Nootropics

Is it a good idea or a big mistake?

Maria Bronova, blog of the clinic "Our time", Habr

Nootropics — for the layman, these are "pills to think better and not want to sleep." In short, there are outright fuflomycins, there are promising drugs with insufficient evidence base for the alleged mechanism of action, which in some cases give the result expected by the consumer, in most cases it is the absence of significant improvements or the development of side effects.

Simply put, no one fully knows the principles of their work and the degree of safety for the human body. But they pay for primitive biohacking, and they pay a lot, so the market is quite developed.

The main intended purpose of these funds is to return the nervous system to normal after its work / damage, improve blood circulation, restore energy exchange and increase the resistance of the brain to various harmful effects. A normally functioning brain does not need them, but they can interfere with some of its functions or the functions of other organs and systems.

Let's understand the practical aspects: is it worth taking nootropics, will they really "disperse" your brain, and what will have to pay for it, of course, from the point of view of scientific medicine.

What is a nootropic?This term was coined by the Belgian scientist Corneliu E. Giurgia back in the 70s of the last century.

In 1964, Giurgia and his colleagues synthesized piracetam. The exact mechanism of its operation was not entirely clear, and at first it was assumed that the substance would help with motion sickness. Later, an interesting side effect was discovered: scientists concluded that piracetam improves cognitive functions and memory. In fact, it increased performance like psychostimulants, but had no side effects peculiar to them.

Then Giurgia realized that a promising idea needed to be given the right name. Nootrope is a fusion of the Greek words: vους — mind and τροπή — I change.

Today, the term is used to describe a group of drugs that are believed to stimulate mental activity, activate cognitive functions and improve learning ability, help the brain fight excessive stress and hypoxia.

What problems would it be great to solve with the help of nootropics? These are, for example:

1. Encephalopathies of various genesis (damage or disease affecting the brain), neurodegenerative diseases (including dementia, Parkinson's disease, etc.).

2. Violation of adaptation to stress, depression.

3. Delays in speech and mental development in children.

4. Disorders of cerebral circulation.

5. "Tablet for the mind" — improving performance.

Why do I give all the previous theses in the subjunctive mood? Because until now, unfortunately, nootropics are still poorly researched. In the USA, for example, the same piracetam is not registered as a medicinal product today, but is sold as part of dietary supplements.

How do nootropics work?As I have already said, the mechanism of action of nootropics has not yet been thoroughly studied.

We know that they can potentially improve synaptic transmission processes in the central nervous system by affecting the main neurotransmitters in the brain (short-lived substances of local action; they are released into the synaptic cleft and transmit a signal to neighboring cells). There are neurotransmitters that inhibit certain processes in the brain, there are those that excite them. And nootropics, respectively, affect neurotransmitters, depressing or exciting them, depending on the goal we want to get.

By chemical nature, the classical main neurotransmitters are amino acids, neuropeptides, monoamines, purines.

Amino acids are, for example:

• GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter of the central nervous system.
• Glycine — it is very similar to GABA in its neurotransmitter "fate": both in the embryonic period are excitatory neurotransmitters. They "train" the developing brain, give it loads in a safe mode. Then, after birth, they gradually "switch" from activating to inhibitory activity in the central nervous system.
• Glutamate (glutamic acid) — in addition to participating in protein synthesis, it performs the function of an excitatory neurotransmitter.

Peptides are, for example, beta-endorphin, which is responsible for analgesic and anti-shock effects, as well as for reducing appetite and lowering the tone of the sympathetic nervous system.

Monoamines are, for example, dopamine, which is an important part of the brain's reward system, causes feelings of pleasure and anticipation, affects learning processes, and serotonin, which we usually know as the "happiness hormone". Although in fact serotonin works somewhat differently. When synthesis is insufficient, a person may have a depressive mood, you look at the carpet and just don't understand why this is all. An overabundance of it in the body may occur, for example, due to improper administration of certain medications (most often antidepressants) or a combination of them with narcotic drugs. This abruptly launches the "factory" for the production of serotonin in our body at full capacity: too much of it is produced, which can cause serotonin syndrome, in fact, "poisoning" with serotonin. This condition can be accompanied by diarrhea, tachycardia, anxiety, motor anxiety, tremor — an unpleasant and generally life-threatening condition.

In domestic practice, nootropics are prescribed, for example, in such cases:

• dementia (for example, in Alzheimer's disease);
• after traumatic brain injuries, with impaired blood circulation in the brain;
• neuropsychiatric disorders;
• depression;
• memory impairment;
• vegetative vascular dystonia syndrome.

