Pills for the mind (1)

Denis Yatsutko, XXII CENTURY 

Not fully understanding yet how the brain works, people, however, have long ago learned to slightly "adjust" it to their needs in various ways and are gradually learning to do it better and better. Last year, the XX2 CENTURY already talked about the drug-free ways of "tuning the mind". A recently published systematic post-review (1), which confirmed the efficacy of modafinil (previously known mainly as a drug for narcolepsy) as a "smart pill", i.e. a drug that improves attention, intelligence, memory and learning ability, prompted us to return to this topic and look at it from a slightly different angle. So, what medications are known today to improve mental abilities and how effective are they?

Racetams and the most famous of them is piracetam. It was first synthesized back in 1964 by the Belgian Corneliu E. Giurgea, who worked at UCB. In 1972, it was put into production under the brand name "Nootropil". The origin of the term nootropics itself is also connected with it (Greek: vους – mind and τροπή – I turn, interfere, change). So it was decided to call piracetam itself and other similar drugs (still unknown at that time), which improve a person's intellectual abilities, but do not have side effects characteristic of psychostimulants (psychotropic substances).

Since the early 1970s, piracetam has remained the most famous nootropic. However, the mechanism of its action is still partly a mystery. It's not even clear if it works at all. It is believed that it affects the AMPA-glutamate receptors and thereby improves metabolic processes in the brain, and, consequently, the work of the latter. For many years, Nootropil has been prescribed to people who have suffered traumatic brain injuries, stroke, and epilepsy. At the same time, studies show that it is more effective in reducing anxiety and treating depression than for improving memory or in combating other cognitive impairments. However, in combination with vasodilating drugs, piracetam seems to be able to improve cognitive functions for a short time. Studies have noted that nootropil also improves the influx of calcium into nerve cells, but the usefulness of this ability is questionable: excess calcium can be harmful (2).

Piracetam derivatives – neurometabolic drugs of the pyrrolidine series - have now been synthesized to hell. All of them together are called racetams. The pharmacokinetics of racetams are unclear to this day, as is the mode of action of piracetam itself. Some of them, for example, levetiracetam, seletracetam and brivaracetam, help with epilepsy, reduce the frequency of seizures, have anticonvulsant and anticonvulsive effects, but whether they somehow affect memory, intelligence, mental performance is unknown. 

Pramiracetam ("Pramistar") deserves a separate mention. This derivative of piracetam also acts incomprehensibly, but stronger. It is known that it has a high degree of affinity for choline, from which the neurotransmitter acetylcholine is synthesized in the body. That is, probably, pramiracetam somehow affects cholinergic receptors, improving the transmission of an electrical impulse from neuron to neuron. Questions still remain, research is underway, but it is reported (2) that the drug helps patients with traumatic brain injury from "cognitive deficits", and in healthy people pramiracetam improves attention and learning ability. Like piracetam, pramiracetam helps well with depression.

Another racetam is phenylpiracetam, aka "Phenotropil", fonturacetam. Developed in Russia, at the Institute of Biomedical Problems. It differs from piracetam by the presence of a phenyl group. It was supposed to help him better penetrate the blood-brain barrier, but whether it really helps has not yet been found out. Nevertheless, somehow this thing works. Back in 2010, a study was conducted on 400 patients who had suffered an ischemic stroke. 200 of them received three courses of phenotropil 400 mg per day for a year after a stroke. Their recovery of neurological functions and adaptation to daily activities were better than in the control group (3). In 2013, a study of phenotropil was conducted on an animal model as an antipsychotic drug. It has been shown to have a noticeable antipsychotic effect, while not causing, unlike most other neuroleptics, side effects such as aggression or drowsiness. A positive effect on the research behavior of animals and their motor activity was also noted (4). Finally, the 2015 study (5) – also, unfortunately, so far on rats, but on diabetic rats, showed that fonturacetam not only improves the learning and memorization of acquired skills, but also has a beneficial effect on the state of mitochondria in neurons.

An additional touch: studies on rats (6) have shown that phenotropil and pramiracetam can also have an antipyretic effect. But nootropil is not.

The latest information is the result of recent studies (7). So far, nefiracetam raises many more questions for researchers than the nootropics described above. Its effectiveness as a "smart pill" is also more often questioned.

