Modafinil (marketed as Provigil) is a highly regarded nootropic that improves mental alertness, cognition and working memory. Unlike most nootropics which take weeks or even months to produce noticeable effects, modafinil’s potency is very pronounced for even first-time users. It is the most popular smart pill that is used off-label, and is sometimes compared to fictional smart drugs like NZT-48 from the movie Limitless, or the CPH4 pill from the movie Lucy.
200-400mg per day
Sublingual Administration (allow to dissolve under tongue)
Do not consume with heart or high blood pressure medications
Avoid large amounts of alcohol
Lots of water, small amounts of caffeine
Choline sources: Alpha-GPC, Choline Bitartrate
Chemical Structure and Properties
Modafinil is a racemic mixture, consisting of two isomers (S-Modafinil and R-Modafinil). The R-Modafinil isomer alone is armodafinil. Modafinil was originally conceived to help with sleep disorders and has demonstrated considerable improvements for mental functioning in sleep deprived conditions.
Modafinil is also referred to as: 2-[(Diphenylmethyl)sulfinyl]acetamide or 2-(Benzhydrylsulfinyl)acetamide, and identified by its molecular formula: C15H15NO2S
In terms of solubility, Modafinil is considered to be insoluble in water, while slightly soluble in ethanol.
Modafinil presents a half-life of about 13-15 hours, resolving to a steady state in serum concentrations within 48 hours of supplementation. This also means that you can expect most of the effects of your dosage to wear off by then.
S-Modafinil, the short isomer, has a much shorter half-life of about 4-5 hours. R-Modafinil, the longer isomer, extends a much longer half-life of about 15 hours. Studies show that armodafinil peaks with a stronger concentration in a more rapid fashion as compared to modafinil (5.4+/-1.6µg/mL relative to 4.6+/-0.7µg/mL).
Modafinil administration is associated with activation of the c-Fos gene following neuronal stimulation: less in the dorsal region of the suprachiasmatic nuclei and brain striatum and cortex, and more in the anterior hypothalamic nucleus. This differs very much from wakefulness following the onset of ingesting amphetamines or methylphenidates.
In a chemical sense, Modafinil works differently from Ritalin or Adderall (which are characterized by widspread neuronal activation). Modafinil only selectively activates regions in the brain. (Hypothalamus and Amygdala)
Research tells us that modafinil has 4 main neurological interactions in the brain. These are namely dopaminergic, adrenergic, serotonergic and orexinergic.
Dopaminergic Interactions: Modafinil appears to boost dopamine levels in nuclear accumbens and within the prefrontal cortex of the brain. It achieves this by occupying the noradrenaline and doapmine receptors. This produces the effect of wakefulness. Dopamine is also regarded as the ‘rewards centre’ of the brain, and increases communication between neurons. Under modafinil, dopamine transporters, which remove modafinil are inhibited. This means the total available dopamine increases.
Adrenergic Interactions: Modafinil acts as an antagonist of adrenergic receptors, specifically within the beta, alpha-1 and alpha receptors. Research has also concluded that modafinil does not depend on the availability of endogenous catecholamines but rather works via the mechanism of enhancement in the alpha-1 and beta receptors.
Serotonergic Interactions: A modest effect of Modafinil is its ability to regulate mood. This is achieved through an increase of dialysate serotonins (5-HT) levels within the central amygdala and cerebal cortex. Serotonergic interactions are useful for memory plasticity due to role of emotions in learning, as well as capability to stimulate neurogenesis. It is important to note however, that the impact to serotonin levels do not actually form part of its wakefulness properties.
Orexinergic Interactions: In nacroleptics, orexin levels appear to be out of sync (exclusively within the lateral hypothalamus) Modafinil acts directly on orexic neurons, activating them. Orexin is widely acknowledged to be the regulator of sleep and wakefulness states. In healthy individuals, modafinil’s effects on orexic neurons do not have any effect. Modafinil basically knocks the sleep-wake cycle out of sync, allowing you to stay awake.
Available medical literature also suggests that modafinil acts on these other mechanisms:
Norepinephrine, or also known as noadrenaline, works in a similar way to adrenaline. It increases heart rate, attention span, wakefulness and reaction times. Under modafinil, norepinephrine levels are increased particularly in the ventrolateral preoptic nucleus and hypothalamus. While it is unsure if the elevated levels are a direct result of the chemical properties of modafinil, or the inhibition of norepinephrine transporters, research is certain that norepinephrine levels are directly contributing to wakefulness in modafinil responders.
