Does It Hurt To Be Smart?
Smart Drugs II
The Next Generation
Date: 9/27/2007 5:33:36 PM ( 17 y ) ... viewed 3233 times
Skeptics about nootropics ("smart
drugs") are unwitting victims of the so-called
Panglossian paradigm of evolution. They believe that our cognitive
architecture has been so fine-honed by natural selection that any
tinkering with such a wonderfully all-adaptive suite of mechanisms is
bound to do more harm than good. Certainly the notion that merely
popping a
pill could make you brighter sounds implausible. It sounds like the
sort of journalistic excess that sits more comfortably in the pages of
Fortean Times than any scholarly journal of repute.
Yet as
Dean,
Morgenthaler and
Fowkes' (hereafter "DMF") book attests, the debunkers are wrong. On
the one hand, numerous agents with
anticholinergic properties are essentially
dumb drugs. They impair memory, alertness, verbal facility and
creative thought. Conversely, a variety of
cholinergic drugs and nutrients, which form a large part of the
smart-chemist's arsenal, can subtly but significantly enhance cognitive
performance on a whole range of tests. This holds true for victims of
Alzheimer's Disease, who suffer in particular from a progressive and
disproportionate loss of
cholinergic neurons. Yet, potentially at least, cognitive enhancers
can aid
non-demented people too. Members of the "normally" ageing population
can benefit from an increased availability of
acetylcholine, improved blood-flow to the brain, increased
ATP production and enhanced oxygen and glucose uptake. Most
recently, research with
ampakines, modulators of neurotrophin-regulating
AMPA-type glutamate receptors, suggests that designer nootropics
will soon deliver sharper intellectual performance even to healthy young
adults.
DMF provide updates from Smart Drugs (1)
on
piracetam,
acetyl-l-carnitine,
vasopressin, and several vitamin therapies. Smart Drugs II
offers profiles of agents such as
selegiline (l-deprenyl),
melatonin,
pregnenolone,
DHEA and
ondansetron (Zofran). There is also a provocative
question-and-answer section; a discussion of
product sources; and a guide to further reading.
So what's the catch? One problem, to which not all
authorities on nootropics give enough emphasis, is the complex interplay
between cognition and
mood. Thus great care should be taken before tampering with the
noradrenaline/acetylcholine
axis. Thought-frenzied
hypercholinergic states, for instance, are characteristic of one "noradrenergic"
sub-type of depression. A predominance of forebrain cholinergic
activity, frequently triggered by chronic uncontrolled
stress, can lead to a reduced sensitivity to
reward, an inability to sustain effort, and
behavioral suppression.
This mood-modulating effect does make some sort of cruel
genetic sense. Extreme
intensity of reflective thought may function as an evolutionarily
adaptive response when things go wrong. When they're going right, as in
optimal states of "flow
experience", we don't need to bother. Hence boosting
cholinergic function, alone and in the absence of further
pharmacologic intervention, can subdue mood. It can even induce
depression in susceptible subjects. Likewise, beta-adrenergic
antagonists (e.g.
propranolol (Inderal)) can induce depression and fatigue.
Conversely, "dumb-drug" anticholinergics may sometimes have
mood-brightening - progressing to
deliriant - effects. Indeed antimuscarinic agents acting in the
nucleus accumbens may even induce a "mindless"
euphoria.
Now it might seem axiomatic that helping everyone think more
deeply is just what the doctor ordered. Yet our education system is
already pervaded by an intellectual snobbery that exalts academic
excellence over
emotional well-being. In the modern era, examination rituals
bordering on institutionalised child-abuse take a heavy toll on young
lives. Depression and anxiety-disorders among young teens are endemic -
and still
rising. It's worth recalling that research laboratories routinely
subject non-human animals to a regimen of "chronic mild uncontrolled
stress" to induce depression in their captive animal population;
investigators then test putative
new antidepressants on the depressed animals to see if their despair
can be experimentally reversed by
patentable drugs. The "chronic mild stressors" that we standardly
inflict on adolescent humans can have no less harmful effects on the
mental health of captive school-students; but in this case, no organised
effort is made to reverse it. Instead its victims often go on to
self-medicate with
ethyl alcohol,
tobacco and
street drugs. So arguably at least, the deformed and emotionally
pre-literate minds churned out by our
schools stand in need of safe, high-octane
mood-brighteners more urgently than cognitive-tweakers.
Memory-enhancers might be more worthwhile if we had more experiences
worth remembering.
