Modafinil

Modafinil is an awakefulness enchancing drug that was created for treatment of daytime sleep related disorders such as Narcolepsy. It seems to have benefits for cognition via increasing levels of stimulatory neurotransmitters in the brain, and is used recreationally as a smart-drug.

The Human Effect Matrix looks at human studies (excluding animal/petri-dish studies) to tell you what effect Modafinil has in your body, and how strong these effects are.

Level of Evidence	EFFECT	Change	Magnitude of Effect Size	Scientific Consensus	Comments
B	Fatigue		Notable	83% See all 6 studies	Fatigue is notably reduced with modafinil supplementation, particularly during instances of sleep deprivation or hypersomnia.
B	Blood Pressure		Minor	33% See all 3 studies	There may be a slight increase in systolic blood pressure with acute usage of modafinil (when measured at its peak blood levels), although it does not appear to modify ... show basal blood pressure values
B	Cognition		Minor	75% See all 4 studies	Cognition is significantly improved in persons undergoing sleep deprivation or other conditions in which attention processing is highly impaired, while other conditions ... show (cognitive decline or drug dependence) experience minor improvements in cognition that are lesser than those seen in sleep deprivation.
B	Reaction Time		Minor	66% See all 3 studies	An improvement in reaction time (decrease) is noted in both healthy and normal persons as well as those undergoing either drug addiction or sleep deprivation. This may ... show be related to the alertness promoting effects of the compound.
B	Working Memory		Minor	100% See all 5 studies	An improvement in working memory is noted in most persons tested, even otherwise healthy and nonfatigued controls.
B	Heart Rate			100% See all 3 studies	Heart rate and pulse do not appear to be influenced from modafinil supplementation, despite a small increase in systolic blood pressure.
C	Sedation		Strong	100% See 2 studies	Modafinil (300mg) taken prior to sleep is as potent as 20mg D-amphetamine in reducing the need to sleep and improving cognitive performance during intentional sleep deprivation. ... show Occasionally, this potency manifests itself as the 'side-effect' of insomnia in some persons who take it in the AM
C	ADHD in Children		Notable	100% See study	Modafinil appears to be able to reduce symptoms of ADHD in children when taken as a daily preventative at the lowest active dose
C	Subjective Well-being		Notable	100% See 2 studies	Subjective well being and enjoyment during cognitive tasks appears to be significantly improved modafinil supplementation, and this is notable as it has been noted to occur ... show in otherwise healthy persons taking modafinil for nootropic purposes
C	Alcohol Dependence		Minor	100% See study	Alcohol dependence, particularly the impulsivity thereof, appears to be slightly reduced with modafinil administration
C	Alertness		Minor	100% See study	An increase in alertness has been reported in persons using modafinil supplementation.
C	Appetite		Minor	100% See study	Modafinil appears to be able to reduce appetite, and 'loss of appetite' is a common side-effect of modafinil supplementation.
C	Attention		Minor	50% See 2 studies	There appears to be somewhat of an increase in subjective attention with modafinil secondary to its arousal promoting effects
C	Impulsivity		Minor	100% See 2 studies	Modafinil can decrease impulsivity in studies assessing addiction, although it appears to only significantly affect those with higher baseline impulsivity (more impulsive ... show at the start of the study) rather than all persons.
C	Memory		Minor	100% See 2 studies	Memory (usually studies investigate short term) appears to be beneficially influenced with modafinil supplementation, possible secondary to the improvements in working ... show memory and attention.
C	Motivation		Minor	100% See study	Motivation to complete a cognitive task appears to be improved in persons supplementing modafinil.
C	Processing Accuracy		Minor	100% See study	There is a possible improvement in processing accuracy with supplementation of modafinil.
C	Symptoms of Multiple Sclerosis		Minor	100% See 2 studies	Memory impairment in multiple sclerosis may be attenuated with supplementation of modafinil (250mg armodafinil), although other cognitive impairments associated with MS ... show do not appear significantly affected.
C	Calmness			100% See study	There do not appear to be any significant influences on self-reported ratings of calmness with supplementation of modafinil.
C	Processing Speed			100% See study	There does not appear to be a significant influence on processing speed, with some evidence suggesting a possible reduction thereof.
C	Weight			0% See study	There is currently no evidence to suggest a significant reduction of weight associated with modafinil, although as a trend to reduce weight has been noted alongside appetite ... show reduction it is thought that modafinil could have a role in weight control.