Here it should be noted the importance of the correct diagnosis by a doctor and its existence in the international classification of diseases (already ICD-11). The same vegetative—vascular dystonia is a close equivalent of the conclusion "possessed by demons, what to treat is unclear." This pseudodiagnosis often masks other real-life diseases and conditions, and the patient simply loses time and money on completely unnecessary medications. This cohort also includes patients who will have a placebo effect from group B vitamins prescribed to them or intravenous saline injection.

Nootropics as a means of stimulation

Nootropics that are used for non-medical purposes can be divided into two such large groups:

1. Psychostimulants are what people most often use to temporarily improve the work of an already normotypic nervous system (disclaimer: prohibited drugs are bad).

2. Nootropics with turbid effects of goodness and improvement of blood circulation.

Cocktails of psychoactive drugs were loved by the on—screen Jordan Belfort - the Wolf of Wall Street. "So, Mr. Belfort, I can inform you, if you are interested, of course, that the test gave a positive reaction to cocaine, methaqualone, benzodiazepine, amphetamines, as well as ecstasy, opiates and marijuana. The only thing you haven't found in your blood is hallucinogens. And what is the problem, actually? Don't you like hallucinogens?"

Stimulants (also called psychostimulants) are a group of psychotropic drugs that increase mental and physical performance, improve the ability to perceive external stimuli (sharpen vision, hearing, etc., accelerate responses), improve mood, relieve fatigue, cheer up and temporarily reduce the need for sleep — in general, everything that we want to get from the body when we sit down to work at one o'clock in the morning. This list will include, for example, caffeine, nicotine, amphetamine, cocaine and others, including narcotic substances, antidepressants, in which stimulation is not the main action, but a convenient side effect for someone when taken in large doses without control.

How do psychostimulants work? Catecholamines are synthesized in the adrenal medulla and cells of the sympathetic nervous system, which is responsible for a quick reaction in stressful situations: these are dopamine, adrenaline and norepinephrine. Stimulants release them from the nerve endings and block the reverse neural capture.

Amphetamine, which was synthesized for the first time at the end of the XIX century, was already used in the treatment of asthma in the XX century. In 1929, biochemist Gordon Alles found psychoactive properties in amphetamine, and in subsequent years it became a well-advertised drug for the treatment of depression, Parkinson's disease, and weight loss.

How amphetamine works: the release of dopamine and norepinephrine increases, and then the reverse capture of dopamine into the cell occurs

For non-medical purposes, amphetamine began to be used around the same time. Its stimulating effects are improving mood, sharpening concentration and attention, boosting performance and relieving drowsiness. From not very pleasant: tremor, panic, insomnia and the likelihood of developing "amphetamine psychosis".

After the Second World War, the global production of amphetamine began to reach, let's say, industrial scale. The alarm was sounded by about the 60s: it was known about psychoses before, but now everyone has clearly put 2 and 2 together and drawn causal relationships.

In some cases, psychosis occurs in people who take psychoactive drugs uncontrollably, which comes with hallucinations, delusions of persecution, paranoid deception of perception, visual and auditory hallucinations against the background of extreme excitement. A vivid example is a full—scale acute "amphetamine psychosis".

By the way, relatively familiar and legal stimulants, for example, caffeine, in theory, can also cause psychotic reactions. If we talk about the mechanism of caffeine, it is the stimulation of the central nervous system and the expansion of blood vessels. If you rarely drink coffee, then after a cup you can stay up half the night and work actively. If you use coffee all the time, then the body will rearrange the synthesis of adenosine, the number and sensitivity of receptors in such a way as to compensate for the constant introduction of caffeine.

About the doses of stimulants:

In large doses, agitation, senseless actions and a drop in productivity are obtained.

Huge investments and garage biologyAbout the "pills for the mind" option.

Not so long ago, the world was covered by the idea of biohacking. Biohackers call the human body wetware — by analogy with hardware and software.

Silicon Valley, of course, has become a kind of mecca for those seeking to hack and become the best version of themselves, and multimillion-dollar investments are pouring into the development of "mind pills". For example, the startup Hvmn, which creates just such nootropics for "pumping" the brain, received a couple of million investment dollars from an American venture fund at the time. The creators of Hvmn at that moment were working on the composition of tablets, experimenting with components that they ordered on Alibaba and on the darknet. They managed to pick up ingredients that are allowed to be used as food additives in the USA. This allowed the sale of "smart pills" without obtaining permission from the US Food and Drug Administration. In 2017, Nootrobox could be bought at any 7 Eleven in San Francisco (the concentration is about the same as ours — "Five").

The products were often criticized. For example, the main active ingredient of Hvmn chewing cubes is regular caffeine. The fact that caffeine is able to shake up and tone up our brain activity for a while is, of course, not news.

But the multimillion-dollar investment market and aggressive marketing, unfortunately, in this case work in such a way that security issues recede into the background.

Throwing nootropil during the periods of tests and sessions is a favorite thing of my student days. That is, we really believed that we were taking out exams and in general all this difficult life thanks to a miracle pill.

