New research reveals that the wake-promoting drug modafinil affects markers of sleep homeostasis differently depending on a person’s genetics.
Key facts:
- Modafinil improved sustained attention in people with a certain gene variant but not others after sleep deprivation.
- Modafinil reduced sleepiness and theta brain waves during wakefulness regardless of genetics.
- Modafinil did not reduce slow wave sleep or delta brain waves during sleep after deprivation, unlike caffeine.
- Modafinil increased certain faster brain waves during sleep only in people with a specific gene variant.
Modafinil is a stimulant drug used to treat excessive sleepiness caused by conditions like narcolepsy.
It works by increasing brain chemicals that promote wakefulness, like dopamine.
Previous research found that modafinil improves cognition and alertness in healthy people deprived of sleep.
But does modafinil affect markers of sleep homeostasis equally in all people?
Sleep homeostasis refers to the body’s drive to sleep after prolonged wakefulness.
Scientists investigated this question by looking at both subjective sleepiness and brain waves during sleep deprivation.
They also considered genetics by selecting participants with different variants of the COMT gene.
COMT and Dopamine
The COMT gene codes for an enzyme called catechol-O-methyltransferase.
This enzyme breaks down catecholamine brain chemicals like dopamine.
A common variant of COMT leads to lower enzyme activity in the prefrontal cortex.
That results in higher dopamine signaling in the brain’s executive control regions.
People can have two copies of the high-activity variant (Val/Val), two copies of the low-activity one (Met/Met), or one of each (Val/Met).
The researchers compared 22 healthy young men with either Val/Val or Met/Met genotypes.
They matched the groups carefully on various traits like sleepiness.
Extended Wakefulness Study (Sleep Deprivation)
In the double-blind study, participants underwent 40 hours of continuous wakefulness.
They received either placebo or modafinil during this time.
The researchers monitored their alertness and brain waves at regular intervals.
They also recorded sleep architecture and brain activity after the deprivation period.
Sustained Attention
On a test of vigilant attention called the psychomotor vigilance task, modafinil maintained performance at baseline levels throughout sleep deprivation.
But this benefit only occurred in people with the Val/Val genotype associated with higher dopamine.
The drug had little effect on those with Met/Met.
Subjective Sleepiness
Both genetic groups reported increased sleepiness as wakefulness extended.
Modafinil attenuated this increase to a similar degree regardless of genotype.
Waking Brain Waves
Prolonged wakefulness increased theta waves (5-8Hz) in the waking EEG, a marker of sleep pressure.
Again modafinil reduced theta waves to an equal extent in both genotypes.
Sleep Architecture
The two genotypes showed typical changes in sleep architecture after sleep deprivation, like more slow wave sleep.
Modafinil did not alter these markers of sleep homeostasis compared to placebo in either genetic group.
Slow Wave Activity
A key marker of sleep need is slow wave activity (delta waves) in non-REM sleep.
Slow wave activity increased after deprivation and declined over sleep episodes similarly with modafinil and placebo.
So modafinil did not suppress this indicator of sleep pressure.
Faster Brain Waves
Although slow waves were unaffected, modafinil increased faster waves in the 3-7Hz and 16-20Hz ranges during non-REM sleep.
This effect only occurred in people with the Val/Val genotype.
No Effects on REM Sleep
Modafinil did not alter REM sleep architecture or brain waves compared to placebo in either genetic group.
Modafinil vs Caffeine on Sleep Homeostasis
These findings contrast with the effects of caffeine on sleep deprivation.
Caffeine is also a stimulant but acts through adenosine instead of dopamine.
Studies show caffeine reduces theta waves while awake and delta waves during sleep after deprivation.
Takeaways: Modafinil’s effect depends on genetics
These results demonstrate some differences in how modafinil affects markers of sleep need based on genetics.
Sustained attention benefits only occurred in Val homozygotes, while effects on sleepiness and theta waves were universal. Modafinil did not suppress slow wave sleep or delta waves like caffeine.
But it boosted select faster waves during non-REM sleep dependent on genotype.
Dissociations were also apparent between attention, sleepiness, and brain waves.
This suggests distinct mechanisms regulate various markers of sleep homeostasis.
The dopamine system appears to play a role in the disparity between performance and EEG measures in particular.
In sum, pharmacological stimulants can have varied effects on sleep deprivation based on their neurotransmitter targets and a person’s genetics.
These findings highlight the importance of considering individual differences in drug responses.
Understanding modafinil’s mechanisms of action may aid the development of improved alertness-promoting therapies.
References
- Study: Effects of modafinil on the sleep EEG depend on Val158Met genotype of COMT
- Authors: Sereina Bodenmann & Hans-Peter Landolt (2010)