One possible solution to this dilemma involves taking a cholinergic agent such as
piracetam (Nootropil) or
aniracetam (Draganon, Ampamet) that also enhances
dopamine function. Some researchers tentatively believe that the
mesolimbic dopamine system acts as the
final common pathway for pleasure in the brain. This hypothesis may
well prove
simplistic. There are certainly
complications: it is not the neurotransmitter dopamine itself, but
the post-synaptic metabolic cascades it triggers, that underlies
motivated bliss. Other research suggests that it is the
endogenous opioid system, and in particular
activation of the
mu opioid receptors, that mediates pure pleasure. Mesolimbic
dopamine amplifies "incentive-motivation":
"wanting" and "liking" may have different
substrates, albeit intimately linked. Moreover there are
mood-elevating memory-enhancers such as phosphodiesterase inhibitors
(e.g. the selective PDE4 inhibitor
rolipram) that act on different neural pathways - speeding and
strengthening memory-formation by prolonging the availability of
CREB. In any event, several of the most popular smart drugs
discussed by DMF do indeed act on both the cholinergic and dopaminergic
systems. In addition, agents like
aniracetam and its analogs increase hippocampal glutaminergic
activity.
Hippocampal function is critical to
memory - and
mood. Thus newly developed
ampakines, agents promoting long-term potentiation of
AMPA-type glutamate receptors, are powerful memory-enhancers and
future
nootropics.
Another approach to enhancing mood and intellect alike
involves swapping or combining a choline agonist with a different,
primarily dopaminergic drug. Here admittedly there are methodological
problems. The improved test score performances reported on so-called
smart dopaminergics may have other explanations. Not all studies
adequately exclude the confounding variables of increased alertness,
sharper sensory acuity, greater motor activity or improved motivation -
as distinct from any "pure" nootropic action. Yet the selective dopamine
reuptake blocker
amineptine (Survector) is both a
mood-brightener and a possible
smart-drug. Likewise
selegiline, popularly known as l-deprenyl, has potentially
life-enhancing properties. Selegiline is a selective, irreversible MAO-b
inhibitor with
antioxidant,
immune-system-boosting and
anti-neurodegenerative effects. It retards the metabolism not just
of dopamine but also of
phenylethylamine, a trace amine also found in
chocolate and released when we're in love. Selegiline also
stimulates the release of superoxide dismutase (SOD);
SOD is a key enzyme which helps to quench damaging free-radicals. Taken
consistently in low doses, selegiline extends the life-expectancy of
rats by some 20%; enhances drive, libido and endurance; and
independently improves cognitive performance in
Alzheimer's patients and in some healthy normals. It is used
successfully to treat canine cognitive dysfunction syndrome (CDS) in
dogs. In 2006, higher dose (i.e. less MAO-b selective) selegiline
was licensed as the antidepressant
EMSAM, a transdermal patch. Selegiline also protects the brain's
dopamine cells from oxidative stress. The brain has only about 30-40
thousand dopaminergic neurons in all. It tends to lose perhaps 13% a
decade in adult life. An eventual 70%-80% loss leads to the
dopamine-deficiency disorder
Parkinson's disease and frequently
depression. Clearly anything that spares so precious a resource
might prove a valuable tool for life-enrichment.
In 2005, a second selective MAO-b inhibitor,
rasagiline (Azilect) gained an EC product license. Its introduction
was followed a year later in the
USA. Unlike selegiline, rasagiline doesn't have amphetamine trace
metabolites - a distinct if modest therapeutic advantage.
Looking further ahead, the bifunctional cholinesterase
inhibitor and MAO-b inhibitor
ladostigil acts both as a cognitive enhancer and a mood brightener.
Ladostigil has neuroprotective and potential
antiaging properties too. Its product-license is several years away
at best.
Does it hurt to be smart?
So what could be the pitfalls here? One snag illustrates a
more general problem with the DMF strategy. Unless it is applied with
extreme caution, a virtue not associated with all
self-experimenters, taking self-designed cocktails of "smart-pills"
may carry significant but unknown risks.
Consider, for instance, the plight of genetically engineered
"smart
mice" endowed with an extra copy of the
NR2B subtype of
NMDA receptor. It is now known that such brainy "Doogie" mice suffer
from a chronically increased sensitivity to
pain. Memory-enhancing drugs and potential gene-therapies targeting
the same receptor subtype might cause equally disturbing side-effects in
humans. Conversely, NMDA antagonists like the
dissociative anaesthetic drug
ketamine exert
amnestic, antidepressant and analgesic effects in humans and
non-humans alike.
