Modafinil is a nonamphetamine nootropic drug with an increasingly therapeutic interest due to its different sites of action and behavioral effects in comparison to cocaine or amphetamine. A review of modafinil (and of its prodrug adrafinil and its R-enantiomer armodafinil) chemical, pharmacokinetic, pharmacodynamic, toxicological, clinical and forensic aspects was performed, aiming to better understand possible health problems associated to its unconscious and unruled use. Modafinil is a racemate metabolized mainly in the liver into its inactive acid and sulfone metabolites, which undergo primarily renal excretion. Although not fully clarified, major effects seem to be associated to inhibition of dopamine reuptake and modulation of several other neurochemical pathways, namely noradrenergic, serotoninergic, orexinergic, histaminergic, glutamatergic and GABAergic. Due its wake-promoting effects, modafinil is used for the treatment of daily sleepiness associated to narcolepsy, obstructive sleep apnea and shift work sleep disorder. Its psychotropic and cognitive effects are also attractive in several other pathologies and conditions that affect sleep structure, induce fatigue and lethargy, and impair cognitive abilities. Additionally, in health subjects, including students, modafinil is being used off-label to overcome sleepiness, increase concentration and improve cognitive potential. The most common adverse effects associated to modafinil intake are headache, insomnia, anxiety, diarrhea, dry mouth and raise in blood pressure and heart rate. Infrequently, severe dermatologic effects in children, including maculopapular and morbilliform rash, erythema multiforme and Stevens-Johnson Syndrome have been reported. Intoxication and dependence associated to modafinil are uncommon. Further research on effects and health implications of modafinil and its analogs is steel needed to create evidence-based policies.
DiamondA. Executive functions. Annu Rev Psychol.2013;64(1):135–168.
2.
FroestlW, MuhsA, PfeiferA. Cognitive enhancers (nootropics). Part 1: drugs interacting with receptors. JAD.2012;32(4):793–887.
3.
SteinerH, Van WaesV. Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants. Prog Neurobiol.2013;100:60–80.
SivaJ. Nootropics and smart drugs: super boost your mental alertness, cognition, memory, focus, creativity and mood. Philadelphia, PA: BookBaby; 2012.
6.
GiurgeaC. The “nootropic” approach to the pharmacology of the integrative activity of the brain 1, 2. Cond Reflex1973;8(2):108–115.
7.
RangHP, RitterJM, FlowerRJ, HendersonG. Rang and Dale's pharmacology. 8th ed. London: Churchill Livingstone; 2016.
8.
KatzungBG, TrevorAJ. Basic & clinical pharmacology. New York, NY: McGraw-Hill; 2018.
9.
WarnerCB, OttmanAA, BrownJN. The role of atomoxetine for Parkinson disease-related executive dysfunction: a systematic review. J Clin Psychopharmacol.2018;38(6):627–631.
10.
Dinis-OliveiraRJ. Metabolomics of methylphenidate and ethylphenidate: implications in pharmacological and toxicological effects. Eur J Drug Metab Pharmacokinet.2017;42(1):11–16.
11.
Dinis-OliveiraRJ. [Licit and ilicit uses of medicines]. Acta Med Port2014;27(6):755–766.
12.
Dinis-OliveiraRJ. Metabolomics of cocaine: implications in toxicity. Toxicol Mech Methods.2015;25(6):494–500.
13.
McLellanTM, CaldwellJA, LiebermanHR. A review of caffeine's effects on cognitive, physical and occupational performance. Neurosci Biobehav Rev.2016;71:294–312.
14.
Kasabova-AngelovaA, TzankovaD, MitkovJ, . Xanthine derivatives as agents affecting non-dopaminergic neuroprotection in Parkinson's disease. Curr Med Chem2018. doi: 10.2174/0929867325666180821153316. In press.
FerreiraGC, McKennaMC. L-carnitine and acetyl-L-carnitine roles and neuroprotection in developing brain. Neurochem Res.2017;42(6):1661–1675.
18.
AugustyniakJ, LenartJ, ZychowiczM, StepienPP, BuzanskaL. Mitochondrial biogenesis and neural differentiation of human iPSC is modulated by idebenone in a developmental stage-dependent manner. Biogerontology.2017;18(4):665–677.
19.
DolceG, CecconiV, ZamponiA, ZylbermanR, MaggiL, BattagliaA. Methodological approach to the clinical evaluation of nootropic drugs. Berlin, Heidelberg, Germany: Springer Berlin, Heidelberg; 1985:215–222.
20.
CastaldiS, GelattiU, OrizioG, . Use of cognitive enhancement medication among northern Italian university students. J Addict Med.2012;6(2):112–117.
21.
CartonL, CabeN, MenardO, . Pharmaceutical cognitive doping in students: a chimeric way to get-a-head?]Therapie.2018;73(4):319–329.
22.
Murillo-RodriguezE, Barciela VerasA, Barbosa RochaN, BuddeH, MachadoS. An overview of the clinical uses, pharmacology, and safety of modafinil. ACS Chem Neurosci.2018;9(2):151–158.
23.
WisorJ. Modafinil as a catecholaminergic agent: empirical evidence and unanswered questions. Front Neurol.2013;4:139.
24.
KalabaP, AherNY, IlicM, . Heterocyclic analogues of modafinil as novel, atypical dopamine transporter inhibitors. J Med Chem.2017;60(22):9330–9348.
25.
LolandCJ, MereuM, OkunolaOM, . R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse. Biol Psychiatry.2012;72(5):405–413.
26.
RobertsonPJr., HellriegelET. Clinical pharmacokinetic profile of modafinil. Clin Pharmacokinet.2003;42(2):123–137.
27.
KumarR. Approved and investigational uses of modafinil: an evidence-based review. Drugs2008;68(13):1803–1839.
28.
DonovanJL, MalcolmRJ, MarkowitzJS, DeVaneCL. Chiral analysis of d- and l-modafinil in human serum: application to human pharmacokinetic studies. Ther Drug Monit.2003;25(2):197–202.
29.
WongYN, KingSP, SimcoeD, . Open-label, single-dose pharmacokinetic study of modafinil tablets: influence of age and gender in normal subjects. J Clin Pharmacol.1999;39(3):281–288.
