Instructions for use of modafinil dosages from 50 to 400+ mg

Welcome! This is a clevermind project and we analyze everything related to the brain. The time has come to turn to an extremely unusual drug, which can be safely added to the list of the most powerful cognitive activators that exist in the still young world of nootropics. In some countries it is on the list of prohibited substances, in others it is not only sold “by prescription”, but is also on a par with conventional dietary supplements, such as Gingko Biloba or Green Tea Extract, by the way, in Ukraine.

Let's talk about Modafinil! This can be said to be the most popular smart drug among students and scientists in the West, Western Phenotropil. And these are not emotions, but facts, and here is the link for you (https://www.ncbi.nlm.nih.gov/pubmed/18980888)! Today there will be more interesting research, and an important amendment : power is never safe, no matter what form it is in. It is prohibited in Russia, we won’t talk about how or how much to drink, just google it and you’ll find everything. In Western countries it is used for military and medical purposes, for its intended purpose (anti-drowsiness).

Types of Modafinil: What Should You Know About Them?

Before we get into modafinil dosage tips, we should talk about its types. There are two types of this drug: modafinil and armodafinil. Both use as an active component that it has two isomers. An isomer is a variation of the same chemical. The simplest example that will help you understand what isomers are is left and right hand. These are, so to speak, different variations of the same thing - hands. They are identical in almost every way, except that they are mirror images of each other. Something similar happens with modafinil.

Armodafinil is an enantiopural compound, meaning that it contains only one type of isomer, the R-isomer, which is considered stronger than the S-isomer. As a result, the general properties of the substance are more pronounced in armodafinil than in modafinil.

Dosage differences between modafinil and armodafinil

It is clear that the differences in chemical structure discussed above influenced the determination of the dosages of these substances. So, the standard dose for modafinil is defined as 200 mg, while the equivalent dose for armodafinil is slightly lower at 150 mg. And even at this dosage, armodafinil has a more intense effect than modafinil.

Comparison of minimum and maximum dosages of modafinil and armodafinil

Hydrafinil course:

Since the substance has been poorly studied in humans, but is similar to Modafinil, similar side effects are real, namely: Hyperstimulation, allergic reactions (due to increased Histamine), tolerance with frequent use.

In general, any powerful compound should not be combined with alcohol or drugs. Suffice it to recall the deaths after mixing a huge dosage of DMAA with Caffeine and Alcohol during physical activity. And it’s stupid to say that DMAA is to blame for everything! The situation is similar with Hydra or Modafinil.

We found another potential effect on DNA (6). At the same time, as they say, “But this is not certain!”

Start taking hydrafinil with 40-50 mg along with water in the first half of the day. The substance does not dissolve! If it is well tolerated, the next time they drink 100-150 mg, no more is needed, although there were reviews of 400 mg at a time, only one had a side effect - a little blood from the nose.

In the West they mention taking it 1-3 times a week to avoid tolerance.

By the way, the potential for addiction of hydrafinil is much less than that of modafinil with comparable effects. This is because hydrafinil works for 4-5 hours, and modafinil - 10-12 + less stimulating effects.

Unofficial instructions for use of modafinil

When it comes to modafinil dosage, everything is very individual. However, many adhere to the scheme, which will be discussed later.

50 mg modafinil

This is the ideal dosage for most people who take this drug throughout the workweek. This is a small dose, but it is enough to get you “kicked” and charged for the next 4-6 hours. Adhering to this dosage, a person feels cheerful, concentrated and full of energy throughout the working day, while the sleep pattern and quality are not disturbed. Side effects usually do not appear at this dose.

75 mg armodafinil

This is a stronger dose than 50 mg of modafinil. The effect of the drug will last for 5-7 hours or more. A person feels more alert, concentrated and able to solve complex problems. The risk of side effects when following this dosage is minimal.

100 mg modafinil

100 mg of modafinil is slightly stronger than 75 mg of armodafinil. The positive effect of the drug lasts for 8 hours or more. This is the ideal dosage if you need to get a lot of work done without feeling tired, but at the same time fall asleep easily after midnight. If a side effect occurs at this dosage, it manifests itself as minor symptoms.

150 mg armodafinil

This is the usual full dose of this type of drug. After taking armodafinil at this dosage, wakefulness remains for 10-12 hours. As a rule, it does not cause side effects. In rare cases, insomnia or dehydration may occur.

200 mg modafinil

This is the gold standard when it comes to noticeably improving cognitive function. For many, at this dosage, the increased concentration remains for 12 hours or more. Adverse reactions are rare; in some cases, insomnia, headaches, and dehydration may occur.

300 mg armodafinil

This dose already exceeds the recommended dose, so it should be used only in exceptional cases. For example, when it is necessary to maintain increased concentration for 18 hours or more. This is essentially a double dose of armodafinil, so it should be taken with extreme caution. It is better to divide it into several doses, as side effects may occur, but they do not pose a serious health risk.

300 mg modafinil

Again, this is a large dose of the drug, so it should be taken with caution. After such an amount of the drug, impeccable concentration is guaranteed for at least the next 18 hours. But it is important to consider that with such a dose, side effects may already appear, including nausea. It is better to divide this dosage into several doses.

400 mg modafinil

If you need to stay awake for 24 hours, then 400 mg of modafinil will help you with this. But you need to be extremely careful with such a dosage if you are not yet accustomed to the drug. As in previous cases, it is better to divide this dose into several doses. It is strictly contraindicated for regular use.

These dosages were determined based on feedback from hundreds of people taking modafinil.

Recommended doses of the drug:

• 200 mg of modafinil - if you need to stay awake during the day and until late at night;
• 75 mg of armodafinil - when it is important to be as productive as possible during the day, but in the evening you can easily fall asleep.

But everything is very individual, and in most cases you have to select the ideal dosage for yourself, starting with the minimum, gradually increasing it.

How does Modafinil work?

Most of all Modafinil is sold in tablet form. So, some desperate individual, in the hope of achieving his base selfish goals, eats 300 mg of the substance, which was then used to make a book, a film and a TV series about a pill for the brain. In the stomach/intestines, this magical substance is absorbed and enters the blood. This desperate subject's blood circulates throughout his body. Modafinil passes through the brain's defenses and, once in it, begins its dark effect, which lasts about 12 hours. There are several isomers of modafinil, and the duration of action varies.

The action itself is not fully understood. And some of the drug's effects remain unclear. Like the butterfly effect, according to research we see action here and here, but what the hell, why does something work here too?

What is known almost 100%:

1. The reuptake of dopamine, norepinephrine and glutamate is partially blocked, their production is enhanced. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2696807/) For those who do not know these substances, read the relevant articles. Action in the style of drugs such as cocaine/amphetamine. In the short term, the combination of release and reuptake inhibition of these catecholamines indicates frantic drive, stimulation, tunnel vision, where you find it easy to concentrate on one thing even when everything around you is moving/jumping/flashing. In simple terms, such a person is difficult to distract; he is collected and concentrated. However, this way you can become paranoid and concentrate, at least believe in Pokemon.

