Sceptics about the possibility of nootropics("smart drugs")are victims of the so-called Panglossianparadigm of evolution. They believe that our cognitive architecture has beenso fine-honed by natural selection that any tinkering with such a wonderfullyall-adaptive suite of mechanisms is bound to do more harm than good. Certainlythe notion that merely popping a pill could make you intellectually brighter sounds implausible - the sort of journalistic excess that sits more comfortably in thepages of Fortean Times than any scholarlyjournal of repute.

Yet as Dean,Morgenthaler and Fowkes'(hereafter "DMF") book attests, the debunkers are wrong. On the one hand, numerousagents with anticholinergicproperties are essentially dumb drugs.Anticholinergics impair memory, alertness, focus, verbal facility and creative thought. Conversely,a variety of cholinergic drugsand nutrients, which form a large part of the smart chemist's arsenal, can subtlybut significantly enhance cognitive performance on a whole range of tests. Thisholds true for victims of Alzheimer'sDisease, who suffer in particular from a progressive and disproportionateloss of cholinergic neurons.Yet, potentially at least, cognitive enhancers can aid non-dementedpeople too. Many members of the "normally" ageing population can benefit from an increasedavailability of acetylcholine,improved blood-flow to the brain, increased ATP production and enhanced oxygen and glucose uptake. Mostrecently, research with ampakines,modulators of neurotrophin-regulating AMPA-typeglutamate receptors, suggests that designer nootropics will soon deliver sharperintellectual performance even to healthy young adults.

DMFprovide updates from Smart Drugs (1) on piracetam,acetyl-l-carnitine,vasopressin, and severalvitamin therapies. Smart Drugs II offers profiles of agents such asselegiline (l-deprenyl), melatonin,pregnenolone,DHEA and ondansetron(Zofran). There is also a provocative question-and-answer section; a discussionof product sources; and aguide to further reading.

Sowhat'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 giveenough emphasis, is the complex interplay between cognition and mood.Thus great care should be taken before tampering with the noradrenaline/acetylcholineaxis. Thought-frenziedhypercholinergic states,for instance, are characteristic of one "noradrenergic"sub-type of depression. A predominance of forebrain cholinergic activity, frequentlytriggered by chronic uncontrolled stress,can lead to a reduced sensitivity to reward,an inability to sustain effort, and behaviouralsuppression.

This mood-modulatingeffect does make some sort of cruel genetic sense. Extreme intensityof reflective thought may function as an evolutionarily adaptive response whenthings go wrong. When they're going right, as in optimal states of "flow experience", we don't need to bother. Hence boostingcholinergic function, aloneand 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" anticholinergicsmay sometimes have mood-brightening - progressing to deliriant- effects. Indeed antimuscarinic agents acting in the nucleus accumbens may eveninduce a "mindless" euphoria.

Now it might seem axiomaticthat helping everyone think more deeply is just what the doctor ordered. Yet our educationsystem is already pervaded by an intellectual snobbery that exalts academic excellenceover social cognition and emotional well-being. In the modern era, examinationrituals bordering on institutionalised child-abuse take a heavy toll on younglives. Depression and anxiety-disorders among young teens are endemic - and stillrising. It's worth recallingthat research laboratories routinely subject non-human animals to a regimen of"chronic mild uncontrolled stress" to induce depression in their captive animalpopulation; investigators then test putative newantidepressants on the depressed animals to see if their despair can beexperimentally reversed by patentabledrugs. The "chronic mild stressors" that we standardly inflict on adolescent humans can have noless 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 toself-medicate with ethyl alcohol,tobacco and streetdrugs. So arguably at least, the deformed and emotionally pre-literate mindschurned out by our schools stand in need of safe, high-octane mood-brightenersmore urgently than cognitive tweakers. Memory-enhancers might be more worthwhile if we had more experiences worth remembering.

