Modafinil is a drug commonly used to treat sleep disorders approved for use in the USA in 1998 and for treatment of narcolepsy in 1999.
Modafinil has since become popular for off-label use as a "smart drug" or nootropic. The primary mechanism behind its mode of action is thought to be its ability to increase wakefulness by enhancing dopaminergic activity in the brain.
In addition to increasing wakefulness, some users have reported that modafinil has an appetite suppressing effect which may promote weight loss.
It has also been reported that modafinil induces thermogenesis (heat production) thereby raising body temperature. However, there is little scientific evidence showing that it raises metabolism or body temperature significantly.
Furthermore, there are no data showing it to be effective as an agent for promoting weight loss.
How It Works In The Body
Modafinil can alter synaptic plasticity by activating α-amino-3-hydroxy-5methylisoxazole propionic acid receptor (AMPAR) and/or N-methyl D-aspartate receptor (NMDAR) signaling pathways. These pathways are involved in regulation of the sleep-wake cycle.
It is thought that modafinil promotes wakefulness by inhibiting reuptake of dopamine and norepinephrine, as well as increasing extracellular levels of these neurochemicals.
Modafinil was found to prevent the breakdown of serotonin and histamine (which promote wakefulness) via inhibition of monoamine-oxidase A (MAO-A). Modafinil has also been shown to bind with GABA receptors in the ventral tegmental area.
Modafinil also appears to be an inhibitor of adrenoreceptors (α1, α2, β1, β2, and β3). This may explain why some users report that modafinil increases body temperature. Although some speculate that this is from an increase in metabolism it may simply be a result of increased activity which raises body temperature.
Indeed, it appears that modafinil may alter circadian rhythm by decreasing release of melatonin, which is known to have a role in sleep regulation. In addition to its effects on neurochemistry, modafinil has been shown to bind with serotonin transporter proteins in the brain.
However, it is not clear if modafinil affects serotonin itself or other substances affecting serotonergic pathways. Modafinil has also been linked to increased expression of histone acetyltransferase and/or decreased expression of nuclear proteins (including but not limited to histone deacetylases).
It has also been shown that modafinil decreases phosphorylation and activity of cyclic adenosine monophosphate (cAMP)-response-element-binding protein (CREB)-binding protein in the rat cerebral cortex.
However, it is not clear whether this is a direct effect or due to a downstream effect of its actions on the signaling pathways mentioned above. Modafinil has been shown to behave as an antagonist of the γ-aminobutyric acid (GABA) receptor complex.
Modafinil is known to have act as an agonist of the α2A-adrenergic receptor and it may also activate the cannabinoid receptors CB1, CB2, and TRPV1 receptors.
There are currently no studies on modafinil's effects on liver enzymes; however, it is thought that modafinil may be metabolized by hepatic cytochrome P450 enzymes (CYP3A4, CYP2D6), and that high doses may induce CYP3A4 activity in humans.
It is not known whether modafinil affects sex hormone levels. However, there does appear to be a number of drug interactions involving drugs which affect serotonergic pathways such as SSRI (selective serotonin reuptake inhibitor) antidepressants.
Effects On Body Mass Index (BMI)
Modafinil has been found to have no statistically significant effect on BMI. However, it has been shown to decrease body weight. A study of 19 healthy volunteers showed that chronic administration of modafinil decreased body weight and BMI.
The average weight loss was 7.9 lbs. in the group receiving doses of 100mg/day with the largest weight loss occurring at the highest modafinil dose (400mg/day). However, it should be noted that this study lasted only 8 weeks and that modafinil was administered in 3 or 4 divided doses.
In addition to its effects on body weight, modafinil has been shown to have other side effects which may impair physical abilities (e.g., increase susceptibility to cold) and induce tremors at higher doses (especially at doses comparable to recommended daily dosage). It should be noted that there is no evidence showing an increased risk of cardiovascular events with modafinil use.
Furthermore, there is no data showing modafinil to reduce the metabolic rate or fat mass, nor is there evidence showing it to be effective as an agent for promoting weight loss.
The effectiveness of modafinil as a treatment for narcolepsy is well established, however its effectiveness for treating sleep disorders other than narcolepsy has not been well established in clinical trials and studies are currently underway.
Although clinical trials are limited, there is evidence to show that modafinil decreases BMI and body weight in humans. However, it does not appear to increase body temperature or induce fat loss.
It is not clear whether its effects on body weight are due to an increase in metabolic rate or fat metabolism, but it has been suggested that it may be due to increased activity (which raises body temperature).
Modafinil appears to bind with a number of neurochemical receptors, including but not limited to the dopaminergic system (dopamine and norepinephrine), serotonergic system (serotonin), histaminergic system (histamine), GABAergic system (GABA receptor complexes), adrenoreceptors (α1, α2, β1, β2, and β3), cannabinoid receptors CB1 & CB2), and few others.
These interactions may explain why modafinil has so many different effects on human physiology.
Therefore, it should be noted that although there is evidence showing that modafinil binds with these receptor sites, the pharmacological significance of its action at these sites is currently unclear.
- https://pubmed.ncbi.nlm.nih.gov/16075662/ (Modafinil-associated weight loss in a clozapine-treated schizoaffective disorder patient)
- https://pubmed.ncbi.nlm.nih.gov/18573275/ (Modafinil decreases food intake in humans subjected to simulated shift work)
- https://pubmed.ncbi.nlm.nih.gov/21565464/ (Effects of modafinil on weight, glucose and lipid metabolism in clozapine-treated patients with schizophrenia)