30.
DowlingG, KavanaghPV, TalbotB, . Outsmarted by nootropics? An investigation into the thermal degradation of modafinil, modafinic acid, adrafinil, CRL-40,940 and CRL-40,941 in the GC injector: formation of 1,1,2,2-tetraphenylethane and its tetra fluoro analog. Drug Test Analysis.2017;9(3):518–528.
31.
KeighronJD, QuartermanJC, CaoJ, . Effects of (R)-modafinil and modafinil analogues on dopamine dynamics assessed by voltammetry and microdialysis in the mouse nucleus accumbens shell. ACS Chem Neurosci.2019;10(4):2012–2021.
32.
WongYN, KingSP, LaughtonWB, McCormickGC, GrebowPE. Single-dose pharmacokinetics of modafinil and methylphenidate given alone or in combination in healthy male volunteers. J Clin Pharmacol.1998;38(3):276–282.
33.
ZhuHJ, WangJS, DonovanJL, . Interactions of attention-deficit/hyperactivity disorder therapeutic agents with the efflux transporter P-glycoprotein. Eur J Pharmacol.2008;578(2–3):148–158.
34.
DarwishM, KirbyM, HellriegelET. Comparison of steady-state plasma concentrations of armodafinil and modafinil late in the day following morning administration: post hoc analysis of two randomized, double-blind, placebo-controlled, multiple-dose studies in healthy male subjects. Clin Drug Investig.2009;29(9):601–612.
RobertsonP, DeCoryHH, MadanA, ParkinsonA. In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil. Drug Metab Dispos.2000;28(6):664–671.
37.
WongYN, SimcoeD, HartmanLN, . A double-blind, placebo-controlled, ascending-dose evaluation of the pharmacokinetics and tolerability of modafinil tablets in healthy male volunteers. J Clin Pharmacol.1999;39(1):30–40.
38.
DingesDF, AroraS, DarwishM, NieblerGE. Pharmacodynamic effects on alertness of single doses of armodafinil in healthy subjects during a nocturnal period of acute sleep loss. Curr Med Res Opin.2006;22(1):159–167.
LuJ, WangX, YangS, . Doping control analysis for adrafinil and its major metabolites in human urine. Rapid Commun Mass Spectrom.2009;23(11):1592–1600.
41.
ChatterjieN, StablesJP, WangH, AlexanderGJ. Anti-narcoleptic agent modafinil and its sulfone: a novel facile synthesis and potential anti-epileptic activity. Neurochem Res.2004;29(8):1481–1486.
42.
DarwishM, KirbyM, RobertsonPJr., HellriegelET. Interaction profile of armodafinil with medications metabolized by cytochrome P450 enzymes 1A2, 3A4 and 2C19 in healthy subjects. Clin Pharmacokinet.2008;47(1):61–74.
43.
DarwishM, BondM, YangR, HellriegelET, RobertsonP.Jr., Evaluation of potential pharmacokinetic drug-drug interaction between armodafinil and aripiprazole in healthy adults. Pharmacopsychiatry.2015;48(4–5):170–175.
44.
DarwishM, BondM, HellriegelET, YouakimJM, YangR, RobertsonP.Jr., Investigation of a possible interaction between quetiapine and armodafinil in patients with schizophrenia: an open-label, multiple-dose study. J Clin Pharmacol.2012;52(9):1399–1409.
45.
DarwishM, BondM, YangR, HellriegelET, RobertsonP. Evaluation of potential pharmacokinetic drug-drug interaction between armodafinil and risperidone in healthy adults. Clin Drug Investig.2015;35(11):725–733.
46.
DarwishM, BondM, YangR, HellriegelET, RobertsonP.Jr., Evaluation of the potential for pharmacokinetic drug-drug interaction between armodafinil and carbamazepine in healthy adults. Clin Ther.2015;37(2):325–337.
47.
RobertsonPJr., HellriegelET, AroraS, NelsonM. Effect of modafinil at steady state on the single-dose pharmacokinetic profile of warfarin in healthy volunteers. J Clin Pharmacol.2002;42(2):205–214.
48.
OliveMF, ClevaRM, KalivasPW, MalcolmRJ. Glutamatergic medications for the treatment of drug and behavioral addictions. Pharmacol Biochem Behav.2012;100(4):801–810.
49.
GonzalezB, TorresOV, JayanthiS, . The effects of single-dose injections of modafinil and methamphetamine on epigenetic and functional markers in the mouse medial prefrontal cortex: potential role of dopamine receptors. Prog Neuropsychopharmacol Biol Psychiatry.2019;88:222–234.
50.
JonesSR, GainetdinovRR, HuXT, . Loss of autoreceptor functions in mice lacking the dopamine transporter. Nat Neurosci.1999;2(7):649–655.
51.
FaucheyV, JaberM, CaronMG, BlochB, Le MoineC. Differential regulation of the dopamine D1, D2 and D3 receptor gene expression and changes in the phenotype of the striatal neurons in mice lacking the dopamine transporter. Eur J Neurosci.2000;12(1):19–26.
52.
WisorJP, NishinoS, SoraI, UhlGH, MignotE, EdgarDM. Dopaminergic role in stimulant-induced wakefulness. J Neurosci.2001;21(5):1787–1794.
53.
SeemanP, GuanHC, HirbecH. Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil. Synapse.2009;63(8):698–704.
54.
WesterinkBH, TuntlerJ, DamsmaG, RollemaH, de VriesJB. The use of tetrodotoxin for the characterization of drug-enhanced dopamine release in conscious rats studied by brain dialysis. Naunyn-Schmiedeberg's Arch Pharmacol.1987;336(5):502–507.
55.
MereuM, ChunLE, PrisinzanoTE, NewmanAH, KatzJL, TandaG. The unique psychostimulant profile of (±)-modafinil: investigation of behavioral and neurochemical effects in mice. Eur J Neurosci.2017;45(1):167–174.
56.
SolinasM, JustinovaZ, GoldbergSR, TandaG. Anandamide administration alone and after inhibition of fatty acid amide hydrolase (FAAH) increases dopamine levels in the nucleus accumbens shell in rats. J Neurochem.2006;98(2):408–419.
