary increases or decreases in circulating
> chemicals so that simply consuming food additives which are
> acetylcholine precursors will not normally increase your brain
> acetylcholine level. And even if it did, increasing neurotransmitter
> activity is no guarantee of increased mental performance; rather, it can
> be positively deleterious to throw chemical spanners into the
> exquisitely balanced biochemical system that is the human brain. More
> does not mean better. The smart thing to do with smart drugs is to
> resist the claim that there is automatically a chemical fix to any or
> all social or psychological problems. For most of us who believe that we
> suffer from a weaker memory than we would like, the old training skills
> offered by the mnemotechnics of the ancients probably stand at least as
> good a chance of helping us as does the most fashionable
> molecule-of-the-moment.
>
>
> * * *
> Steven Rose is head of the Brain and Behavior Research Group at the Open
> University.
>