Nootropia: A smart new world?

Originally published by National Institute for Medical Research

by Sam Cooke
[from Mill Hill Essays 2004, ISBN 0-9546302-2-X]

This century will see the arrival of lifestyle drugs to enhance the power of our minds. These ‘smart’ drugs, or nootropics, will be substances that increase the speed of our learning and the capacity of our memory. We will also have the technology to select the memories we wish to retain and those we wish to discard. These predictions may seem like science fiction lifted from the pages of an Aldous Huxley novel, but they are a fast-approaching reality. Research into learning and memory is yielding a wide range of targets for drug companies in search of the perfect nootropic. Currently incurable cognitive disorders such as Alzheimer’s disease, Down’s syndrome, schizophrenia and autism provide an admirable incentive for these companies, but it is the huge market that exists beyond, of grade-hungry students and ailing professionals, that really entices the pharmaceutical industry to invest so heavily. Drug companies are banking on a ‘smart’ new world of Nootropia in which lifestyle enhancement crosses new boundaries.

Degenerative disorders of the mind have a devastating impact. Not only do they profoundly affect the life of the individual sufferer but they also place a tremendous burden upon their friends and family. Society as a whole has to share the burden because of the huge cost to the state in medical care. These problems are set to grow as the average age of the human population increases year by year. The 2001 national census revealed that, for the first time, there were more people over the age of sixty in Britain than those under sixteen. The data collected in the census each decade predict that the number of Britons over sixty will comprise forty percent of the country’s population by 2030. This dramatic change is due to an improvement in the quality of our diet and lifestyle, advances in medical care, and a decrease in the level of fertility as we defer having children until later in life. Disorders of the elderly such as Alzheimer’s disease, mild cognitive impairment and other forms of senile dementia are now one of the fastest-growing medical problems in the developed world. There are half a million Alzheimer’s sufferers in Britain alone. Dementia as a whole affects one in twenty people over the age of sixtyfive and one in five over the age of eighty, making it a considerable concern to our ageing population. These degenerative diseases must be recognised as one of the defining problems of the modern age.

Scientific research into the causes of Alzheimer’s disease has revealed the cellular pathology that underlies the gradual degeneration of brain function. However, neither the causes of this pathology nor the mechanisms by which symptoms develop are yet clear. It is known that the early progression of Alzheimer’s, in which memory loss is the primary symptom, is accompanied by the death of brain cells that produce the chemical neurotransmitter acetylcholine. The relatively selective loss of cells that produce acetylcholine (cholinergic cells) may be due to a genetic predisposition but it is also correlated with high blood pressure, high cholesterol levels, head trauma and Down syndrome. The lifestyle choices that we must make to avoid the disease are unclear at present but leading an active life and eating a healthy diet are recommended. The one thing we know for sure is that the above hypothesis has some basis. The drugs developed specifically to treat the symptoms of Alzheimer’s have so far targeted acetylcholine with some positive results.

While scientists in basic medical research investigate the root causes of disorders, a parallel strand of medical research seeks simply to identify substances that will remedy the symptoms. The treatments that are currently available for Alzheimer’s disease increase levels of acetylcholine in the brain. A drug called Aricept is the most commonly prescribed treatment. It inhibits the enzyme acetylcholinesterase, which is responsible for breaking down and recycling acetylcholine in healthy humans, thereby increasing acetylcholine levels in the degenerating brain. The drugs Exelon and Remenyl are other commonly applied cholinesterase inhibitors. All three have been tested in placebo-controlled studies that clearly demonstrate beneficial effects on memory in Alzheimer’s patients. These drugs do, however, produce disruptive side effects including diarrhoea, vomiting, severe nausea, depression and disrupted sleep patterns. They are not liberally prescribed by GPs and consequently drug companies are now looking for nootropics that do not target the cholinergic system.