57.
MinzenbergMJ, CarterCS. Modafinil: a review of neurochemical actions and effects on cognition. Neuropsychopharmacol.2008;33(7):1477–1502.
58.
PerugiG, VannucchiG, BedaniF, FavarettoE. Use of Stimulants in Bipolar Disorder. Curr Psychiatry Rep.2017;19(1):7.
59.
CaoJ, PrisinzanoTE, OkunolaOM, . Structure-activity relationships at the monoamine transporters for a novel series of modafinil (2-[(diphenylmethyl)sulfinyl]acetamide) analogues. ACS Med Chem Lett.2011;2(1):48–52.
60.
CaoJ, SlackRD, BakareOM, . Novel and high affinity 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) analogues as atypical dopamine transporter inhibitors. J Med Chem.2016;59(23):10676–10691.
61.
ReithME, BloughBE, HongWC, . Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter. Drug Alcohol Depend.2015;147:1–19.
62.
BallonJS, FeifelD. A systematic review of modafinil: potential clinical uses and mechanisms of action. J Clin Psychiatry.2006;67(04):554–566.
63.
IshizukaT, MurotaniT, YamatodaniA. Action of modafinil through histaminergic and orexinergic neurons. Vitam Horm.2012;89:259–278.
64.
LinJS, HouY, JouvetM. Potential brain neuronal targets for amphetamine-, methylphenidate-, and modafinil-induced wakefulness, evidenced by c-fos immunocytochemistry in the cat. Proc Natl Acad Sci U S A.1996;93(24):14128–14133.
65.
EngberTM, KouryEJ, DennisSA, MillerMS, ContrerasPC, BhatRV. Differential patterns of regional c-Fos induction in the rat brain by amphetamine and the novel wakefulness-promoting agent modafinil. Neurosci Lett.1998;241(2–3):95–98.
66.
ScammellTE, EstabrookeIV, McCarthyMT, . Hypothalamic arousal regions are activated during modafinil-induced wakefulness. J Neurosci.2000;20(22):8620–8628.
67.
de Saint HilaireZ, OroscoM, RouchC, BlancG, NicolaidisS. Variations in extracellular monoamines in the prefrontal cortex and medial hypothalamus after modafinil administration: a microdialysis study in rats. Neuroreport.2001;12(16):3533–3537.
68.
SchmidtA, MullerF, DolderPC, . Comparative effects of methylphenidate, modafinil, and MDMA on response inhibition neural networks in healthy subjects. Int J Neuropsychopharmacol.2017;20(9):712–720.
69.
MinzenbergMJ, WatrousAJ, YoonJH, UrsuS, CarterCS. Modafinil shifts human locus coeruleus to low-tonic, high-phasic activity during functional MRI. Science.2008;322(5908):1700–1702.
70.
WongYN, WangL, HartmanL, . Comparison of the single-dose pharmacokinetics and tolerability of modafinil and dextroamphetamine administered alone or in combination in healthy male volunteers. J Clin Pharmacol.1998;38(10):971–978.
71.
HellriegelET, AroraS, NelsonM, RobertsonP.Jr., Steady-state pharmacokinetics and tolerability of modafinil given alone or in combination with methylphenidate in healthy volunteers. J Clin Pharmacol.2001;41(8):895–904.
72.
HellriegelET, AroraS, NelsonM, RobertsonP.Jr., Steady-state pharmacokinetics and tolerability of modafinil administered alone or in combination with dextroamphetamine in healthy volunteers. J Clin Pharmacol.2002;42(4):450–460.
73.
BilliardM, BessetA, MontplaisirJ, . Modafinil: a double-blind multicentric study. Sleep.1994;17(suppl_8):S107–S112.
74.
NishinoS, MaoJ, SampathkumaranR, SheltonJ. Increased dopaminergic transmission mediates the wake-promoting effects of CNS stimulants. Sleep Res Online.1998;1(1):49–61.
75.
WoodS, SageJR, ShumanT, AnagnostarasSG. Psychostimulants and cognition: a continuum of behavioral and cognitive activation. Pharmacol Rev.2014;66(1):193–221.
76.
MadrasBK, XieZ, LinZ, . Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro. J Pharmacol Exp Ther.2006;319(2):561–569.
77.
GoldbergJF, ChengappaKN. Identifying and treating cognitive impairment in bipolar disorder. Bipolar Disord.2009;11 (Suppl 2):123–137.
78.
AnacletC, FerrariL, ArrigoniE, . The GABAergic parafacial zone is a medullary slow wave sleep-promoting center. Nat Neurosci.2014;17(9):1217–1224.
79.
AnacletC, GriffithK, FullerPM. Activation of the GABAergic parafacial zone maintains sleep and counteracts the wake-promoting action of the psychostimulants armodafinil and caffeine. Neuropsychopharmacol.2018;43(2):415–425.
80.
YanWW, YaoLH, ChenC, . Effects of modafinil on behavioral learning and hippocampal synaptic transmission in rats. Int Neurourol J.2015;19(4):220–227.
81.
FerraroL, AntonelliT, OʼconnorWT, TanganelliS, RambertF, FuxeK. The antinarcoleptic drug modafinil increases glutamate release in thalamic areas and hippocampus. Neuroreport.1997;8(13):2883–2887.
82.
FerraroL, AntonelliT, O'ConnorWT, TanganelliS, RambertFA, FuxeK. The effects of modafinil on striatal, pallidal and nigral GABA and glutamate release in the conscious rat: evidence for a preferential inhibition of striato-pallidal GABA transmission. Neurosci Lett.1998;253(2):135–138.
83.
FerraroL, AntonelliT, TanganelliS. The vigilance promoting drug modafinil increases extracellular glutamate levels in the medial preoptic area and the posterior hypothalamus of the conscious rat: prevention by local GABAA receptor blockade. Neuropsychopharmacology.1999;20(4):346–356.
84.
FerraroL, FuxeK, TanganelliS, TomasiniMC, RambertFA, AntonelliT. Differential enhancement of dialysate serotonin levels in distinct brain regions of the awake rat by modafinil: possible relevance for wakefulness and depression. J Neurosci Res.2002;68(1):107–112.
85.