Onepossible solution to this dilemma involves taking a cholinergic agent such aspiracetam (Nootropil) or aniracetam(Draganon, Ampamet) that also enhances dopamine function. In the late twentieth century, many researchersbelieved that the mesolimbicdopamine system acts as the finalcommon 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, severalof the most popular smart drugs discussed by DMF do indeed act on both the cholinergicand dopaminergic systems. In addition, agents like aniracetamand its analogs increase hippocampal glutaminergic activity. Hippocampalfunction is critical to memory- and mood. Thusnewly developed ampakines,agents promoting long-term potentiation of AMPA-typeglutamate receptors, are powerful memory-enhancers and future nootropics.

Another approach to enhancingmood 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-brightenerand a possible smart-drug. Likewiseselegiline, popularly known as l-deprenyl,has potentially life-enhancing properties. Selegiline is a selective, irreversibleMAO-b inhibitor with antioxidant,immune-system-boosting andanti-neurodegenerative effects. It retards the metabolism not just of dopaminebut also of phenylethylamine, atrace amine also found in chocolate andreleased when we're in love. Selegiline also stimulates the release of superoxidedismutase (SOD); SOD is a key enzymewhich helps to quench damaging free-radicals. Taken consistently in low doses,selegiline extends the life-expectancy of ratsby some 20%; enhances drive, libido and endurance; and independently improvescognitive performance in Alzheimer'spatients and in some healthy normals. It is used successfully to treat caninecognitive 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 dopaminecells from oxidative stress. The brain has only about 400,000 - 600,000 dopaminergicneurons in all. We lose perhaps 13% a decade in adult life. An eventual70%-80% loss leads to the dopamine-deficiency disorder Parkinson'sdisease and frequently depression.Clearly anything that spares so precious a resource might prove a valuable toolfor 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.

Consider,for instance, the plight of genetically engineered "smartmice" endowed with an extra copy of the NR2Bsubtype of NMDA receptor.It is now known that such brainy "Doogie" mice suffer from a chronically increasedsensitivity to pain.Memory-enhancing drugs and potential gene-therapies targeting the same receptorsubtype might cause equally disturbing side-effects in humans. Conversely, NMDAantagonists like the dissociative anaesthetic drug ketamineexert amnestic, antidepressant and analgesic effects in humans and non-humansalike.

Amplified memory canitself be a mixed blessing. Even among the drug-nave and chronically forgetful,all kinds of embarrassing, intrusive and traumatic memories may haunt our lives.Such memories sometimes persistfor months, years or even decades afterwards. Unpleasant memories can sour thewell-being even of people who don't suffer from clinical PTSD.The effects of using all-round memory enhancers might do something worse thanmerely fill our heads with clutter. Such agents could etch traumatic experiencesmore indelibly into our memories. Or worse, such all-round enhancers might promotethe 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 ofchemical tools that empower us selectively to forget unpleasant memoriesmay prove to be at least as life-enriching as agents that help us remember moreeffectively. Unlike the software of digital computers, human memories can't bespecifically deleted to order. But this design-limitation may soon be overcome.The synthesis of enhanced versions of protease inhibitors such as anisomycinmay enable us selectively to erase horrible memories. If such agents can be refinedfor our personal medicine cabinets, then we'll potentially be able to rid ourselvesof nasty or unwanted memories at will - as distinct from drowning our sorrows withalcohol or indiscriminatelydulling our wits with tranquillisers.In future, the twin availability of 1] technologies to amplify desirable memories,and 2] selective amnestics to extinguish undesirable memories, promisesto improve our quality of life far more dramatically than use of today's lame smartdrugs.

Such a utopianpharmaceutical 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 receptorsub-type without eliciting compensatory and often unwanted responses from others.Life's successful, dopamine-driven go-getters, for instance, whether naturallypropelled or otherwise, maybe highly productive individuals. Yet they are rarely warm, relaxed and sociallyempathetic. 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-boundconception 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 "emotionalIQ", isn't some second-rate substitute for people who can't do IQ tests. Onthe contrary, according to the Machiavellianape hypothesis, the evolution of human intelligence has been driven by oursuperior "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 adaptationto social problem-solving and the selective advantages it brings. Yetpharmaceuticals that enhance our capacity for empathy,enrich our socialskills, expand our "state-space" of experience, or deepen our introspectiveself-knowledge are not conventional candidates for smart drugs. For such facultiesdon't reflect our traditional [male] scientific value-judgements on what qualifiesas "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 quantifyscientifically than mathematical puzzle-solving ability or performance in verbalmemory-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 criticallyexamining which capacities one wants to enhance; and to what end?

