professor barbara sahakian portrait

Nootropics: the drugs that make you smarter

You are one of the leaders of professional discussions about “smart pills”: drugs originally intended to help patients with ADHD or dementias, being currently widely used as cognitive enhancement for healthy people. Are they good for us?

We have studied methylphenidate, also known as Ritalin, the most common drug treatment for ADHD in the UK – prescribed for patients with ADHD but also used by healthy people. One of our findings suggests that Ritalin improves attention in healthy people, not only those with ADHD. It tends to have greater impact on cognition if you have trouble concentrating, but it does improve cognitive performance in people who do not experience this kind of issues. We conducted a research study on students in Cambridge and found that their cognitive performance, e.g.  their working memory, attention etc., also improved.

We have also conducted many studies with Modafinil. Modafinil is approved in the UK and USA to treat to treat patients with narcolepsy, excessive daytime sleepiness. In the USA it is also used to treat sleep disturbance due to shift-work and has been found to reduce accidents in shift-workers. The results of our experiments repetitively suggested that Modafinil improves cognition in healthy people. We administered different doses and it turned out that 200 mg is the most effective dose when given orally; 100 mg showed similar effects however was weaker and 300 mg did not work as well either.

We used Modafinil in patients with schizophrenia as an add-on to their antipsychotic medication – and it improved their cognition. It also improves cognition in healthy people. In a meta-analyses study of Modafinil by Battleday Brem, the authors combined the results of many single research studies and this demonstrated that Modafinil really is a cognitive enhancing drug in healthy people.

According to last year´s article in the Telegraph, one in ten students in the UK tried Modafinil to enhance their cognitive performance. Are there any risks related to widespread use of this and similar drugs by healthy people?

We do not have long-term safety and efficacy studies in healthy people. The FDA and EMA (organizations approving drugs in the US and in the EU), approve drugs for treatments of disorders and diseases.

I think we should have long-term studies on Modafinil in healthy people to determine safety and cognitive enhancing effects in the long term. Modafinil might be the most interesting among the smart drugs, for number of reasons. We found that people do improve: healthy people, people recovering from depression, people with schizophrenia – in all of them Modafinil helps cognition. Furthermore, unlike the classic stimulants (e.g. amphetamine and methylphenidate), so far nobody has demonstrated abuse potential for Modafinil. Because of that and since most of the side effects are quite low, especially in the 200 mg dose, this is the drug attracting more and more attention of healthy people, certainly in the UK.

I would think that it would be time for the government to collaborate with the pharmaceutical industry to determine whether Modafinil is safe for healthy people to use in the long term. Because people in the UK currently buy it over the Internet, which is very unsafe way to obtain prescription only medication. Drugs purchased over the internet are not made by established pharmaceutical companies that are regulated and produce drugs for human consumption.

Lord Ara Darzi and I conducted a study of Modafinil in sleep deprived doctors. Lord Darzi is a surgeon at Imperial College in London. He was concerned about surgeons drinking large amounts of coffee in order to stay awake at night when they were working. Hand tremor is of course a common side effect of caffeine. Clearly hand tremor is to be avoided in a surgeon. Lord Darzi thought that Modafinil might therefore be a better awake alerting agent than caffeine in coffee for doctors who have to work at night.

There may also be other groups of people, such as the military, who need to stay awake and alert for long periods of time to keep themselves or their colleagues safe. Since Modafinil has relatively low side effects and does not have demonstrated abuse potential, Modafinil may be a possibility.

So, would it be recommendable for me as a healthy person to try Modafinil? Or should I wait for further research?

What I recommend to healthy people, is exercise. Because exercise increases neurogenesis, new brain cells, in areas of the brain, including the hippocampus, which is important for memory. Exercise is very good for your cognition – but also for your physical health and even for your mood. I always think this is the best way for healthy people to enhance themselves: to run or take other forms of exercise. However, some people who need to stay alert for their own safety or other people´s safety, may need to take drugs for this purpose.

We now know that our brains are still in development until late adolescence and young adulthood. Some people may need medication, for example if a young person has severe attention deficit hyperactivity disorder, he or she would require methylphenidate (Ritalin) if CBT was not a sufficient treatment. It is important to treat with a drug if required, because otherwise the young person would not be able to concentrate at school and would not receive a proper education. Indeed, the young person might drop out of school because they were not able to focus attention and learn

However, when considering healthy young people, we need to be concerned about the risks of using drugs in the healthy developing brain. Therefore, healthy young people should not be using drugs which are not required and it would be better for them to do exercise to cognitively enhance themselves.