Amplified memory can itself be a mixed blessing. Even among
the drug-naïve and chronically forgetful, all kinds of embarrassing,
intrusive and
traumatic memories may haunt our lives. Such memories sometimes
persist for months, years or even decades afterwards. Unpleasant
memories can sour the well-being even of people who don't suffer from
clinical
PTSD. The effects of using all-round memory enhancers might do
something worse than merely fill our heads with clutter. Such agents
could etch traumatic experiences more indelibly into our memories. Or
worse, such all-round enhancers might promote the involuntary recall of
our nastiest memories with truly nightmarish intensity.
By contrast, the design of chemical tools that empower us
selectively to forget unpleasant memories may prove to be at
least as life-enriching as agents that help us remember more
effectively. Unlike the software of digital computers, human memories
can't be specifically deleted to order. But this design-limitation may
soon be overcome. The synthesis of enhanced versions of protease
inhibitors such as
anisomycin may enable us selectively to erase horrible memories. If
such agents can be refined for our personal medicine cabinets, then
we'll potentially be able to rid ourselves of nasty or unwanted memories
at will - as distinct from drowning our sorrows with
alcohol or indiscriminately dulling our wits with
tranquillisers. In future, the twin availability of 1] technologies
to amplify desirable memories, and 2] selective amnestics to extinguish
undesirable memories, promises to improve our quality of life far
more dramatically than use of today's lame
smart drugs.
Such a
utopian pharmaceutical toolkit is still some way off. Given our
current primitive state of knowledge, it's hard to boost the function of
one neurotransmitter signalling system or receptor sub-type without
eliciting compensatory and often unwanted responses from others. Life's
successful, dopamine-driven go-getters, for instance, whether
naturally propelled or
otherwise, may be highly productive individuals. Yet they are rarely
warm, relaxed and socially
empathetic. This is because, crudely, dopamine overdrive tends to
impair "civilising serotonin" function. Unfortunately, tests of putative
smart drugs typically reflect an impoverished and culture-bound
conception of intelligence. Indeed today's "high IQ" alpha males may
strike posterity as more akin to idiot savants than imposing
intellectual
giants.
IQ tests, and all conventional scholastic examinations, neglect
creative and practical intelligence. They simply ignore
social cognition. Social intelligence, and its cognate notion of "emotional
IQ", isn't some second-rate substitute for people who can't do IQ
tests. On the contrary, according to the
Machiavellian ape hypothesis, the evolution of human intelligence
has been driven by our superior "mind-reading" skills.
Higher-order intentionality [e.g. "you believe that I hope that
she thinks that I want...", etc] is central to the lives of advanced
social beings. The unique development of human mind is an adaptation to
social problem-solving and the selective advantages it brings.
Yet pharmaceuticals that enhance our capacity for
empathy, enrich our
social skills, expand our "state-space"
of experience, or deepen our
introspective self-knowledge are not conventional candidates for
smart drugs. For such faculties don't reflect our traditional [male]
scientific value-judgements on what qualifies as "intelligence". Thus in
academia, for instance, competitive dominance behavior among "alpha"
male human primates often masquerades as the pursuit of scholarship.
Emotional literacy is certainly harder to
quantify scientifically than mathematical puzzle-solving ability or
performance in verbal memory-tests. But to misquote Robert McNamara, we
need to stop making what is measurable important, and find ways to make
the important measurable. By some criteria, contemporary IQ tests are
better measures of high-grade autism than mature intelligence. So before
chemically manipulating one's mind, it's worth critically examining
which capacities one wants to enhance; and to what end?
In practice, the first and most boring advice is often the
most important. Many potential users of smart pills would be better and
more simply advised to stop taking
tranquillisers,
sleeping tablets or
toxic recreational drugs; eat
omega-3 rich foods, more
vegetables and generally improve their
diet; and try more mentally challenging tasks. One of the easiest
ways of improving
memory, for instance, is to increase the flow of oxygenated blood to
the
brain. This can be achieved by running, swimming, dancing, brisk
walking, and more
sex. Regular vigorous
exercise also promotes
nerve cell growth in the hippocampus. Hippocampal brain cell growth
potentially enhances
mood, memory and cognitive vitality alike. Intellectuals are prone
to echo
J.S. Mill: "Better to be an unhappy Socrates than a happy pig". But
happiness is typically good for the hippocampus; by contrast, the
reduced hippocampal volume anatomically characteristic of
depressives correlates with the length of their depression.
In our current state of ignorance, homely remedies are still
sometimes best. Thus moderate consumption of
adenosine-inhibiting, common-or-garden
caffeine improves concentration, mood and alertness; enhances
acetylcholine release in the hippocampus; and statistically reduces
the risk of
suicide. Regular coffee drinking induces competitive and reversible
inhibition of MAO enzymes type A and B owing to coffee's neuroactive
beta-carbolines. Coffee is also rich in
antioxidants. Non-coffee drinkers are around
three times more likely to contract Parkinson's disease. A Michigan
study found caffeine use was correlated with enhanced male virility
in later life.