2. Increases histamine levels. No sleep . (https://www.ncbi.nlm.nih.gov/pubmed/22640618) Probably few people know that most medications for allergies and rashes are antihistamines. Histamine develops and enhances the body’s reaction to an irritant; it seems to say: “You ate or smelled this in vain - now you have a rash on your arms and a couple of pimples on your back. Your great-grandfather almost died from this bullshit, this information was encoded in a special gene so that you, a fool, would not repeat the mistakes. Nothing personal!". Antihistamines, as the name suggests, suppress it. On the contrary, Modafinil enhances its production, making the body more sensitive and irritable. And the increased level of histamine completely destroys all drowsiness. That is why it is believed that modafinil is primarily for narcoleptics who constantly want to sleep.
3. Promotion IQ. And here is the link (https://www.ncbi.nlm.nih.gov/pubmed/16140369). This is one of those effects that is understudied. IQ is related to Acetylcholine, but modafinil has little or no effect on acetylcholine. Perhaps there is a substance that changes under today's drug, causing an indirect improvement in the functioning of the brain, its cognitive functions. And it’s hard to say what this might mean in 30-40 years. IQ increases especially strongly in people with low brain development.

Reading a major study of modafinil on IQ (English) - https://emilkirkegaard.dk/wp-content/uploads/Cognitive-effects-of-modafinil-in-student-volunteers-may-depend-on-IQ.pdf

1. Improving short-term memory . On this point, most likely, the truth lies in the influence of the dopaminergic system. After all, it is dopamine and its receptors that are responsible for the so-called “focus,” concentration, and attentiveness.
2. Suppression of GABA secretion . (https://www.ncbi.nlm.nih.gov/pubmed/22640618) This property is designed to completely kill all calm, serenity and tranquility.

Microdoses of modafinil

The standard dosage of modafinil is 200 mg. Many people take just this amount of the drug in the morning to feel alert and maintain cognitive function at its best until late at night.

Others divide this dose into two doses: 100 mg of modafinil in the morning and the same amount in the afternoon. This scheme allows you to maintain cognitive abilities at the same high level throughout the day, thereby providing an additional boost of energy after lunch.

However, not everyone takes standard doses of the drug. Many people prefer to divide this amount into “microdoses.” This is especially true for people who do not need to maintain increased concentration throughout the day, but just get a charge for 4-7 hours.

Taking the drug in so-called microdosages has many benefits. First of all, the risk of side effects is virtually eliminated. After completing the necessary work, the person relaxes and easily falls asleep.

Let's look at how microdoses usually work on the adult body.

50 mg modafinil taken in the morning

The pronounced cognitive improvement lasts for 5-7 hours, after which the manifestation of symptoms typical of modafinil begins to subside. About 13 hours after taking the nootropic, you can easily fall asleep, which will not happen after taking 200 mg of the drug. In addition, the 50 mg dosage does not cause any side effects.

25 mg modafinil morning and afternoon

This dosage paired with a cup of espresso helps increase concentration over the next 4 hours. This dosage regimen may be ideal for people whose workday ends at 6 p.m., and then they can relax.

It is unlikely that you will be able to “move mountains” by using the drug in microdosages, but it is easy to slightly increase cognitive abilities. If it is necessary to maintain wakefulness and increased attention for 12 hours, then it is preferable to resort to standard dosages.

Where to buy modafinil online

Neither branded Modafinil nor its analogues can be purchased in Russian pharmacies, since this drug is banned in the Russian Federation. Meanwhile, there are many sellers who sell this medicine via the Internet. For example, from India. In addition, this method of purchasing generics has many advantages.

Free shipping

Considering that when you order modafinil online, it is usually sent to Russia from India, then having free shipping is a big advantage. Thus, you only have to pay for the product itself.

No prescription needed

Purchasing modafinil online has many advantages, but perhaps the most important is the ability to buy the drug without a prescription. Even in those countries where this medicine is allowed, you can’t just buy it at the pharmacy - you will always need a prescription. And residents of Russia can order it online without a prescription.

Huge discounts

No pharmacy in the world will ever offer customers such huge discounts on modafinil as online stores. Firstly, pharmacies usually sell a brand-name drug, which is much more expensive than the generics sold by online suppliers. And this despite the fact that the chemical composition and effect of the “real” and the analogue are identical. Moreover, generic drugs undergo the same quality checks as brand-name drugs.

By the way, if you place an order on HighStreetPharma, do not forget to use the code ENJOYMXL10, which entitles you to a 10% discount on the total purchase amount.

What doses of modafinil and armodafinil should I take?

The recommended dosage of modafinil and armodafinil may vary depending on the reason for which these drugs are taken. Let's look at the most common ones.

Modafinil for the treatment of ADHD and narcolepsy

If modafinil was prescribed for medical reasons, then you must adhere to the recommendations specified in the instructions for use. But as a rule, for attention deficit hyperactivity disorder, as well as for the treatment of narcolepsy, 200 mg of modafinil or 150 mg of armodafinil are usually prescribed. In some cases, the dosage may be increased to 500 mg modafinil and 250 mg armodafinil [1] [2].

Typically, patients with ADHD take medication daily, taking a break of 1-2 days a week. This regimen avoids long-term side effects.

With narcolepsy, as a rule, breaks in therapy are not taken, since it only takes 1 day without taking the medicine and the symptoms of the disease worsen.

Modafinil to improve cognitive function

The dosage of modafinil to improve cognitive abilities can vary from 50 to 400 mg, depending on the characteristics of the body and the wishes of the person taking the drug. When determining the dose, you should take into account the body's reactions and the frequency of taking the medication.

Small doses to improve cognitive function (50 mg)

Some people prefer to take modafinil in small doses. This method minimizes the risk of side effects. In addition, this is the safest regimen for long-term use of the drug.

A dosage of 50 mg or less, in the case of modafinil, is considered a microdose. That is, this dose is below the therapeutic threshold.

Using microdoses produces less pronounced effects than, say, 100, 200 or 400 mg. But nevertheless, for many, such a portion of the drug is enough, especially if you take it regularly.

For most users, a microdose of modafinil serves as an analogue of caffeine - it helps to wake up easier in the morning. With this method of administration, after 30-45 minutes a person feels a surge of energy and wakefulness.

Modafinil is not typically produced in 50 mg dosages. Therefore, in order to receive a microdose, it is necessary to divide a 100 mg tablet in half or into 4 parts of 200 mg. If you plan to take the drug in a microdose, then it is better to buy tablets with a dosage of 100 mg - they are easier to divide into equal parts. Although some people use a different method to obtain microdoses: they grind the tablet into powder, and then divide it into the required number of servings. By the way, if you add modafinil in powder form, for example, to juice or smoothie and drink it in this form, then it will penetrate the bloodstream faster, which means that the effect will also come in a shorter time.

And keep in mind that if you take armodafinil in microdosage, the effect from it will be slightly stronger than from a similar dose of modafinil.

Indications for taking modafinil at a dosage of 50 mg:

• there is increased sensitivity to the drug;
• you are just starting to take this remedy;
• plan to take pills daily for a long time;
• want to minimize the risk of side effects.

Usual Dosage for Cognitive Enhancement (200 mg)

200 mg is the most popular dosage used to improve cognitive function. And by the way, most generic modafinil, for example, Modalert, are produced in exactly this dosage. But do not forget that the equivalent dose for armodafinil is 150 mg, so Artvigil and Waklert come with exactly this dose.

Benefits of taking 200 mg modafinil:

• causes a noticeable improvement in cognitive functions;
• most studies of the effect of modafinil on the human body are related to this dosage;
• convenient form for reception;
• In online stores they most often sell exactly this dosage.

Large doses to improve cognitive function (400 mg)

In some cases, you may need to take a higher dose of modafinil. The maximum safe dose of the drug is 400 mg. Higher levels significantly increase the risk of unwanted side effects.

