• The Inexorable Rise of “Smart” Drug Abuse by Dr Jack

    Tired doctors can feel a duty to neutralise fatigue by taking smart drugs (photo courtesy of photostock)

    Cosmetic psychopharmacology, cognitive enhancement or simply smart drugs, call it what you will, the use of pharmaceutical agents like methylphenidate (Ritalin) and modafinil (Provigil) for performance enhancement and sleep avoidance is rife. Throughout big business, software development, academia, poker tournaments and – according to a recent academic paper – even the medical establishment itself, many healthy individuals are opting to optimise brain function with drugs specifically intended for the treatment of illnesses, simply to keep up with the breakneck pace of life in the 21st century.

    This summer a paper was published in the Journal for Law, Medicine and Ethics discussing a pretty unusual moral dilemma. Some medical doctors have concluded that their “ethical duty to reduce error during periods of fatigue” extends to dosing themselves with smart drugs, such as modafinil, to improve concentration and alertness in circumstances where their punishing schedule leaves them feeling utterly exhausted. Medical physicians are also finding themselves under pressure from patients to dish out prescriptions for “smart drugs” to help them keep up with the incessant demand for increased efficiency and competitiveness placed on them by work, family and friends. It may sound reasonable upon first glance but the upshot is that, in either case, it is quite simply illegal for these drugs to be prescribed for such purposes and, irrespective of issues of jurisprudence, it places patient, physician and society “at risk for dangerous health and social consequences.”

    In 2008, results of an online poll were published in the journal Nature, revealing that 20% of respondents (predominantly academics) had used such nootropic substances for non-medical purposes like improving concentration, memory or to counteract jetlag. This inspired a large number of newspaper and magazine articles and a flurry of scientific studies to further investigate this phenomenon.

    Hollywood got in on the act earlier this year with the blockbuster film Limitless. It spun a typically high-octane tale of the meteoric rise (and inevitably crushing fall) of a failing author who temporarily manages to transform himself into a super-intelligent, ultra-motivated, overachieving writer, linguist and stock trader through regular doses of a transparent, fictitious and exceptionally effective smart drug. (Un?)Fortunately, in the real world, pharmaceutical neuroenhancement quite simply does not result in such dramatically transformative effects.

    A businessperson hell-bent on performing to the best of their abilities in spite of jetlag may elect to emulate the example set by the military, which can actually require their staff to neutralise the debilitating cognitive consequences of fatigue under circumstances of “operational necessity,” by using modafinil to gain the competitive edge. Yet a recent meta-analysis of a large number of studies investigating the use of popular neuroenhancing drugs in healthy people highlighted the gap between people’s expectations and the actual effects of such substances. In sleep deprived individuals a single dose of modafinil does have a strong positive effect on executive function and improvement in memory – an effect that wears off during continued sleep deprivation. But were they to take a single dose when not sleep deprived, they would find it has the opposite effect; under these conditions it actually induces drowsiness. Furthermore, repeated doses of modafinil when not sleep deprived increases both positive and negative affect, which means you would simultaneously feel slightly happier and more anxious.

    Methylphenidate (Ritalin) is a drug prescribed for people with ADHD which is also used by healthy people in an effort to improve concentration and alertness

    As pressure to succeed continues to mount in higher education, business and medicine, a wide range of different people from all walks of life are beginning to find themselves under increasing pressure to jump on the smart drug bandwagon just to keep up with their peers. Given that the 2008 Nature poll also found that “one-third of respondents said they would feel pressure to give cognition-enhancing drugs to their children if other children at school were taking them” – it is perhaps unsurprising that the competitiveness epidemic may already be spilling over into the school system. Indeed, confidential sources (an ex-pupil) tell me that it has become common practice in many British public schools for those prescribed Ritalin for ADHD to sell it on to other pupils at extortionate rates. Interestingly, the market appears to be not the usual suspects – that inevitable group in every secondary school who become enamoured with with recreational drug experimentation –  but instead the conscientious geeky types who are hell bent on doing whatever they can to ace their exams. The sad thing is they are almost certainly wasting their money.

    Methylphenidate, the drug branded as Ritalin, is a funny old drug. Much confusion has, quite understandably, arisen from the counterintuitive concept of using an amphetamine-derivative in the treatment of Attention Deficit Hyperactivity Disorder (ADHD). A typical response to this revelation is: “Why would anyone want to give a hyperactive child speed?” The explanation is, in fact, reasonably straightforward. Methylphenidate has a very different effect on the brain to the other amphetamines. Whilst amphetamines generally elevate levels of neurotransmitters such as dopamine across the whole brain, a low dose of methylphenidate has a different impact on levels of these neurotransmitters in different brain areas. The trick with methylphenidate is that it slightly increases dopamine and noradrenaline in prefrontal brain areas involved  in maintaining attention and inhibiting impulsive behaviours, whilst having a minimal impact on levels of those same brain chemicals elsewhere in the brain that lead to the hyperexcitability usually associated with amphetamine drugs. But what effect do such drugs have on a healthy, normal brain? Overall there is minimal evidence to suggest any objective improvement on alertness, attention, mood or memory (apart from spatial memory) when healthy people take methylphenidate. So my message to school kids (or their parents for that matter) who are considering buying into the promise of Ritalin enhanced grades? Don’t believe the hype!

