Modafinil is most often supplied as tablets of 100 mg and 200 mg.
Modafinil is a central nervous system stimulant, with a structure similar to adrafinil. It has the chemical name 2 [(diphenylmethyl) sulfinyl] acetamide.
Structure and characteristics
Modafinil is a drug for the treatment of diseases associated with sleep disorders. It also improves mental state during the long waking hours.
The term "modafinil" refers to a racemic mixture of two isomers, R-modafinil and S-modafinil. R-isomer is called armodafinil. Modafinil is a racemic mixture of S-modafinil and R-modafinil, while armodafinil is presented by only R-modafinil.
The half-life of modafinil is 13-15 hours, while its serum concentration in the equilibrium state amounts to 2 days after administration. Half-life of S-isomer of modafinil is equal to 4-5 hours, whereas half-life of the R-isomer of modafinil is longer (15 hours). And thus the administration of armodafinil is almost equivalent to the administration of modafinil. The data from the experiments shows that the concentration of armodafinil in the blood is higher by 18% than the concentration of modafinil (5.44 +/- 1.64 mg/ml vs 4.61 +/- 0.73 mg/ml), and accumulates in a shorter period of time (1.8 hours versus 2.5 hours), while the total concentration of armodafinil in the urine is higher by 32-40%. Although both versions of modafinil (modafinil and armodafinil) have the same half-life, the impact of armodafinil on the body is stronger (according to the content in the urine and in the serum).
According to immunocytochemistry of c-Fos gene (a gene responsible for responding to stimulation and detected by neural stimulation or sleep deprivation), administration of modafinil to cats causes severe activation of c-Fos gene in the anterior hypothalamic nucleus and in the adjacent areas and mild activation in the suprachiasmatic nucleus. It causes minimal gene activation in other areas such as the cerebral cortex or striatum. A similar point activation of the hypothalamus was noticeable everywhere, amygdala was also involved in the process. Studies in humans have shown clear differences between human exposure to modafinil and amphetamine. In contrast to the excessive cheerfulness caused by amphetamine or methylphenidate (which indicates a widespread neural activation), modafinil effect is selective: it related to the hypothalamus and amygdala only.
Modafinil can increase the extracellular levels of dopamine in the prefrontal cortex of rats and in the caudate nucleus of dogs. Modafinil affects dopamine and noradrenaline receptors (in the striatum) and the absence of such effects in mice was associated with the disappearance of sleep-associated effects. This was confirmed by the fact that the mechanism of action of modafinil really affects sleep. Recent studies have shown lack of influence of modafinil on dopaminergic system, which may be associated with a lower dosage used in previous studies.
Invigorating effect of modafinil is significantly attenuated by adrenergic receptor antagonists (both alpha and beta). However the use of inhibition of catecholamine synthesis by α-methylparathyrosin does not reduce the effect of modafinil.