Scientists' opinions on the use of nootropics as a "pill for the mind"Opinions about the effectiveness of nootropics are divided even among researchers who are dealing with the problem of studying them in large institutions that receive serious financial investments to conduct these studies.

For example, Barry Gordon, head of the Department of Cognitive Neurology and Neuropsychology at Johns Hopkins University Hospital, believes that there is no convincing evidence that any of the supplements that are currently being sold because of their supposed ability to improve memory are useful. It's unclear if they work, and it's unclear if they're safe. The schemes involved in human mental processes are very complex and have not been fully studied. You can't just "turn the handle up" that easily. He notes that people who believe that their mental performance has improved thanks to nootropics are largely influenced by the placebo effect.

Chris D'Adamo, MD, who directs research at the Center for Integrative Medicine at the University of Maryland, has a different opinion. He believes that the main tool for optimizing cognitive function is healthy sleep, stress management and nutrient—rich foods. But once all this is done, nootropics will serve as a good supportive tool and help you think more clearly and acutely, reducing the likelihood of deterioration of cognitive function with age.

I believe that it is also important to understand the reasons for the decline in working capacity in an adult: it can be burnout, fatigue, accumulated stress and lack of sleep. He may have a single mild depressive episode, that is, a reaction to some event in his life or to failures at work. In this case, sports, good sleep, rest and proper nutrition will help him perfectly. If this is, for example, some more complex condition - severe affective disorder, eating disorders, etc. — then, for example, cognitive behavioral psychotherapy, antidepressants/neuroleptics or a combination of both will help. That is, to begin with, it would be nice to ask yourself why you needed it before you start buying supplements or untested drugs on well-known sites.

Clinical studiesIn order to be confident in the work of nootropics and safely prescribe them, it is necessary, of course, that not only their effectiveness, but also their safety be proven.

Clinical studies of the same piracetam, for example, were conducted in a large number of cases on very unconvincingly small groups of people of 20, 30, 115 people.

There are studies, they have been conducted since the 90s, but such that there was a normal sample - for example, 3,000 people and at least two groups, one of which was with a placebo — such studies were not conducted.

In addition, the results of using piracetam, for example, in dementia are contradictory. A meta-analysis conducted in 2002 demonstrates convincing evidence of the effectiveness of piracetam in elderly patients with cognitive impairment or dementia. At the same time, two systematic reviews in 2004 and 2015. (one of them — with meta-analysis) did not confirm the effectiveness of piracetam in various types of dementia, including Alzheimer's disease and other cognitive disorders. The results obtained in systematic reviews do not support the use of piracetam for the treatment of Alzheimer's disease.

Clinical studies on cortexin do not stand up to criticism of connoisseurs of high-quality research on citicoline, for example, two decent meta-analyses give opposite estimates of its effectiveness in traumatic brain injury: in one (12 RCTs, 2,706 participants), the authors conclude that there is significant evidence of the benefits of citicoline, and in the other (five studies, 1 355 participants) — about the lack of effect.

If we talk about experiments with learning and memory of animals, then in general you need to be very careful with the interpretation of the results. For example, the same rats: individuals who were injected with nootropics passed the maze faster and were the first to reach the finish line. But it may be that the nootrope just made them hungrier, and that was the reason for winning the race.

About side effectsIf we are talking about children, then a big problem in domestic medical practice is the appointment of nootropics right and left.

Let's say that a family came to a neurologist for an appointment in Moscow or another big city, and we see a delay in the mental and/or speech development of the child. We will say that you do not need magic pills, but professional psychological and pedagogical work with a child. Parents will find a specialist and begin to study intensively, and his intellectual development and speech will improve.

And if we take a family from a small town, a village, it very often happens that they simply do not have such professional help as a class. And here it would be great to appoint a supertablet who will take on the role of a psychologist and sort everything out in the child's head on the shelves. But due to the fact that we still do not have enough data not only on the effectiveness, but also on the safety of such funds, naturally, we avoid such appointments. Although as a working tool it would be very useful to us here.

Sometimes nootropics are prescribed to children with a decrease in academic performance. But here it is very important to analyze what caused it. Maybe there are increased loads at school, and the child simply does not have time to rest, maybe conflicts with classmates or with a teacher. Or maybe parental expectations just turn out to be overstated. In such cases, again, competent psychological and pedagogical support is needed, because, unfortunately, no pill can compensate for such a complex of measures today.

At one time I received a lot of messages in the mail about the side effects of children: this is a strong excitement, tantrums, tears, sleep problems, abdominal pain, dizziness. There were significantly more side effects than the result.