Histamine, a neurotransmitter, is elevated (hypothalamic histamine). Histamine neurons are found mainly in the tuberomammilary nuclei and hypoathalamus. This neurotransmitter is known to be an important agent is sleep/wake cycle regulation.
GABA is reduced, particularly in the posterior hypothalamus and medial preoptic regions. GABA promotes sleep and relaxation, and modafinil specifically stifles this. Some studies have also suggested a cause-effect relationship in that reduced GABA levels increase histamine.
Glutamate, an anion of glutamic acid is a chemical that is responsible to send signals to other cells. As a neurotransmitter, it is responsible for over 90% of synaptic links in our brains. Studies show that glutamate levels under modafinil are elevated; similar to that when under the influence of caffeine. As a main excitatory neurotransmitter, glutamate is chiefly involved in major aspects of cognitive functions including working memory and attention span. It would appear that glutamate is also responsible for long-term creation of association between neurons in our brains. This is also to suggest that increased glutamate levels, leading to brain plasticity, create a suitable environment for learning.
As a yardstick, studies conclude that 300mg of pure modafinil appear to produce wakefulness potencies similar to 20mg of D-amphetamine (present in central nervous stimulants such as Adderall), without the associated cardiovascular risks. The studies were successful in extending sleep deprivation up to 64 hours while dosing 300mg of modafinil every 15 hours.
A general conclusion of the study is the dosing Modafinil prior to sleep, will highly disrupt the sleep cycle and reduce the cognitive and mood impairments associated with sleep deprivation.
While amphetamine-based drugs seem to produce a state of significant sleepiness post-usage (Rebound Hypersomnia), research seems to conclude that Modafinil users do not experience the same effect. Post-usage, modafinil does not appear to cause rebound hypersomnia. This means that users do not appear to accrue a “sleep debt” when undergoing extended wakefulness during dosages.
Working Memory & Cognition
Studies have concluded that 100-200mg of modafinil taken at least 2 hours prior to cognitive testing improved the working memory (number sequencing), reaction times and visuospatial reasoning within test subjects. Also experiencing improvements were cognitive tasks which required higher-order thinking. Interestingly, participants also reported increased motivation and enjoyment levels while the task was being carried out. While the effects of improved mood most likely stems on the drug’s effect on serotonin receptors, the cognitive boosts are acquired from the myriad of neurological interactions.
In users who exhibited a dependency to methamphtamines, 400mg of modafinil for three consecutive days improved the working memory and fatigue levels of test subjects who fared poorly in baseline scores. However, in test subjects who had higher baseline scores the effects of modafinil’s cognition improvements were not as pronounced.
In a study of 164 people, it is estimated that 16% of respondents to modafinil report a suppression in appetite.
While there is weak evidence to suggest long-term usage of modafinil and its appetite suppression properties may lead to weight loss, the consensus is that the claim is not backed by sufficient statistical significance to be considered a meaningful conclusion.
As modafinil does not activate neuronal pathways associated to addiction, it is generally agreed that modafinil has a low potential for abuse compared to other drugs. While modafinil does increase dopamine levels (which are a pronounced effect of Amphetamine and Methylphenidate) It does not appear to act as fast or as aggressively as drugs like Adderall and Ritalin.
Another reason for the lack of addictive properties is that Modafinil users do not report euphoria (the state of being ‘high’). The lack of stimulation does not present a significant risk to create habit-forming behavior or addiction. While it is still possible to be psychologically dependent on the drug, its chemical properties do not seem to encourage this behavior.
For these reasons Modafinil has a much better safety profile in terms of addiction, and is regulated under Schedule IV as opposed to Adderall and Ritalin, which are Schedule II. Modafinil has also demonstrated an ability to inhibit prepotent responses, which are strongly linked to impulsive behavior. However, it is important to note this was only reported to affect individuals with a lower baseline score compared to the group.
Toxicology & Overdose
Side effects reported under the dose of Modafinil include: insomnia, sleepiness, loss of appetite, headaches, dizziness, nervousness, restlessness, nausea, dry mouth and gastrointestinal pain. Studies also note that reports of these side effects do not differ significantly from placebo, and it is generally agreed that Modafinil is well tolerated.
Modafinil presents a very low risk of overdose. In clinical trails, intentional overdosages (up to 4500mg per day, or 22 times the standard dose) did not result in any life-threatening effects. Participants reported anxiety, aggressiveness, confusion, nausea and diarrhea. Reports of fatal overdose have so far been accompanied by other drugs do not authoritatively conclude the drug’s profile in cases of accidental or intentional overdosage.