An Overview of The Clinical Uses, Pharmacology and Safety of Modafinil

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An overview of the clinical uses, pharmacology and safety of modafinil
Eric Murillo-Rodriguez, André Barciela Veras, Nuno Barbosa Rocha, Henning Budde, and Sérgio Machado
ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.7b00374 • Publication Date (Web): 08 Nov 2017
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Page 1 of 38 ACS Chemical Neuroscience
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3 An overview of the clinical uses, pharmacology and safety of modafinil
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6 Eric Murillo-Rodríguez 1, 2, 3, §, André Barciela Veras 3, 4, 5,
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Nuno Barbosa Rocha 3, 6, Henning Budde 3, 7, 8, 9, and Sérgio Machado 3, 5, 10
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11 Laboratorio de Neurociencias Moleculares e Integrativas, Escuela de Medicina
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13 División Ciencias de la Salud. Universidad Anáhuac Mayab
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15 Mérida, Yucatán. México
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Grupo de Investigación en Envejecimiento. División Ciencias de la Salud
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18 Universidad Anáhuac Mayab. Mérida, Yucatán. México
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20 Intercontinental Neuroscience Research Group
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22 Grupo de Pesquisa Translacional em Saúde Mental
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Universidade Católica Dom Bosco. Campo Grande, Mato Grosso del Sur. Brazil
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Panic and Respiration Laboratory, Institute of Psychiatry
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27 Federal University of Rio de Janeiro. Rio de Janeiro, Brazil
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29 Health School, Polytechnic Institute of Porto. Porto, Portugal
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31 Faculty of Human Sciences, Medical School Hamburg, Hamburg, Germany
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Physical Activity, Physical Education, Health and Sport Research Centre
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34 (PAPESH), Sports Science Department, School of Science and Engineering,
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36 Reykjavik University. Reykjavik, Iceland
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38 Lithuanian Sports University. Kaunas, Lithuania
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Physical Activity Neuroscience Laboratory, Physical Activity Sciences
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41 Postgraduate Program-Salgado de Oliveira University
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43 Salgado de Oliveira University. Niterói, Brazil
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ACS Chemical Neuroscience Page 2 of 38
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6 § Corresponding author:
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8 Eric Murillo-Rodríguez, PhD.
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Laboratorio de Neurociencias Moleculares e Integrativas
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13 Escuela de Medicina, División Ciencias de la Salud
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15 Universidad Anáhuac Mayab
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Carretera Mérida-Progreso Km. 15.5
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20 A.P. 96 Cordemex C.P. 97310
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22 Mérida, Yucatán. México
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25 Tel + 52 (999) 942-4800 Ext. 664
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27 Email: eric.murillo@anahuac.mx
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3 Abstract: Modafinil (MOD) is a wakefulness-inducing compound prescribed for
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6 treatment of excessive daytime sleepiness as a consequence of sleep
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8 disturbances such as shift work sleep disorder, obstructive sleep apnea, restless
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leg syndrome or narcolepsy. While providing effective results in patients with
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13 sleepiness, MOD also produces positive outcomes in the management of fatigue
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15 associated with different conditions including depression, cancer, or tiredness in
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military personnel. Although there is a clear evidence of the stimulant effects of
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20 MOD, current data also show that administration of this drug apparently induces
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22 positive neurobiological effects, such as improvement in memory. However,
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25 serious concerns have been raised since some reports have suggested MOD
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27 dependence. Taken together, these findings highlight the need to characterize the
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29 changes induced by MOD which have been observed in several neurobiological
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32 functions. Moreover, further work should follow up on the likely long-term effects of
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34 this drug if used for treatment of drowsiness and tiredness. Here, we review and
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summarize recent findings of the medical uses of MOD in the management of
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39 sleepiness and fatigue associated with depression or cancer as well as
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41 exhaustion in military personnel. We also discuss the available literature related
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44 with the cognitive enhancing properties of this stimulant, as well as what is known
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46 and unknown about MOD addiction.
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51 Keywords: Sleep, dopamine, hypocretin, treatment, drug, addiction.