Inpractice, the first and most boring advice is often the most important.Many potential users of smart pills would be better and more simply advised tostop taking tranquillisers, sleeping tablets or toxic recreational drugs; practise good sleep discipline; eat omega-3 rich foods, more vegetables and generally improvetheir diet; and try more mentally challengingtasks. One of the easiest ways of improving memory,for instance, is to increase the flow of oxygenated blood to the brain. Enhanced cerebrovascular function canbe achieved by running, swimming, dancing, brisk walking, and more sex.Regular vigorous exercisealso promotes nervecell growth in the hippocampus. Hippocampal brain cell growth potentiallyenhances mood, memory andcognitive 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 moderateconsumption of adenosine-inhibiting,common-or-garden caffeineimproves concentration, mood and alertness; enhances acetylcholinerelease 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 threetimes more likely to contract Parkinson's disease. A Michigan studyfound caffeine use was correlated with enhanced male virility in later life.

Before resorting to pills, aspiringintellectual heavyweights might do well to start the day with a low-fat/high carbohydratebreakfast: muesli ratherthan tasty well-buttered croissants. This will enhance memory, energy and bloodglucose 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 onefeeling muddle-headed, drowsy and lethargic. If one wants to stay sharp, and toblunt the normal mid-afternoon dip, then eating big fatty lunches isn't a goodidea either. Fat releases cholecystokinin(CCK) from the duodenum. Modest intravenous infusions of CCK makeone demonstrably dopey and subdued.

To urgesuch caveats is not to throw up one's hands in defeatist resignation. Creativepsychopharmacology 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-1adrenergic agonist adrafinil (Olmifron) typicallydo 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 CNSaction ensures it doesn't cause unwanted peripheral sympathetic stimulation.

Unfortunately the lay public iscurrently ill-served, a few shining exceptions aside, by the professionals. A conditionof ignorance and dependence is actively fostered where it isn't just connivedat in the wider population. So there's often relatively little point in advisinganyone contemplating acting on DMF's book to consult their physician first. Forit's likely their physician won't want to know, or want them to know, in the firstinstance.

As traditional formsof censorship, news-management and governmental information-control break down,however, and the Net insinuates itself into ever more areas of daily life, moreand more people are stumbling upon - initially - and then exploring,the variety of drugs and combination therapies which leading-edge pharmaceuticalresearch puts on offer. They are increasingly doing so as customers,and not as patronisingly labelled role-bound "patients". Those outside the charmed circle havepreviously been cast in the obligatory role of humble supplicants. The more jaundicedor libertarian among the excluded may have felt themselves at the mercy of prescription-wielding,or -withholding,agents of one arm of the licensed drugcartels. So when the control of the cartels and their agents falters, thereis an especially urgent need for incisive and high-quality information to be madereadily accessible. Do DMF fulfil it?

SmartDrugs 2 lays itself wide open to criticism; but then it takes on an impossibletask. In the perennial trade-off between accessibility and scholarly rigour, compromisesare made on both sides. Ritual disclaimers aside, DMF's tone can at times seemtoo uncritically gung-ho. Their drug-profiles and cited studies don't always givedue weight to the variations in sample size and the quality of controls. Nor dothey highlight the uncertain calibre of the scholarly journals in which some ofthe most interesting results are published. DMFs inclusion of anecdote-studdedpersonal testimonials is almost calculated to inflame medical orthodoxy. Moreoverit should be stressed that the scientific gold-standard of large, placebo-controlled,double-blind cross-over prospective trialsare still quite rare in this field as a whole.

Looking ahead, this century'smood-boosting, intellect-sharpening,empathy-enhancingand personality-enriching drugs arethemselves likely to prove only stopgaps. This is because invincible, life-longhappiness and supergeniusintellect may one day be geneticallypre-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 producingdysthymic pharmacological illiterates, SmartDrugs 1 and 2 offers a warmly welcome start.

DP (1998, 2017).

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nootropics / smart drugs