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Modafinil is one of the most well-known drugs used for pro-cognitive purposes. Its performance profile supports long and efficient work. For this reason, it is a leading representative of the class of "smart drugs," and it is even said that its effects inspired the creation of the fictional substance NZT-48 in the script for the movie *Limitless*.
Modafinil is a treatment for narcolepsy, a condition characterized by excessive daytime sleepiness. It affects the activity of brain regions responsible for controlling sleep and wakefulness rhythms. It belongs to the group of eugeroics. Eugeroics are substances that promote alertness. It is also a nootropic drug, often used off-label.
Taking modafinil late in the day can cause sleep problems. In normal situations, this is unwise, but there are occasionally emergencies where we need to stay alert for all or most of the night. It’s hard to imagine a better option than modafinil for such cases.
In fMRI studies of healthy elderly individuals, modafinil was shown to enhance neural connectivity in the cerebellum and cerebral cortex [2]. Studies also indicate that modafinil’s effectiveness somewhat depends on the user’s IQ. Among healthy students, it was observed that in individuals with lower IQs, modafinil was significantly more effective [3].
Rapid development of tolerance to its effects is often reported, but when used for therapeutic purposes, even over many weeks, it performs adequately.
Due to its mechanism of action and effects, modafinil has therapeutic potential for a range of conditions.
Narcolepsy is excessive daytime sleepiness, which may even manifest as uncontrollable falling asleep. Treating narcolepsy is the primary use of modafinil, and it excels in this role. This is supported by numerous studies on relatively large groups of patients [1].
As with narcolepsy, modafinil’s ability to reduce fatigue and boost energy helps individuals struggling with chronic fatigue. This includes people dealing with sleep apnea or working shift schedules.
Modafinil’s effects make thinking clearer and improve concentration, making it one of the most effective specialized tools for enhancing cognition. It also improves neural connectivity, memory, and the speed of information processing.
Due to its positive impact on well-being and activation, combined with a favorable safety profile, modafinil can be used in substitution therapy for addiction. It is used for cocaine [5][6] or methamphetamine [7] addiction.
Other applications include: recovery from anesthesia the day after surgery, treatment of certain types of depression, and reducing sleepiness in myotonic dystrophy [1].
Modafinil has an exceptionally broad spectrum of action, making its effects unique.
It inhibits the activity of the dopamine transporter (DAT), increasing its presence in synaptic clefts. This allows dopamine to become more active, as a greater amount activates postsynaptic receptors. It works similarly with the norepinephrine transporter, but the dominant effect is on dopamine. Modafinil’s inhibition of DAT is similar to that of cocaine, but it does not share cocaine’s effects, so it is called an atypical DAT inhibitor [8].
Histamine is primarily associated with allergies, but it also acts as an activating neurotransmitter involved in regulating circadian rhythms, as does orexin. Orexin, on the other hand, is a neuropeptide produced in the hypothalamus. Working with other brain systems, it regulates the sleep-wake cycle. Modafinil activates orexinergic neurons, which in turn increase histamine release in the hypothalamus [9].
As is known, glutamate and GABA have opposing effects. One stimulates, while the other inhibits, like yin and yang. Modafinil reduces extracellular GABA concentrations by inhibiting its release, an effect mediated by serotonin system receptors [10]. In parallel, modafinil also enhances glutamate activity, shifting the balance between these neurotransmitters toward greater stimulation [11]. Glutamate increases in areas such as the thalamus, hippocampus, striatum, medial preoptic area, and posterior hypothalamus [1]. Ultimately, this leads to greater activation of the central nervous system and more efficient neuroplasticity.
Effects of modafinil on individual neurotransmitters
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800148/
We can clearly see here that modafinil affects psychomotor activation through multiple mechanisms. This maximizes the likelihood of therapeutic success, as, for example, if a patient does not respond strongly to increased dopamine, they may experience effects from increased orexin, histamine, and glutamate. This also sets it apart from methylphenidate and amphetamines.