Nootropics can be divided into several subsets depending on how they act on cognition. The word ‘cognition’ itself covers a wide range of facets of brain function, including learning, memory, attention and motivation. Deficits in attention, for instance, can lead to poor performance in school children with otherwise normal intellect. A drug called Ritalin has proved to be a very successful pharmacological means of raising academic performance in children with attention deficit disorder and it is therefore regarded as a nootropic. Motivation and attention are aspects of cognition that vary particularly with wakefulness. Caffeine and amphetamine counteract drowsiness and thereby enhance cognition. Another currently available nootropic is Modafinil, a drug that was originally identified as a treatment for narcolepsy, the brain disorder that results in an individual suddenly, and without warning, falling asleep. This drug induces a state of alertness in which we perform at our cognitive peak. As yet Modafinol has not been proven to be any more effective than high doses of caffeine in enhancing cognitive function. Nonetheless, it has very much come into fashion as a ‘smart’ drug. There are also drugs that enhance cognition simply by increasing blood flow, and therefore oxygen, to the brain. As we age, our blood vessels narrow due to fatty deposits laid along their inner walls. This characteristic of ageing can contribute to stroke but can also have further detrimental effects by reducing blood flow and associated brain oxygenation, thus slowing cognition. Substances that open up blood vessels have largely been developed for the prevention of stroke in those at risk but they seem also to impact on brain function. A fungal extract, Hydergine, is one such drug that is now being used to treat senile dementia. Finally there are the most obviously useful classes of drugs that act directly on the processes of information storage; learning and memory. These include recently developed nootropics such as memantine, the ampakines and rolipram.

We have not yet fully unlocked the secrets of memory formation in the brain. Its ability to process information at high speed and to change instantaneously to incorporate new information is truly a natural wonder. The speed of processing is accomplished through the combined use of electricity to pass impulses along the length of specialised brain cells known as neurons, and chemicals known as neurotransmitters, to pass information from one such cell to the next at specialised communication points called synapses. The synapse is a focus of scientific investigation into learning. The ability of these junctions to change as we form new memories, by a process called long-term potentiation (LTP), first identified by a Norwegian neuroscientist Terje Lomø together with Tim Bliss of NIMR, Mill Hill, is relatively well understood and presents potential targets for nootropics. The details of LTP mechanisms seem to vary across different brain regions but some of the general features are now being unravelled.

Synaptic transmission is the process of communication between two neurons. Electrical impulses pass along the length of one neuron and cause the release of neurotransmitters. These drift across the small gap between the neurons known as a synaptic cleft and are collected on the other side of this cleft where they are converted back into electrical impulses at a second neuron. This sequence of events requires molecules that respond to electrical energy and then interact with other molecular mechanisms which release the chemical neurotransmitters. It also requires receptor molecules that bind the transmitter molecule and then convert this chemical message back into an electrical signal in the receiving neuron. Several factors can have a long-term enhancing effect on communication between neurons: an increase in the number of neurotransmitter molecules released for every electrical event, the number or efficiency of the receptor molecules which collect these neurotransmitters, changes in the conversion of this chemical signal into electrical impulses, or physical alterations of the shape or number of synapses. Neuroscientists believe that memories may be formed through these processes of LTP. Pharmaceutical companies have an interest in LTP because it presents potential targets for nootropics.

CORTEX is one of the small companies started solely for the purpose of designing effective nootropics. This company is based in San Francisco and was set up to develop drugs that target the AMPA receptor, a key element of synaptic transmission. This receptor molecule is one of three types of receptor that bind a neurotransmitter molecule called glutamate, one of the major substances that the central nervous system uses for neurotransmission. AMPA receptors are simply channels through cell membranes that connect the outside of the cell to the inside, and allow the passage of positively charged particles, called cations, into the cell. The channel is closed until a molecule of glutamate, which is a negatively charged particle, binds to a specialised site on its outside surface. This interaction causes the channel to change shape and to open for cations to flow through, thereby altering the electrical voltage that exists between the inside and the outside of the cell. These small electrical events effectively serve as units of communication between neurons.