FerraroL, FuxeK, TanganelliS, FernandezM, RambertFA, AntonelliT. Amplification of cortical serotonin release: a further neurochemical action of the vigilance-promoting drug modafinil. Neuropharmacology.2000;39(11):1974–1983.
86.
CalikMW. Update on the treatment of narcolepsy: clinical efficacy of pitolisant. Nss.2017;9:127–133.
87.
UrbanoFJ, BisagnoV, Garcia-RillE. Arousal and drug abuse. Behav Brain Res.2017;333:276–281.
88.
LinJS, RousselB, GasparA, . The unfinished journey with modafinil and discovery of a novel population of modafinil-immunoreactive neurons. Sleep Med.2018;49:40–52.
89.
MereuM, BonciA, NewmanAH, TandaG. The neurobiology of modafinil as an enhancer of cognitive performance and a potential treatment for substance use disorders. Psychopharmacology (Berl).2013;229(3):415–434.
90.
NasrS, WendtB, SteinerK. Absence of mood switch with and tolerance to modafinil: a replication study from a large private practice. J Affect Disord.2006;95(1–3):111–114.
91.
LankfordDA. Armodafinil: a new treatment for excessive sleepiness. Expert Opin Investig Drugs.2008;17(4):565–573.
92.
LinJS, RousselB, AkaokaH, FortP, DebillyG, JouvetM. Role of catecholamines in the modafinil and amphetamine induced wakefulness, a comparative pharmacological study in the cat. Brain Res.1992;591(2):319–326.
93.
StoneEA, CotecchiaS, LinY, QuartermainD. Role of brain alpha 1B-adrenoceptors in modafinil-induced behavioral activity. Synapse.2002;46(4):269–270.
94.
SheltonJ, NishinoS, VaughtJ, DementWC, MignotE. Comparative effects of modafinil and amphetamine on daytime sleepiness and cataplexy of narcoleptic dogs. Sleep.1995;18(10):817–826.
95.
Pal ChinaS, PalS, ChattopadhyayS, . The wakefulness promoting drug Modafinil causes adenosine receptor-mediated upregulation of receptor activator of nuclear factor kappaB ligand in osteoblasts: negative impact of the drug on peak bone accrual in rats. Toxicol Appl Pharmacol.2018;348:22–31.
BarateauL, DauvilliersY. Recent advances in treatment for narcolepsy. Ther Adv Neurol Disord.2019;12:175628641987562–1756286419875622.
99.
BarateauL, LopezR, DauvilliersY. Management of narcolepsy. Curr Treat Options Neurol.2016;18(10):43.
100.
ThorpyMJ. Modafinil/armodafinil in the treatment of narcolepsy. In: GoswamiM, ThorpyMJ and Pandi-PerumalSR eds. Narcolepsy: a clinical guide. Cham, Switzerland: Springer International Publishing; 2016:331–339.
AbadVC, GuilleminaultC. New developments in the management of narcolepsy. Nat Sci Sleep.2017;9:39–57.
103.
SchwartzJR, FeldmanNT, FryJM, HarshJ. Efficacy and safety of modafinil for improving daytime wakefulness in patients treated previously with psychostimulants. Sleep Med.2003;4(1):43–49.
104.
KaserM, DeakinJB, MichaelA, . Modafinil improves episodic memory and working memory cognition in patients with remitted depression: a double-blind, randomized, placebo-controlled study. Biol Psychiatry Cogn Neurosci Neuroimaging.2017;2(2):115–122.
105.
DeBattistaC, LembkeA, SolvasonHB, GhebremichaelR, PoirierJ. A prospective trial of modafinil as an adjunctive treatment of major depression. J Clin Psychopharmacol.2004;24(1):87–90.
106.
DeBattistaC. Executive dysfunction in major depressive disorder. Expert Rev Neurother.2005;5(1):79–83.
107.
Dell'OssoB, KetterTA. Use of adjunctive stimulants in adult bipolar depression. Int J Neuropsychopharm.2013;16(1):55–68.
108.
Dell'ossoB, TimtimS, HooshmandF, . Superior chronic tolerability of adjunctive modafinil compared to pramipexole in treatment-resistant bipolar disorder. J Affect Disord.2013;150(1):130–135.
109.
Dell'OssoB, KetterTA, CremaschiL, SpagnolinG, AltamuraAC. Assessing the roles of stimulants/stimulant-like drugs and dopamine-agonists in the treatment of bipolar depression. Curr Psychiatry Rep.2013;15(8):378–378.
110.
AndradeC, KiselyS, MonteiroI, RaoS. Antipsychotic augmentation with modafinil or armodafinil for negative symptoms of schizophrenia: systematic review and meta-analysis of randomized controlled trials. J Psychiatr Res.2015;60:14–21.
111.
BoboWV, WoodwardND, SimMY, JayathilakeK, MeltzerHY. The effect of adjunctive armodafinil on cognitive performance and psychopathology in antipsychotic-treated patients with schizophrenia/schizoaffective disorder: a randomized, double-blind, placebo-controlled trial. Schizophr Res.2011;130(1–3):106–113.
112.
FreudenreichO, HendersonDC, MacklinEA, . Modafinil for clozapine-treated schizophrenia patients: a double-blind, placebo-controlled pilot trial. J Clin Psychiatry.2009;70(12):1674–1680.
113.
KaneJM, D'SouzaDC, PatkarAA, . Armodafinil as adjunctive therapy in adults with cognitive deficits associated with schizophrenia: a 4-week, double-blind, placebo-controlled study. J Clin Psychiatry.2010;71(11):1475–1481.
114.
LohrJB, LiuL, CaligiuriMP, . Modafinil improves antipsychotic-induced parkinsonism but not excessive daytime sleepiness, psychiatric symptoms or cognition in schizophrenia and schizoaffective disorder: a randomized, double-blind, placebo-controlled study. Schizoph Res.2013;150(1):289–296.
115.
LillicrapT, KrishnamurthyV, AttiaJ, . Modafinil in debilitating fatigue after stroke (MIDAS): study protocol for a randomised, double-blinded, placebo-controlled, crossover trial. Trials2016;17(1):410–410.
116.