Rolipram stands apart among racetams. It is being studied especially actively now (also, however, mainly on rats), but it is interesting to researchers not only as a nootropic: with its help, for example, they hope to treat neuropathic pain in cancer patients undergoing chemotherapy, and it seems like it has the potential for this (8). Cognitive functions in rats, diabetic patients (9) rolipram seems to improve too. But while the research is in full swing.

A little bit about personal experience with racetams. When I was about 30 years old, I was once given piracetam intravenously for a week. After this course, I felt much better, my mind became clearer, and my working capacity increased significantly. However, considering that at the same time I was injected intramuscularly with vitamins B6 and B12 (a dubious event, but more on that later), plus, in order to have time to go to the day hospital by a certain time under a drip, I was forced to somewhat streamline the daily routine, I can't guarantee that the effect was from piracetam.

I drank nootropil in tablets and phenotropil in courses repeatedly, combining them with multivitamins, sometimes sets of amino acids, lecithin, fish oil (omega-3 polyunsaturated fatty acids), potassium and magnesium preparations, other medications and supplements. Sometimes some effect was felt, sometimes not. In the end, I noticed for myself that the presence or absence of these racetams in my personal "maintenance complex", if it affects something, it is so insignificant that, like that flying crocodile from the joke, it is even imperceptible. Unfortunately, I can't add anything from myself about other racetams.

So they are all necessary for normal life. With a balanced and varied diet, we get all the necessary vitamins with food. If you doubt that your diet is balanced, you can easily make up for the lack of vitamins by taking a multivitamin preparation. There are thousands of them on the market – choose your taste. Personally, I chose for myself (at the moment, we'll see there) the Man's formula complex from PharmaMed. It's not jeans. In fact, I have tried God knows how many multivitamins – my health really improves from pharmacovigilance, I become livelier and more cheerful. I admit that this is a placebo effect, I do not exclude the possibility of a particularly successful individual compatibility, but the body feels a positive effect as a fact, and I am willing to share this fact with you.

In terms of the effect on the brain and the nervous system as a whole, we will pay special attention to the already mentioned vitamins B6 (these are several substances: mainly pyridoxine, pyridoxal and pyridoxamine) and B12 (cobalamines, primarily cyanocobalamin).

Vitamin B6 is found in cereals, buckwheat, nuts, potatoes, cabbage, tomatoes, strawberries, cherries, citrus fruits, legumes, meat, fish and milk, eggs, grapes and many other products. It is difficult to imagine what you need to eat to deprive the body of this substance.

Vitamin B6 is present in the body in all three of its main forms, the biological role of which is more or less the same. Vitamin B6 is necessary for... in short, for everything. It is also a coenzyme of proteins involved in the processing of amino acids and protein assimilation, and an indispensable participant in the synthesis of all neurotransmitters (GABA, serotonin, adrenaline, norepinephrine, aspartic acid, etc.), fatty acids and hemoglobin, it is necessary for the normal functioning of the nervous system and for red blood cells to carry oxygen, and cells to be supplied with glucose and calcium (10). With a lack of vitamin B6, the nervous system crashes, the brain gets tired, the muscles get tired, everything gets tired, and then it starts to fall apart. The hair falls out first. Then everything else. Of course, it rarely comes to this, but if you feel fatigue, nervousness, if the pressure jumps, a little B6 will not be superfluous. But a lot – maybe. However, in order for B6 to become a lot, it must be absorbed in absolutely horse doses, repeatedly exceeding the daily norm by hundreds of times. This is not so simple, and therefore occurs most often with therapeutic use (large doses of B6 are prescribed, for example, in the treatment of epilepsy and autism). Signs of hypervitaminosis with vitamin B6: sensitivity disorders, pain throughout the body, limbs may be taken away, in short, this condition is called polyneuropathy. And these are not just symptoms – the result of an overdose of pyridoxine can be degeneration of nerve cells with irreversible loss of sensory and motor functions (11) So if you suddenly read somewhere that vitamin B6 is useful for the brain, got a bucket of it and are thinking of using this bucket to become smarter, it will still be smarter than this not to do (12).

Vitamin B6 should be treated with caution in pregnant women. A recent study (true, on chickens, but nevertheless) showed that the effect of pyridoxine on the developing embryo can have teratogenic consequences: underdevelopment of muscles and nervous system (13).