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3 1. Introduction
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6 The sleep-wake cycle comprises the following neurobiological states: Wakefulness,
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8 slow wave sleep and rapid eye movement sleep. For our purposes, sleep is
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defined as “...a recurring, reversible neuro-behavioral state of relative perceptual
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13 disengagement from and unresponsiveness to the environment. Sleep is typically
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15 accompanied (in humans) by postural recumbence, behavioral quiescence, and
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closed eyes...”1. This definition of sleep emphasizes a relationship between
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20 concepts such as duration, efficiency, and timing which leads us to assume that
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22 sleep, like many other physiological phenomena, also displays pathological
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25 features with abnormal duration, altered efficiency and disrupted timing. Hence,
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27 sleep disturbances have been integrated for easier comprehension in the
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29 International Classification of Sleep Disorders2. The most common sleep problems
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32 among the population are insomnia and excessive daytime sleepiness3, 4, the latter
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34 being characterized by the tendency to fall asleep during the day. This sleep
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alteration is present in approximately 20% of population5-7. The etiology of
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39 excessive daytime sleepiness comprises diverse factors and sometimes an
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41 underlying sleep disturbance is involved (e.g., insomnia, obstructive sleep apnea,
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44 narcolepsy or restless leg syndrome)8-12. There are behavioral, psychological, and
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46 pharmacological treatments aimed at managing excessive daytime sleepiness13-16.
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48 Although tiredness is a common problem in the population which can be mistaken
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51 for excessive daytime sleepiness, tiredness is a neurobehavioral reaction to
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53 physical and/or mental exhaustion which is usually relieved after rest or sleep17-21.
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3 A significant number of patients receiving treatments for depression or cancer
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6 report fatigue which differentiates from tiredness, compared to the rest of
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8 population22. Importantly, excessive daytime sleepiness (derived from obstructive
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sleep apnea, restless leg syndrome or narcolepsy), or fatigue (associated to
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13 depression or cancer) is regulated by using modafinil (MOD). Given our increasing
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15 knowledge of the neuropsychopharmacological properties of MOD, it would indeed
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be ambitious to describe all available evidence. Thus, in this review, we present a
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20 general overview of some recent publications available in PubMed regarding the
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22 uses of MOD to control excessive daytime sleepiness23-29. We also discuss the
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25 basic understanding of the uses of MOD to control fatigue associated with
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27 depression, cancer or tiredness in military personnel. Next, we describe the
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29 putative cognitive enhancing abilities of MOD. Finally, we discuss what is known
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32 and unknown about MOD addiction. In-depth examination of the use of MOD for
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34 treatment of excessive daytime sleepiness is beyond the scope of this review.
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39 2. Modafinil
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42 MOD is a drug that is commercially sold under the brand names of
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44 AlertecTM, ModavigilTM, or ProvigilTM. Due to its possible addictive profile, this
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compound has been classified as a Schedule IV controlled substance in the United
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49 States of America. Decades of research have demonstrated that the wakefulness-
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51 promoting properties of MOD are present in multiple species, including humans23-
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53 28
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. Besides, the toxicology profile of MOD has shown fewer or no adverse effects
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3 compared to those reported in traditional psychostimulants such as amphetamine
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6 or cocaine29-31. In addition, MOD is generally well tolerated in animal models in
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8 contrast with other stimulants32 and shows very low abuse liability (low reinforcing
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effects) in non-drug abusing individuals33. Finally, as in the case of other
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13 stimulants, official indications for MOD usage include the following critical
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15 information: “...serious side effects including a serious rash or a serious allergic
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reaction that may affect parts of your body such as your liver or blood cells. Any of
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20 these may need to be treated in a hospital and may be life-threatening...”34.