A dosage of 400 mg may be needed for very large people, as well as for people who have developed an addiction to it due to prolonged use of the drug.

This dosage is contraindicated for individuals who are just starting to take modafinil. They may cause a variety of side effects, including insomnia and anxiety. Even people with taller than average height should start taking modafinil with a small dosage of 50 or 100 mg. This will allow you to determine your sensitivity to the drug, as well as ensure that you are not allergic to it.

The equivalent dose of 400 mg of modafinil is 250 mg of armodafinil. Meanwhile, we draw your attention to the fact that most manufacturers of armodafinil produce it in a dosage of 150 mg. But if you take 2 tablets at once, you get 300 mg of armodafinil, which is much more than the equivalent of 400 mg of modafinil.

Benefits of modafinil 400 mg:

• the ability to get the most powerful effect without exceeding the safe dosage;
• a more acceptable option for people of large build;
• more suitable for people with rapid metabolism of drugs;
• A good option for short-term use of modafinil.

Choosing an antidepressant based on effectiveness and tolerability

Summary

A classification of side effects of antidepressants is presented. Side effects may be toxic or neuronal. Neuronal side effects are divided into “non-therapeutic” (persistent or reversible) and “para-therapeutic” side effects. Seven categories of antidepressant tolerability have been defined. The lowest category VII included clomipramine, imipramine, maprotiline, agomelatine. Category VI includes amitriptyline, V - pipofezin, trazodone, mianserin and mirtazapine, IV - vortioxetine, III - venlafaxine and duloxetine, II - sertraline, paroxetine, citalopram, escitalopram, fluoxetine, fluvoxamine and milnacipran, I - pirlindole and moclobemide. Among the most effective antidepressants (amitriptyline, imipramine, venlafaxine in high daily doses), venlafaxine had the best tolerability category. This drug is the most effective and tolerable antidepressant. Other options for the practical use of classifications are discussed.

Summary

A classification of the side effects of antidepressants is presented. Side effects can be toxic or neuronal. Neuronal side effects are divided into “extratherapeutic” (persistent or reversible), as well as “paratherapeutic”. Seven antidepressant tolerance categories have been identified. The lowest category VII included clomipramine, imipramine, maprotiline, agomelatine. Amitriptyline belongs to the VI category, pipofezin, trazodone, mianserin and mirtazapine to the V category, vortioxetine belongs to the IV category, venlafaxine and duloxetine to the III category, sertraline, paroxetine, citalopram, escitalopram, fluoxetine, fluvoxamine and milnacipran to the II category, and pirlindole and moclobemide to the I category. Among the most effective antidepressants (amitriptyline, imipramine, venlafaxine in high daily doses), venlafaxine was in the best category of tolerance. This drug is the most effective and tolerable antidepressant. Other options for the practical use of classifications are discussed.

The previous article presented a description of the mechanism of action of various antidepressants (tricyclic - TcA, sertonin-modulating - SMA, tetracyclic - CtsA, reversible inhibitors of monoamine oxidase type "A" - OIMAO-A, selective serotonin reuptake inhibitors - SSRIs, selective serotonin and norepinephrine reuptake inhibitors – SNRIs, norepinephrine and selective serotonin – NaSSA, melatonergic – MeA, multimodal – MmA) (Table 1).

Table 1. Antidepressants known in Russia, their effect on neurons and the “formula” of the mechanism of action (1-4).

* - white color - the drug does not affect neurons, dark gray - a pronounced increase in activity, light gray - a moderate increase in activity, ** - in high doses, IOR - neurotransmitter reuptake inhibitors, SVRR - agents affecting regulatory receptors, OIMAO-A are reversible inhibitors of monoamine oxidase type “A”.

All these drugs, to varying degrees, contribute to the activation of serotonin (↑C or ↑c), norepinephrine (↑H or ↑n), dopamine (↑D or ↑d) or melatonin (↑M or ↑m) neurons, the “tone” of which decreases for depression. But the most pronounced effect on the vital activity of neurons is ↑SNd antidepressants: amitriptyline and imipramine (TcA), as well as venlafaxine (SNRI) in high daily doses. It is no coincidence that many experts consider them to be the most effective drugs for treating depression (5).

Of course, the choice of any antidepressant should be related not only to its therapeutic properties (efficacy), but also to side effects (tolerability). The vast majority of authors agree that tolerability is best with SSRIs and worse with TCAs (6–9), with other drugs falling in between (1). This assessment of the tolerability of antidepressants is correct, but is of a generalized nature. To clarify it, you should refer to data on the mechanisms of side effects.

A minority of them are due to the toxic effect of antidepressants on the organs and tissues of patients. These “toxic” side effects are very dangerous (10). For example, while taking some TCAs (clomipramine, imipramine), as well as MeA (agomelaptine), drug-induced hepatitis is observed, which leads to the death of patients (10, 11). Maprotiline also has serious toxic side effects, causing agranulocytosis and leukopenia (12). Fortunately, toxic side effects are very rare and can be detected promptly by test results.

For example, when it was discovered that agomelatine causes severe and drug-induced hepatitis, detailed precautions were added to its instructions (11). They include a biochemical blood test, which is prescribed to all patients (without exception) before prescribing the drug, as well as while taking it. Similar analysis is required in patients receiving clomipramine and imipramine (13,14). However, when prescribing these antidepressants, biochemical analysis is required only for patients with existing liver diseases. Finally, regular general blood tests to detect agranulocytosis and leukopenia are also necessary during maprotiline treatment (12).

Obviously, the need for additional tests can significantly complicate the use of antidepressants. Fortunately, this is only required when using the medications listed. When prescribing other antidepressants, there is no need to resort to additional examinations. However, their tolerability may be impaired due to the drugs' adverse effects on neurons. As a result, “neural” side effects are formed, which, however, do not directly threaten the lives of patients and are easily diagnosed based on their complaints.

Some of the neuronal side effects are due to the effect of the antidepressant on histamine and acetylcholine neurons, which do not reduce their activity in the formation of mental disorders that are indications for the prescription of antidepressants (2,15). Accordingly, such pharmacological properties can be designated as “non-therapeutic” (extra, unrelated to the treatment process) side effects. They only increase the number of neuronal systems that the patient suffers. Most often, “non-medicinal” side effects are persistent. They may occur throughout the course of treatment, particularly when the antidepressant blocks excitatory receptors on histamine and acetylcholine neurons (15).

This mechanism of action, characteristic of neuroleptics rather than antidepressants, leads to a sharp drop in the activity (inhibition) of these nerve cells (↓G and ↓A) (1,2). Moreover, normal histamine and acetylcholine neurons cannot restore their functions, since there are no effective compensatory mechanisms for this. Accordingly, patients develop persistent mental and somatic symptoms, which seriously complicate treatment (Table 2).

Table 2. The main “non-therapeutic” side effects of antidepressants associated with the blockade of excitatory receptors on histamine and acetylcholine neurons (1,2)

Characterized by drowsiness, fatigue, deterioration of memory and attention. There are complaints of dry mouth, disturbances of accommodation and urination, constipation, pain in the eyes due to increased intraocular pressure, heart rhythm disturbances, increased appetite and weight gain.

