Modafinil – what is it?

Modafinil is one of the most famous drugs that is used for procognitive purposes. Its operating profile is conducive to long and effective work. For this reason, he is a leading representative of the smart drugs class, and it is even said that his action was an inspiration to create the idea of ​​a fictitious drug NZT-48 in the script of the film Limitless.

Modafinil – what is it?

Modafinil is a drug for narcolepsy, a disease involving excessive daytime sleepiness. It affects the activity of areas of the brain that control the rhythm of sleep and wake. It belongs to the group of eugeroics . Eugeroics are substances that put you on alert and alert. It is also a nootropic drug that is often used off label.

The most famous form is the racemate, a mixture of two enantiomers – R and S-modafinil. The R-enantiomer, also known as armodafinil , is the stronger “brother”, therefore in isolated form it is also produced as a drug, and its effectiveness is visible at slightly lower doses than in the case of modafinil.

How does Modafinil work?

The main and the most noticeable effect of modafinil is the reduced feeling of fatigue and an increase in energy and motivation to act. It has a long operating time (up to 12 hours) , so one portion taken in the morning gives a stable energy level throughout the day, which is very convenient. It does not suppress the appetite like other stimulants .

It is estimated that the bioavailability of modafinil is 40-65% , and the peak concentration is reached after 2-3 hours [1] . A noticeable effect appears about an hour after taking it. Taking after a meal may delay the effect, but is unlikely to affect the amount ingested in general.

Modafinil used late will make us have huge problems with sleep. In normal situations this is unwise, but there are sometimes emergencies in which, however, we must remain on standby for all or a significant part of the night. It’s hard to imagine a remedy better than modafinil for such occasions.

FMRI studies in healthy, older people noted that modafinil improves communication neuron Alna in the cerebellum and cerebral cortex [2] . Research also shows that the effectiveness of modafinil is to some extent dependent on the size of the user’s IQ . Among healthy students, it was noticed that in those with a lower IQ, modafinil was much more effective [3] .

A number of positive effects on cognition have been observed in healthy people without sleep deprivation. These include: improvement of spatial working memory, better planning and more efficient decision making, as well as improved results in PRM ( Pattern Recognition Memory ) tests . It was also noticed that participants found performing tasks more enjoyable [4] .

The positive effects of modafinil include:

  • increased energy and reduced fatigue
  • faster information processing and reduction of brain fog
  • greater motivation and better well-being
  • memory improvement
  • more efficient processing of emotions
  • improvement of sports condition

Reviews on modafinil appear to be generally very positive. It is extremely popular among people who deal with highly intellectually engaging topics – lawyers, programmers, corporate CEOs, students of difficult faculties.

Rapid building of tolerance to its effects is often reported, so it is usually adopted ad hoc or in specific protocols so that the effects remain at a satisfactory level for as long as possible. However, when used for therapeutic purposes, even for many weeks, it works adequately.

Modafinil uses

Due to the mechanism of action and the effects of modafinil, it has therapeutic potential in several disease entities.

Narcolepsy

Narcolepsy is excessive daytime sleepiness, which is manifested even by falling asleep uncontrollably. Treatment of narcolepsy is the main use for modafinil, and this one does a great job with it. It is confirmed in several studies on quite large groups of patients [1] .

Chronic Fatigue Syndrome

As with narcolepsy, the fatigue-reducing and energizing properties of modafinil help those struggling with chronic fatigue. This includes people who struggle with sleep apnea or work shifts.

ADHD

Patients struggling with this condition usually respond very well to drugs that increase dopamine. In such people, paradoxically, stimulants help to tame raging thoughts and calm down. Modafinil has a safer profile of action than amphetamine and methylphenidate, which is why some doctors prescribe it for ADHD, although it has not been officially approved for this purpose by the FDA due to its noted dermatological toxicity. Studies have shown that the effectiveness is similar to that of amphetamines and methylphenidate [1] .

Cognitive disorders

The action of modafinil makes your thinking clearer and improves concentration, and therefore it is one of the most effective ad hoc measures to improve cognition. It also improves communication between neurons, improves memory and increases the speed of information processing.

Addiction therapy

Due to its positive effect on well-being and activation, combined with a favorable safety profile, modafinil can be used in addiction substitution therapy. It is used in addicted to cocaine [5] [6] or methamphetamine [7] .

Other applications include: regeneration after anesthesia for the day after surgery, treatment of some types of depression, reduction of sleepiness in myotonic dystrophy [1] .

What is the modafinil mechanism of action?

Modafinil has an exceptionally wide range of activities, which makes its effects unique.

Modafinil is a dopamine and norepinephrine reuptake inhibitor.