Before we finish the discussion on cognitive enhancements, I would also like to mention than Modafinil increases task related motivation. It helps people to get into the flow related to their work and stay in the flow. So that is why people use it as a work drug or studying drug, because it helps them to get down to doing work-relates tasks that they have been putting off. I want to emphasise that the effects of Modafinil are on task-related motivation and are not a general euphoric effect.

When is the right time for antidepressants?

And considering medication in rather less severe mental issues? If I imagine depressive states or sleep problems, how should a person decide whether to take medication or not?

For depression or sleep problems, obviously the psychological treatment, such as mindfulness should be tried, or trying to relax, for example with yoga. Looking at beautiful art, focusing on it, thinking about it in a mindful manner affects your brain in a very positive way. Mindfulness could be practised while looking at beautiful trees, for example Professor Andreas Meyer-Lindenberg from Germany has demonstrated that practicing mindfulness in green spaces where there are trees has beneficial effects.

In regard to sleeping well, it is important that you are relaxed when you go to bed. Don’t be stressed out, try to be calm, also don’t look into your emails or do work, just before going to bed. Otherwise your mind is still very active and work-related problems may become stressful and disrupt your sleep. Some people find that exercise and a warm shower before sleeping is useful to get a good night sleep.

But given that the borders between mental health and illness are fuzzy: is there any point when I should say “well, I had enough, now I should opt for the pharmacotherapy”?

The trouble is many people are unable to detect when they are getting depressed. We need to be better discussing emotions with people, especially with our friends, and talking about how we feel. Because first of all, it might prevent you from getting depressed. And secondly, if you do get depressed, somebody will probably help you seek help earlier on. Because if depression is mild, psychological treatments work well. CBT can be very helpful and effective. However, when the depression is severe, then chemicals in the brain called neurotransmitters such as serotonin may change. Serotonin is important for normal mood regulation and wellbeing.

But if someone gets very low and are very stressed over a long period of time, he or she can become severely depressed. Severe depression usually requires drug treatment, such as an SSRI (drugs like Prozac) to normalise neurotransmitters such as serotonin. However, even when having a drug treatment, it is important to also have psychological therapy.

It has been shown that psychological therapy is very good at helping you not relapse so sometimes if you just take a drug, you are prone to relapse again with the depression. But if you get a psychological treatment, it will help stop the relapse. If you are very ill you probably need both – and both can hopefully make you better and keep you better.

What I think are the cognitive hallmarks of depression are things like negative attentional bias. I am often lecturing groups of people – and usually people are looking at me, nodding and making eye contact, everybody is very positive about my lecture. Because of me being a healthy person, not being depressed, I can be happy that they enjoy my lectures and I feel great. However, if the person lecturing was depressed, then he or she would look up in this big audience to find the one person who is maybe falling asleep or looking down to their phone or looking bored and they would just focus on this particular person, and begin thinking that this is not going very well. They would ruminate on negative topics, having negative thoughts. This is another target for CBT, for example stopping people ruminating or having their negative automatic thoughts, when they keep thinking like “I am not interesting” or “I never do anything right”, “I am not popular”, all those sorts of negative thoughts.

Depression is all about the way you think – if you think positively, if you try to be optimistic, generally most things will go well for you. And this is what healthy people do, most of them have a slight positive bias, while depressed people have negative biases.

Another aspect of depression is what we call response to negative feedback, which is especially important for functioning well at university or work, for being able to work effectively and for taking criticism well. We need to learn new things – and sometimes we get them right and sometimes we get them wrong. A healthy person would concentrate on the informational content of the feedback: if they get it right, they would think “I should do something similar the next time” and if they get it wrong, they would say “well I got it wrong this time, so let me think what I need to do to get it correct the next time”. The healthy person would focus on the information from the feedback.  However, nobody likes to be told “you are wrong”, so you need to dampen down the emotional area of your brain, the amygdala, by using your frontal cortical function. By using the top-down cognitive control over the amygdala, you can focus on learning and not on negative emotions. And while healthy people are able to do that, our study has shown that when you are depressed, you get overwhelmed by the emotional feedback, the negative “you did it wrong” – and you cannot focus on the informational component. This type of problem, termed over-sensitivity to negative feedback, affects performance at work.

