MODAFINIL SUMMARY

Description
Modafinil is a wake promoting agent (FDA Approved) for narcolepsy* and
shift work sleep disorder. It can be used secondary for obstructive sleep
apnea/hypopnea syndrome* (Ballon, 2006).
*Narcolepsy is a chronic sleep disorder, characterized by excessive daytime sleepiness
(EDS), cataplexy, hypnagogic hallucinations, and sleep paralysis. Possible due to
hypocretin ligand deficiencyn (Nishino, 2010).
*Apnea and hypopnea are caused by the airway being sucked close on inspiration during
sleep. This occurs as the upper airway dilating muscles, which are also striated muscles,
normally relax during sleep. In patients with OSAHS, the dilating muscles can no longer
successfully oppose negative pressure within the airway during inspiration. The patients
have narrow upper airways. The airway is kept patent by the dilating muscles which have
higher than normal activity during wakefulness. But during sleep, the muscle tone falls
and airway narrows. Snoring may then occur; followed by airway occlusion and
subsequent apnea (Ambata, 2012).

Possible Mechanisms of Action and Behavioral Effects

- Mechanisms remain unknown but evidence strongly suggests that its
mechanism differs from that of amphetamine-derived stimulants (ADS)
(Ballon, 2006).
- ADS works mostly on the dopamine (re)uptake system, and was also
used for narcolepsy, but due to many side effects, tolerance and
dependence a new drug like Mod was created. Test results in mice show
that the dopaminergic system is not so much involved and might work
completely different than that from ADS (Simon, 1995). Although, it does
bind on DA transport inhibitors and it depends on the production of
catecholaminergic substances ((nor)adrenaline, dopamine, . . ), but in a
very selective way (Wison, 2013).
- Modafinil (Mod) is associated with increased adrenergic, histaminergic,
glutaminergic and hypocretin activity and decreased GABA activity in
specific parts of the brain (Ballon, 2006).
Loci:
- Mod and ADS increase both neural activation (Ballon, 2006).
- ADS activates in more spread brain parts : striatum, cortex and caudate
nucleus (Ballon, 2006).
- Mod shows activities in more localized parts of the brain : paraventricular
and suprachiasmic nuclei, anterior hypothalamus, amygdala and
tuberomammillary nucleus. It is thus active in more wakefulness areas
than ADS (Ballon, 2006).
Neurotransmitter:
- It has shown a decrease in GABA nuclei (GABA has in inhibitory function).
A secondary effect is a weak dopaminergic increase (Ballon, 2006 ; Wood,
2013).
- It possibly increases serotonin levels (Accepted manuscript).

- It shows an increase of glutamate (works stimulating) in hippocampus and

areas in thalamus. This may cause its vigilance-enhancing properties
(Ballon, 2006 ; Wood, 2013).
- It modulates the hipocretin system (Wood, 2013). Therefore its use in
narcolepsy and problems in arousal regulation (Ballon, 2006).
- Hipocretin peptides stimulate the release of histamine, which is important
in the sleep-wake cycle (Ballon, 2006).
Effects:
- Increases time in wakefulness but not wake with ambulation (more
locomotoric activity) (Wisor, 2013). Also increases Working Memory and
executive functions. Although when dosage is too high, disruptive memory
can occur (Wood, 2013)
- Enhanced behavioral learning curve (in rats) (Yan, 2015) and spatial
working memory functions (Karabakac, 2015).
General Safety and Tolerantibilty
Mod is over 90% metabolized in the liver. The other 10% is excreted
renally. Its well tolerated (Ballon, 2006).
Mod has been reported a safe drug (Ballon, 2006).
No effect on sleep architecture, nor on REM sleep even on long term use
(Ballon, 2006).
Dosage
Between 100 mg/day up to 600 mg/day are effective (Ballon, 2006).
Side effects are possible : headache, nausea, diarrhea, nervousness,
anxiety, dyspepsia and insomnia (Ballon, 2006).
Approved Clinical Uses (Ballon, 2006).
- Narcolepsy (300mg/d)
- Shift work sleep disorder (200mg/d for 12 weeks)
- Obstructive Sleep Apnea/Hypopnea syndrome : (200 400 mg/d)
Potential Nonapproved Clinical Uses (Ballon, 2006).
Fatigue and sedation associated with specific medical conditions : For
example Multiple Sclerosis, Parkinsons Disease, HIV, Chronic Fatigue
syndrome, dementia, sleep problems, fibromyalgia, ADHD, Depression,
cocaine dependence, schizophrenia, obesity
Risk for Abuse
It does not give a high or euphoria (like in e.g. cocaine) and therefore
its suggested not to be addictive. No signs of abuse (Ballon, 2006 ; Wisor,
2013).
When taken simultaneously with cocaine, people report that Mod blunts
the effect of cocaine. It also has been reported that the use of Mod helps in
abstinence of cocaine (Wisor, 2013).

S. Freud is know for chewing on coca wines or taking cocaine on a very low
dosage (not uncommon for that period in time). He reported an increase
of self-control and possessing more vitality and capacity for work. Long
intensive physical work is performed without any fatigue. (Wood, 2013).