1. Structure and Properties

1.1. Origin

Modafinil is a pharmaceutical designed for usage in sleep-related disorders, and is related to improved mental function in a sleep deprived state.^[2]

1.2. Forms of Modafinil

The term 'modafinil' refers to a racemic mixture of two isomers, R-modafinil and S-modafinil. The R-isomer by itself is referred to as armodafinil.^[3]

Modafinil is a racemic mixture of S-modafinil and R-modafinil, whereas Armodafinil is just the R-modafinil by itself

2. Pharmacology

2.1. Serum

The half-life of modafinil appears to be 13-15 hours, and steady state concentrations in serum are reached 2 days following supplementation.^[3] Although the S-isomer by itself seems to have a short elimination half-life (4-5 hours) whereas the R-isomer is more prolonged (15 hours)^[4][5] ingesting armodafinil does not appear to significantly differ from modafinil.^[3][6][7]

An analysis of studies has noted, however, that armodafinil has an 18% higher C_max value (5.44+/-1.64µg/mL relative to 4.61+/-0.73µg/mL) with a more rapid T_max (1.8 hours relative to 2.5)^[3] and that the overall AUC of armodafinil appears to be 32-40% greater than modafinil.^[3]

Although the two variants of modafinil (modafinil and armodafinil) appear to have similar half-lives, armodafinil has a higher overall exposure to the body (assessed by AUC) as well as a higher and more rapid peak in the blood

2.2. Localization

According to c-Fos immunocytochemistry (c-Fos being a gene that rapidly activates in response to stimuli^[8][9] and can be detected following neuronal stimulation^[10][11] or sleep deprivation^[12]), modafinil administration to cats is associated with strong c-Fos activation in the anterior hypothalamic nucleus and surrounding areas with weaker activation in the dorsal portion of the suprachiasmatic nuclei (SCN) with minimal activation in other brain regions such as the cortex or striatum.^[13] This selective activation of the hypothalamus has been noted elsewhere, and the amygdala also implicated.^[14][15] Modafinil has been confirmed in humans to have a different profile than does amphetamine.^[16]

In contrast to amphetamine or methylphenidate induced wakefulness (characterized by widespread neuronal activation), modafinil appears to be somewhat selective for the hypothalamus and amygdala with some influence on the SCN

3. Neurology

3.1. Dopaminergic interactions

Modafinil seems to be able to increase extracellular levels of dopamine in the rat nucelar accumbens^[17] and prefrontal cortex^[18] and the dog caudate nucleus.^[19] It has been shown to occupy both the dopamine and noradrenaline receptors (in the striatum)^[20] and prevention of dopamine receptor occupancy abolishes the sleep-promoting effects in mice^[21], suggesting this mechanism of action is crucial to the sleep-promoting effects.^[22]

Past studies have noted a lack of potency of modafinil on dopaminergic systems^[23][24][25] which may be due to the lower dosages they used in those studies relative to more recent ones.

3.2. Adrenergic interactions

The wakefulness effects of modafinil are significantly attenuated by antagonists of adrenergic receptors (both alpha and beta subunits)^[26] although inhibiting catecholamine synthesis via α-methylparatyrosine does not appear to impair these effects.^[26][27][28]

3.3. Serotonergic interactions

3.4. Orexinergic interactions

In those with faulty orexin levels (narcoleptics)^[29], modafinil shows benefit possibly by acting on orexic neurons directly.^[30][31] This effect is more potent in orexin-knockout mice than in normal mice^[32], and the effects of modafinil on the orexin system of healthy persons is unknown.^[2]

3.5. Sedation and Alertness

Some studies assess the effects of modafinil on intentional sleep deprivation, and modafinil (300mg) appears to be effective in reducing the disturbed mood and cognition seen during sleep deprivation with a potency comparable to 20mg D-amphetamine.^[33][1] Elsewhere, it has been noted that the impairment of self-monitoring (ability to accurately assess oneself and their environment) is effectively reversed to a degree where an overconfidence effect (higher percieved assessment of skills relative to actual skills) is seen.^[34]

These studies have extended up to 64 hours (two nights sleep deprivation) with a single dose of modafinil every 15 hours.^[33][1]

Modafinil intervention prior to sleep can highly disrupt the sleep cycle and accompanying sedation, and usage of modafinil in this manner can attenuate the side-effects of sleep deprivation (cognitive and mood impairment)

Rebound hypersomnia is the phenomena where an anti-sleep agent is successful in reducing sleep, but after the effects of the drug wear off the user is significantly sleepier than before. Unlike amphetamine based drugs, modafinil does not appear to be associated with rebound hypersomnia in the cat^[26][35] nor rats^[36][37][38] or mice.^[39] In humans who miss two nights sleep due to modafinil intervention (64 continuous hours awake), there does not appear to be any rebound hypersomnia like is seen with D-amphetamine.^[1]