Modafinil shows good results in people with orexin deficiency (drug-abusers) directly affecting the orexin neurons. This effect has the greatest impact on deficient mice. The effects of modafinil on the orexin system of healthy animals and humans are unknown. Sedative and stimulating effect. The results of some studies regarding the impact of modafinil during intentional sleep deprivation are negative, because the effect of 300 mg of modafinil during sleep deprivation is equivalent to such effect caused by 20 mg of D-amphetamine. However, it was noted that deterioration of self-control (the ability to assess yourself and surroundings accurately) changes to the overconfidence (incorrect assessment of what you are really capable of). These studies lasted for 64 hours (two nights without sleep) with a single dose of modafinil every 15 hours. Intake of modafinil at bedtime may seriously alter the sleep cycle and lead to subsequent flaccidity, and can also cause some side effects (worsening of mood and mental abilities). Recurrent hypersomnia is a phenomenon in which after the elimination of drugs against sleepiness one feels drowsy even more than before the intake. In contrast to preparations based on amphetamine, modafinil doesn’t cause such phenomenon in cats, rats, and mice. In people with a sleep deprivation for 64 hours who took modafinil this phenomenon did not occur, unlike those people received D-amphetamine. Modafinil does not cause recurrent hypersomnia. Sharpening of attention is observed in case of sleep deprivation after 10-12 hours following administration of a single dose of modafinil 300 mg which is equal to 20 mg of D-amphetamine. 300 mg of modafinil against sleepiness is equivalent to 20 mg of D-amphetamine. Brain sleep cycle is a balance of "ascending activating system" consisting of activating neurotransmitters (catecholamines, acetylcholine, orexin, etc.) and neurotransmitters (GABA, galanin) that inhibit the stimulation and promote sleep. Changing levels of activation and suppression of neurotransmitter forms a kind of cycle "switch on – switch off". In general, regulation of wakefulness and relaxation cycle depends on the one hand on the circadian biorhythm caused by suprachiasmatic nucleus and on the other hand - on homeostatic need for sleep which occurs during wakefulness. Modafinil is able to contact with various stimulatory systems, including serotonergic, noradrenergic, dopaminergic, glutaminergic, histaminergic, orexinergic, and GABAergic pathways. In some studies Modafinil was used in the treatment of other diseases, and it was found that such side effect as insomnia lasted longer than in the placebo group and that modafinil received at bedtime didn’t let participants of experiment to sleep. Intake of modafinil promotes coping with mental stress.
Memory and thought processes
In healthy people administration of 100-200 mg of modafinil for 2 hours before testing (arithmetic test) improved memory properties, spatial and visual perception and the time of reaction. Short-term memory and accuracy of information processing were improved after taking 200 mg of modafinil. In addition to the above-noted data, there are improvements in the performance of tasks in general: increased motivation, enjoyment of the performed work. In methamphetamine-dependent people with cognitive impairment the dose of modafinil 400 g divided into 3 days is able to improve the properties of short-term memory which was not possible previously. However a single dose of modafinil 200 mg is not able to cause such effects.
Impact on appetite
Sometimes researchers condemning the drug report loss of appetite as a side effect in 16% of cases (164 people). Some researchers believe this fact causes a weight loss in a week, but statistically this has no confirmations.
Modafinil is not able to activate the neural pathway that occurs in case of addiction. Therefore it is considered that the drug has a relatively low threshold of addiction if compare to other drugs. It is unlikely that modafinil will be used as a narcotic drug in drug abusers. Modafinil can help to ease the breaking of methamphetamine addiction, alcoholics and gamers. However the effect varies. Modafinil also reduces impulsivity in drug abusers, but this effect is actual only in subjects whose impulsivity threshold before the experiment was lower.
Effects of the drug on people with certain diseases
Single dose of armodafinil (250 mg) in patients with multiple sclerosis showed improvement of mnemonic play. This effect was comparable to the placebo effect. However the drug had no effect on the fatigue, ability to focus on purposeful activity and speed of information processing.
Studies revealed the following adverse effects of the drug - headache, dizziness, diuresis, palpitations, tachycardia, anxiety, nervousness, gastrointestinal problems such as nausea and dry mouth, and abdominal pain. Besides the above-noted side effects modafinil is considered to be a well-tolerated drug. Common side effects of modafinil include insomnia and decreased appetite.
Modafinil side effects
Adverse effects of modafinil are typically associated with stimulation of the central nervous system and may include nervousness, insomnia, tremor, euphoria, personality changes, and agitation. The drug may also cause gastrointestinal disorders such as nausea, vomiting, abdominal pain, dry mouth, anorexia, and headache. Sometimes there may be high blood pressure, heart palpitations or abnormal heart rhythm. In rare cases we can see an allergic rash, increased serum level of alkaline phosphatase or violation of intentional movements.
Modafinil can be found in more than two dozen countries. The drug, however, is not particularly popular on the black market and is not a profitable target for counterfeiting. Modafinil can be sold through medical prescription only.