Before resorting to pills, aspiring intellectual heavyweights
might do well to start the day with a low-fat/high carbohydrate
breakfast: muesli rather than tasty well-buttered croissants. This
will enhance memory, energy and blood glucose levels. An
omega-3 rich diet will enhance all-round emotional and intellectual
health too. A large greasy fry-up, on the other hand, can easily leave
one feeling muddle-headed, drowsy and lethargic. If one wants to stay
sharp, and to blunt the normal mid-afternoon dip, then eating big fatty
lunches isn't a good idea either. Fat releases
cholecystokinin (CCK) from the duodenum. Modest intravenous
infusions of CCK make one demonstrably dopey and subdued.
To urge such caveats is not to throw up one's hands in
defeatist resignation.
Creative psychopharmacology can often in principle circumvent such
problems, even today. Complementary and sometimes effective combinations
such as sustained-release
methylphenidate (Ritalin)
and
SSRIs such as
fluoxetine (Prozac),
for instance, are arguably still under-used. They could be more widely
applied both in clinical psychiatry and, at least in the context of a
general harm-reduction strategy, on the street. There may indeed be no
safe drugs but just safe
dosages. Yet some smart drugs, such as
piracetam, really do seem to be at worst pretty innocuous. Agents
such as the
alpha-1 adrenergic agonist
adrafinil (Olmifron) typically do have both mood-brightening and
intellectually invigorating effects. Adrafinil, like its chemical cousin
modafinil (Provigil), promotes alertness, vigilance and mental
focus; and its more-or-less pure CNS action ensures it doesn't cause
unwanted peripheral sympathetic stimulation.
Unfortunately the lay public is currently ill-served, a few
shining
exceptions aside, by the
professionals. A condition of ignorance and dependence is actively
fostered where it isn't just connived at in the wider population. So
there's often relatively little point in advising anyone contemplating
acting on DMF's book to consult their physician first. For it's likely
their physician won't want to know, or want them to know, in the first
instance.
As traditional forms of censorship, news-management and
governmental information-control break down, however, and the Net
insinuates itself into ever more areas of daily life, more and more
people are stumbling upon - initially - and then
exploring, the variety of drugs and combination therapies which
leading-edge pharmaceutical research puts on offer. They are
increasingly doing so as
customers, and not as patronisingly labelled role-bound "patients".
Those outside the charmed circle have previously been cast in the
obligatory role of humble supplicants. The more jaundiced or libertarian
among the excluded may have felt themselves at the mercy of
prescription-wielding, or -withholding,
agents of one arm of the licensed
drug cartels. So when the control of the cartels and their agents
falters, there is an especially urgent need for incisive and
high-quality information to be made readily accessible. Do DMF fulfil
it?
Smart
Drugs 2 lays itself wide open to criticism; but then it takes on an
impossible task. In the perennial trade-off between accessibility and
scholarly rigour, compromises are made on both sides. Ritual disclaimers
aside, DMF's tone can at times seem too uncritically gung-ho. Their
drug-profiles and cited studies don't always give due weight to the
variations in sample size and the quality of controls. Nor do they
highlight the uncertain calibre of the scholarly journals in which some
of the most interesting results are published. DMFs inclusion of
anecdote-studded personal testimonials is almost calculated to inflame
medical orthodoxy. Moreover it should be stressed that the scientific
gold-standard of large, placebo-controlled, double-blind cross-over
prospective
trials are still quite rare in this field as a whole.
Looking
ahead, this century's
mood-boosting,
intellect-sharpening,
empathy-enhancing and
personality-enriching drugs are themselves likely to prove only
stopgaps. This is because invincible, life-long
happiness and
supergenius intellect may one day be
genetically pre-programmed and possibly
ubiquitous in our
transhuman successors. Taking drugs to repair Nature's deficiencies
may eventually become
redundant. Memory- and intelligence-boosting gene therapies are
already
imminent. But in repairing the deficiencies of an educational system
geared to producing dysthymic pharmacological illiterates,
Smart Drugs 1 and 2 offers a warmly welcome start.
References
and
further reading
HedWeb
Future Opioids
BLTC Research
Utopian Surgery?
Nutritional Medicine
Wirehead Hedonism
The Good Drug Guide
Critique Of Brave New World
MDMA: Utopian Pharmacology
Nootropics/Smart Drugs: Sources
e-mail
info@nootropics.com
www.nootropics.com
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