Modafinil Mechanism – Know The Cheat Sheet

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– Weakly Inhibits NET, increasing arousal
– Thalamus, rostro-medial Hypothalamus, Locus Coeruleus, Cortex
– Madras et al, 2006



– Increases neuronal excitability
– Accumbens, Striatum, Cortex, Posterior Hypothalamus, Ventral- & medial-preoptic areas
– Tanganelli et al, 1992, 1994, 1995



– Weakly Inhibits DAT, hijacking reward circuitry
– Accumbens, Striatum, Cortext
– Madras et al, 2006



– Modulates wakefulness
– Cortex, Accumbens, Striatum, Hypothalamus, Tubero-Mammilary Nucleus
– Ishizuka et al, 2003



– LTP and excitatory signaling
– Thalamus, rostro-medial Hypothalamus, Locus Coeruleus, Cortex
– Ferraro et al, 1997a



– Wakefulness-promoting peptide
– Lateral Hypothalamus
– Chemelli et al, 1999



– Learning and Memory
– Striatum, Latero-dorsal pedunculopontine tegmental nuclei, Cortex, Basal-forebrain nuclei
– Chemelli et al, 1999



– Mood
– Accumbens, Cortext, Striatum, Dorsal Rache, Central Nucleus of Amygdala
– de Saint Hilaire et al, 2001




Sensi’s work was among 24 papers included in a 2015 review of modafinil in healthy people. The studies used a variety of cognitive tests, and the review found that, on average, modafinil did seem to help — particularly with decision-making, planning and fluid intelligence. The more complex the task, the more that modafinil helped. “On the basis of the evidence,” says Battleday, “modafinil is improving people’s performance.” But the results were not uniformly positive. Not every test showed benefits and, in a couple, the drug seems to have stunted creativity.


The review authors also noted that many cognitive tests had been designed to assess impairment, not enhancement. For exam- ple, people with a brain injury or demen- tia may struggle with a clock-drawing test, but someone with normal cognition will usually get it right — leaving no room for smart drugs to assist. Psychologists have few options to adequately measure cognition in healthy people, says review co-author Anna- Katharine Brem, a neuropsychologist at the University of Oxford, UK.


*Dance A. Smart drugs: A dose of intelligence. Nature. 2016;531(7592):S2-3.*




FDA-Approved Indications

– Narcolepsy
– Obstructive Sleep Apnea
– Shift-Work Sleep Disorder


Investigational Uses

– Parkinson’s Disease
– Myotonic Dystrophy
– Traumatic Brain Injury
– Psychiatric Disorders
– ADHD Major
– Depressive Disorder
– Bipolar Depression
– Schizophrenia
– Cocaine Addiction
– Chronic Fatigue Syndrome
– Recovery From General Anesthesia



Madras BK, Xie Z, Lin Z, Jassen A, Panas H, Lynch L et al (2006). Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro. J Pharmacol Exp Ther 319: 561–569.

Tanganelli S, Ferraro L, Bianchi C, Fuxe K (1994). 6-hydroxy-dopamine treatment counteracts the reduction of cortical GABA release produced by the vigilance promoting drug modafinil in the awake freely moving guinea-pig. Neurosci Lett 171: 201–204.

Ishizuka T, Sakamoto Y, Sakurai T, Yamatodani A (2003). Modafinil increases histamine release in the anterior hypothalamus of rats. Neurosci Lett 339: 143–146.

Ferraro L, Antonelli T, O’Connor WT, Tanganelli S, Rambert F, Fuxe K (1997a). The antinarcoleptic drug modafinil increases glutamate release in thalamic areas and hippocampus. Neuroreport 8: 2883–2887.

Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C et al (1999). Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98: 437–451.

de Saint Hilaire Z, Orosco M, Rouch C, Blanc G, Nicolaidis S (2001). Variations in extracellular monoamines in the prefrontal cortex and medial hypothalamus after modafinil administration: a microdialysis study in rats. Neuroreport 12: 3533–3537.