Vitamin B12 promotes the formation of red blood cells, as well as the growth of nerve cells and nervous activity in general. In addition, it catalyzes the conversion of homocysteine to methionine. Why is this important? Because homocysteine is one of the causes of endothelial damage, provoking the formation of blood clots and atherosclerotic plaques. High levels of homocysteine increase the likelihood of Alzheimer's disease and senile dementia. Knowing this, many believe that taking vitamin B12 can help reduce homocysteine levels, and therefore, if not improve cognitive abilities, then at least keep them at a decent level. This misconception has long been shared by many doctors who prescribed B12 to all patients in a row who had memory problems, nervous disorders, etc. The fact, however, is that if we regularly eat at least a little meat, our body receives from it as much B12 as it needs (especially a lot of cobalamines in beef liver). At the same time, our daily need for cyanocobalamin is scanty, from 0.9 to 3 micrograms per day, and with daily food we eat at least 5 micrograms per day, that is, even with a margin. The stock is simply excreted with excrement. And no additional doses will make our mind sharper and our memory better. Unfortunately. A double-blind, placebo-controlled study conducted in Taipei in 2007 showed that additional doses of vitamin B12 did not help with Alzheimer's disease either. For 26 weeks, patients suffering from this ailment received a multivitamin containing B12, B6 and folic acid. As a result, no statistically significant differences were observed in terms of homocysteine content in the organisms of patients of the main and control groups (14).

Is it worth taking vitamin B12 at all? If you regularly eat meat, then, in general, there is no need. In moderate doses, it won't hurt, but whatever you take will just go down the toilet. Vegans should think about taking B12 (lactovegetarians quite get it from dairy products) and people who are completely on sports nutrition and similar food substitutes. Chronic smokers may have problems getting cobalamines from meat. They also need to swallow them as part of a multivitamin. B12 is needed in the form of a supplement for patients with insufficient production of gastric juice: their body simply will not be able to extract vitamin from meat. And it is worth taking care of those who do not produce the so–called internal factor (Castle factor, IF) in their stomach - a special substance under the influence of which cobalamin passes into a form that can be absorbed in the intestine. Because even if you take B12 in tablets, without the Castle factor coming from the stomach, it simply won't get into the blood. So with such a problem, it is necessary not just to take a vitamin in the form of a supplement, but this supplement should contain a ready-made internal factor (15). Another solution may be vitamin injections.

Vitamin B6 has an interesting derivative – pyritinol ("Pyriditol", "Pyrithioxin", "Enerbol", "Encephabol" and many other trade names). Structurally, it is a doubled pyridoxine molecule containing a disulfide "bridge". It is advertised as a good nootropic, and it is possible that it is such. Back in 1990, the Indian Journal of Experimental Biology published the results of a study conducted on white rats (16). The unfortunate animals were deprived of food even in the wombs of their rat mothers. That is, simply pregnant rats were very poorly fed. As a result, the animals were born with memory impairments and very poor learning ability. The rats born, grown up and tested for congenital stupidity were divided into unequal groups and began to be subjected to various influences. One of the groups received pyritinol. And it was she who became champions. The conclusion made by the researchers: pyritinol can be useful in training learning ability and in overcoming memory deficits caused by malnutrition and other hardships.

In any case, it is allowed and indicated for use for the treatment of various nervous disorders, as well as as a nootropic in Austria, Germany, France, Italy, Portugal and Greece. In Russia, too. In the journal "Issues of Modern Pediatrics" (2013, volume 12, No. 4), in the article "Clinical use of pyritinol in neuropediatrics" a review of various studies of pyritinol is published:

[...] recent studies have confirmed the positive effects of Encephabol pharmacotherapy in children with perinatal CNS lesions and their consequences, delays in psychomotor and speech development, dyslexia and dysgraphia, ADHD, cognitive impairment and learning difficulties (including epilepsy, chronic tics and Tourette syndrome). The pronounced nootropic effect of the drug, including neurometabolic, neuroprotective, neurodynamic and other mechanisms, determines the possibilities of its wide application in neuropediatric practice.

The safety of the drug was noted separately, although side effects were mentioned: insomnia, increased excitability, anxiety, as well as cholestatic syndrome.

Meanwhile, the authors of an article published back in 2004 in the BMJ describe six cases of severe pyritinol-induced cholestatic liver damage that required hospitalization in young previously completely healthy patients who took pyritinol to improve memory (19, 20). It seems that six cases are a drop in the bucket, but the authors of the publication believe otherwise: since most doctors are convinced of the safety of encephabol, they often simply do not associate the liver problems of their patients with the nootropin they take.