It inhibits the activity of the dopamine transporter (DAT), which increases its amount in synaptic clefts. This allows dopamine to become more active, as greater amounts of it activate the postsynaptic y-receptor. It has a similar effect in relation to the norepinephrine transporter, but the effect on dopamine is dominant in this case. DAT inhibition by modafinil is the same as in the case of cocaine, but it does not share the effects of its use, therefore it is called an atypical DAT inhibitor [8] .

Modafinil affects the histamine and orexin systems.

Histamine is mainly associated with allergies, but it also acts as an activating neurotransmitter that participates in the regulation of circadian rhythms, as does orexin. Orexin, on the other hand, is a neuropeptide that is produced in the hypothalamus. By cooperating with other systems in the brain, it regulates the rhythm of sleep and wakefulness. Modifinil activates orexynergic neurons, which in turn increases the release of histamine in the hypothalamus [9] .

Modafinil affects the ratio of glutamate to GABA.

As we know, glutamate and GABA work opposite. One stimulates and the other inhibits like yin and yang. Modafinil reduces the concentration of extracellular GABA by inhibiting its release, and this effect is mediated by the receptors of the serotonin system [10] . Parallel to this action, modafinil also enhances the action of glutamate, changing the balance between these neurotransmitters into a more stimulating one [11] . Glutamate grows in regions such as the thalamus , hippocampus , striatum, medial preoptic field, and posterior hypothalamus [1] . Ultimately, it results in greater activation of the central nervous system and more efficient neuroplasticity.

Modafinil did not significantly increase serotonin levels in humans, although an interaction was noted in in vitro and in vivo animal studies. In studies on rodents, a synergistic effect was observed with drugs from the SSRI group, consisting in a more effective increase in the concentration of serotonin, however, this effect was not confirmed in human studies.

We can clearly see here that modafinil influences psychomotor activation through multiple mechanisms . In this way, the chance of therapeutic success is maximized, because if, for example, a patient does not respond particularly to an increase in dopamine, the effect of an increase in orexin and histamine and glutamate may be felt. Thanks to this, it also stands out from methylphenidate and amphetamines.

Is Modafinil Safe?

At the beginning it is worth noting that it does not have a narcotic effect and does not cause euphoria , like methylphenidate or amphetamines. Unlike other popular stimulants, modafinil has a low risk of addiction [12] . This may be partly due to the long duration of action – fast-acting measures are more addictive.

In people with narcolepsy, the use of an average dose of 330 mg for 16 weeks was effective and well tolerated [13] .

Modafinil is on the WADA Prohibited List. Active athletes undergoing doping tests run the risk of a positive test result when they take modafinil.

Side effects are not common, but of course they do. The most common are: increased anxiety, palpitations, increased blood pressure, hyperactivity, nervousness, and headache and dizziness.

Due to the fact that modafinil raises histamine, it may not be indicated for people who have problems with its tolerance.

Modafinil affects the activity of several cytochrome P450 enzymes that metabolize other drugs. So if you were to take modafinil alongside other medications, it would be good to first check for an interaction at this level. The greatest influence is exerted on the enzymes CYP2C19 (inhibition) and CYP3A4 (activation) [14] .

Chemical structure of the S and R enantiomers of modafinil. Source: wikipedia

Modafinil dosage

Modafinil is most commonly found in 200 mg tablets (150 mg armodafinil) in black market products, and the original Provigil comes in 100 and 200 mg versions. Typical doses are 100 or 200 mg once, but there are variations in both directions. People with high sensitivity or those who only need a light action but for a longer period use up to 50 mg per day. In contrast, people with more severe problems or low sensitivity take 300 mg a day. In studies, you can come across doses of up to 800 mg, but they were quite specific – they were to determine the recreational potential of modafinil, and the participants were people with polytoxicomania in their card. At such doses, however, side effects are already quite pronounced and often force you to stop using it.

Modafinil metabolism is altered in people with hepatic impairment. The dose should be half the normally recommended dose, although some caution is suggested. Kidney disorders should also be taken into account as modafinil is rather inadvisable.

Where to buy modafinil?

Unfortunately, this is a drug that is quite heavily controlled and non-pharmacy distribution is forbidden, so over-the-counter modafinil is not legally available. However, trading on the black market is doing quite well, which of course I do not recommend using, because you can never be sure what will be inside and in what dose. There is no preparation with modafinil in Polish pharmacies, and when the doctor decides that the patient needs it, import is necessary. For this reason, it is not a particularly popular drug in Polish medicine.

The price of modafinil on the black market is quite high, as it fluctuates on average in the range of PLN 70-100 for a blister of 10 tablets , but there are still plenty of applicants. Armodafinil is even more expensive, because the prices here are in the range of PLN 100-120. The pharmacy modafinil is called Provigil , while the trade names for black market products are Modvigil and Modalert .

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