You and your colleagues developed the neuro-psychological model of depression that shows that while CBT influences so called “top-down processes” which influence our direction of thinking, whether we concentrate on the good or the bad, pharmacotherapy targets the “bottom-up processes”, the inputs our higher brain and the consciousness is receiving. Could you please explain how is that possible that both, the biological and psychological treatment work?

The antidepressant medications, such as the Selective Serotonin Reuptake Inhibitors (SSRIs), can help people get into the right state to engage with psychological therapies, such as CBT. However, CBT can alter the way you think, helping you to interpret events in a positive way and to learn that your life can be different and can improve. Medications can improve mood states and that can help promote positive change in thoughts and actions, which are targets of psychological therapies.

CBT requires the patient to work on their thoughts and actions to get better. It is not a passive process. The patient needs to use their support network, by going out with friends, by taking exercise and by other activities. Antidepressant drugs put you in the state to get better – but you must do the work required to improve and to stay well.

When depression is detected early, it can often be treated successfully with cognitive behavioural therapy (CBT). However, when someone is very severely ill with depression, then drug treatments, such as the selective serotonin reuptake inhibitors (SSRIs) are used to boost serotonin in the brain.

Drug treatments should be used with psychological treatments, which are useful in understanding the patient’s thoughts about what caused the depression and to help prevent relapse. The combination of pharmacological and psychological treatments can be very effective in cases of severe depression.

How can we imagine the combination of pharmacological and psychological treatment in practise?

Once I was referred an elderly, depressed gentleman for cognitive behavioural treatment of his depression. I went onto his hospital ward to assess him for cognitive behavioural therapy. However, the patient was not only depressed, but very anxious and agitated, so much so that he could not remain seated while we talked, but kept getting out of his chair, and moving around before sitting down again. I introduced myself and asked how he was feeling and why he was in the hospital.

“It’s my shoes, Doctor. It’s my shoes. They are all shabby,” he replied.

I explained that I was there to discuss his thoughts and feelings and the events that led up to his being in hospital. He repeated, “It’s my shoes. They are shabby.”

I tried to engage him in discussion a few more times, but was unable to.

I knew that he had only recently been given an antidepressant drug, which take a week or more before patients’ mood symptoms improve. I told him that I would return to see him in a couple of weeks when his medication was working to help him feel better and we would speak again then. During this time, the nurses on the ward had taken him shoe shopping, but that had no effect on his depression.

When I came back to see him, his antidepressant medication had helped treat his symptoms of depression, anxiety and agitated behaviour. He was able to sit still and listen to me and respond appropriately to my questions. I was able to begin psychological therapy with him and found out in our discussion that he felt worthless and thought that his grand-daughters would be better off if he was dead. These were false thoughts, distorted negative thoughts. His grand-daughters loved him and had been very concerned about his depression. With a combination of an antidepressant drug and individual and family therapy, he was able to recover from depression and to be discharged from hospital.

Where are you heading, neuroscience?

In 2013, you summed up the expected development in brain science in the next ten years. Now we are just in the middle of this period. What happened in neuroscience in the last 5 years?

Some of it has been very exciting and successful – and some of it has been a disappointment. So far we do not have any neuroprotective drugs for Alzheimer´s disease. This research work and pharmaceutical company studies seemed highly promising. I and colleagues published an article in The Lancet on one of the first of concept studies of the cholinesterase inhibitors that treat some cognitive symptoms, including those with attention and concentration, in patients with Alzheimer’s disease. This class of drug is approved for the treatment of cognitive symptoms in Alzheimer’s disease. However, we still need better, more effective symptomatic drug treatments for the memory problems that patients experience and which impair their ability to carry out their activities in daily life.

Scientists in academia and in the biotech and pharmaceutical industries are working on inventing and developing neuroprotective drugs that would treat the underlying disease process. Unfortunately, they have not yet been successful.  Many of the original studies used patients with quite advanced Alzheimer’s disease. More recently, studies have focused on patients with more mild forms, what we call mild cognitive impairment, which is the early stage of Alzheimer´s disease.  This is an important thing to do, because unfortunately when someone receives a diagnosis of Alzheimer´s disease, they have already have considerable brain damage in terms of neuropathology, the plaques and tangles in the brain. So it is very important to detect mild cognitive impairment in the elderly, the very early stage of Alzheimer’s disease and to treat it early. Early detection is important both for symptomatic treatments or neuroprotective ones, when neuroprotective drugs become available.

