Modafinil, an atypical CNS stimulant?

Abstract

Modafinil is a central nervous system stimulant approved for the treatment of narcolepsy and sleep disorders. Due to its wide range of biochemical actions, modafinil has been explored for other potential therapeutic uses. Indeed, it has shown promise as a therapy for cognitive disfunction resulting from neurologic disorders like ADHD, and as a smart drug in non-medical settings. The mechanism(s) of actions underlying the therapeutic efficacy of this agent remains largely elusive. Modafinil is known to inhibit the dopamine transporter, thus decreasing dopamine reuptake following neuronal release, an effect shared by addictive psychostimulants. However, modafinil is unique in that only a few cases of dependence on this drug have been reported, as compared to other psychostimulants. Moreover, modafinil has been tested, with some success, as a potential therapeutic agent to combat psychostimulant and other substance use disorders. Modafinil has additional, but less understood, actions on other neurotransmitter systems (GABA, glutamate, serotonin, norepinephrine, etc.). These interactions, together with its ability to activate selected brain regions, are likely one of the keys to understand its unique pharmacology and therapeutic activity as a CNS stimulant. In this chapter, we outline the pharmacokinetics and pharmacodynamics of modafinil that suggest it has an “atypical” CNS stimulant profile. We also highlight the current approved and off label uses of modafinil, including its beneficial effects as a treatment for sleep disorders, cognitive functions, and substance use disorders.

1.0. Introduction

Only a few central nervous system (CNS) stimulants are US Food and Drug Administration (FDA) approved and available for clinical use. Among them are methylphenidate, amphetamine, solriamfetol, bupropion, and modafinil. Methylphenidate and amphetamine are medications approved for treatment of ADHD. Solriamfetol and modafinil (Provigil) are approved for treatment of narcolepsy and sleep disorders. Bupropion is approved for the treatment of depression and for smoking cessation (Clark et al., 2023). The exact mechanism of action related to the range of therapeutic targets and efficacies of these CNS stimulants is not fully understood. For instance, the main pharmacologic mechanism of action of methylphenidate appears related to its high affinity for the dopamine transporter (DAT), and the inhibition of dopamine (DA) reuptake, resulting in increased extracellular levels of DA. Amphetamine is a substrate of DAT, inhibits vesicular monoamine transporter 2 (VMAT2), and reverses the transport of DA into the synapses thus increasing DA extracellular levels. Bupropion and solriamfetol inhibit both DAT and norepinephrine transporter (NET) with high affinity, which result in increased brain levels of DA and norepinephrine. Modafinil and its R-enantiomer, armodafinil, show low, but selective affinity for DAT, as compared to other neurotransmitter uptake sites and receptors, and inhibit DA reuptake. Thus, the common pharmacologic targets for all these stimulant drugs appear related to their effects on DAT and DA neurotransmission.

Under physiological conditions, the effects of DA released in the synapses is terminated primarily by its removal from the extracellular space by reuptake into presynaptic DA terminals via DAT proteins located on DA neuronal membranes. Pathological dysfunctions in the regular, physiological functioning of brain DA systems lead to diseases that involve both motor and emotional domains, like schizophrenia, Parkinson’s disease, and depression (Delva & Stanwood, 2021; Seeman & Niznik, 1990). Certain genetic variations of DAT are associated with specific neurologic disorders (Herborg, Andreassen, Berlin, Loland, & Gether, 2018). Finally, the rewarding, potentially dependence-producing effects of CNS stimulants have been mainly related to the inhibition of DA reuptake by DA neurons (M. J. Kuhar, M. C. Ritz, & J. W. Boja, 1991). It is of particular interest that even though DAT is a pharmacologic target shared by addictive substances like cocaine and amphetamines, not all drugs that inhibit DAT produce addiction/dependence after repeated use, as initially predicted (M. J. Kuhar et al., 1991; M. C. Ritz, R. J. Lamb, S. R. Goldberg, & M. J. Kuhar, 1987). In this context, modafinil has been frequently reported as “not a classic” or an “atypical” DAT blocker. Indeed, only a limited number of cases of modafinil addiction/dependence have been reported in the literature (see section 3.5), in contrast with typical CNS stimulants (i.e., amphetamine, cocaine, and methylphenidate) that interact with DAT.