Doctors, of course, should be aware of alternative methods of care. Then, with enuresis, they will not prescribe nootropics, but an enuretic alarm clock: tell that it exists at all and how it works. Because sometimes parents come to us and don't know the banal things. No one told them about it, but they managed to prescribe unsafe pills to the child. In addition, it is not enough to tell about the existence of any method of assistance, it is also important to set up the family that the result will not be quick, patience, strength and efforts of all family members are needed.

Enuresis is an inability to properly control urination. Enuresis alarm clock is actually a banal device that wakes up the child at the right moment and forms his reflex to wake up and go to the toilet. Such a tool really forms a reflex, unlike nootropic drugs with unclear effectiveness.

The side effects that nootropics cause sometimes outweigh the supposed positive effect of their use. This is from the series "expectation — reality":

That is, waiting is an increase in activity, an improvement in activity, and in fact you can get nervous excitement, dizziness, abdominal pain and sleep disturbance. Often the side effects were much stronger than the desired effect, for example, with severe diarrhea or intense headache, it will no longer be particularly important to you whether your mind has become sharper.

To date, we still have very little data on how nootropics interact with other groups of drugs, for example, what will happen if you combine them with some types of antidepressants, or how the body will react if you have smoked marijuana in the past.

The topic of clinical recommendations is very sad for me. They sometimes prescribe treatment protocols with drugs with unclear efficacy, and doctors indiscriminately prescribe them. Here, as I and many of my colleagues believe, a lot of work should be done, and it's time to rewrite a number of clinical recommendations. But this, of course, is such a difficult and not very pleasant part of the question.

Unfortunately, if we are talking about taking the CHI format, then the doctor usually has 10-15 minutes to prescribe the drug, and there is no time to immerse the patient in detail in the topic of his problems and explain everything. My opinion is that it is better to go to a doctor who will have these 40-60 minutes to tell you about all the details in as much detail as possible. Because the brain is kind of obviously an important part of your body.

When is the appointment of nootropics justified?I repeat that nootropics as an idea is a great tool!

When patients come to me and we discuss some medications, I always have my laptop open, and I show everything in detail: which resources to go to, where to read, what to study.

For example, for the treatment of Alzheimer's disease, no medicine has been created to date, but it is known that drugs (nootropics) containing cholinesterase inhibitors temporarily improve cognitive functions. Piracetam, for example, is sometimes used in the treatment of progressive myoclonic epilepsy: there are no major clinical studies, but there is evidence that it works, and epileptologists use it.

As a neurologist, I sometimes lead children with complex developmental delays, and sometimes they are caused by congenital genetic diseases. They are very rare, and it is difficult to conduct any large-scale clinical studies on such.

For example, take a mutation in the GRIN2A gene. This is a fairly rare mutation, the syndrome was discovered in 2010 and is associated with a malfunction of glutamate receptors: with it, one of the two copies of the GRIN2A gene ceases to function as it should. The reason may be an error in the sequence of nucleotides in the gene or due to the loss of one copy of the gene (or some part of it). Among the main manifestations are epilepsy, speech delay, cognitive impairment.

Here a dilemma immediately arises: should I prescribe an empirically nootropic drug or wait for the correct blind placebo-controlled studies? Given the rarity of pathology, it may take decades to wait for such studies. Therefore, in this case, it makes sense to try to get a potential positive effect and help a particular child.

So, for example, it is described that memantine in a number of cases (this is an international patented name) facilitates the course of epilepsy in these children. These studies, of course, are not large, but such data are still available.

So what's up with the magic NZT pill?The main task for this group of drugs is not to make you smarter, faster and more mobile.

The theoretical task of nootropics, adjusted for the evidence base, is to return to normal the brain, which works in a suboptimal way. The main expected effects are improvement of cerebral circulation, energy metabolism and resistance to damaging effects.

What we have in the endOf course, nootropics should be well studied on the whole body.

In the last 30 years, many nootropic drugs being investigated for the treatment of neurodegenerative diseases do not go beyond preclinical trials. Even if there is an effect in the nerve cell, reaching the scale of the whole organism, they give such side effects on other organs and systems that their use in clinical practice is not possible.

Nootropics could be a cool tool in solving important neurological issues. As a neurologist, I would very much like them to be sufficiently studied and they become a reliable and safe way of helping with the same cognitive disorders, traumatic brain injuries and neurodegeneration processes in children and adults.

This is very important for hereditary encephalopathies of development in children, Alzheimer's disease, other types of dementia, Parkinson's disease and many other diseases.

Clinical recommendations regarding the appointment of nootropics need serious adjustment. It is wrong to prescribe them with a decrease in working capacity in adults or academic performance in children, without understanding the true causes of this condition.

In any incomprehensible situation, it is better to sleep well and adjust the mode of work and rest. This will do more good than trying to swallow a bunch of drugs conceived for rehabilitation after a stroke.

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