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25 Along with MOD, armodafinil (commonly known by the brand names of
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27 ArtvigilTM and WaklertTM) is the enantiopure formulation of MOD which displays
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29 slightly more pharmacological potency and duration as a wakefulness-inducing
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32 compound compared to MOD35-41. Unlike the racemic formulation in 50/50 mix of
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34 both the (S) and (R) enantiomers, the molecular structure of armodafinil contains
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only the (R)-enantiomer of MOD. Despite the pharmacological characterization
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39 of armodafinil, sharing many behavioral effects with MOD , the mechanisms of
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41 action of armodafinil remain to be described in detail. Lastly, it is worth mentioning
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44 that in contrast to the positive therapeutic uses of MOD in controlling excessive
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46 daytime sleepiness, recent reports have suggested possible setbacks of abuse and
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48 addiction to this drug42, 43.
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3 3. Medical uses of modafinil
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6 3.1 Positive results using modafinil to control excessive daytime sleepiness
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8 There is evidence showing the positive outcomes of using MOD for treatment of
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11 excessive daytime sleepiness caused by sleep disturbances such as shift work
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13 sleep disorder, obstructive sleep apnea or narcolepsy. There is both experimental
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15 and clinical data supporting the efficiency and efficacy of MOD in the management
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18 of excessive daytime sleepiness44-47. Moreover, several reports have indicated the
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20 positive uses of MOD for treatment drowsiness associated with non-sleep
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disorders.
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25 The existence of evidence regarding the contribution of MOD to managing
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27 excessive daytime sleepiness has been widely recognized. Here, we have
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presented a general overview of the positive pharmacological benefits of MOD in
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32 treating excessive somnolence in some recent publications3-15, 20, 23-30, 38, 46-48. The
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34 data available suggest that MOD also controls excessive somnolence and fatigue
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37 in non-sleep disturbance circumstances. In the following sections, we present this
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39 evidence.
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44 3.2 Prescription of modafinil decreases sleepiness and fatigue associated with
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46 depression or cancer
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Depression is a mood disorder characterized by distressing symptoms such as
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51 persistent sadness, thoughts of suicide, anxiety, loss of interest or pleasure in
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53 hobbies or usual activities, feelings of hopelessness, excessive sleepiness and
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3 fatigue. In addition, depression is prevalent in patients with health disorders,
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6 including cancer49. It is well established that cancer patients often report fatigue,
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8 which is defined as extreme tiredness caused by a deficit of energy as a
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consequence of chemotherapy50, 51
. Numerous reports have demonstrated that
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13 intake of MOD mitigates drowsiness in depressed patients and blocks the fatigue
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15 linked to cancer. In this regard, a daily dosage of 100-200mg of MOD given to
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these patients promotes feelings of energy and alertness52-58. Although sleepiness
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20 and tiredness associated with depression or cancer are effectively controlled with
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22 MOD, further work is needed to distinguish the mechanism of action of this drug in
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25 the modulation of drowsiness and fatigue associated with both clinical conditions,
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27 with emphasis on subject characteristics, including comorbidity of depression or
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29 cancer.
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34 3.3 Modafinil intake alleviates drowsiness and tiredness in military operational
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37 environments
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39 Sleepiness and fatigue are critical problems faced by military personnel undergoing
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41 sleep deprivation as a consequence of prolonged waking in combat
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44 environments59, 60
. The effectiveness of stimulants such as caffeine and
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46 amphetamines in handling drowsiness and tiredness in military personnel has been
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previously studied61, 62
. For example, when oral doses of MOD were given to
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51 military operations personnel, their drowsiness was reduced compared to a control
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53 group63. One well-designed study has been carried out on helicopter pilots who
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3 received 3 doses of MOD (100mg) at 4h intervals during periods of 40h of
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6 continuous alertness. After MOD intake, the subjects showed higher levels of
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suggests that MOD controls sleepiness and fatigue in military personnel61-64.