Modafinil does not appear to be associated with rebound hypersomnia

The increase in alertness during sleep deprivation seen with 300mg modafinil appears to be comparable to 20mg D-amphetamine over the course of 10-12 hours following one-time administration.^{[33][16][1][34]}

The anti-sleep efficacy of modafinil (300mg) appears to be comparable to 20mg D-amphetamine

The sleep wake cycle of the brain is a balance of the 'ascending arousal system' consisting of arousing neurotransmitters (catecholamines, acetylcholine, orexin, etc.) and the neurotransmitters (GABA, Galanin) which act to suppress stimulation and promote sleep.^[40][41] Varying levels of arousing and depressing neurotransmitters form an 'on-off' switch for arousal and sleep.^[2]

Overall regulation of the wakefulness and rest cycle seems to be in part due to the circadian rhythm, mediated by the Suprachiasmatic Nuclei (SCN), and in part due to homeostatic needs for sleep that are gained during wakefulness.^[40][41]

Modafinil seems to be able to interact with a multitude of stimulatory systems including serotonergic, noradrenergic, dopaminergic, glutaminergic, histaminergic, and orexinergic pathways; and also influences GABAergic pathways.^[42]

Some studies that use modafinil for the treatment of some other states note that the side-effect of insomnia persists more than placebo^[43] and modafinil is able to prevent participants from voluntarily falling asleep when taken prior to sleep.^[44]

Supplementation of modafinil is able to preserve cognition in fatiged states.^[44]

3.6. Memory and Cognition

In otherwise healthy persons, 100mg or 200mg of modafinil taken two hours prior to cognitive testing is able to improve working memory (digit span tests), visuospatial planning, and reaction time^[45] whereas elsewhere it was found to improve cognition (task enjoyment, planning, and working memory) in completely normal and non-sleep deprived persons at 200mg.^[46] Working memory and processing accuracy have been found to be improved with 200mg elsewhere.^[47]

Alongside the improvements in working memory are improvements in the actual performance of the task, most notably an increase in motivation and enjoyment for undergoing the task.^[46]

There is some cognitive enhancing properties of modafinil acute usage in otherwise healthy persons, and may increase motivation and enjoyment from doing a cognitive task

In methamphtamine dependent persons (known to have a degree of cognitive impairment^[48][49]), modafinil at 400mg for three days is able to improve working memory and trended to improve fatigue in those with worse baseline scores yet was unable to improve performance in those with higher baseline scores^[50] and 200mg for a single dose does not appear to be cognitive enhancing in this same population.^[51]

In persons with possible cognitive decline associated with methamphetamine usage, modafinil has the potential to improve cognition although acute usage doesn't appear to be effective and the overall cognitive enhancement is relatively minor

3.7. Appetite

Studies that assess the effects of modafinil sometimes report a reduction in appetite as a side-effect, measured at 16% (164 persons^[43])

Studies that note reductions in appetite sometimes note trends towards weight loss over a period of weeks, but usually do not reach statistical significance.^[43]

3.8. Attention

Supplementation of modafinil in the range of 170–425mg for six weeks (dose titrated up from 170mg to 425mg unless tolerance was compromised) was able to reduce symptoms of ADHD as assessed by both CGI-I and ADHD-RS-IV in youth.^[43]

3.9. Addiction

Due to the inability for modafinil to activate neuronal pathways involved in addiction, it is thought to have a low abuse potential relative to other drugs.^[52][53]

It is thought that modafinil has a low potential for wide-spread drug abuse

Response inhibition (the ability to inhibit a prepotent response,^[54] and thought to be indicative of impulsivity in persons undergoing drug abuse^[55]) is improved in rats^[56] and humans (alcohol dependence,^[57] methamphetamine dependence,^[51] and gambling^[58]) with modafinil, but only in those with worse baseline scores rather than the whole group.

It is possible for modafinil to reduce impulsivity in persons addicted to drugs or some addictive behaviours, although this only appears to be significantly effective for persons with worse impuslivity prior to testing

4. Interaction with Medical Conditions

4.1. Multiple Sclerosis

Acute supplementation of armodafinil (250mg) in persons with multiple sclerosis has noted improvements in memory recall relative to placebo, although other measured parameters (fatigue, executive function, processing speed) were unaffected by supplementation.^[59] This inefficacy on fatigue and arousal has not been noted elsewhere, where modafinil is attributed to possessing an antifatigue effect in MS.^[60]

5. Safety and Toxicology

5.1. General

Adverse effects usually reported in trials are predominantly headache, dizziness, increased diuresis, palpitations and tachycardia, restlessness, nervousness, gastrointestinal complains such as nausea, dry mouth and abdominal pain. Despite these isolated adverse events, they usually do not differ significantly from placebo and thus modafinil is seen as well tolerated.