    In addition to these brainposts at: www.drjack.co.uk, you can get a daily #braintweet by following Dr Jack on Twitter.

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  • The Future of Schizophrenia by Dr Jack Lewis

    Schizophrenia often involves hallucinations and delusions

    Schizophrenia often involves hallucinations and delusions

    One in a hundred adults suffer from the brain illness known as schizophrenia (for full fact sheet please click here), which means that you probably know somebody who developed this condition during the transition between adolescence and adulthood. If you happened to know them quite well, you may have noticed the very drugs that suppress the “positive symptoms”  – e.g. delusions and hallucinations – also have several unwanted side that can exacerbate the “negative symptoms” that leave them listless, unable to concentrate, unmotivated, unsociable, unemotional and, quite frankly, bored out of their brains.

    Positive symptoms are usually reliably controlled in most schizophrenic people (assuming they can tolerate the side effects) using clozapine – an anti-psychotic medication that works in mysterious ways and even in the majority of patients who gain no benefit from the wide variety of other drugs. With psychosis successfully supressed by such drug therapy, it is the negative symptoms and cognitive dysfunction that are by far the most severe impediment to a schizophrenic individual being properly integrated into society and able to live a relatively normal, independent life. The biggest hope for an effective therapy in the coming few decades stems from a combination of drugs that increase brain plasticity and cognitive training, which together might help schizophrenic people to develop a whole host of social skills and basic mental processes that have become compromised during disease progression.

    In this article I have tried to give an easily comprehensible overview of the state of play in schizophrenia treatment to date and where it might be headed in the next few decades. Please leave a comment at the very bottom of this page to let me know how successful I have (or have not!) been in achieving this aim.


    Cannabis strains bred to have very high levels of THC such as "skunk" are a common trigger of schizophrenia


    I became interested in schizophrenia, well before I started my Neuroscience B.Sc., as a couple of childhood friends developed it in their teens; a typical scenario with this disease. The schizophrenia was almost certainly triggered in one of these boys through smoking copious amounts of an extremely powerful strain of Cannabis sativa known as skunk; selectively bred to contain excessively high levels of the neuroactive cannabinoid delta-9-tetra-hydrocannabinol (“THC”). The trigger in the other was almost undoubtedly chronic emotional distress suffered at home and at school. I thought it was a curious brain illness even then because it clearly involved both a genetic predisposition (both had a history of schizophrenia in their families) as well as an environmental trigger (psycho-active “chemical” trigger in the first and “anxiety” trigger in the second).

    Regarding possible causes of schizophrenia, genetic abnormalities typically found in families with a high incidence of schizophrenia is becoming extremely well-defined thanks to some extensive gene linkage studies. However it seems that bacterial and/or viral infections in the womb may also potentially play a role in predisposing a developing foetus to schizophrenia later in adult life.


    Schizophrenia is a broadly misunderstood brain illness. This may stem from the original naming of the condition back in the days when it was first identified and poorly understood. Eugen Bleuler cut and shut together the Greek words for split (“skhizein”) and mind (“phren”), thus planting a misleading seed by suggesting that schizophrenia is defined by some degree of split personality (it is not).


    An artists portrayal of a schizophrenic auditory hallucination

    An artists portrayal of a schizophrenic auditory hallucination

    As mentioned briefly above, schizophrenia is a psychotic condition featuring a variety of “positive symptoms” – a term which collectively describes the effects of brain processes that are “in addition” to the “normal” functioning of the mind, and “negative symptoms” – describing attributes which suggest a removal or lessening of emotional responses or certain healthy thought processes.

    Positive symptoms include hallucinations – seeing and/or hearing things that are not actually there, delusions – mistaken beliefs that are not consistent with the real world, often involve an element of paranoia and the idea that thoughts are being implanted or monitored by some kind of external force to guide behaviour or snoop on private thoughts: e.g. couch potatos might believe that this external force is the television, religious individuals might attribute this perceived external influence as God, die hard X-files fans and UFO spotters may be inclined to believe it is some kind of extraterrestrial force etc. The intrusion of hallucinations and deluded thought processes makes normal interaction with the outside world much more challenging and lead to considerable confusion.

    Larger fluid filled ventricles (black holes in image) in twin with schizophrenia compared to twin without

    Larger fluid filled ventricles (black holes in image) in twin with schizophrenia compared to twin without

    Negative symptoms include low levels of motivation, social withdrawal, absence of emotional responses and depression. The negative symptoms are often overlooked in favour of the more bizarre and attention grabbing aspects of psychosis, however it is these negative symptoms that psychiatrists are almost powerless to treat effectively.