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15 4. Modafinil could be modulating sleep homeostasis mechanisms
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18 While this compound promotes wakefulness by reducing sleepiness, we do not
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20 exclude the plausible possibility that MOD might exert an influence on sleep
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homeostasis. Under normal conditions, the homeostatic drive of sleep is enhanced
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25 when alertness is maintained beyond habitual bedtime, and it dissipates with an
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27 enhancement in the intensity and duration of sleep. This neurobiological feature is
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known as “sleep rebound”65, 66
. Although long-term effects of MOD in patients
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32 with excessive daytime sleepiness have shown it to be effective and well
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34 tolerated67, 68
, sleep rebound effects caused by chronic use of MOD as a
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37 consequence of sleep homeostasis disruption are still unknown. Indeed, we do not
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39 yet know the effects that MOD might induce in sleep rebound. This intriguing but as
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41 yet unexplored observation raises questions about the properties of MOD in the
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44 control of neurobiological mechanisms of sleep homeostasis. Thus, these
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46 assumptions highlight the need for studies aimed to test whether MOD plays a role
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in sleep homeostasis control. Since many of the therapeutic uses of MOD are
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6 5. Modafinil as a presumed cognitive enhancer
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8 Memory is the neurobiological function whereby critical information is retained and
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11 recalled at a later time69. Cognitive improvements have been reported in
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13 experimental animals receiving MOD (200m-300g/kg)70, and such changes have
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15 also been demonstrated in humans. In line with this, potential uses of MOD for
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18 improving memory in disorders such as neurodegenerative diseases or psychiatric
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20 conditions have been suggested. For example, Fernández et al. (2015) reported
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that students that used MOD improved their answers in the Stroop Test71. Similar
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25 findings were observed in patients with multiple sclerosis that received a single
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27 daily oral dose of MOD (200mg). They showed an enhancement in working
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memory tasks tested in the Wechsler Adult Intelligence Scale-III72. In support of
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32 this, Lees et al (2017) reported that MOD (200mg) improved learning in patients
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34 with early schizophrenia73. Taken together, the emerging evidence suggests that
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37 MOD seems to promote cognitive enhancement73-79. These findings have been
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39 partially explained by neurobiological changes such as hippocampal
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41 neurogenesis80. However, it is worth noting that these results appear to be related
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44 to single doses, so prospective and/or longitudinal studies should be considered in
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46 the near future to investigate:
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49 i) What are the long-term neurobiological effects in learning and memory after
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51 chronic use of MOD?
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3 ii) What are the neuromolecular mechanisms activated by long-term MOD
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6 intake for memory improvement in healthy volunteers, multiple sclerosis or
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11 To expand our knowledge, we should try to design new experiments aimed at
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13 addressing these unanswered questions.
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17 6. Mechanism of action of modafinil
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19 It is widely accepted that MOD induces alertness by activating wakefulness-related
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systems such as hypocretin, histamine, α-adrenergic, glutamate, and dopamine
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24 (DA)81, 82. Most of the evidence regarding the wakefulness-promoting properties of
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26 MOD has been obtained by studying the role of this drug in dopaminergic
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neurotransmission. Experimental studies have suggested that MOD blocks the
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31 activity of DA transporter (DAT) increasing the contents of DA83. Complementarily,
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33 MOD modulates norepinephrine (NET) or serotonin (SERT) transporter activity as
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36 well. For example, Madras and coworkers (2006) described how, in rhesus
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38 monkeys, MOD occupied striatal DAT sites (5mg/Kg, corresponding to 35% of
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40 occupancy) whereas in the thalamus, MOD bound to NET at 16% (5mg/Kg)84.
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43 Moreover, in vitro studies have reported that MOD inhibited [3H]dopamine (IC50 =
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45 6.4µM), [3H]norepinephrine (IC50 = 35.6µM), and [3H]serotonin (IC50 > 500µM)
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transport via human DAT, NET, and SERT85. The wakefulness-promoting effects of
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50 MOD might be produced by binding to allosteric sites on the DAT in similar fashion
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52 to cocaine86-88.