There is, however, an antidepressant whose “non-medicinal” side effects are not persistent. This drug is vortioxetine. It does not inhibit histamine and acetylcholine neurons (due to blockade of excitatory receptors), but increases their “tone” due to its influence on regulatory receptors (16). On the one hand, this provides vortioxetine with a unique nature of “non-therapeutic” side effects. In particular, when taking this antidepressant, agitation, anger, “unusual” dreams, and insomnia may occur (Table 3).

Table 3. “Non-medicinal” side effects of vortioxetine (16,17).

Characterized by ketoacidosis, somatic complaints of dizziness, itching (including generalized), sweating, hot flashes, nausea, diarrhea, vomiting. On the other hand, these side effects are fundamentally reversible, since neurons have special mechanisms that are aimed at combating excessive activation. To do this, they can, for example, reduce the sensitivity of their regulatory receptors (a mechanism known as autoregulation). Therefore, “non-therapeutic” side effects of vortioxetine often reduce spontaneously in the first two weeks of treatment (16).

Moving now to the rest of the antidepressants, we point out that the vast majority of them do not have any “non-therapeutic” side effects that increase the number of affected neuronal systems (2). Many drugs do not affect histamine and acetylcholine neurons. Moreover, they increase the activity of only those neurons (serotonin, norepinephrine and dopamine) whose “tone” decreases in mental disorders that are indications for the prescription of antidepressants. However, even this feature cannot relieve antidepressants from “neural” side effects. The latter will arise due to the fact that within any affected neuronal system, the activity of only part of the nerve cells decreases, while the functions of the other part are not impaired. Antidepressants both activate “damaged” neurons and create therapeutic effects, and increase the “tone” of normally functioning nerve cells and cause side effects.

At the same time, the tolerability of antidepressants paradoxically turns out to be “hostage” to their therapeutic properties. The more effectively the drug activates the affected neurons, the more it affects similar nerve cells that are still functioning at the proper level. Therefore, it is advisable to designate the side effects under consideration as “paratherapeutic”. They are manifested by restlessness, restlessness, insomnia and anxiety (Table 4).

Table 4. Main “paramedical” side effects of antidepressants (15)

Somatic complaints are represented by sexual dysfunction, disruption of the digestive system and heart rhythm, and fluctuations in blood pressure. As a rule, “paratherapeutic” side effects are reversible. They may resolve on their own in the second or third week of treatment (18). This is due to the already noted above ability of “normal” neurons to quickly adapt to excessive activation, reducing their sensitivity to neurotransmitters (2)2.

The presented data on toxic and neuronal side effects can be used to classify antidepressants into seven tolerability categories, with the seventh being the worst and the first being the best (Table 5).

Table 5. Categories of tolerability of antidepressants, taking into account toxic and neuronal side effects.

Thus, antidepressants from the lowest category VII (clomipramine, imipramine, maprotiline, agomelatine) have toxic side effects that directly threaten the lives of patients. Moreover, when prescribing them, additional examination of patients is required. Problems with tolerability of other antidepressants are due to neuronal side effects. All of them are not fatal, and their identification usually does not require additional examination.

Neuronal side effects are divided into “non-therapeutic” and “para-therapeutic” side effects. The first, as already mentioned above, are associated with “additional” dysfunction of histamine and acetylcholine neurons, which do not reduce their activity in mental disorders that are indications for the prescription of antidepressants. Accordingly, “non-therapeutic” side effects that expand the range of affected neuronal systems determine whether drugs belong to lower tolerability categories (VI, V and IV). In particular, amitriptyline promotes a persistent decrease in the activity of histamine and acetylcholine neurons and is therefore classified as tolerability category VI. “Non-therapeutic” side effects of antidepressants classified as category V are more limited. After all, pipofezin, trazodone, mianserin and mirtazapine contribute to a persistent decrease in the activity of only histamine neurons. Vortioxetine is classified into the next higher tolerability category IV. This antidepressant has the ability to increase the activity of histamine and acetylcholine neurons. However, the associated side effects are often reversible.

The highest tolerability categories I – III include antidepressants that act only on serotonin, norepinephrine and dopamine neurons, which suffer in mental disorders that are indications for prescribing drugs. These drugs are characterized by “paratherapeutic” side effects that do not increase the number of affected neuronal systems (Table 5). They arise due to the activation of part of the serotonin, norepinephrine and dopamine neurons, which still maintain normal “tone” (2). At the same time, the severity of “paratherapeutic” side effects depends, first of all, on the ability of the antidepressant to affect serotonin and norepinephrine nerve cells, since they all have a weak effect on dopamine nerve cells (Table 1).

Accordingly, tolerability category III includes antidepressants that simultaneously effectively activate serotonin and norepinephrine neurons. These drugs are venlafaxine and duloxetine (Tables 1 and 5). The first of them, depending on the dose, is a ↑SN- or ↑SNd-antidepressant. As for duloxetine, it has the properties of a ↑CH drug. Category II includes antidepressants that promote pronounced activation of only serotonin or only norepinephrine neurons (Tables 1 and 5). These include all ↑C-antidepressants (sertraline, paroxetine, citalopram, escitalopram, fluoxetine, fluvoxamine), as well as the ↑sND antidepressant – milnacipran. Finally, the highest category I of tolerability is possessed by drugs that are not capable of strongly activating serotonin and norepinephrine neurons (Tables 1 and 5). These are two ↑SND antidepressants - pirlindole and moclobemide.

In conclusion, it should be noted that the presented classification of antidepressants by tolerability does not pretend to be comprehensive. However, it provides clear criteria for assessing the main side effects, which allow different drugs to be compared with each other. This seems to be especially significant in a situation where there are no clear recommendations for taking into account side effects when prescribing antidepressants. For example, a generalized formula is currently used in various publications and instructions. It is recommended that an antidepressant be used “only after a careful assessment of the expected benefits versus risks in patients” (11). But the results of such a “careful assessment” are usually in favor of prescribing the drug.

In particular, about agomelatine they write that if all the requirements of the instructions for prescribing an antidepressant are met, then the risk of developing drug-induced hepatitis becomes minimal (19). At the same time, the unique mechanism of action attributed to agomelatine allows us to state that the benefits of prescribing an antidepressant are much greater than the certain inconveniences that are associated with its hepatotoxicity (19). Meanwhile, the uniqueness of the mechanism of action of agomelatine comes down to the possibility of influencing the neurons of the suprachiasmatic nucleus, the neurotransmitter of which is melatonin. And this effect is not at all required for the treatment of depression, since any antidepressant that activates serotonin and norepinephrine neurons can compensate for the deficiency of melatonin activity (20).

The “careful assessment” recommendations presented here are not the only example of facile judgments regarding the tolerability of antidepressants. Some authors believe that side effects are poorly related to the mechanism of action of the drugs. It is argued that side effects are nonspecific, probabilistic and therefore almost unpredictable (18). Other authors are at least looking for the reasons for the formation of side effects in order to take them into account when prescribing antidepressants. Unfortunately, they find these reasons not in the mechanisms of action of the drugs, but in the characteristics of depression, public opinion or the psychology of the patient.

Thus, it is reported that even with the use of any “most easily tolerated drugs in 80% of patients with mild to moderate depression” (21), heterogeneous adverse events are observed. They most often occur in dysthymia, early depressive states, with anxiety and somatic symptoms (21, 22), in people over 45 years of age, with high body weight deficiency (22), and a history of negative placebo reactions (23). It is reported that poor tolerability of antidepressants is associated with patients’ high demands on quality of life (24) and their concerns about social maladjustment (25). An initially negative attitude towards psychiatry on the part of public opinion, the patient’s low awareness of his own illness and the therapy recommended by the doctor, unsatisfactory experience of previous treatment, etc. also contribute to the problem. (22, 26).

