SMART DRUGS 2

THE NEXT GENERATION

by
Ward Dean, John Morgenthaler and Steven Fowkes
(ISBN 0 9627418 7 6)
Sceptics 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
behavioural 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 behaviour 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.