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3 On the other hand, it has been also demonstrated that MOD enhances excitatory
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6 glutamatergic neurotransmission in several brain areas such as the ventromedial
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8 and ventrolateral hypothalamic nuclei, thalamus and hippocampus89-94. In addition,
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c-Fos expression in hypocretinergic neurons in hypothalamus in MOD-treated rats
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13 was found higher compared to respective controls95. In a later study, MOD
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15 administered to hypocretin null mice (10, 30 and 100mg/Kg) increased waking
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compared to wild-type animals96. At present, therefore, the hypocretinergic system
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20 also responds to MOD pharmacological challenge97, 98
. Finally, several
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25 of sleep-inducing systems such as GABA91, 99. Nevertheless, there are areas that
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27 require further research. For example, the progress that has been limited pertains
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29 to the field of sleep-inducing molecules, including adenosine (AD). In this regard,
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32 the results of one study showed that systemic administration of MOD (30mg/Kg) at
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34 the beginning of the lights-on period of rats, decreased extracellular levels of AD as
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determined by microdialysis and HPLC means100. Future studies should aim at
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39 providing an additional picture of the pharmacological properties of MOD in the
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41 modulation of sleep-promoting compounds.
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47 7. Addiction to modafinil
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49 Despite the efficacy of MOD for managing excessive daytime sleepiness and
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51 fatigue, and apparently improving cognitive functions3-15, 20, 23-30, 38, 46-64, 67, 68, 70-80,
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54 critical studies are required to fully understand the likely risk of addiction to this
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3 drug (Table 1). In recent years, special attention has been given to a limited but
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6 growing body of evidence suggesting that MOD has a potentially addictive profile,
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8 since this drug promotes reward as described in cocaine-dependent humans101. In
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this regard, Dhillon et al., (2015) reported a case of MOD addiction in a 23-year old
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13 man who was under a schedule of using this compound (200mg) during 6 weeks to
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15 treat daytime sleepiness and fatigue following methamphetamine withdrawal42.
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Similar findings of addiction to MOD have been reported in schizophrenic
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20 patients102 as well as in experimental animals. For instance, Mereu et al., (2013)
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22 reported that systemic injections of MOD (17-300mg/Kg) in mice showed cocaine-
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25 like subjective effects76. Importantly, cocaine-treated animals showed an
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27 enhancement in dependence when cocaine and MOD were administered in
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29 combination. Despite these hazardous results, MOD has been proposed as a
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32 candidate for the treatment of cocaine addiction103, 104
. However, it is unclear if
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34 MOD would be considered as a pharmacological approach for managing
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cocaine addiction. Whether or not MOD is addictive, it should be under vigilance as
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39 suggested105-108. Altogether, it is difficult to predict whether addiction to MOD
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41 represents a public health problem based on few and limited studies (Table 1). In
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44 particular, there are individual case reports but no long-term pharmacovigilance
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46 studies or dependence/tolerance data. Approaches to elucidating the probability of
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48 addiction to MOD should consider an integrative perspective addressing the
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51 behavioral disorder profile (by drug self-administration procedures), brain reward
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53 circuitry activity (neurobiochemical studies or electrophysiological experiments
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3 using the novel technique of optogenetics) and gene expression (including analysis
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6 of CREB [cAMP response element binding protein])109, 110.
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PLEASE INSERT TABLE 1 ABOVE HERE
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15 8. Conclusions and future directions
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As mentioned, MOD manages excessive daytime sleepiness, fatigue, and
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20 improves learning and memory3-15, 20, 23-30, 38, 46-64, 67, 68, 70-80
. However, there is
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22 evidence that suggests the putative risk of developing addiction to this drug42, 101,
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24 102, 105-108
25 . To fully understand the pharmacological effects of MOD on the control of
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27 fatigue and improvement in cognition, the mechanism of action of this drug should
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29 be described (Figure 1). On the other hand, along with evidence showing the
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32 positive outcomes of MOD in controlling sleepiness and fatigue associated with
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34 depression or cancer, as well as drowsiness reported in military personnel, missing
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data regarding its positive effects in controlling drowsiness in diseases such as
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39 fibromyalgia, anemia, diabetes, and burnout syndrome, among others, is required.