The speculative nature of such constructions is obvious. To refute them, it is enough to say that the side effects of drugs, according to the WHO definition, are caused by their pharmacological properties (37). It is difficult to imagine that inhibition of histamine and acetylcholine neurons arises due to the patient’s high demands on quality of life, excessive activation of serotonin, norepinephrine and dopamine neurons due to negative attitudes towards psychiatry from public opinion, and drug-induced hepatitis due to concerns about social maladjustment.

Thus, the presented classification of antidepressants according to tolerability categories allows us to return the study of side effects to the mainstream of biological psychiatry. In addition, this classification is easy to use in practical medicine. In particular, the lower the category of tolerability of an antidepressant, the greater the need for a special justification for its prescription (efficacy, positive experience of treatment in the past, the patient’s desire, etc.). In turn, the appearance of such a detailed justification in the medical history will allow one to avoid many problems (psychological, social and other) that arise during the treatment process between the doctor and his patient.

Using the presented classification, it is easy to resolve the issue of choosing the most effective and tolerable antidepressant. This requires only comparing the tolerability categories of the most effective drugs: amitriptyline (TcA), imipramine (TcA) and venlafaxine (SNRI) (5). The first of them (amitriptyline) belongs to category VI of tolerability (Table 5). The side effects of the second antidepressant (imipramine) are even more serious. This drug belongs to category VII of tolerability. As for venlafaxine, the side effects of this antidepressant are much weaker, and this drug belongs to category III of tolerability. Thus, venlafaxine, when used in high doses, is the most effective and tolerable drug in the treatment of depression.

Venlafaxine is well known in our country under the trade name Velaxin (Egis). This drug has been studied in leading scientific organizations conducting advanced research in the field of psychiatry. Among them are the Federal State Budgetary Institutions “State Scientific Center for Social and Forensic Psychiatry named after V.P. Serbsky" and "Moscow Research Institute of Psychiatry" of the Russian Ministry of Health, St. Petersburg Research Institute named after. V.M. Bekhterev (28,29). Long-acting capsules (Velaxin retard) are also well known (30), with the use of which there is a significant reduction in the frequency of such side effects of the drug as nausea (31). In addition, the study of Velaxin was successfully carried out not only in psychiatry, but also in neurology (32).

A video by M.Yu. Drobizhev on the same topic can be viewed at the link: https://www.youtube.com/watch?v=SwtO_bC_838&t=11s

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4. Shagiakhmetov F.Sh., Anokhin P.K., Shamakina I.Yu. Vortioxetine: mechanisms of multimodality and clinical effectiveness. Social and Clinical Psychiatry 2016;26(4): 84-96
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6. Anderson I.M. SSRIS versus tricyclic antidepressants in depressed inpatients: a meta-analysis of efficacy and tolerability. Depress. Anxiety. 1998;7(Suppl 1):11-17.
7. Anderson IM, Nutt DJ, Deakin JF. Evidence based guidelines for treating depressive disorders with antidepressants: a revision of the 1993 British Association for Psychopharmacology guidelines. J Psychopharmacol. 2000;14:3-20.
8. Peretti S, Judge R, Hindmarch I. Safety and tolerance considerations: tricyclic antidepressants vs. selective serotonin reuptake inhibitors. Acta Psychiatr. Scand. 2000; Suppl. 403: 17-25.
9. Wilson K, Mottram P, Sivanranthan A, Nightingale A. Antidepressant versus placebo for depressed elderly. 2001. Cochrane. Database. Syst. Rev. CD000561.) and worse in TsA
10. LiverTox. https://livertox.nlm.nih.gov
11. Valdoxan - instructions for medical use of the drug. https://medi.ru/instrukciya/valdoksan_5084/
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13. Anafranil tablets - instructions (information for specialists) on the use of the drug. https://medi.ru/instrukciya/anafranil-tabletki_8616/
14. Melipramine tablets - official instructions for use. https://medi.ru/instrukciya/melipramin-tabletki_4780/
15. Drobizhev M.Yu., Ovchinnikov A.A., Kikta S.V. Why do antidepressants have side effects? Pharmateka. 2015. No. 20 (313). pp. 72-77.
16. Brintellix. https://www.rlsnet.ru/tn_index_id_87791.htm
17. Subeesh V, Singh H, Maheswari E, Beulah E. Novel adverse events of vortioxetine: A disproportionality analysis in USFDA adverse event reporting system database. Asian J Psychiatr. 2017 Dec;30:152-156. doi: 10.1016/j.ajp.2017.09.005.
18. Borodin V.I. Tolerability of treatment in patients with depressive disorders (comprehensive analysis). Author's abstract. for the job application ... doc. honey. Sci. Moscow. 2009.
19. Freiesleben SD, Furczyk KJ A systematic review of agomelatine-induced liver injury. Mol Psychiatry. 2015 Apr 21;3(1):4. doi:10.1186/s40303-015-0011-7. eCollection 2015.
20. Drobizhev M.Yu. Time of meta-analyses and the effectiveness of antidepressants in depression. Social and clinical psychiatry. 2017;4:81-88.
21. Aldushin A.A. Prediction of tolerability and refusal of antidepressant therapy based on the analysis of nocebo effects. Russian Psychiatric Journal. 2009; 3:55-61.
22. Avedisova A.S., Borodin V.I., Aldushin A.A. Comparison of the effectiveness and tolerability of antidepressants of different groups for mild and moderate depression. Journal of Neurology and Psychiatry. S.S. Korsakov. 2006;11:15-19.
23. Lapin I.P. Personality and medicine. Introduction to the psychology of pharmacotherapy. -SPb.: Dean, 2001.-416С.
24. Roberis H. Neurotic patients who terminate their own treatment. Br. J. Psychiatry. 1985; 146 (4):443-445.
25. Mosolov S.N., editor. A reference guide to psychopharmacology. Psychopharmacological and antiepileptic drugs approved for use in Russia: 2nd ed. BINOM, Moscow, 2004. - 304C.
26. Avedisova A.S., Borodin V.I. Noncompliance or refusal of psychopharmacotherapy? Russian Psychiatric Journal. 2006; 1:61-65.
27. https://vmede.org/sait/?id=Farmakologija_klin_farm_y4ebnik_kykes_2009&menu=Farmakologija_klin_farm_y4ebnik_kykes_2009&page=7
28. Krasnov V.N., Kryukov V.V. Velaxin® (venlafaxine) in modern treatment of depression: results of the first Russian multicenter study of effectiveness and safety. Psychiatry and psychopharmacotherapy. 2007;9 (4), https://www.consilium-medicum.com/magazines/special/psychiatry/article/15426
29. Mosolov S.N., Kostyukova E.G., Gorodnichev A.V., Timofeev I.V., Ladyzhensky M.Ya., Serditov O.V. Clinical efficacy and tolerability of venlafaxine (Velaxin) in the treatment of moderate and severe depression. Modern therapy of mental disorders. 2007;3:58-63.
30. Avedisova A.S., Zakharova K.V., Kanaeva L.S., Vazagaeva T.I., Aldushin A.A.. Comparative study of the effectiveness and tolerability of Velaxin and long-acting Velaxin. Psychiatry and psychopharmacotherapy. 2009;11(1):36-40.
31. Avedisova A.S. Venlafaxine (Velaxin): results of international studies of a third generation antidepressant. Psychiatrist. and psychopharmacoter. 2006; 11 (2): 2-7.
32. Mosolov S.N. Clinical use of modern antidepressants. St. Petersburg, 1995.-565С.).