In this article, we will focus on the currently known mechanisms of action of modafinil, their involvement in the therapeutic efficacy of its approved clinical uses, and its suggested potential (off-label) use for neuropsychiatric disorders. As we will see in the next sections, the primary mechanism(s) of action of modafinil may differ depending on the therapeutic effects suggested for different disorders. The “atypical” DAT inhibitory effects would provide, together with its actions at other potential targets, a unique pharmacologic stimulant profile. It is also important to note that the therapeutic efficacy of modafinil is comparable or better than other CNS stimulants, and it is accompanied by relatively less undesired, serious/severe side effects. Based on the literature, we suggest modafinil as a non-classic, unique CNS stimulant.

2.0. Modafinil pharmacology

Modafinil (chemical name: 2-[(diphenylmethyl)sulfinyl]acetamide; commercial names: Alertec, Modavigil, or Provigil ^™) was approved by the FDA in 1997 as a wake-promoting agent for the treatment of sleep disorders and narcolepsy (Murillo-Rodríguez, Barciela Veras, Barbosa Rocha, Budde, & Machado, 2018; Sousa & Dinis-Oliveira, 2020; J. Wisor, 2013). The chemical structure for modafinil can be seen in Figure 1. Modafinil is a racemic mixture of S- and R-enantiomers (or d and l-enantiomers, respectively) around the sulfoxide chiral center (see Figure 1) (J. Cao et al., 2011; Loland et al., 2012; Robertson & Hellriegel, 2003). The R- and S-enantiomers of modafinil produce equipotent pharmacological effects but divergent pharmacokinetics (Robertson & Hellriegel, 2003; Wong, King, Laughton, McCormick, & Grebow, 1998; Wong, King, et al., 1999). R-modafinil (Nuvigil, Artvigil and Waklert ^™) is also commercially available and shows increased and extended potency over racemic modafinil alone, as an agent for wakefulness (Murillo-Rodríguez et al., 2018; Robertson & Hellriegel, 2003). Modafinil is classified as a Schedule IV controlled substance for its possible misuse potential in the US (FDA, 2015). Modafinil pharmacokinetics are well described (see Table 1), but its mechanism of action remains far less resolved (Ballon & Feifel, 2006; R. Kumar, 2008; Murillo-Rodríguez et al., 2018; Robertson & Hellriegel, 2003; Sousa & Dinis-Oliveira, 2020).

Figure 1:

Mechanisms of action of modafinil (MOD) on neurotransmitter systems. Structures of modafinil (made up of the enantiomers: R-MOD and S-MOD) are shown in the center circle. The known effects of modafinil on different neurotransmitter systems are shown as a positive “+” (enhancement or increase) or negative “-” (blunting or decrease). Some effects of modafinil are not fully elucidated and marked as a question mark “?”.

Table 1:

Modafinil Pharmacokinetics

Pharmacokinetics	Details
Adsorption	-Oral doses of 50–800 mg are readily absorbed [1,2]. -Comparable absorption rates were observed with the R- and S-modafinil enantiomers [3–5]. -In humans, bioavailability is estimated between 45 and 65% absorption based on drug and metabolite urine recovery rates [4,6]. -Maximum plasma concentrations are obtained about 2–4 hours after administration [4,6].
Distribution	-Volume of distribution following single or multiple oral administrations is 0.8 L/kg [2,3,4]. -Modafinil binds to blood plasma proteins at a percentage of about 60% (primarily to the protein albumin) [3,4].
Metabolism	-Modafinil is largely removed via metabolism (90%) and renal elimination (10%) [7]. -Modafinil is metabolized to modafinil acid (primary) and modafinil sulfone. -R-modafinil shows higher rates of metabolic stability and a longer half-life than S-modafinil or modafinil [5]. -Metabolism of modafinil activates cytochrome P450 enzyme systems (CYP1A2, CYP2B6, and CYP2A4/5) [8].
Elimination	-Modafinil plasma clearance rates are reportedly low (50 mL/min), and half-life is reportedly high (12–15 hours) [2,4]. -S-modafinil is eliminated faster than R-modafinil, with reported elimination half-life of 3 and 10 hours, respectively [4].
Toxicology	-Side effects or adverse experience to modafinil have been reportedly mild to moderate with the most common side effects being anxiety, diarrhea, dyspepsia, headaches, insomnia, nausea, and nervousness [4,9].