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41 Moreover, it remains to be demonstrated whether MOD is able to improve cognitive
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44 impairment in learning disabilities, including attention deficit hyperactivity disorder,
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46 executive dysfunction, and dyslexia, just to mention a few. Our knowledge of the
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48 possible long-term effects of using MOD is extremely limited, partially because of
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51 associated factors such as dosage (low or high dose), frequency of usage (daily
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53 vs. intermittently), and route of administration (central of peripheral), among other
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3 circumstances. Lastly, several randomized, double-blind, placebo-controlled
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6 studies have determined the efficacy of MOD for the treatment of
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8 excessive daytime sleepiness, fatigue, and cognitive functioning109-115. However,
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this body of evidence is still incomplete since there is the need for external validity
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13 of data as well as longitudinal studies that follow up on whether the positive
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15 outcomes of medical uses of MOD persist across time and whether addiction to
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this drug can be discounted.
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22 PLEASE INSERT FIGURE 1 ABOVE HERE
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28 Abbreviations
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30 Adenosine= AD
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32 cAMP response element binding protein= CREB
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34 Dopamine= DA
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36 DA transporter= DAT
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38 Modafinil= MOD
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40 Norepinephrine transporter= NET
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42 Serotonin transporter= SERT
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46 Author Information
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48 Corresponding author: Eric Murillo-Rodríguez, PhD.
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3 Laboratorio de Neurociencias Moleculares e Integrativas. Escuela de Medicina,
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6 División Ciencias de la Salud. Universidad Anáhuac Mayab. Mérida, Yucatán.
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8 México. Email: eric.murillo@anahuac.mx
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13 Author Contributions: E M-R designed, and wrote the manuscript. A BV, N BR,
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15 HB, S M revised the manuscript sections. All authors revised the whole paper and
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approved the final version of the manuscript.
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21 Conflict of Interest: The authors declare that they have no conflict of interest.
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25 Acknowledgments: This work was supported by The University of California
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Institute for Mexico and the United States (UC MEXUS) and Consejo Nacional de
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30 Ciencia y Tecnología (CONACyT; Grant CN-17-19) and Escuela de Medicina,
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32 Universidad Anáhuac Mayab Grant (PresInvEMR2014) given to E M-R. Authors
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35 thank David J. Phillips for editing the manuscript for English usage.
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37
38 References
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40 1. Carskadon, M.A. and Dement, W.C. (2005). Normal human sleep: an
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45 practice of sleep medicine. 4th ed. Philadelphia, PA: Elsevier Saunders; pp.
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29 Figure legends
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34 Table 1. Summary of some medical uses of modafinil to control excessive
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sleepiness and fatigue associated with depression or cancer, managing tiredness
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39 in military personnel or as a cognitive enhancer. No current evidence is available
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41 regarding the neuromolecular mechanism of action of modafinil in controlling
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44 fatigue linked to depression, cancer or tiredness in military staff as well as putative
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46 addiction to this compound.
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51 Figure 1. Modafinil combats sleepiness and fatigue, and enhances learning and
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54 memory. Despite the positive outcome of MOD, further evidence is needed to
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Physiological Pharmacological effects of Neuromolecular mechanism References
6 condition modafinil of action
7
8
9 Decrease significantly the Partially described: Evidence of [3-15, 20, 23-30, 38, 46-48]
10 SLEEPINESS somnolence observed in the activation of glutamatergic,
11 sleep disorders such as dopaminergic, hypocretinergic,
12 narcolepsy histaminergic, α-adrenergic
13 system and decreases activity of
14 GABAergic neurotransmission
15
16
17 FATIGUE Reduce significantly the Unknown [52-58]
18 ASSOCIATED fatigue and depressive
19 TO symptoms in patients with
20 DEPRESSION depression
21
22
23 FATIGUE Diminish significantly the Unknown [52-58]
24 ASSOCIATED fatigue in patients with
25 TO cancer under chemotherapy
26 CANCER
27
28
29 FATIGUE Decline significantly fatigue Unknown [61-64]
30 ASSOCIATED and promotes well-being
31 TO feelings in soldiers
32 MILITARY
33 COMBAT
34
35
36 COGNITION Facilitate learning and Unknown [70-79]
memory
37
38
39
ADDICTION Potentially promote addiction Unknown [42, 76, 105-108]
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48
ACS Chemical Neuroscience
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An Overview of The Clinical Uses, Pharmacology and Safety of Modafinil

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