M.Yu. Drobizhev , Doctor of Medical Sciences, Head of the educational department of the Training Center of the Association of Medical and Pharmaceutical Universities of Russia. Contact Information -

E.Yu. Antokhin , Candidate of Medical Sciences, Associate Professor, Head of the Department of Clinical Psychology and Psychotherapy of the Orenburg State Medical University of the Russian Ministry of Health.

R.I. Palaeva is an assistant at the Department of Clinical Psychology and Psychotherapy at the Orenburg State Medical University of the Russian Ministry of Health.

S. V. Kikta , Candidate of Medical Sciences, Head. Department of the Federal State Budgetary Institution "Polyclinic No. 3" of the Administration of the President of the Russian Federation, Moscow

1 There are probably side effects due to excessive activation of melatonin nerve cells. However, they are not yet described even in the instructions for agomelatine, a melatonergic drug that has a direct effect on them (11).

2 Theoretically, “para-therapeutic” side effects can be observed even against the background of “non-therapeutic” side effects. After all, any antidepressant activates serotonin, norepinephrine or dopamine neurons to varying degrees. However, the drugs are dominated by “non-therapeutic” side effects, if only because they are most often persistent. At the same time, “paratherapeutic” side effects are always reversible. In addition, not all antidepressants that have “non-therapeutic” side effects are capable of seriously activating serotonin, norepinephrine and dopamine neurons.

Side effects of modafinil

Like most pharmaceuticals, modafinil can cause side effects in some cases. As a rule, they are minor and are not hazardous to health. Most often, side effects manifest themselves in the form of insomnia, discomfort in the digestive system, headaches, dry mouth, and decreased appetite. Such symptoms most often appear when taking high doses of the drug.

A dosage of 50 mg extremely rarely causes adverse reactions, while people taking 400 mg of modafinil quite often complain of headaches and insomnia.

Side effects can be prevented by reducing the dosage of the medication and not combining it with other stimulants such as coffee or tea. A good way to protect yourself from the side effects of modafinil or reduce their intensity is to drink plenty of water daily (2-3 liters).

Effects of Hydrafinil:

- Wakefulness. The substance has recently begun to be used in medicine to suppress daytime sleepiness.

- Stimulation. The secondary effect is an increase in stimulating neurotransmitters.

- Mood. The secondary effect, an increase in serotonin, can improve well-being in low mood, but not in normal mood.

- Learning ability. Hydrafinil improves acetylcholine metabolism in 2 ways at once! This helps bring the brain to a better state for intellectual tasks.

Overall, people report a powerful, smooth effect. The speed of task completion increases, along with quality. It becomes easier to carry out routine activities. There are also more expressive reviews, you can Google them yourself with a translator!

Recommended dosages for beginners

You should start taking any medicine or dietary supplement (dietary supplement) with a minimum dosage, gradually increasing it. This method allows you to check how the body reacts to the components of the drug, whether there is an allergy to them, and also determine how quickly the metabolism and elimination of the active substance occurs.

Almost all medications entering the human body are metabolized in the liver. To do this, the liver uses a set of specific enzymes that break down chemicals. Each of them is programmed by specific genes, which are called CYP450 isoenzymes.

Because all CYP450 genes are unique, some people are better able to break down some chemicals but less able to break down others. In fact, this phenomenon explains why some people need to constantly drink coffee throughout the day to maintain their energy, while others remain active after only one cup of drink. The fact is that the organisms of the latter cannot break down caffeine as efficiently as the former. And the reason for this is the polymorphism of CYP450.

The same thing happens with modafinil. Therefore, before using maximum doses immediately, it is necessary to check the rate of breakdown of the substance. People whose bodies have difficulty breaking down modafinil will feel its effects for quite a long time, even if a small dose was taken.

In addition, if you take the medicine daily, its concentration in the blood increases over time. And this also requires a dose reduction.

Recommended dosage schedule for beginners

Modafinil can be an extremely useful drug when it comes to improving performance and productivity. However, due to possible unwanted side effects, it is very important to maintain a safe dosage of this medication. Start taking this remedy with 50 or 100 mg, gradually increasing your personal daily requirement. Remember, the safe amount of modafinil (Modalert, Modvigil) is 100-400 mg, and the safe amount of armodafinil (Wakler, Artvigil) is 50-250 mg.

And do not forget that while taking modafinil it is important to eat properly and drink plenty of clean water. This will help prevent possible side effects.

VIAGRA FOR THE BRAIN

Stephen Hall

Neuroscientists are intensively studying new generation drugs designed to improve memory and mental performance. Meanwhile, there has been a noisy discussion in society about their possible use by healthy people.

On a cold April day, Tim Tully and I were in the laboratory trying to peer into the future of human memory and thinking. The capricious elements of spring covered Long Island spread out outside the window with snow. The snowfall suddenly reminded me of the distant winters in the Midwest, where my friend and I spent our childhood. The powerful power of memory has inspired the coming revolution in neuropharmacology.

Tim Tully is a neuroscientist and founder of Helicon Therapeutics, one of the main developers of a new class of drugs that can improve partially lost memory. The drugs were born as a result of complex research into one of the most mysterious and amazing abilities of our brain, thanks to which we remember snowfalls 30 years ago and the place where we left the car 30 minutes ago.

On that memorable day in April, Tim and I stood in front of an experimental box in which a laboratory mouse was solving a tricky problem called “Object Recognition Learning.” A friend explained to me that the day before the animal was placed in a box where there were two bizarre knobby objects that differed in olfactory, tactile and other sensory characteristics. “We let the mouse explore its environment for 15 minutes,” Tully said, “but it remembers it so well that the next day it immediately detects any small change. But a rodent, who is given only 3.5 minutes to familiarize himself with the box, does not have enough time for long-term memorization of the situation.”

Our mouse had to learn to recognize objects in 3.5 minutes. But Tully decided to demonstrate this experiment to me because the animal had previously been administered a certain pharmacological drug. Hastily, like a sports commentator, the friend described the course of events when the mouse’s attention was riveted for a long time by a new object in the box. “There she is, approaching him. Goes around. Climbs up. And at the same time, zero attention to a familiar object,” the scientist explained. The mouse indeed sniffed and circled exclusively around the new object, completely ignoring the old one - the one that it had already examined the day before.

To show such intense curiosity, the animal had to remember the objects that were in the box the day before. And this requires the formation of long-term memory. And although many years of experimental work have found that mice typically do not detect any changes within 3.5 minutes, ours coped with the task without difficulty. And all thanks to the memory stimulant, known by the abbreviation CREB (the drug must pass a safety test at the end of this year).

Today, the main “consumers” of the latest pharmacological drugs are “erudite mice” and “intellectual rats.” They are used to test substances that may be able to stimulate human mental activity, improve memory in patients with neurodegenerative diseases, in stroke victims and people with mental retardation. The potential market for such drugs is truly enormous. In the United States alone, 4 million people have Alzheimer's disease, 12 million have a disorder known as mild cognitive decline (which often precedes the development of Alzheimer's disease), and 76 million people over 50 have forgetfulness or more. serious forms of memory impairment. Ginkgo biloba preparations are sold in the United States for more than $1 billion annually (even though there is almost no evidence that this plant improves memory). The drug's sales in Germany exceed those of all acetylcholinesterase inhibitors used to halt memory decline in Alzheimer's disease, including donepezil (Aricep), rivastigmine (Exelon) and galantamine (Reminyl).