    Schizophrenia involves decreased prefrontal brain function (inducing impaired cognitive function), grey matter loss and enlarged ventricles. I distinctly remember learning during my first degree that schizophrenic brains had enlarged third ventricles and that there was something of a chicken-and-egg debate going on at the time regarding whether this was a cause or an effect of the condition. This debate has moved on over the past decade to the proposition that neuroinflammation might cause the schizophrenic brain to deviate from the normal course of neurodevelopment. The possibility of using anti-inflammatory agents to reduce disruption to normal brain development in schizophrenia and other brain illnesses is now a subject of active research.


    Anti-psychotics like risperidone work by preventing dopamine from binding with their receptors facing into the synapse and thus reducing the effect of any released dopamine on adjacent brain cells

    Anti-psychotics like risperidone work by preventing dopamine from binding with their receptors facing into the synapse and thus reducing the effect of any released dopamine on adjacent brain cells

    Positive symptoms like hallucinations and delusions are adequately controlled in the majority schizophrenic patients using anti-psychotic drugs to suppress the excessive levels of dopamine in the mesolimbic system that actually causes the psychosis. But once a person starts feeling better, and “back to normal” they, quite understandably, can feel like they are “all fixed up” and so stop taking their drugs. Of course without the drugs to suppress the “crazy thoughts” (a term we could use to put hallucination/delusion into everyday parlance) the psychosis returns… with a vengance. This is because the medication isn’t “fixing” the brain in anyway. Anti-psychotic medication is merely plugging a leaky pipe with a cork, not soldering the hole permanently shut! The treatment only works by keeping levels of the drug swimming around in the brain at just the right concentration to “normalise” limbic dopamine levels. This can only be achieved by adding regular doses of fresh drug to replace that which has been broken down by the body and brain’s natural metabolic processes. Once the drug levels in the brain begin to diminish there is nothing there to dampen the excessive dopamine hyperexcitability in the mesolimbic systems that generates the psychosis in the first place and so the psychotic thoughts gradually returns. Take the “cork” away and the “waters of madness” start to flow again (strictly speaking a more accurate metaphor would be along the lines of laying down some plastic sheeting so that the floor doesn’t get wet – but hopefully you get the gist!).


    Drugs that affect dopamine levels will alter communication not just in mesolimbic tract (desired target of anti-psychotic drugs) but also nigrostriatal tract (undesired side effects)


    Keeping schizophrenic patients motivated to keep taking their anti-psychotics is half the struggle for psychiatrists. Unfortunately this job is made even harder because it is not possible to focus a drug effects on any one brain system. Once a psychoactive drug crosses the blood brain barrier – which acts like a passport control at immigration, only letting substances that have the correct “documents” into the brain and refusing entry to all others – it is then free to move anywhere in the brain and will spread more-or-less evenly throughout it.

    Anti-psychotic drugs are given with the intention of reducing dopamine levels in the network of brain areas involved in causing the psychosis, but unfortunately it also reduces dopamine levels everywhere else in the brain. This means that all brain systems that use dopamine to send messages across the synapse from one brain cell to the next will also be slightly suppressed. Therefore patients on dopamine-suppressing medications benefit from a reduced incidence of hallucinations and delusional thought processes (i.e. the desired dopamine-suppressing effects on mesolimbic networks), but also suffer side effects such as their movement becoming jerky and harder to initiate (i.e. the undesired, but unavoidable, dopamine-suppressing effects on nigrostriatal networks). Over the past decade our understanding of which of the many available anti-psychotic drugs cause the fewest or least severe unwanted side effects has improved dramatically and now psychiatrists are very good at tailoring treatment to individual needs.


    Recent gene linkage studies have confirmed that sections of DNA involved with the dopamine system don’t seem to be quite right in schizophrenic patients, but have also indicated that genes involved in the regulation of the glutamate neurotransmitter system are also disrupted. The increasing acceptance of the glutamate hypothesis of schizophrenia has reinvigorated hope for much needed novel drugs to treat all facets of this condition. It has stimulated a flurry of research activities which are now proving to hold great promise for future drug therapies that might target not just the positive symptoms of psychosis but also the negative symptoms and cognitive dysfunctions like poor verbal memory and information processing problems that pose such difficulties for schizophrenic people.

    Negative symptoms of schizophrenia include social withdrawal

    Negative symptoms of schizophrenia include social withdrawa

    Indeed, drugs that reduce NMDA glutamate activity in the prefrontal cortex are known to induce many of the negative symptoms observed in schizophrenia. The flip side of this is that drugs that boost glutamate activity might be able to reverse both the cognitive deficits and alleviate the negative symptoms that so profoundly reduce the quality of life of schizophrenic individuals. Again even these potential future therapies will suffer the same old problems of unwanted side effects that unavoidably arise with all psychoactive drugs, particularly as glutamate communication across the synapse is very prevalent throughout the whole brain. That said if the aim is to improve neural plasticity to make cognitive training and other non-drug therapies more effective, then possibly the side effects may not prove quite as tricky as with modulating dopamine levels. We have a long way to go before these therapies are fully tested and ready to roll out in the battle against schizophrenic negative symptoms and cognitive dysfunction… but if anything is going to dramatically change the lives of the millions of schizophrenic patients across the world present and future… it is going to stem from glutamate.

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