Improves daytime wakefulness in people with uncontrollable sleepiness caused by narcolepsy or sleep apnea. Also used in people who are sleep deprived from working odd hours such as a night shift.
Formal Name：MODAFINIL-DEA SCHEDULE IV;CRL-40476
Molecular Weight: 273.35 g/mol
CAS Number: 68693-11-8
storage temp. Store at +4°C
solubility DMSO: 18 mg/mL, soluble
(RS)-2-(diphenylmethylsulfinyl)acetamide, Provigil, Modalert, Modiodal, Alertec, Modavigil, Carim, Modasomil, Resotyl, Stavigile, Vigia, Vigil.
What Is 2-[(Diphenylmethyl)sulfinyl]-acetamide?
Piracetam was developed in 1960s in Belgium as a ‘smart drug’. It is a recurring plagiaristic form of GABA, also known as aminobutyric acid. Since its discovery and usefulness detection, piracetam has been used as a nootropic agent for the enhancement of memory in human beings. Piracetam is an exeptional nootropic with low contagiousness and insalubrity levels and incurs a small number of side effects. Its effectiveness in the treatment of ischemia, cognitive impairment, stroke, and dementia is acknowledged widely. It also contributes in the cognition enhancement of dyslexic and dyspraxic children. Moreover, its usefulness is also apparent in Down Syndrome patients whereby piracetam is employed to slow down the rapid aging of brain. It also contributes as a modulator of brain metabolism, neuroprotection and neuroplasticity. Piracetam is also known to have antiseizure or antiepileptic effects. Moreover, it is also used for the reduction of symptoms associated with anxiety, withdrawal from alcohol, and clinical depression (Grossman, Stewart, Gaikwad, Utterback, Wu, Dileo, Frank, Hart, Howard & Kalueff, 2011).
Modafinil was originally developed in France by neurophysiologist and emeritus experimental medicine professor Michel Jouvet and Lafon Laboratories. Modafinil originated with the late 1970s invention of a series of benzhydryl sulfinyl compounds, including adrafinil, which was first offered as an experimental treatment for narcolepsy in France in 1986. Modafinil is the primary metabolite of adrafinil, lacking the polar -OH group on its terminal amide, and has similar activity to the parent drug but is much more widely used. It has been prescribed in France since 1994 under the name Modiodal, and in the US since 1998 as Provigil. It was approved for use in the UK in December 2002. Modafinil is marketed in the US by Cephalon Inc., who originally leased the rights from Lafon, but eventually purchased the company in 2001.
Despite extensive research into the interaction of modafinil with numerous neurotransmitter systems, its precise mechanism or mechanisms of action remain unclear. Modafinil elevates hypothalamic histamine levels, leading some researchers to consider modafinil a "wakefulness-promoting agent" rather than a classic amphetamine-like stimulant. Modafinil seems to inhibit the reuptake action of the dopamine transporter, thus leading to an increase in extracellular and thus synaptic concentrations of dopamine.
The locus of the monoamine action of modafinil has also been the target of studies, identifying effects on dopamine in the striatum and nucleus accumbens, norepinephrine in the hypothalamus and ventrolateral preoptic nucleus, and serotonin in the amygdala and frontal cortex.
A considered mechanism of action involves brain peptides called orexins, also known as hypocretins. Orexin neurons are found in the hypothalamus but project to many parts of the brain, including several areas that regulate wakefulness. Activation of these neurons increases dopamine and norepinephrine in these areas, and excites histaminergic tuberomammillary neurons increasing histamine levels there. It has been shown in rats that modafinil increases histamine release in the brain, and this may be a possible mechanism of action in humans. There are two orexin receptors, namely orexin receptor 1 (OX1/hcrt1) and orexin receptor 2 (OX2/hcrt2). Animals with defective orexin systems exhibit signs and symptoms similar to narcolepsy, for treatment of which modafinil is FDA-approved. Modafinil seems to activate these orexin neurons in animal models, which would be expected to promote wakefulness. However, modafinil is also able to promote wakefulness with similar efficacy to amphetamine in dogs with complete loss-of-function mutations in orexin receptor 2, suggesting that orexin activation is not required for these effects of modafinil. Additionally, a study of orexin-knockout mice found that not only did modafinil promote wakefulness in these mice, but that it did so even more effectively than in wild-type mice.
Modafinil's substantial, but incomplete, independence from both monoaminergic systems and those of the orexin peptides has proven difficult to explain, in contrast to the better-understood mechanisms of stimulants such as cocaine or substituted amphetamines. Alternative mechanisms of action that have been proposed include the activation of glutamatergic circuits while inhibiting GABAergic neurotransmission. Enhanced electrotonic coupling by enhancing the effectiveness of direct gap junctions between neurons has also been suggested by several studies. Most neurons are separated by synapses, and communication between cells is accomplished via release and diffusion of neurotransmitters. However, some neurons are directly connected to one another via gap junctions, and it is proposed that modafinil influences the effectiveness of these connections. Modafinil increased activity via this mechanism in the thalamocortical loop, which is critical in organizing sensory input and modulating global brain activity. Administration of the gap junction blocker mefloquine abolished this effect, providing good evidence that this result was a consequence of improved electrical coupling. The calmodulin kinase II (CaMKII) inhibitor, KN-93, abolishes modafinil's enhancement of electrotonic coupling. Modafinil's effect is mediated, at least in part, by a CaMKII-dependent exocytosis of gap junctions between GABAergic interneurons and possibly even glutamatergic pyramidal cells. Additionally, modafinil has pro electrotonic effects on specific populations of neurons in two sites in the reticular activating system. These sites, the subcoeruleus nucleus and the pedunculopontine nucleus, are thought to enhance arousal via cholinergic inputs to the thalamus.