Saavedra-VelezC, YusimA, AnbarasanD, LindenmayerJ-P. Modafinil as an adjunctive treatment of sedation, negative symptoms, and cognition in schizophrenia: a critical review. J Clin Psychiatry.2009;70(1):104–112.
117.
WittkampfLC, ArendsJ, TimmermanL, LancelM. A review of modafinil and armodafinil as add-on therapy in antipsychotic-treated patients with schizophrenia. Ther Adv Psychopharmacol.2012;2(3):115–125.
118.
MyrickH, MalcolmR, TaylorB, LaRoweS. Modafinil: preclinical, clinical, and post-marketing surveillance–a review of abuse liability issues. Ann Clin Psychiatry.2004;16(2):101–109.
119.
Perez-ManaC, CastellsX, TorrensM, CapellaD, FarreM. Efficacy of psychostimulant drugs for amphetamine abuse or dependence. Cochrane Database Syst Rev.2013;(9):Cd009695.
120.
KarilaL, ReynaudM. Therapeutic approaches to cocaine addiction. Rev Prat.2009;59(6):830–834.
121.
SangroulaD, MotiwalaF, WagleB, ShahVC, HagiK, LippmannS. Modafinil treatment of cocaine dependence: a systematic review and meta-analysis. Subst Use Misuse.2017;52(10):1292–1306.
122.
MarianiJJ, LevinFR. Psychostimulant treatment of cocaine dependence. Psychiatr Clin North Am.2012;35(2):425–439.
123.
DackisC, O'BrienC. Glutamatergic agents for cocaine dependence. Ann N Y Acad Sci.2003;1003(1):328–345.
124.
KampmanKM, LynchKG, PettinatiHM, . A double blind, placebo controlled trial of modafinil for the treatment of cocaine dependence without co-morbid alcohol dependence. Drug Alcohol Depend.2015;155:105–110.
125.
AndersonAL, ReidMS, LiSH, . Modafinil for the treatment of cocaine dependence. Drug Alcohol Depend.2009;104(1–2):133–139.
126.
MorganPT, AngaritaGA, CanavanS, . Modafinil and sleep architecture in an inpatient-outpatient treatment study of cocaine dependence. Drug Alcohol Depend.2016;160:49–56.
127.
MorganPT, Pace-SchottE, PittmanB, StickgoldR, MalisonRT. Normalizing effects of modafinil on sleep in chronic cocaine users. Am J Psychiatry.2010;167(3):331–340.
128.
ZhangHY, BiGH, YangHJ, . The novel modafinil analog, JJC8-016, as a potential cocaine abuse pharmacotherapeutic. Neuropsychopharmacol.2017;42(9):1871–1883.
129.
LapidMI, KuntzKM, MasonSS, . Efficacy, safety, and tolerability of armodafinil therapy for hypersomnia associated with dementia with lewy bodies: a pilot study. Dement Geriatr Cogn Disord.2017;43(5–6):269–280.
130.
StintonC, McKeithI, TaylorJP, . Pharmacological management of lewy body dementia: a systematic review and meta-analysis. Am J Psychiatry.2015;172(8):731–742.
131.
ScorielsL, BarnettJH, MurrayGK, . Effects of modafinil on emotional processing in first episode psychosis. Biol Psychiatry.2011;69(5):457–464.
132.
ScorielsL, BarnettJH, SomaPK, SahakianBJ, JonesPB. Effects of modafinil on cognitive functions in first episode psychosis. Psychopharmacology (Berl).2012;220(2):249–258.
133.
SofuogluM, WatersAJ, MooneyM. Modafinil and nicotine interactions in abstinent smokers. Hum Psychopharmacol Clin Exp.2008;23(1):21–30.
134.
MakrisAP, RushCR, FrederichRC, KellyTH. Wake-promoting agents with different mechanisms of action: comparison of effects of modafinil and amphetamine on food intake and cardiovascular activity. Appetite.2004;42(2):185–195.
135.
MartinCA, LileJ, GuenthnerG, AnestisJC, BattenSR, KellyTH. Behavioral effects of modafinil and nicotine, alone and in combination, in tobacco-deprived young adult smokers. J Clin Psychopharmacol.2014;34(2):278–281.
136.
SchnollRA, WileytoEP, PintoA, . A placebo-controlled trial of modafinil for nicotine dependence. Drug Alcohol Depend.2008;98(1–2):86–93.
137.
BerensonJR, YellinO, ShamasunderHK, . A phase 3 trial of armodafinil for the treatment of cancer-related fatigue for patients with multiple myeloma. Support Care Cancer.2015;23(6):1503–1512.
138.
DavisJ, AhlbergFM, BerkM, AshleyDM, KhasrawM. Emerging pharmacotherapy for cancer patients with cognitive dysfunction. BMC Neurol.2013;13(1):153.
139.
JolyF, RigalO, NoalS, GiffardB. Cognitive dysfunction and cancer: which consequences in terms of disease management?Psychooncology2011;20(12):1251–1258.
140.
ConleyCC, KamenCS, HecklerCE, . Modafinil moderates the relationship between cancer-related fatigue and depression in 541 patients receiving chemotherapy. J Clin Psychopharmacol.2016;36(1):82–85.
141.
Jean-PierreP, MorrowGR, RoscoeJA, . A phase 3 randomized, placebo-controlled, double-blind, clinical trial of the effect of modafinil on cancer-related fatigue among 631 patients receiving chemotherapy: a University of Rochester Cancer Center Community Clinical Oncology Program Research base study. Cancer2010;116(14):3513–3520.
142.
MorrowGR, GilliesLJ, HickokJT, RoscoeJA, PadmanabanD, GriggsJJ. The positive effect of the psychostimulant modafinil on fatigue from cancer that persists after treatment is completed. J Clin Oncol.2005;23(16_suppl):8012–8012.
143.
KohliS, FisherSG, TraY, . The effect of modafinil on cognitive function in breast cancer survivors. Cancer2009;115(12):2605–2616.
144.
LundorffLE, JonssonBH, SjogrenP. Modafinil for attentional and psychomotor dysfunction in advanced cancer: a double-blind, randomised, cross-over trial. Palliat Med.2009;23(8):731–738.
145.