Other sites on the AMPA receptor, on both the inside and outside of the cell membrane, bind to various substances and more subtly change the shape of the channel to affect its function. AMPAkines are a group of substances that have been developed by CORTEX to increase the efficacy of the AMPA receptor by binding at sites on its surface. Some of these substances have a significant effect in rodents, enhancing both LTP and learning and memory, although a major side effect is an increase in the chances of epileptic seizure. Seizure results from over-excitability in the nervous system. Enhancement of AMPA receptor function increases electrical excitability in neurons and thereby promotes seizure. The best AMPAkines are therefore those that have the subtlest effect. These drugs are now ready to be tested in human patients. In around five years time we are likely to know if this avenue of research has been successful.

Much of our cognition is governed by fast events within the synapse. The stabilisation of a learned experience into a memory, however, requires additional slower signaling mechanisms within the synapses. Further molecular machinery may be required to transform a short-term memory into a long-term memory. Formation of long-term memory seems to require signals that pass out of the synapse and into the nucleus of the cell. Within the nucleus, which acts as a kind of control centre for the cell, these signals induce changes in the expression of various genes. The proteins encoded by these genes return to the synapse and change its properties as it undergoes long-term potentiation. One such signalling molecule is called CREB (cAMP-responsive element binding protein) and it is thought to serve as a switch between short and long-term memory. Changes that occur during learning begin a chain of molecular events that culminates in the activation of CREB. Several of our genes contain a coded sequence that is recognised by CREB which then binds to this sequence and induces expression of proteins encoded by this sub-set of genes. It is suggested that CREB acts in this way to orchestrate the events that lead to LTP at a synapse. Several companies are committed to developing nootropic drugs that target CREB and associated molecules, in the belief that a superdrug to combat Alzheimer’s and other forms of senile dementia is nearly upon us.

Drugs such as Ritalin, Modafinil, Hydergine and amphetamines are now used widely by people with normal to high IQ to enhance cognitive performance. Perhaps the most commonly taken drug in this regard is Piracetam, also known as Nootropyl. Piracetam was the first officially categorised nootropic and it is still amongst the best selling. Anecdotal reports suggest that Piracetam ‘wakes up the brain’ but there have been no successfully conducted scientific experiments to demonstrate its nootropic properties. Herbal ‘enhancers’ such as Gingko biloba are also unproven as memory enhancers but these substances sell in large quantities. Nootropics, whether they are proven to be effective or not, will become a multi-billion pound industry, perhaps with university students and middle-aged professionals providing the major market. Most nootropic drugs have not been approved by the Food and Drug Administration (FDA) in the U.S.A. so there is currently a black market trade in such substances. A large number of pharmacies have recently sprung up in Tijuana, just across the Mexican border from California, to cater for the frequent visits of Americans coming to get their fix of nootropics.

There are two possible outcomes to the introduction of cognitive enhancement as a way of life. Nootropics may prove to be a great leveller, reducing the variation in cognitive ability that exists across the human population and enabling more individuals to enter cognitively demanding professions. This could occur if the drugs are cheap and made freely available. However, nootropics are likely to be expensive initially due to the heavy investment made by pharmaceutical companies. Under these circumstances the introduction of cognitive enhancement will probably lead to a cognitive divide. It seems that, in societies such as Great Britain and the United States at least, such a divide will arise. The new world of Nootropia may therefore be one in which the rich get smarter and the poor do not.

The impending arrival of Nootropia brings with it other problems. Our capacity for learning and cognition is clearly not at its maximum, otherwise nootropics would not work at all. Genetic engineering has demonstrated this. Scientists have created several mutant mice with enhanced learning and memory: the socalled ‘smart’ mice. Just by changing the expression levels of particular proteins it is possible to increase the speed at which a mouse learns. So why has natural selection not maximised the cognitive powers of mice and men? Both species may just be intermediary steps on the way to far more intelligent organisms. Alternatively, enhancing cognition further may, in some way, incur too great a cost on the organism. We have already discussed some of the side effects of nootropics and there are also certainly side effects to engineering ‘smart’ mice. Some mutants show increased sensitivity to pain and others are unable to forget. Perhaps too good a memory is not a desirable attribute. Memory men, such as A.R. Luria’s famous case study Shereshevsky, are capable of incredible memory feats but often unable to lead a normal life due to their inability not to learn. Shereshevsky was capable of incredible feats but his mind was full of useless information. As we all know from our own experiences, it is not always the cleverest who reach the top. Nootropics may not, therefore, prove to be the secret to success. Perhaps our brain is adapted as much to forget as it is to remember.