Pyritinol is not licensed in the UK and USA. On English-language sites selling nootropics, it is quite possible to buy it, however, as a rule, there is a postscript under the product description: "This compound has not been approved by the FDA and should only be used for research purposes."

Now let's briefly talk about inositol, the former – no matter how strange it may sound – vitamin of group B. This substance participates in fat metabolism and is a so-called secondary mediator, that is, a substance that triggers a number of cellular processes, including those necessary for the growth and restoration of nervous tissue and the release of neurotransmitters. A necessary thing, in general. It used to be called vitamin B8. Why was she excluded from vitamins? And for the fact that most of the inositol necessary for the body is synthesized by the body itself. A rare meager disadvantage is easily filled with everyday food. Nevertheless, the fact that inositol is involved in the construction of nerve cells and the launch of processes associated with neurotransmission, could not but lead scientists and doctors to the idea that increased doses of it can somehow positively stimulate nervous activity and even treat certain types of nervous and cerebral disorders. The former vitamin has been tested in several double-blind tests on people with panic disorders, drug addiction, depression, autism, ADHD, schizophrenia, Alzheimer's disease and cognitive impairment caused by electroshock therapy (21, 22, 23). All these studies have shown that increased doses of inositol have a therapeutic effect in these cases. It has also been found that inositol-containing supplements reduce the likelihood of developing diabetes mellitus in pregnant women (24). I have not been able to find studies on how additional inositol affects the cognitive abilities of healthy people. Unfortunately. And to the joy – there was also no information about cases of overdose or poisoning with inositol. But I regularly manage to find inositol-containing drinks in the nearest store. The multivitamin complex, which I use regularly, also contains inositol. According to my subjective impressions, all this in some way improves my ability to concentrate, memorize and everything like that. Of course, there, again, is not only inositol, and sensations are a subjective matter, but they are there. I see no reason not to share them – with all the appropriate reservations.

We still have to talk about GABA, about glycine, about extracts of some plants, actually about modafinil, which has recently made so much noise, and something else.

To be continued.

Literature:

1 R. M. Battleday, A.-K. Brem. Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review. // European Neuropsychopharmacology, Published Online: August 19, 2015.

2 Malykh AG, Sadaie MR. Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders. // Drugs. 2010 Feb 12;70(3):287–312. // PubMed.

3 Koval’chuk VV, Skoromets AA, Koval’chuk IV, Stoianova EG, Vysotskaia ML, Melikhova EV, Il’iaĭnen EV. Efficacy of phenotropil in the rehabilitation of stroke patients. // Zh Nevrol Psikhiatr Im SS Korsakova. 2010;110(12 Pt 2):38–40. // PubMed.

4 Akhapkina VI, Akhapkin RV. Identification and evaluation of the neuroleptic activity of phenotropil. // Zh Nevrol Psikhiatr Im SS Korsakova. 2013;113(7):42–6. // PubMed.

5 Zhiliuk VI, Mamchur VI, Pavlov SV. Role of functional state of neuronal mitochondria of cerebral cortex in mechanisms of nootropic activity of neuroprotectors in rats with alloxan hyperglycemia. // Eksp Klin Farmakol. 2015;78(2):10–4. // PubMed.

6 Zhilyuk VI, Levykh AE, Mamchur VI. A study of the mechanisms for antiaggregant activity of pyrrolidone derivatives in rats with chronic hyperglycemia. // Bulletin of experimental biology and medicine. 2014 Apr;156(6):799-802. doi: 10.1007/s10517-014-2454-8. Epub 2014 May 3. // PubMed.

7 Omotuyi OI, Ueda H. Molecular dynamics study-based mechanism of nefiracetam-induced NMDA receptor potentiation. // Computational biology and chemistry. 2015 Apr;55:14-22. doi: 10.1016/j.compbiolchem.2015.01.004. Epub 2015 Jan 23. // PubMed.

8 Kim HK, Kwon JY, Yoo C, Abdi S. The Analgesic Effect of Rolipram, a Phosphodiesterase 4 Inhibitor, on Chemotherapy-Induced Neuropathic Pain in Rats. // Anesthesia and analgesia. 2015 Sep;121(3):822–8. doi: 10.1213/ANE.0000000000000853. // PubMed.