RoscoeJA, GarlandSN, HecklerCE, . Randomized placebo-controlled trial of cognitive behavioral therapy and armodafinil for insomnia after cancer treatment. J Clin Oncol.2015;33(2):165–171.
146.
PeoplesAR, GarlandSN, PerlisML, . Effects of cognitive behavioral therapy for insomnia and armodafinil on quality of life in cancer survivors: a randomized placebo-controlled trial. J Cancer Surviv.2017;11(3):401–409.
147.
GarlandSN, RoscoeJA, HecklerCE, . Effects of armodafinil and cognitive behavior therapy for insomnia on sleep continuity and daytime sleepiness in cancer survivors. Sleep Med.2016;20:18–24.
148.
HecklerCE, GarlandSN, PeoplesAR, . Cognitive behavioral therapy for insomnia, but not armodafinil, improves fatigue in cancer survivors with insomnia: a randomized placebo-controlled trial. Support Care Cancer.2016;24(5):2059–2066.
149.
NourbakhshB, RevirajanN, WaubantE. Treatment of fatigue with methylphenidate, modafinil and amantadine in multiple sclerosis (TRIUMPHANT-MS): Study design for a pragmatic, randomized, double-blind, crossover clinical trial. Contemp Clin Trials.2018;64:67–76.
150.
ShangyanH, KuiqingL, YuminX, JieC, WeixiongL. Meta-analysis of the efficacy of modafinil versus placebo in the treatment of multiple sclerosis fatigue. Mult Scler Relat Disord.2018;19:85–89.
151.
Ford-JohnsonL, DeLucaJ, ZhangJ, ElovicE, LengenfelderJ, ChiaravallotiND. Cognitive effects of modafinil in patients with multiple sclerosis: a clinical trial. Rehabil Psychol.2016;61(1):82–91.
152.
MillerP, SoundyA. The pharmacological and non-pharmacological interventions for the management of fatigue related multiple sclerosis. J Neurol Sci.2017;381:41–54.
153.
YangTT, WangL, DengXY, YuG. Pharmacological treatments for fatigue in patients with multiple sclerosis: a systematic review and meta-analysis. J Neurol Sci.2017;380:256–261.
154.
KuanYC, WuD, HuangKW, . Effects of modafinil and armodafinil in patients with obstructive sleep apnea: a meta-analysis of randomized controlled trials. Clin Ther.2016;38(4):874–888.
155.
LavaultS, DauvilliersY, DrouotX, . Benefit and risk of modafinil in idiopathic hypersomnia vs. narcolepsy with cataplexy. Sleep Med.2011;12(6):550–556.
156.
RuginoT. A review of modafinil film-coated tablets for attention-deficit/hyperactivity disorder in children and adolescents. Neuropsychiatr Dis Treat.2007;3(3):293–301.
157.
BiedermanJ, SwansonJM, WigalSB, . 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;116(6):e777–784.
158.
KotagalS. Treatment of narcolepsy and other organic hypersomnias in children. Paediatr Respir Rev.2018;25:19–24.
SwansonJM, GreenhillLL, LopezFA, . Modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, fixed-dose study followed by abrupt discontinuation. J Clin Psychiatry.2006;67(01):137–147.
161.
TaylorFB, RussoJ. Efficacy of modafinil compared to dextroamphetamine for the treatment of attention deficit hyperactivity disorder in adults. J Child Adolesc Psychopharmacol.2000;10(4):311–320.
VolkowND, FowlerJS, LoganJ, . Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications. JAMA.2009;301(11):1148–1154.
164.
ZackM, PoulosCX. Effects of the atypical stimulant modafinil on a brief gambling episode in pathological gamblers with high vs. low impulsivity. J Psychopharmacol.2009;23(6):660–671.
165.
AmarJ, LieberA, MontastrucF, BagheriH, PathakA, MontastrucJL. Arterial hypertension and resistance to antihypertensive treatment: a new adverse drug reaction with modafinil. Therapie.2013;68(1):53–54.
166.
BlackJE, HullSG, TillerJ, YangR, HarshJR. The long-term tolerability and efficacy of armodafinil in patients with excessive sleepiness associated with treated obstructive sleep apnea, shift work disorder, or narcolepsy: an open-label extension study. J Clin Sleep Med.2010;6(5):458–466.
167.
KinslowCJ, ShapiroSD, GrunebaumMF, MillerEC. Acute hypertensive crisis and severe headache after concurrent use of armodafinil and tranylcypromine: case report and review of the literature. J Neurol Sci.2018;393:1–3.
168.
OskooilarN. A case of premature ventricular contractions with modafinil. Am J Psychiatry.2005;162(10):1983–1984.
169.
RasettiR, MattayVS, StankevichB, . Modulatory effects of modafinil on neural circuits regulating emotion and cognition. Neuropsychopharmacol.2010;35(10):2101–2109.
170.
WangSM, HanC, LeeSJ, . Modafinil for the treatment of attention-deficit/hyperactivity disorder: a meta-analysis. J Psychiatr Res.2017;84:292–300.
171.
DackisCA, LynchKG, YuE, . Modafinil and cocaine: a double-blind, placebo-controlled drug interaction study. Drug Alcohol Depend.2003;70(1):29–37.
172.
ShearerJ, DarkeS, RodgersC, . A double-blind, placebo-controlled trial of modafinil (200 mg/day) for methamphetamine dependence. Addiction.2009;104(2):224–233.
173.
DolderPC, MullerF, SchmidY, BorgwardtSJ, LiechtiME. Direct comparison of the acute subjective, emotional, autonomic, and endocrine effects of MDMA, methylphenidate, and modafinil in healthy subjects. Psychopharmacology (Berl).2018;235(2):467–479.
174.
KetterTA, YangR, FryeMA. Adjunctive armodafinil for major depressive episodes associated with bipolar I disorder. J Affect Disord.2015;181:87–91.
175.
SchmidtA, MullerF, DolderPC, . Acute effects of methylphenidate, modafinil, and MDMA on negative emotion processing. Int J Neuropsychopharmacol.2018;21(4):345–354.
176.
OoiT, WongSH, SeeB. Modafinil as a stimulant for military aviators. Aerosp Med Hum Perform.2019;90(5):480–483.
