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smart drugs 2: the next generation
Ward Dean, John Morgenthaler and Steven Fowkes
(ISBN 0 9627418 7 6)
Sceptics about the possibility of nootropics ("smart drugs") are 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 intellectually brighter sounds implausible - 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. Anticholinergics impair memory, alertness, focus, 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. Many 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? Unfortunately, there are many. Large, well-controlled, long-term trials of putative nootropics are scarce: the whole field of cognitive enhancement is rife with self-deception, snake-oil, hucksterism and (at best) publication bias. Another 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. Cholinergics 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 social cognition and 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. In the late twentieth century, many researchers believed that the mesolimbic dopamine system acts as the final common pathway for pleasure in the brain. This hypothesis turned out to be simplistic at best. The mesolimbic dopamine system is most directly implicated in motivation and the capacity to anticipate future pleasures. 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 mood-elevating memory-enhancers such as phosphodiesterase inhibitors (e.g. the selective PDE4 inhibitor rolipram) 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 400,000 - 600,000 dopaminergic neurons in all. We 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. Ironically, a popular smart drug such as modafinil can be used experimentally to">prevent long-term memory consolidation in “animal models" - not quite the effect pill-popping students cramming for exams have in mind. Like most psychostimulants, modafinil may also have a subtle anti-empathetic effect.

        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. Likewise, testosterone functionally antagonises pro-social oxytocin in the CNS. 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. IQ tests 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 full-spectrum 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; practise good sleep discipline; 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. Enhanced cerebrovascular function 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. There may indeed be no safe drugs but just safe dosages. Yet some smart drugs, such as piracetam, are relatively innocuous. If the user doesn't like their effects, (s)he can simply stop taking them. 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.

and further reading

Talks (2015)
Future Opioids
BLTC Research
Utopian Surgery?
Social Media (2017)
Nutritional Medicine
Wirehead Hedonism
The Good Drug Guide
Nootropics (Wikipedia)
The Abolitionist Project
Reproductive Revolution
Critique Of Brave New World
MDMA: Utopian Pharmacology
Nootropics/Smart Drugs: Sources
The Biointelligence Explosion (2013)
Male intelligence vs female intelligence
Humans and AI: Co-evolution, Fusion or Replacement? (2013)