Reported side-effects that sometimes occur significantly more than placebo include insomnia and sleeplessness as well as appetite reduction.^[43]

General side-effects of modafinil include insomnia and/or sleeplessness as well as a reduction in appetite

References

1. Buguet A, et al Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. II. Effects on two nights of recovery sleep . J Sleep Res. (1995)
2. Approved and Investigational Uses of Modafinil: An Evidence-Based Review
3. Darwish M, et al Armodafinil and modafinil have substantially different pharmacokinetic profiles despite having the same terminal half-lives: analysis of data from three randomized, single-dose, pharmacokinetic studies . Clin Drug Investig. (2009)
4. Wong YN, et al A double-blind, placebo-controlled, ascending-dose evaluation of the pharmacokinetics and tolerability of modafinil tablets in healthy male volunteers . J Clin Pharmacol. (1999)
5. Wong YN, et al Open-label, single-dose pharmacokinetic study of modafinil tablets: influence of age and gender in normal subjects . J Clin Pharmacol. (1999)
6. Robertson P Jr, Hellriegel ET Clinical pharmacokinetic profile of modafinil . Clin Pharmacokinet. (2003)
7. Darwish M, et al Pharmacokinetic profile of armodafinil in healthy subjects: pooled analysis of data from three randomized studies . Clin Drug Investig. (2009)
8. Sheng M, Greenberg ME The regulation and function of c-fos and other immediate early genes in the nervous system . Neuron. (1990)
9. Morgan JI, Curran T Stimulus-transcription coupling in neurons: role of cellular immediate-early genes . Trends Neurosci. (1989)
10. Shiromani PJ, et al Cholinergically induced REM sleep triggers Fos-like immunoreactivity in dorsolateral pontine regions associated with REM sleep . Brain Res. (1992)
11. Fritschy JM, Frondoza CG, Grzanna R Differential effects of reserpine on brainstem catecholaminergic neurons revealed by Fos protein immunohistochemistry . Brain Res. (1991)
12. Pompeiano M, Cirelli C, Tononi G Effects of sleep deprivation on fos-like immunoreactivity in the rat brain . Arch Ital Biol. (1992)
13. Potential brain neuronal targets for amphetamine-, methylphenidate-, and modafinil-induced wakefulness, evidenced by c-fos immunocytochemistry in the cat
14. Engber TM, et al Differential patterns of regional c-Fos induction in the rat brain by amphetamine and the novel wakefulness-promoting agent modafinil . Neurosci Lett. (1998)
15. Scammell TE, et al Hypothalamic arousal regions are activated during modafinil-induced wakefulness . J Neurosci. (2000)
16. Chapotot F, et al Distinctive effects of modafinil and d-amphetamine on the homeostatic and circadian modulation of the human waking EEG . Psychopharmacology (Berl). (2003)
17. Modafinil enhances extracellular levels of dopamine in the nucleus accumbens and increases wakefulness in rats
18. de Saint Hilaire Z, et al Variations in extracellular monoamines in the prefrontal cortex and medial hypothalamus after modafinil administration: a microdialysis study in rats . Neuroreport. (2001)
19. Dopaminergic Role in Stimulant-Induced Wakefulness
20. Madras BK, et al Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro . J Pharmacol Exp Ther. (2006)
21. Modafinil inhibits rat midbrain dopaminergic neurons through D2-like receptors
22. Dopheide MM, et al Modafinil evokes striatal {(3)H}dopamine release and alters the subjective properties of stimulants . Eur J Pharmacol. (2007)
23. Lack of pre-synaptic dopaminergic involvement in modafinil activity in anaesthetized mice: In vivo voltammetry studies
24. Mignot E, et al Modafinil binds to the dopamine uptake carrier site with low affinity . Sleep. (1994)
25. Akaoka H, et al Effect of modafinil and amphetamine on the rat catecholaminergic neuron activity . Neurosci Lett. (1991)
26. Lin JS, et al Role of catecholamines in the modafinil and amphetamine induced wakefulness, a comparative pharmacological study in the cat . Brain Res. (1992)
27. Simon P, et al Non-amphetaminic mechanism of stimulant locomotor effect of modafinil in mice . Eur Neuropsychopharmacol. (1995)
28. Duteil J, et al Central alpha 1-adrenergic stimulation in relation to the behaviour stimulating effect of modafinil; studies with experimental animals . Eur J Pharmacol. (1990)
29. The hypocretin/orexin system in health and disease