References are as follows: [1] (McClellan & Spencer, 1998), [2] (Wong, Simcoe, et al., 1999), [3] (Wong et al., 1998), [4] (Robertson & Hellriegel, 2003), [5] (R. Kumar, 2008), [6] (Wong, King, et al., 1999), [7] (Ballon & Feifel, 2006), [8] (Robertson, DeCory, Madan, & Parkinson, 2000), [9] (FDA, 2015).

2.1. Pharmacodynamics & mechanism of action

A distinct mechanism of action that accounts for modafinil therapeutic efficacy remains elusive. Current literature points to a broad spectrum of actions that likely contribute to behavioral and neurochemical effects. Herein, the actions of modafinil on the dopaminergic system are highlighted, as well as the actions on other neurotransmitter systems and miscellaneous effects.

2.1.1. Mechanism of action: dopamine

The main DA brain systems, meso-striatal and mesocortical-limbic systems, originate from DA neurons located in the substantia nigra (SN) and in the ventral tegmental area (VTA), respectively. Axons from these neurons innervate brain regions, including the cortex, striatum, and nucleus accumbens. The role of DA and the dopaminergic system is well-documented in motor activity, cognitive function, reward, motivation, and mood. Activity of DA physiologically released in these brain areas is mediated by DA receptors (D1R-D5R), for which expression and location varies depending on the brain region (Beaulieu & Gainetdinov, 2011). Thus, tonic and phasic changes in DA levels are under control of negative and positive feedback that involve neuronal firing and synthesis of DA. Impairments in DA neurotransmission are linked to diseases like Parkinson’s disease and substance use disorder (reviewed in: Channer et al., 2023).

Modafinil has inhibitory activity at the plasma membrane DA transporter, DAT, thereby blunting DA clearance and increasing the concentration of DA in the extracellular space (E Mignot, Nishino, Guilleminault, & Dement, 1994). In clinical studies using positron emission tomography (PET), modafinil displaced ¹¹C-cocaine and ¹¹C-raclopride (a D2R receptor ligand) (Volkow et al., 2009). Many commonly misused/addictive psychostimulants share this mechanism of action, however, modafinil has a notably low affinity for DAT (K_i = 2.3 μM) but a high selectivity (J. Cao et al., 2016; Loland et al., 2012; Okunola-Bakare et al., 2014).

In preclinical studies, modafinil administration increased striatal, as well as nucleus accumbens, extracellular DA levels in mice and rats (L. Ferraro et al., 1996; Loland et al., 2012; Maddalena Mereu et al., 2017; M. Mereu et al., 2020; Murillo-Rodríguez, Haro, Palomero-Rivero, Millán-Aldaco, & Drucker-Colín, 2007; Rowley et al., 2014; Zolkowska et al., 2009). Similar increases in extracellular DA levels were observed following administration of R-modafinil (Keighron, Giancola, et al., 2019; Loland et al., 2012; X.-F. Wang et al., 2015). In voltametric studies, modafinil and R-modafinil increased electrically evoked DA in the striatum and the nucleus accumbens, as well as slowed DA clearance in rodents (Bobak et al., 2016; M. Hersey et al., 2023; J. D. Keighron et al., 2023; Keighron, Giancola, et al., 2019; Keighron, Quarterman, et al., 2019). The limited effects of modafinil on stimulation of DA levels were suggested to resemble a kind of “ceiling” effect (Maddalena Mereu et al., 2017; M. Mereu et al., 2020).

2.1.2. Mechanism of action: other neurotransmitters

In addition to effects on DA neurotransmission, modafinil alters the brain neurochemistry of neurotransmitters and neurotransmitter systems like norepinephrine, serotonin, GABA, glutamate, histamine, orexin, adenosine, and acetylcholine (Figure 1). Most of modafinil’s effects on changes in brain neurochemistry are not due to its direct interactions with neurotransmitter receptors/sites. For example, even though modafinil binding affinity for NET and serotonin transporter (SERT) is very low, some in-vivo studies show possible activity at NET (Madras et al., 2006), as will be discussed further in the next sections.