177.
BisagnoV, GonzalezB, UrbanoFJ. Cognitive enhancers versus addictive psychostimulants: the good and bad side of dopamine on prefrontal cortical circuits. Pharmacol Res.2016;109:108–118.
178.
DackisCA, KampmanKM, LynchKG, . A double-blind, placebo-controlled trial of modafinil for cocaine dependence. J Subst Abuse Treat.2012;43(3):303–312.
179.
McGregorC, SrisurapanontM, MitchellA, WickesW, WhiteJM. Symptoms and sleep patterns during inpatient treatment of methamphetamine withdrawal: a comparison of mirtazapine and modafinil with treatment as usual. J Subst Abuse Treat.2008;35(3):334–342.
180.
NewmanJL, NegusSS, LozamaA, PrisinzanoTE, MelloNK. Behavioral evaluation of modafinil and the abuse-related effects of cocaine in rhesus monkeys. Exp Clin Psychopharmacol.2010;18(5):395–408.
181.
MakrisAP, RushCR, FrederichRC, TaylorAC, KellyTH. Behavioral and subjective effects of d-amphetamine and modafinil in healthy adults. Exp Clin Psychopharmacol.2007;15(2):123–133.
182.
GoldLH, BalsterRL. Evaluation of the cocaine-like discriminative stimulus effects and reinforcing effects of modafinil. Psychopharmacology (Berl).1996;126(4):286–292.
183.
RushCR, KellyTH, HaysLR, BakerRW, WootenAF. Acute behavioral and physiological effects of modafinil in drug abusers. Behav Pharmacol.2002;13(2):105–115.
184.
MalcolmR, BookSW, MoakD, DeVaneL, CzepowiczV. Clinical applications of modafinil in stimulant abusers: low abuse potential. Am J Addict.2002;11(3):247–249.
185.
Deroche-GamonetV, DarnauderyM, Bruins-SlotL, PiatF, Le MoalM, PiazzaPV. Study of the addictive potential of modafinil in naive and cocaine-experienced rats. Psychopharmacology (Berl).2002;161(4):387–395.
186.
FerraroL, TanganelliS, O'ConnorWT, AntonelliT, RambertF, FuxeK. The vigilance promoting drug modafinil increases dopamine release in the rat nucleus accumbens via the involvement of a local GABAergic mechanism. Eur J Pharmacol.1996;306(1–3):33–39.
187.
ShumanT, CaiDJ, SageJR, AnagnostarasSG. Interactions between modafinil and cocaine during the induction of conditioned place preference and locomotor sensitization in mice: implications for addiction. Behav Brain Res.2012;235(2):105–112.
188.
Wuo-SilvaR, FukushiroDF, HollaisAW, . Modafinil induces rapid-onset behavioral sensitization and cross-sensitization with cocaine in mice: implications for the addictive potential of modafinil. Front Pharmacol.2016;7:420.
189.
Wuo-SilvaR, FukushiroDF, BorcoiAR, . Addictive potential of modafinil and cross-sensitization with cocaine: a pre-clinical study. Addict Biol.2011;16(4):565–579.
190.
JasinskiDR. An evaluation of the abuse potential of modafinil using methylphenidate as a reference. J Psychopharmacol.2000;14(1):53–60.
191.
KateN, GroverS, GhormodeD. Dependence on supratherapeutic doses of modafinil: a case report. Prim Care Companion CNS Disord.2012;14(5):PCC.11l01333.
192.
KrishnanR, CharyKV. A rare case modafinil dependence. J Pharmacol Pharmacother.2015;6(1):49–50.
193.
DhillonR, WuX, BastiampillaiT, TibrewalP. Could modafinil be a drug of dependence?Aust N Z J Psychiatry.2015;49(5):485–486.
194.
SwapnajeetS, BnS, GouravG. Modafinil dependence and hypersexuality: a case report and review of the evidence. Clin Psychopharmacol Neurosci.2016;14(4):402–404.
195.
JerryJM, ShirvaniN, DaleR. Addiction to armodafinil and modafinil presenting with paranoia. J Clin Psychopharmacol.2016;36(1):98–100.
196.
HermantJF, RambertFA, DuteilJ. Awakening properties of modafinil: effect on nocturnal activity in monkeys (Macaca mulatta) after acute and repeated administration. Psychopharmacology (Berl).1991;103(1):28–32.
197.
TsengYL, UraletsV, LinCT, KuoFH. Detection of modafinil in human urine by gas chromatography-mass spectrometry. J Pharm Biomed Anal.2005;39(5):1042–1045.
198.
CaglayanMG, SheykhiS, MoscaL, AnzenbacherP. Fluorescent zinc and copper complexes for detection of adrafinil in paper-based microfluidic devices. Chem Commun.2016;52(53):8279–8282.
199.
World Anti-Doping Code (WADA). Prohibited list January 2020. The World Anti-Doping Code: International Standart, Montreal; 2020.
200.
DeventerK, RoelsK, DelbekeFT, Van EenooP. Prevalence of legal and illegal stimulating agents in sports. Anal Bioanal Chem.2011;401(2):421–432.
201.
JacobsI, BellDG. Effects of acute modafinil ingestion on exercise time to exhaustion. Med Sci Sports Exerc.2004;36(6):1078–1082.
202.
DubeyS, AhiS, ReddyIM, KaurT, BeotraA, JainS. A novel study of screening and confirmation of modafinil, adrafinil and their metabolite modafinilic acid under EI-GC-MS and ESI-LC-MS-MS ionization. Indian J Pharmacol.2009;41(6):278–283.
203.
BattledayRM, BremAK. Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: a systematic review. Eur Neuropsychopharmacol.2015;25(11):1865–1881.
204.
SahakianBJ, Morein-ZamirS. Pharmacological cognitive enhancement: treatment of neuropsychiatric disorders and lifestyle use by healthy people. Lancet Psychiatry.2015;2(4):357–362.
205.
FrankeAG, BagusatC, RustS, EngelA, LiebK. Substances used and prevalence rates of pharmacological cognitive enhancement among healthy subjects. Eur Arch Psychiatry Clin Neurosci.2014;264(S1):83–90.
206.