30. Chemelli RM, et al Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation . Cell. (1999)
31. Hypothalamic Arousal Regions Are Activated during ModafinilInduced Wakefulness
32. Modafinil more effectively induces wakefulness in orexin-null mice than in wild-type littermates
33. Pigeau R, et al Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. I. Effects on mood, fatigue, cognitive performance and body temperature . J Sleep Res. (1995)
34. Baranski JV, Pigeau RA Self-monitoring cognitive performance during sleep deprivation: effects of modafinil, d-amphetamine and placebo . J Sleep Res. (1997)
35. Lin JS, et al Effects of amphetamine and modafinil on the sleep/wake cycle during experimental hypersomnia induced by sleep deprivation in the cat . J Sleep Res. (2000)
36. Wisor JP, et al Armodafinil, the R-enantiomer of modafinil: wake-promoting effects and pharmacokinetic profile in the rat . Pharmacol Biochem Behav. (2006)
37. Touret M, Sallanon-Moulin M, Jouvet M Awakening properties of modafinil without paradoxical sleep rebound: comparative study with amphetamine in the rat . Neurosci Lett. (1995)
38. Edgar DM, Seidel WF Modafinil induces wakefulness without intensifying motor activity or subsequent rebound hypersomnolence in the rat . J Pharmacol Exp Ther. (1997)
39. Willie JT, et al Modafinil more effectively induces wakefulness in orexin-null mice than in wild-type littermates . Neuroscience. (2005)
40. Hypothalamic regulation of sleep and circadian rhythms
41. Neurobiology of the Sleep-Wake Cycle: Sleep Architecture, Circadian Regulation, and Regulatory Feedback
42. Modafinil: A Review of Neurochemical Actions and Effects on Cognition
43. Biederman J, et al Efficacy and safety of modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, flexible-dose study . Pediatrics. (2005)
44. Gill M, et al Cognitive performance following modafinil versus placebo in sleep-deprived emergency physicians: a double-blind randomized crossover study . Acad Emerg Med. (2006)
45. Turner DC, et al Cognitive enhancing effects of modafinil in healthy volunteers . Psychopharmacology (Berl). (2003)
46. Müller U, et al Effects of modafinil on non-verbal cognition, task enjoyment and creative thinking in healthy volunteers . Neuropharmacology. (2013)
47. Müller U, et al Effects of modafinil on working memory processes in humans . Psychopharmacology (Berl). (2004)
48. Seiden LS, Fischman MW, Schuster CR Long-term methamphetamine induced changes in brain catecholamines in tolerant rhesus monkeys . Drug Alcohol Depend. (1976)
49. Woolverton WL, et al Long-term effects of chronic methamphetamine administration in rhesus monkeys . Brain Res. (1989)
50. Kalechstein AD, De La Garza R 2nd, Newton TF Modafinil administration improves working memory in methamphetamine-dependent individuals who demonstrate baseline impairment . Am J Addict. (2010)
51. Dean AC, et al Acute modafinil effects on attention and inhibitory control in methamphetamine-dependent humans . J Stud Alcohol Drugs. (2011)
52. Myrick H, et al Modafinil: preclinical, clinical, and post-marketing surveillance--a review of abuse liability issues . Ann Clin Psychiatry. (2004)
53. Jasinski DR, Kovacević-Ristanović R Evaluation of the abuse liability of modafinil and other drugs for excessive daytime sleepiness associated with narcolepsy . Clin Neuropharmacol. (2000)
54. Evenden JL Varieties of impulsivity . Psychopharmacology (Berl). (1999)
55. Impulsivity and Inhibitory Control
56. Eagle DM, et al Differential effects of modafinil and methylphenidate on stop-signal reaction time task performance in the rat, and interactions with the dopamine receptor antagonist cis-flupenthixol . Psychopharmacology (Berl). (2007)
57. Schmaal L, et al Effects of modafinil on neural correlates of response inhibition in alcohol-dependent patients . Biol Psychiatry. (2013)
58. Zack M, Poulos CX Effects of the atypical stimulant modafinil on a brief gambling episode in pathological gamblers with high vs. low impulsivity . J Psychopharmacol. (2009)
59. Bruce J, et al Impact of armodafinil on cognition in multiple sclerosis: a randomized, double-blind crossover pilot study . Cogn Behav Neurol. (2012)
60. Niepel G, et al Association of a deficit of arousal with fatigue in multiple sclerosis: effect of modafinil . Neuropharmacology. (2013)

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