Mechanism of action: norepinephrine

Norepinephrine neurons originate from the locus coeruleus and project throughout the brain including the cortex, hippocampus, and cerebellum. The role of norepinephrine neurotransmission is well documented in attention, arousal, and response to stress. Norepinephrine is removed from the synapse by NET. Impairments in the norepinephrine system is linked to attention deficit hyperactivity disorders (ADHD), sleep disorders, and neurodegenerative disorders like Parkinson’s and Alzheimer’s diseases (reviewed in: Benarroch, 2009). The norepinephrine system is also sensitive to stimulants like modafinil. PET studies in monkeys found that modafinil binds to NET in addition to DAT, and displaced radiolabeled NET ligands in the thalamus (Madras et al., 2006). However, it remains unclear if this is a direct effect of modafinil on NET (due to its very low affinity for NET) or, more likely, an indirect effect mediated by elevated DA levels competing for other monoamine transporters (Raiteri, Del Carmine, Bertollini, & Levi, 1977). Contrary to the implication of selectivity for each monoamine, monoamine transporters have overlapping functions and unselectively take up other monoamines (Daws, 2009; G. Tanda, Pontieri, Frau, & Di Chiara, 1997). Thus, it might be possible that inhibition of DAT by modafinil would increase levels of DA in brain areas that contain both DAT and NET which would then compete with norepinephrine for transport by NET. The result would be a reduction in norepinephrine clearance rates in those brain areas. This theory is supported by the higher affinity (about 4 times) of DA for NET, as compared to norepinephrine (Raiteri et al., 1977). Modafinil administration increased tonic norepinephrine levels in the hypothalamus and prefrontal cortex of rats (de Saint Hilaire, Orosco, Rouch, Blanc, & Nicolaidis, 2001). Thus, it is possible that both direct and indirect actions of modafinil on NET, and on the norepinephrine system, may account for some of the agent’s effects on wakefulness and attention.

Mechanism of action: serotonin

The neurotransmitter serotonin is found in the periphery and in the brain, where its neurons, which originate from the raphe nucleus of the brainstem, project throughout the brain, including to limbic regions like the hippocampus. Serotonin neurotransmission is implicated in various physiological and biological processes like appetite, attention, memory, and mood. A major target of the serotonin system is the serotonin transporter (SERT), which largely mediates the removal of serotonin following release. Alterations of brain serotonin levels or impairments in the serotonergic system are implicated in diseases such as anxiety & depression, obesity, etc. (reviewed in: Berger, Gray, & Roth, 2009). Modafinil administration indirectly increased serotonin levels in the amygdala, cerebral cortex, and the dorsal raphe nucleus of rodents (L Ferraro et al., 2000; Luca Ferraro et al., 2002). However, the precise mechanism of the indirect actions of modafinil on serotonin remain to be fully elucidated. These effects suggest that actions of modafinil on serotonin may account for some of its effects on mood, attention, and cognition.

Mechanism of action: GABA

GABA (γ-aminobutyric acid) is the main inhibitory neurotransmitter found in the brain and plays a major role in mediating control of neuronal excitability. Impairments in GABAergic function have been linked to diseases like epilepsy, anxiety, and schizophrenia (reviewed in: Ting Wong, Bottiglieri, & Snead III, 2003). Modafinil administration decreased extracellular concentration of GABA in the globus pallidum, nucleus accumbens, and substantia nigra of rats as shown by microdialysis (Cid-Jofré, Moreno, Sotomayor-Zárate, Cruz, & Renard, 2022; Luca Ferraro et al., 1997b; L. Ferraro et al., 1998; Luca Ferraro et al., 1996). This effect was not produced by the psychostimulant amphetamine, highlighting a unique action of modafinil on brain GABA neurotransmission (Luca Ferraro et al., 1997b). Interestingly, D1R agonists also produce decreases in GABA extracellular levels, as shown by microdialysis, suggesting that these neurotransmitter systems affects may be linked (Abekawa, Ohmori, Ito, & Koyama, 2000). Of note, serotonin antagonism blunted modafinil-induced changes in GABA neurotransmission, suggesting that these neurotransmitter systems may also be linked in mechanistic actions of modafinil (L. Ferraro et al., 1996; Tanganelli, Fuxe, Ferraro, Janson, & Bianchi, 1992). It remains unclear if the actions of modafinil on GABA are direct or indirect, via modulatory actions of other neurotransmitters more directly influenced by modafinil (like DA or serotonin). Regardless, modafinil can modulate brain GABA levels, and this effect may account for some of the modafinil’s actions as an anxiolytic agent.