It’s worth noting at the outset that it does not produce narcotic effects or euphoria, unlike methylphenidate or amphetamines. Unlike other popular stimulants, modafinil has a low risk of addiction [12]. This may be partly due to its long duration of action—fast-acting substances tend to be more addictive.
In people with narcolepsy, an average dose of 330 mg over 16 weeks was effective and well-tolerated [13].
Side effects are uncommon but do exist. The most common include:
Because modafinil increases histamine levels, it is not recommended for individuals with histamine intolerance.
Modafinil affects the activity of several cytochrome P450 enzymes that metabolize other drugs. Therefore, if you plan to take modafinil with other medications, it’s worth checking for interactions at this level. The most significant effects involve the enzymes CYP2C19 (inhibition) and CYP3A4 (activation) [14].
Modafinil is most commonly available in 200 mg tablets (150 mg for armodafinil). Typical doses are 100 or 200 mg taken once, but there are variations on both sides. Individuals with high sensitivity or those needing only a mild effect but over a longer period may use up to 50 mg per day. On the other hand, people with more severe issues or low sensitivity may take 300 mg per day. Studies have reported doses up to 800 mg, but these were highly specific—aimed at determining modafinil’s recreational potential, with participants who had a history of polysubstance abuse. At such doses, side effects are quite pronounced and often lead to discontinuation.
Modafinil metabolism is altered in individuals with hepatic insufficiency. The dose should be half the usual recommended dose, though caution is advised. Renal dysfunction should also be considered, as modafinil is not recommended in such cases.
Author: Wojciech Nowosadu.
Sources:
[1] https://www.gwern.net/docs/modafinil/2008-kumar.pdf
[2] Miriam Punzi et al. “Modafinil-Induced Changes in Functional Connectivity in the Cortex and Cerebellum of Healthy Elderly Subjects” Front Aging Neurosci. 2017; 9: 85.
Randall DC et al. “Cognitive effects of modafinil in student volunteers may depend on IQ.” Pharmacol Biochem Behav. 2005 Sep;82(1):133-9.
[4] U. Müller et al. “Effects of modafinil on non-verbal cognition, task enjoyment, and creative thinking in healthy volunteers” Neuropharmacology. 2013 Jan;64(5):490–495.
[5] Charles A. Dackis et al. “A double-blind, placebo-controlled trial of modafinil for cocaine dependence” Neuropsychopharmacol 30, 205-211 (2005).
[7] Dorota Zolkowska et al. “Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafinil” J Pharmacol Exp Ther. 2009 May;329(2):738–746.
[9] Ishizuka T. et al. “Modafinil activates the histaminergic system through orexinergic neurons.” Neurosci Lett, 2010 Oct 15;483(3):193-6.
[10] Ferraro L. et al. “The alertness promoting drug modafinil decreases GABA release in the medial preoptic area and in the posterior hypothalamus of the awake rat: possible involvement of the serotonergic 5-HT3 receptor.” Neurosci Lett, 1996 Dec 6;220(1):5–8.
[11] Ferraro L. et al. “The antinarcoleptic drug modafinil increases glutamate release in thalamic areas and hippocampus.” Neuroreport. 1997 Sep 8;8(13):2883-7.
[12] Jasinski DR. “An evaluation of the abuse potential of modafinil using methylphenidate as a reference.” J Psychopharmacol. 2000 Mar;14(1):53-60.
[13] H. Moldofsky et al. “A randomized trial of the long-term, continued efficacy and safety of modafinil in narcolepsy” Sleep Medicine, Volume 1, Issue 2, 1 April 2000, Pages 109–116.
[14] Darwish M. et al. “Interaction profile of armodafinil with medications metabolized by cytochrome P450 enzymes 1A2, 3A4, and 2C19 in healthy subjects.” Clin Pharmacokinet. 2008;47served as inspiration for the fictional drug NZT-48 in the film *Limitless*.
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