Despite the constant flow of information about the coming revolution in the creation of drugs, figuratively called “Viagra for the brain” by one magazine, one can hardly expect their appearance on the market in the near future. Cortex Pharmaceuticals has developed a new class of memory stimulants called ampakines, which are thought to increase levels of the neurotransmitter glutamate in nerve tissue. They are currently being tested for their effectiveness in treating Alzheimer's disease, mild cognitive decline, and schizophrenia.

The number of such studies is steadily growing. In early 2004, memory-enhancing drugs developed by Helicon Therapeutics and Memory Pharmaceuticals will begin testing. The New York company Axonyx is busy testing its drug phenserine, a powerful acetylcholinesterase inhibitor intended to treat Alzheimer's disease.

The famous neuroscientist from Princeton University, Joe Z. Tsien, suggested that Eurekal Pharmaceuticals from San Francisco, collaborating with scientists from Shanghai, develop drugs that would combine the achievements of modern genetics with the properties of drugs used in ancient Chinese herbalism.

Although most of the new generation of drugs will not soon receive official approval from the authorities, their possible use has already caused a strong public outcry. The head of the President's Council on Bioethics, moral philosopher Leon R. Kass, believes that “in those areas of human life where people have hitherto achieved success solely through discipline and dedication, achievements obtained through the use of pills, genetic engineering or technical transplants, smack of fraud or cheapness.”

On the other hand, the consumption of “mental stimulants” has become an integral part of the human lifestyle since people started drinking coffee. If the new “brain activators” are indeed destined to become “brain Viagra” and take a strong place in our daily lives, then a logical question arises: how can this happen and how widespread can their use become? Let us recall the history of previous generations of “psychomotor stimulants” that at one time received official approval from the authorities: methylphenidate (other names - Meridil, Ritalin, etc.), donepezil and modafinil, which were developed exclusively for therapeutic purposes. Today, these drugs are taken by many healthy people hoping to increase mental performance. They firmly believe in their miraculous properties, despite the fact that almost no scientific evidence has been found. As some experts hint, these medications are no different in their “stimulating” effect from the products that make up our regular breakfast.

Invincible caffeine

Researchers from military departments have been searching for means to stimulate the cognitive functions of the brain for many years. Nancy Jo Wesensten of the Walter Reed Army Research Institute is developing pharmacological drugs to increase the level of alertness (and therefore combat readiness) of soldiers forced to go without sleep for long periods of time. In July 1998, she happened to stop at the booth of the biotech company Cephalon and chatted with its sales representative. At that time, the company was just awaiting approval from the US Food and Drug Administration (FDA) for the clinical use of the drug under the international name modafinil. Under the patented name Provilig, the drug is used to treat narcolepsy - deep daytime sleepiness, which affects more than 125 thousand Americans. When it became clear that modafinil could find use in the US Army, Cephecon provided it for military research.

The events described took place five years ago. In December 1998, the FDA approved the sale of modafinil as a treatment for narcolepsy, and today more than $200 million worth of the drug is produced annually, which some experts say is far more than what narcoleptics living in the United States need. “Psychiatrists prescribe it to patients a ton to improve their mood,” says Helene Emsellem, who directs the Sleep-Wake Disorders Center in Chevy Chase, Maryland. In fact, modafinil has emerged as a means of stimulating mental performance, reducing the need for sleep, treating depression, multiple sclerosis, and enhancing performance.

But let's return to Nancy Wesenstein's research. “We were particularly interested in whether modafinil had any benefits over caffeine, which we think is very effective at counteracting the negative effects of insomnia,” she says. “In addition, the drug is available to the general population and has almost no side effects.” Wesenstein conducted a test on 50 volunteers who remained awake for 54 hours. Forty hours after the start of the experiment, they received a placebo, 600 mg of caffeine (a dose equivalent to six cups of strong coffee) or one of three doses of modafinil (100, 200 or 400 mg) and then completed a series of tests designed to assess mental performance and the severity of side effects. effects of drugs.

At the highest doses (400 mg), modafinil effectively relieved fatigue and restored mental activity. But caffeine had exactly the same effect. The side effects of modafinil (as well as caffeine) were very minor. “I believe there is no reason to use modafinil instead of caffeine,” Wesensteen says. “The substances are almost identical in their effects.”

Means for increasing the performance of military personnel are also being intensively studied by US Air Force specialists.
According to sleep disorder specialist John A. Caldwell, the use of amphetamines as "readiness pills" for pilots was approved during World War II. In 1993, Caldwell found that dextroamphetamine almost completely restored the performance of pilots who spent 40 hours without sleep. The researcher later compared the stimulant effects of modafinil and dextroamphetamine and their impact on the performance of military personnel subjected to forced long-term insomnia. Modafinil effectively relieved fatigue and restored cognitive function of the brain, but caused nausea in some subjects. “I think modafinil will eventually find its way into the world and get official approval as a drug,” the scientist says. “But I don’t think it will replace our tried and tested “combat readiness pill.” Dextroamphetamine has undergone numerous laboratory tests and has been performing well in combat situations for half a century. But modafinil is still a dark horse. HOW “MEMORY STIMULANTS” WORK

A number of drugs designed to improve memory act primarily on two processes that develop in neurons during memory consolidation: membrane depolarization and activation of the CREB protein. Depolarization occurs after the release of the excitatory neurotransmitter glutamate at the synapse (the area of ​​contact between two nerve cells) stimulates AMPA receptors on the surface of the neuron receiving the nerve signal. Under the influence of depolarization, another surface protein, the NMDA receptor, also reacts to glutamate. As a result, a complex sequence of molecular interactions is activated inside the cell, including the formation of cyclic AMP and, as a consequence, the activation of the CREB protein. (The broken arrows indicate parts of this process, omitted to simplify the diagram.) The latter event is crucial for memory consolidation: activated CREB helps “turn on” the genes responsible for the synthesis of proteins that strengthen certain synapses.

Some other drugs speed up memory processes by enhancing the response of AMPA receptors to glutamate, i.e. by facilitating depolarization. And still others increase the level of active CREB in cells - for example, by suppressing the activity of the phosphodiesterase enzyme, which destroys cyclic AMP.

Modafinil, Ritalin, donepezil...

Modafinil is one of a long line of drugs that have a large following among healthy people. There are legends about the miraculous aid Ritalin provides to students in their studies. The medicine is usually prescribed to hyperactive children with impaired ability to concentrate. However, both students and businessmen are addicted to it. “That's true,” says Eric Heiligenstein, chief psychiatrist at the University of Wisconsin Health Services. “Although it is almost impossible to accurately determine the amount of Ritalin consumed by students, it is clear that the number of regular users is very small, but much higher than the number of modafinil adherents - after all, Ritalin is “readily available, relatively cheap and does not cause much harm to health.”