Drugs and synonyms
Modafinil (Alertec, Provigil, Modalert)
Anyone who didn’t sleep for two nights knows what it means to suffer from extreme fatigue. Nothing can defeat the desire to sleep. Nothing but, apparently, modafinil. In the study reported in the Journal of Psychopharmacology http://www.sagepub.com/journal.aspx?pid=31 it was found that it had increased the effectiveness of training of pilots in helicopter simulators after sleep deprivation. When testing on helicopter simulators, the pilots who received 600 mg of modafinil in 3 doses kept the readiness in the mode "8 hours of sleep for 88 hours of wakefulness". In other tests pilots of F-117 deprived of sleep and received 300 mg of modafinil (3 doses of 100) preserved about 27% of skills to fly the plane. Professor Barbara Sahakian from the University of Cambridge http://www.psychiatry.cam.ac.uk/pages/profiles/sahakian.html who tested Modafinil in the series of experiments on volunteers found that they had a greater concentration, faster training and improved mental agility. Modafinil can act as an antidepressant and neuroprotective agent. It significantly improves the number of indicators of working memory (the number of stored numbers, counting, symbol recognition). There is controversial data on the improvement of other indicators. Part of the positive effects can be manifested only in people with low IQ. The research of doctors deprived of sleep showed that taking Modafinil (200 mg after one sleepless night) improves information processing, makes thinking more flexible and enhances the speed of decision making as compared to placebo. However, the quality of simple procedural action (operation on the simulator) did not improve. Modafinil has been successfully used in the US for the treatment of attention deficit disorder and chronic fatigue syndrome in both adolescents and adults. It was also successfully used to assist in the jet-lag (flights to a distant time zone).
Mode of action
Despite intensive studies of modafinil interaction with a large number of neurotransmitters, the exact mechanism or set of mechanisms of interaction remains unclear. Probably, modafinil, like other stimulants, increases the release of monoamines, especially catecholamines norepinephrine and dopamine, from synaptic gaps. However, modafinil increases hypothalamic histamine levels, which made some researchers consider modafinil “a drug against insomnia” rather than a classic amphetamine-like stimulant. Studies show that modafinil "has a low potential for serious abuse" and "does not make an addiction after the first use". The combined effect of modafinil on both catecholamine and histamine pathways reduces the potential for abuse as compared to traditional stimulant medications. At the same time the effectiveness of medications for insomnia is preserved.
Safety and side effects
During the studies and sales (Alertec, Provigil) showed no side effects, except for mild nausea and headache in rare cases. Today modafinil is considered to be safer than caffeine and more effective than amphetamines. The Ministry of Health of Canada has approved the new information about possible complications of modafinil (Alertec) use Modafinil may cause life-threatening skin and other hypersensitivity reactions: Severe cutaneous adverse reactions (SCAR), including toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, Drug reaction with eosinophilia and systemic symptoms (DRESS) in both adults and children; Angioedema, anaphylactic reactions and multiorgan hypersensitivity reactions caused at least one death; Modafinil can’t be used in children for any indication (although there were studies in children that showed its general safety); Modafinil can cause psychiatric disorders; Modafinil is not recommended for use in patients with a history of left ventricular hypertrophy or in patients with clinically significant mitral valve prolapse during treatment with psycho stimulants. Perhaps Modafinil causes addiction although the majority of data and the personal experience militates against it. It does not cause narcotic abuse and euphoria (buzz), so psychological abuse is also absent or unlikely. In the drug label there is information that side effects usually occur in the first 12 weeks of treatment, and hence patients already taking the drug don’t need to terminate its administration.
If you need to preserve the "readiness" for the whole day, take 100 mg of Modafinil in the morning and 100 mg at lunchtime. If you want to stay awake throughout the whole night, then add another dose of 100 mg in the evening (in other words, 100 mg for every 8 hours). Intake of an increased dose (200 mg) is not dangerous.