Mechanism of action: glutamate

Glutamate, the main excitatory neurotransmitter in the brain, is known to mediate synaptic plasticity, learning, and memory. Impairments in glutamatergic function are linked to CNS diseases like epilepsy, neurodegenerative diseases, and schizophrenia (reviewed in: Willard & Koochekpour, 2013). Glutamate excitatory transmission is increased in the hypothalamus, hippocampus, thalamus, and striatum following modafinil administration (Luca Ferraro et al., 1997a; Luca Ferraro et al., 1999; Haris et al., 2014; Tahsili-Fahadan, Carr, Harris, & Aston-Jones, 2010; Touret et al., 1994). There is evidence that DA agonists can also increase striatal extracellular glutamate levels (Exposito, Sanz, Porras, & Mora, 1994; Porras & Mora, 1995). Similar to GABA, it remains unknown if the actions of modafinil on glutamate are direct or indirect (via neuromodulation by other neurotransmitters) (J. Wisor, 2013). Overall, the actions of modafinil on glutamate may contribute to the cognitive enhancements associated with modafinil administration.

Mechanism of action: orexin

Orexin-A and -B (hypocretin-1 and −2) are endogenous neuropeptides synthesized by hypothalamic neurons (Sun, Tisdale, & Kilduff, 2021). These peptides have excitatory functions, and orexin receptors can be found in several brain regions other than the hypothalamus, including the cerebral cortex, limbic areas (accumbens, amygdala, and bed nucleus of stria terminalis), and brain regions where neurons of the main monoaminergic neurotransmitter systems are located, like substantia nigra, ventral tegmental area, locus coeruleus, and dorsal raphe (The Orexin System. Basic Science and Role in Sleep Pathology, 2021; Sun et al., 2021). Orexin is known to modulate sleep/wake cycle, emotion, feeding, and reward. Impairments in the orexin system are connected to diseases like narcolepsy (reviewed in: Tsujino & Sakurai, 2013). The orexin system is also sensitive to modafinil administration. Modafinil increased activity levels of brain regions containing orexin neurons (Chemelli et al., 1999; Lin, Hou, & Jouvet, 1996; Scammell et al., 2000), elevating CSF levels of orexin-A (Zeitzer, Buckmaster, Landolt, Lyons, & Mignot, 2009), and producing long-term potentiation of glutamatergic transmission over lateral hypothalamus orexin neurons (Rao et al., 2007), suggesting its ability to modulate levels of orexin in the brain. Also, modafinil administration increased neuronal activation of the hypothalamus in rodents (Chemelli et al., 1999; Scammell et al., 2000). Histamine neurons, which originate in the tuberomammillary nucleus of the hypothalamus, receive a dense innervation from orexin neurons. Thus, the orexin system can modulate the stimulating effects of modafinil on brain histamine (Ishizuka, Murotani, & Yamatodani, 2010; Yamanaka et al., 2002).

Important for wakefulness/arousal, orexin stimulates glutaminergic neurotransmission in relevant circuits of the hypothalamus (Li, Gao, Sakurai, & van den Pol, 2002). On the other hand, orexin knockout mice displayed increased wakefulness following modafinil administration compared to wild-type controls (Willie et al., 2005). As suggested by the authors, orexin might not be essential for the wakefulness-promoting actions of modafinil, but it may play a role in its alertness effects. These results may also be explained by a yet to be identified compensatory mechanism affected by modafinil administration to promote arousal even when orexin is removed. Thus, it is likely that the actions of modafinil on brain orexin are not the only mechanism underlying the wake promoting effects of this agent.