9 Miao Y, He T, Zhu Y, Li W, Wang B, Zhong Y. Activation of Hippocampal CREB by Rolipram Partially Recovers Balance Between TNF-α and IL-10 Levels and Improves Cognitive Deficits in Diabetic Rats. // Cellular and molecular neurobiology. 2015 May 23. [Epub ahead of print] // PubMed.

10 Dakshinamurti S, Dakshinamurti K. Antihypertensive and neuroprotective actions of pyridoxine and its derivatives.. // Canadian journal of physiology and pharmacology. 2015 May 11:1-8. [Epub ahead of print] // PubMed.

11 Michelle C. Potter, Krystyna M. Wozniak, Noelle Callizot, Barbara S. Slusher. Glutamate Carboxypeptidase II Inhibition Behaviorally and Physiologically Improves Pyridoxine-Induced Neuropathy in Rats. // PLoS One. 2014; 9(9): e102936. // PDF.

12 An overdose of almost anything, including vitamins, is generally not useful. See, for example, about the non–usefulness of horse doses of vitamin C - http://22century.ru/docs/history-of-immortality (chapter "Ascorbinka").

13 Sharp AA, Fedorovich Y. Teratogenic effects of pyridoxine on the spinal cord and dorsal root ganglia of embryonic chickens. // Neuroscience. 2015 Mar 19;289:233-41. doi: 10.1016/j.neuroscience.2014.12.067. Epub 2015 Jan 13. // PubMed.

14 Sun Y, Lu CJ, Chien KL, Chen ST, Chen RC. Efficacy of multivitamin supplementation containing vitamins B6 and B12 and folic acid as adjunctive treatment with a cholinesterase inhibitor in Alzheimer’s disease: a 26-week, randomized, double-blind, placebo-controlled study in Taiwanese patients. // Clinical therapeutics. 2007 Oct;29(10):2204-14. // PubMed.

15 By the way: while preparing this article, I came across an extremely interesting correspondence of doctors about vitamin B12, I recommend: http://yarchive.net/med/b12.html .

16 Jaiswal AK, Upadhyay SN, Bhattacharya SK. Effect of pyritinol, a cerebral protector, on learning and memory deficits induced by prenatal undernutrition and environmental impoverishment in young rats. // Indian journal of experimental biology. 1990 Jul;28(7):609-15. // PubMed.

17 Zykov VP, Begasheva OI. Cognitive disturbances in patients with tics and Tourette’s syndrome and their correction with encephabol. // Zh Nevrol Psikhiatr Im SS Korsakova. 2003;103(11):10-4. // PubMed.

18 Hayder M. Alkuraishy, Ali I. Al-Gareeb, Ali K. Albuhadilly. Vinpocetine and Pyritinol: A New Model for Blood Rheological Modulation in Cerebrovascular Disorders–A Randomized Controlled Clinical Study. // BioMed Research International. 2014; 2014: 324307. Published online 2014 Dec 7. doi: 10.1155/2014/324307 // PDF.

19 That is, actually as a nootropic, a "smart pill".

20 Vasco Maria, Adriana Albuquerque, Ana Loureiro, Ana Sousa, Rui Victorino. Severe cholestatic hepatitis induced by pyritinol. // British Medical Journal (BMJ). 2004 Mar 6; 328(7439): 572–574. doi: 10.1136/bmj.328.7439.572 // PDF.

21 Palatnik A, Frolov K, Fux M, Benjamin J. Double-blind, controlled, crossover trial of inositol versus fluvoxamine for the treatment of panic disorder. // Journal of clinical psychopharmacology. 2001 Jun;21(3):335-9. // PubMed.

22 Levine J, Barak Y, Gonzalves M, Szor H, Elizur A, Kofman O, Belmaker RH. Double-blind, controlled trial of inositol treatment of depression. // The American journal of psychiatry. 1995 May;152(5):792-4. // PubMed.

23 Levine J. Controlled trials of inositol in psychiatry. // European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology. 1997 May;7(2):147-55. // PubMed.

24 Noventa M, Vitagliano A, Quaranta M, Borgato S, Abdulrahim B, Gizzo S. Preventive and Therapeutic Role of Dietary Inositol Supplementation in Periconceptional Period and During Pregnancy: A Summary of Evidences and Future Applications. // Reproductive sciences (Thousand Oaks, Calif.). 2015 Jul 14. pii: 1933719115594018. [Epub ahead of print] // PubMed.

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23.09.2015