I co-invented the CANTAB computerised tests for early detection of memory problems in the elderly, that can screen for memory problems in the elderly and then they can be invited to participate in the appropriate research studies or clinicians can be aided in their decisions of clinical pathways for patients. The use of the modern technology such as CANTAB on iPads or delivered over the internet is useful for rapid cognitive assessments and accumulating very large data sets.

Novel techniques to visualise and understand the brain better are developing rapidly. These new techniques will hopefully be used in translational studies in future to find new treatment for neurodevelopmental disorders, such as attention deficit hyperactivity disorder, autism and schizophrenia, and also disorders of aging, including forms of dementia, such as multi-infarct dementia, frontotemporal dementia and Alzheimer’s disease.

For example, in my Laboratory, we are working on games to improve memory in people with schizophrenia and in people with mild cognitive impairment. Cognitive training games, based on studies of neuroimaging, cognition, neuropsychology. In schizophrenia, people have three types of problems: psychotic symptoms, such as hallucinations and delusions, which many people have heard of. However, those psychotic symptoms can be treated with the current drugs that are available, the antipsychotics.

However, patients with schizophrenia still have two other types of problems: poor cognition and lack of motivation. People with schizophrenia have cognitive impairment, including poor memory. if we can improve their cognition, people with schizophrenia will have better functional ability and might be able to go back to university or work, post diagnosis.

Yet another symptom they have is lack of motivation. That is one reason why we use games to improve their cognitive functions, because we hope playing the game will keep them motivated to progress with their cognitive training– which is does. This type of technology can be seen as akin to individualized or personalised medicine, because when you play, the game level progresses if you are doing well, but if the level becomes too challenging, then the difficulty  level decreases until you are ready to progress again.These ‘brain training’ games are on iPads or mobile phones. The cognitive training in the games (Wizard and Game Show) activates and drives neuro-circuitry in the brain, including the hippocampal formation which is crucial for memory.

The University of Cambridge/PEAK Advanced Training Programme and the Wizard apprentice are available through games company PEAK.

How shall we imagine such a game?

The Wizard Game is like a Harry Potter type game, you have a wizard in it and you can have battles with other wizard-like creatures. The game requires you to learn and remember where symbols are placed in different chests– and if you do remember, you get to a higher level of the game, and, importantly you win different spells that you can cast, and some treasure rewards.

And besides such games?

There are a number of companies with interesting ideas and inventions to monitor or improve mental health and which utilize wearable tech, mobile apps or the internet.  Some people are delivering cognitive behavioural therapy over the internet – and that has the advantage that people can engage in the psychological therapy such as cognitive behavioural therapy (CBT) whenever they need to and when it is most convenient for them.

And with machine learning, some scientists are trying to find what are the important features of CBT that helps to people improve.  Possibly, in the future, there will be CBT therapy delivered by a computer, except for those people who do not improve with ‘computer therapists’ or ‘robot therapists’.

But isn’t the human relationship one of the very essential parts of psychotherapy?

The most effective therapists are very cognitively flexible, are empathetic and able to listen carefully and effectively use the information that the patient has given to them. This is the key, because people are very different and they respond differently, so you have to listen to what they say and design a good therapy programme with them and for them. And you have to understand what they feel about their symptoms.  For example, try to imagine that you are a young person with obsessive compulsive disorder (OCD) or depression and how distressing it is. These young people may have problems at school, establishing friendships and learning effectively due to their symptoms.

Barbara J. Sahakian is a leading British neuroscientist, Professor at the Cambridge University and Past President and Founder Member of the International Neuroethics Society. As a psychopharmacologist, she is known for her research on Alzheimer’s and nootropics, drugs originally intended for people with dementias or ADHD that also improve cognition on healthy people. She co-invented a set of neuropsychological tests being used world-wide.  In the last decade, however, she is especially known for her comments on the neuroscience as a field, being engaged in ethical discussions about application of the knowledge of the brain.