The effects of Ritalin and similar drugs on healthy people have been little studied. But at least one study has shown that long-term use of one of the “psychostimulants” actually improves mental performance. In July 2002, Jerome A. Yesavage of Stanford University and Peter J. Whitehouse of Case Western Reserve University wrote about the effects of donepezil on pilot performance. Donepezil (trade name Aricept) is one of many drugs that have received FDA approval for the treatment of progressive memory loss in Alzheimer's disease. Two groups of pilots were trained to perform a series of tasks in a flight simulator. Then, for 30 days, subjects in one group received a placebo, and in the other, donepezil at a dose of 5 mg per day (less than the usual therapeutic dose of the drug). After which the pilots from both groups were again subjected to ingenious tests in the simulator cockpit.

Pilots had to perform complex "air" maneuvers and at the same time respond to periodic emergencies (for example, a sharp change in instrument readings indicating a drop in oil pressure). After a month, the pilots who received donepezil performed significantly better on test tasks than those in the control group (especially in cases where the task involved “plane landing” or unexpected failures in the operation of control systems). According to Yesavage, if it turns out that intellectually competent people can improve their mental abilities with the help of chemical drugs, serious legal, administrative and ethical issues could arise. And if this prophecy comes true in relation to donepezil, modafinil and other drugs, it will even more affect the “smart pills” of the new generation - after all, they are created not thanks to random scientific discoveries, but as a result of a powerful and targeted attack by scientists on human memory.

Drugs that can improve cognitive activity of the brain are used mainly to treat dementia and other diseases. Some commercially available drugs are being tested or are already being used to improve performance in healthy people (for example, to combat drowsiness in night shift workers or to improve the performance of pilots under stress).

Mind-blowing memory

When Axel Unterbeck, president and chief scientific officer of the pharmaceutical company Memory Pharmaceuticals, showed me around his vast holdings in northern New Jersey, he ended almost every segment of our lengthy tour with the words: “Top notch!” And in the electrophysiology laboratory, where researchers study the effects of potential “memory stimulants” on individual neurons and brain slices of animals, and in the vivarium, where drugs are tested on adult rodents, and in the pharmacokinetics rooms, where the incessantly clicking and humming machines tirelessly analyze blood samples animals and people, everywhere - “At the highest level!”

In early 2003, Memory Pharmaceuticals began testing the safety of a drug intended to improve memory and mental performance, a compound called MEM 1003. This substance, which regulates the transport of calcium ions into neurons, is designed to restore calcium balance in brain cells during illness. Alzheimer's, mild mental decline, or "vascular dementia." “In terms of pharmacokinetics and toxicology, the trials are going extremely well,” says Unterbeck. “The substance is completely safe for people.” However, another drug from the company, MEM 1414, is attracting more attention from specialists. It is capable of activating a molecular pathway that plays a key role in the process of memory consolidation - the transformation of short-term sensations and skills into long-term memory traces. The most important part in this process is a protein called CREB (see page 34).

In the mid-1990s. T. Tully and Jerry Yin genetically engineered a special line of Drosophila fruit flies with truly phenomenal photographic memory: insects are able to learn to perform certain tasks and remember the skills they have developed during one experimental session, while their “normal” relatives require 10 to do this. training sessions. Scientists achieved this amazing improvement in memory by activating a single gene called CREB. Studies have shown that when animals learn to perform a task and memorize the resulting skill, the synapses responsible for forming the memory trace are rebuilt and strengthened as a result of a process that requires the activation of genes. It turned out that the formation of a memory trace is accompanied by the formation of an intermediary molecule in the cell - cyclic AMP (cAMP). This molecule, in turn, “triggers” the formation of a protein that binds to the DNA of the nerve cell. As a result, a whole set of genes responsible for the synthesis of proteins is activated, which “complete” synapses and thereby increase their efficiency. This process underlies the consolidation of a memory trace. The protein that “triggers” it received the complex name cAMP response element binding protein (CREB) - a protein that binds to a cAMP-dependent element. The higher the CREB level in a neuron, the faster memory consolidation occurs. This is at least the case with shellfish, fruit flies and mice. What about a person?

Typically, cyclic AMP in the cell is destroyed by the enzyme phosphodiesterase (PDE). Theoretically, suppression of PDE activity leads to an increase in the availability time of CREB, and therefore, the efficiency and speed of the memory formation process. But PDE inhibitors have a very dubious reputation among specialists. With the help of one of them, they tried to treat depression in Japan, but the medicine caused people a side effect - nausea. However, in preliminary trials, PDE inhibitors have proven to be effective memory enhancers. It is therefore not surprising that pharmaceutical companies have begun developing drugs based on PDE (a class of compounds known as PDE-4).

Scientists have high hopes for the drug MEM 1414. Interestingly, primates and rodents in old age experience exactly the same memory decline as older people. In old age, 50% of animals lose the ability to form new memory traces, and MEM 1414 restores it to almost normal levels.

The opinion that CREB is the best basis for creating “memory stimulants” is not shared by all scientists. The choice of this gene is not very justified from a biological point of view, especially when it comes to mammals. After all, CREB is expressed everywhere in the body. Some researchers even believe that the new drugs will be no more effective than caffeine. In addition, CREB is far from the only way to manipulate memory. Thus, the well-known neuroscientist Joe Qin, already mentioned by us, studies the neurotransmitter receptor NMDA, which is present only in the forebrain, and the attention of Cortex Pharmaceuticals is focused on another system of neurotransmitters. “Frankly speaking, our knowledge is negligible,” admits Joe Qin. - We do not know either the principles of memory operation or the set of operations it performs. We know a lot about genes, but we don’t have a clear understanding of their functions, and this, in my opinion, has become the main problem of all therapeutic research.”

“Scientists only care about one thing: making these drugs work,” says Tim Tully, who has long been keenly interested in the social implications of scientific developments. — Will they be used for other purposes if their clinical effectiveness is confirmed? I think yes. After all, these drugs can also improve motor skills necessary, for example, to play the piano or master a foreign language.” In the end, Viagra began to be used for other purposes, but they did not stop taking Ritalin and amphetamines. However, self-medication is dangerous, because... may cause unexpected side effects. A person, for example, may experience unknown mental disorders.

We are five to ten years away from the epoch-making event when new generation drugs reach people. And before “smart pills” hit pharmacies, we still have a lot of interesting things to learn about them. But judging by a small incident that occurred at Princeton University, where I was visiting Joe Qin, things may turn out differently. When the scientist showed me the vivarium where the famous “intellectual mice” he had genetically engineered are kept, a laboratory assistant walked past us. In his hand he carried the most primitive mousetrap, in which sat two unfortunate animals. Qin looked at the rodents “with an increased level of cognitive abilities,” shook his head and said with a sigh: “They’re not that smart...”

ABOUT THE AUTHOR: Writer Stephen Hall

(Stephen S. Hall) lives and works in New York. He has written four books on the modern history of science. The latest, Merchants of Immortality (Houghton Mifflin, 2003), focuses on stem cells and cloning research.

ADDITIONAL LITERATURE:

• Memory: From Mind to Molecules. Larry R. Squire and Eric Kandel. Scientific American Library, No. 69. W. H. Freeman and Company, 1999.
• Remembering and Forgetting: Sessions 3 and 4 of the President's Council of Bioethics, October 17, 2002. Available online at
• Targeting the CREB Pathway for Memory Enhancers. Tim Tully, Rusiko Bourtchouladze, Rod Scott and John Tallman in Nature Reviews: Drug Discovery, Vol. 2, No. 4, pages 267-277; April 2003.
• Eric Kandel's Nobel address is available online at

Date of publication of material on the site: May 17, 2007