Looking more closely at electrotonic coupling, gap junctions permit the diffusion of current across linked cells and result in higher resistance to action potential induction since excitatory post-synaptic potentials must diffuse across a greater membrane area. This means, however, that when action potentials do arise in coupled cell populations, the entire populations tend to fire in a synchronized manner. Thus enhanced electrotonic coupling results in lower tonic activity of the coupled cells while increasing rhythmicity. Agreeing with data implicating catecholaminergic mechanisms, modafinil increases phasic activity in the locus coeruleus (the source for CNS norepinephrine) while reducing tonic activity with respect to interconnections with the prefrontal cortex. This implies an increased signal-to-noise ratio in the circuits connecting the two regions. Greater neuronal coupling theoretically could enhance gamma band rhythmicity, a potential explanation for modafinil's nootropic effects. Modafinil's beneficial effects on working memory and motor networks are suggestive of heightened gamma band activity.
Administration of modafinil enhances arousal-specific P13 evoked potentials in a gap-junction dependent manner which provides a direct link between electrotonic coupling and wakefulness. Tying into inconclusive effects on monoamine systems, enhanced electrotonic coupling is thought to reduce activity in localized populations of GABAergic neurons whose normal function is to reduce neurotransmitter release in other cells. For example, dopamine release in the nucleus accumbens has been demonstrated to be the result of decreased GABAergic tone. Thus, while modafinil's unique stimulant profile features interactions with monoamine systems, these may very well be downstream events secondary to effects on specific, electrotonically-coupled populations of GABAergic interneurons. It is likely that modafinil's exact pharmacology will feature the interaction of direct effects on electrotonic coupling and various receptor-mediated events.
Recently, modafinil was screened at a large panel of receptors and transporters in an attempt to elucidate its pharmacology. Of the sites tested, it was found to significantly act only on the dopamine transporter (DAT), inhibiting the reuptake of dopamine with an IC50 value of 4 μM. Accordingly, it increases locomotor activity and extracellular dopamine concentrations in a manner similar to the selective dopamine reuptake inhibitor vanoxerine, and also blocks methamphetamine-induced dopamine release. As a result, it appears that modafinil exerts its effects by acting as a weak dopamine reuptake inhibitor, though it cannot be ruled out that other mechanisms may also be at play. On account of its action as a dopamine reuptake inhibitor and lack of abuse potential, modafinil was suggested as a treatment for methamphetamine addiction by the authors of the study.
The (R)-enantiomer of modafinil, known as armodafinil, has also recently been found to act as a D2 receptor partial agonist, with a Ki of 16 nM, an intrinsic activity of 48%, and an EC50 of 120 nM, in rat striatal tissue. The (S)-enantiomer is inactive with respect to the D2 receptor (Ki > 10,000).
The primary benefit for which modafinil is currently prescribed is in wakefulness promoting. In normal conditions, sleep deprivation has been shown to impair hippocampal-dependent memory. Modafinil has been shown to prevent impairment of cognitive function by reducing the number of errors compared to placebo and by upregulating synapsin I expression within the dorsal hippocampus. In a study involving sleep deprived ER physicians, modafinil displayed ability to improve performance on tests of higher cognitive function, compared to the baseline, albeit, failed to show gains in performance, with respect to psychomotor tasks . Similarly, in studies concerning patients dependent on methamphetamine, modafinil showed a direct relationship between cognitive improvement and amount of methamphetamine use.
There have been attempts, by the owners of the original patent, to clear modafinil as indicated for conditions of ADHD/ADD. However, such attempts have proven unwielding; as study after study has proven it ineffective for purposes of attention deficit in adults. In children, however, when compared to methylphenidate, using the Test of Variables of Attention, modafinil proved to be as effective as when considering the improvements seen.
2-[(Diphenylmethyl)sulfinyl]-acetamide Mechanism of Action
Die genaue Wirkweise von Modafinil ist bislang nicht vollständig erforscht. In Studien konnte allerdings der Anstieg verschiedener Monoamine wie Dopamin, Noradrenalin und Serotonin nachweisen werden. Modafinil soll die glutamaterge Reizfortleitung aktivieren und die GABAerge dafür hemmen. Anhand diverser Experimente im Modellorganismus Maus, konnte gezeigt werden, dass Modafinil eine Histaminausschüttung im ZNS bewirkt, was die Wachheit fördert. Dies wird als mögliche Erklärung für die Wirkung herangezogen.
Weight loss, decreased appetite, insomnia, headache, nausea, nervousness, dry mouth, and hypertension.
May have some abuse potential, although none have been reported to date
Generally 50-200mg would be a reasonable dose. With such powerful stimulants, starting small is always a good idea. Consider taking 50mg upon waking and assess from there. If using for sleep deprivation purposes, consider 50-100mg every 8 hours.