EickenhorstP, VitzthumK, KlappBF, GronebergD, MacheS. Neuroenhancement among German university students: motives, expectations, and relationship with psychoactive lifestyle drugs. J Psychoactive Drugs.2012;44(5):418–427.
207.
PartridgeB, BellS, LuckeJ, HallW. Australian university students’ attitudes towards the use of prescription stimulants as cognitive enhancers: perceived patterns of use, efficacy and safety. Drug Alcohol Rev.2013;32(3):295–302.
DursunS, DunnM, McKayFH. The availability and acquisition of modafinil on the internet. Drug Alcohol Rev.2019;38(6):699–702.
210.
RandallDC, ShneersonJM, PlahaKK, FileSE. Modafinil affects mood, but not cognitive function, in healthy young volunteers. Hum Psychopharmacol Clin Exp.2003;18(3):163–173.
211.
TurnerDC, RobbinsTW, ClarkL, AronAR, DowsonJ, SahakianBJ. Cognitive enhancing effects of modafinil in healthy volunteers. Psychopharmacology (Berl).2003;165(3):260–269.
212.
MullerU, SteffenhagenN, RegenthalR, BublakP. Effects of modafinil on working memory processes in humans. Psychopharmacology (Berl).2004;177(1–2):161–169.
213.
MinzenbergMJ, YoonJH, CarterCS. Modafinil modulation of the default mode network. Psychopharmacology (Berl).2011;215(1):23–31.
214.
BaranskiJV, PigeauR, DinichP, JacobsI. Effects of modafinil on cognitive and meta-cognitive performance. Hum Psychopharmacol Clin Exp.2004;19(5):323–332.
215.
RandallDC, ViswanathA, BharaniaP, . Does modafinil enhance cognitive performance in young volunteers who are not sleep-deprived?J Clin Psychopharmacol.2005;25(2):175–179.
216.
RandallDC, FleckNL, ShneersonJM, FileSE. The cognitive-enhancing properties of modafinil are limited in non-sleep-deprived middle-aged volunteers. Pharmacol Biochem Behav.2004;77(3):547–555.
217.
CopeZA, MinassianA, KreitnerD, . Modafinil improves attentional performance in healthy, non-sleep deprived humans at doses not inducing hyperarousal across species. Neuropharmacology.2017;125:254–262.
218.
RandallDC, ShneersonJM, FileSE. Cognitive effects of modafinil in student volunteers may depend on IQ. Pharmacol Biochem Behav.2005;82(1):133–139.
219.
Winder-RhodesSE, ChamberlainSR, IdrisMI, RobbinsTW, SahakianBJ, MüllerU. Effects of modafinil and prazosin on cognitive and physiological functions in healthy volunteers. J Psychopharmacol.2010;24(11):1649–1657.
220.
MullerU, RoweJB, RittmanT, LewisC, RobbinsTW, SahakianBJ. Effects of modafinil on non-verbal cognition, task enjoyment and creative thinking in healthy volunteers. Neuropharmacology.2013;64:490–495.
221.
RycroftN, HuttonSB, ClowryO, GroomsbridgeC, SierakowskiA, RustedJM. Non-cholinergic modulation of antisaccade performance: a modafinil-nicotine comparison. Psychopharmacology (Berl).2007;195(2):245–253.
222.
FernandezA, MascayanoF, LipsW, PainelA, NorambuenaJ, MadridE. Effects of modafinil on attention performance, short-term memory and executive function in university students: a randomized trial. Medwave.2015;15(5):e6166.
223.
BaranskiJV, PigeauRA. Self-monitoring cognitive performance during sleep deprivation: effects of modafinil, d-amphetamine and placebo. J Sleep Res.1997;6(2):84–91.
224.
KredlowMA, KeshishianA, OppenheimerS, OttoMW. The efficacy of modafinil as a cognitive enhancer: a systematic review and meta-analysis. Journal of Clinical Psychopharmacology.2019;39(5):455–461.
225.
BellebaumC, KuchinkeL, RoserP. Modafinil alters decision making based on feedback history - a randomized placebo-controlled double blind study in humans. J Psychopharmacol.2017;31(2):243–249.
226.
SpillerHA, HaysHL, AleguasA.Jr., Overdose of drugs for attention-deficit hyperactivity disorder: clinical presentation, mechanisms of toxicity, and management. CNS Drugs.2013;27(7):531–543.
227.
CarstairsSD, UrquhartA, HoffmanJ, ClarkRF, CantrellFL. A retrospective review of supratherapeutic modafinil exposures. J Med Toxicol.2010;6(3):307–310.
CairnsR, DanielsB, WoodDA, BrettJ. ADHD medication overdose and misuse: the NSW poisons information centre experience, 2004–2014. Med J Aust.2016;204(4):154.
230.
NeumanG, ShehadehN, PillarG. Unsuccessful suicide attempt of a 15 year old adolescent with ingestion of 5000 mg modafinil. J Clin Sleep Med.2009;5(4):372–373.
231.
AndersonAL, LiSH, BiswasK, . Modafinil for the treatment of methamphetamine dependence. Drug Alcohol Depend.2012;120(1–3):135–141.
JoosL, DocxL, SchmaalL, SabbeBG, DomG. [Modafinil in psychiatric disorders: the promising state reconsidered]. Tijdschr Psychiatr.2010;52(11):763–773.
234.
KimD. Practical use and risk of modafinil, a novel waking drug. Environ Health Toxicol.2012;27:e2012007.
235.
DanaherJ. Should we use commitment contracts to regulate student use of cognitive enhancing drugs?Bioethics.2016;30(8):568–578.
236.
LamkinM. Cognitive enhancements and the values of higher education. Health Care Anal.2012;20(4):347–355.
237.
MaierLJ, HaugS, SchaubMP. The importance of stress, self-efficacy, and self-medication for pharmacological neuroenhancement among employees and students. Drug Alcohol Depend.2015;156:221–227.
238.
SattlerS, MehlkopG, GraeffP, SauerC. Evaluating the drivers of and obstacles to the willingness to use cognitive enhancement drugs: the influence of drug characteristics, social environment, and personal characteristics. Subst Abuse Treat Prev Policy.2014;9(1):8.