Humans often end up remembering things they would rather not. We all have painful memories, or at least embarrassing ones, and in some cases they can prove debilitating. Phobias, superstitions and post-traumatic stress disorder are all examples of neuroses that arise from memory. The recent film ‘Eternal sunshine of the spotless mind’ presents an imaginary new technology in which unwanted memories can be targeted and eradicated from our brains. Such a scenario seems based in fantasy because our memories are not easily-identified localised units in the brain, like a tumour, that we can attempt to remove. Instead each individual memory is distributed across many different cells and synapses. This makes them difficult to target. Moreover, we have long believed that memory passes from a state of vulnerability, when it is reliant upon shortterm changes at synapses, to a stable state in which it is stored for a lifetime. This means that we should only have a short window of time after we have learned something in which to try and erase it. Current research suggests, however, that memory may not follow such a simple two-stage lifecycle from temporary to permanent. In fact, some memories return to a flexible and vulnerable state every time they are recalled.

Substances that transiently prevent the synthesis of new protein can be injected into rodents without causing any large scale disruption or distress to the animal. If they are injected shortly after the animal has learned something new these protein synthesis inhibitors prevent long-term memory storage, demonstrating that a memory is actually built from new protein. Injections several hours after learning do not prevent memory storage so it is also clear that the memory is built during a short period post-learning. Recent experiments show, however, that injection of protein synthesis inhibitors after an old memory is re-activated may also abolish the memory. This finding suggests that memories can switch back to their former state of vulnerability and need to be rebuilt every time they are recalled. It presents us with the intriguing possibility that we could erase memories simply by recalling them and then obliterating them with protein synthesis inhibitors, or some more selective agent. As predicted on the cinema screen we could soon have the technology to eradicate troublesome memories and thereby treat medical conditions such as phobias or post-traumatic stress disorder. Of course, this erasure technology would doubtless be open to the same non-medical abuse as nootropics. In theory it could be used to wipe memories of hated ex-lovers or even just painfully embarrassing experiences from our youth. Should we invest in these new technologies for the sake of medicine in the full knowledge that they will eventually be used instead as a lifestyle ‘enhancer’?

The excitement that accompanies almost every great scientific discovery is now tempered by an ethical debate on the ramifications for society. Today the public meets each breakthrough with heavy scrutiny. Biologists are no longer the accepted authority they once were. Every advance that is made in the name of medicine now carries with it the risk that the same technology could be used 30 31 to enhance normal human function. In recent times we have seen plastic surgery, initially for the purpose of facial reconstruction after serious injury, become a technology of cosmetic enhancement. Athletes achieve superhuman feats in sport using illegal performance-enhancing substances discovered by scientists with originally benevolent intent. More recent examples of performance-enhancing technologies include the massive-selling drug Viagra. Developed as a treatment for angina, Viagra soon became recognised for one of its major side effects. It is now sold in huge quantities as a treatment for impotence and is used widely as a recreational drug to enhance normal sexual performance. The public is well aware of these developments and is consequently concerned about other technologies such as genetic engineering and cloning, despite scientists’ claim that these will greatly increase the future success of transplantation therapies. There is a general fear that instead we are heading for a future filled with designer babies. In much the same way, nootropics developed for the treatment of Alzheimer’s disease, mild cognitive impairment, Parkinson’s-related dementia and Down syndrome pose ethical concerns. On one hand it seems morally proper for us to find drugs that can be used to treat these disorders, but on the other hand we know that a large subset of these substances will be used to enhance cognition in already perfectly intelligent individuals. Only time will tell whether nootropics are accepted by society but history suggests that we will come to use and abuse them as we have all other technology. We are on the road to the ‘smart’ New World of Nootropia whether we like it or not.