Mechanism of action: histamine

In the brain, histamine is synthesized by neurons in the tuberomammillary nucleus of the hypothalamus. Histamine neurons project throughout the brain, including to brain stem regions that control acetylcholine, DA, norepinephrine, and serotonin neurotransmitter systems. Neuronal histamine is removed from the synapse by a wide range of transporters, including organic cation transporter (OCT), NET, and SERT (Melinda Hersey, Samaranayake, et al., 2021). Brain histamine is well known for its role in physiological functions like sleep/wake cycles and neuroinflammation. Impairments in the histaminergic system have been linked to sleep disorders, autoimmune diseases, mood disorders, and neurodegenerative disorders (reviewed in: Haas, Sergeeva, & Selbach, 2008). Brain histamine concentration increases following systemic administration of modafinil, but not after its local administration into the tuberomammillary nucleus (Ishizuka, Sakamoto, Sakurai, & Yamatodani, 2003). This finding supports the theory that changes in brain histamine following modafinil administration are dependent on other systems, likely including the orexin system, which is linked to modulation of sleep/wakefulness (Ballon & Feifel, 2006). The actions of modafinil on brain histamine are related to the agent’s role in sleep modulation; however, the effects are not limited to a single action. Histamine’s robust action as a neuromodulator of other neurotransmitters, and its strong association with another sleep/wake promoting neurotransmitter, orexin, suggests that its activation may modulate/regulate a much wider range of effects (Haas et al., 2008).

Mechanism of action: acetylcholine

Acetylcholine is a neurotransmitter known for its neuromodulatory actions. Impairment in acetylcholine signaling has been linked to addiction, depression, and motor diseases like Huntington’s and Parkinson’s diseases (reviewed in: Picciotto, Higley, & Mineur, 2012). The acetylcholine system, while implicated in sleep neurochemistry, does not appear to be sensitive to modafinil administration. Studies in guinea pigs demonstrated that acetylcholine release in the cortex was not significantly modified by modafinil administration (Tanganelli et al., 1992). In addition, modafinil and nicotinic acetylcholine receptors do not directly interact (Dopheide, Morgan, Rodvelt, Schachtman, & Miller, 2007). Thus, the actions of modafinil on the acetylcholine system are still not fully clarified. Interestingly, modafinil administration in rats produced decreases in brain acetylcholinesterase activity, possibly promoting increases in acetylcholine signaling as a downstream result (M. Kumar & Maqbool, 2020).

2.1.3. Mechanism of action: miscellaneous

Suggestions about other potential modafinil mechanisms of action, related to its therapeutic efficacy on sleep disorders, include effects on electrotonic coupling and gap-junctions (Duchêne et al., 2016; Garcia-Rill, Heister, Ye, Charlesworth, & Hayar, 2007; Liu et al., 2013; M. Mereu et al., 2020; Urbano, Leznik, & Llinás, 2007). Modafinil effects on gap junctions have been suggested by recent studies showing that pretreatments with an inhibitor of electrotonic coupling reversed the potentiating effects of modafinil on cocaine self-administration behavior (M. Mereu et al., 2020).

Modafinil also decreases neuroinflammation, including cytokines, glial cells, monocytes, and T-cells (Brandao, Andersen, Palermo-Neto, Peron, & Zager, 2019; Han, Chen, Liu, & Zhu, 2018; Raineri et al., 2012; reviewed in: Zager, 2020; Zager et al., 2018). Additional positive neuroprotective effects of modafinil include decreased oxidative stress, decreases in unnecessary apoptosis, and increases in brain derived neurotrophic factor (BDNF) (Y. Cao et al., 2019; Garbossa et al., 2022).

Some additional effects of modafinil administration include elevated mitogen-activated protein kinase (MAPK) phosphorylation (Stone, Cotecchia, Lin, & Quartermain, 2002) and regional differences in brain glucose utilization in neuronal axons and dendrites (Engber, Dennis, Jones, Miller, & Contreras, 1998).

2.2. Modafinil: an atypical stimulant

A number of CNS stimulants interact with DAT and exert behavioral and neurochemical activities that have been associated with their recreational use, which might progress to drug addiction and dependence. Depending on their chemical structure, a subset of stimulants, including amphetamine and amphetamine-like drugs, compete with endogenous DA, acting as a DAT substrate (Reith et al., 2015). Another subset of stimulants, cocaine and cocaine-like drugs, bind to DAT and inhibit its biological function to take up DA from the extracellular space after its release from DA neurons. These actions on DAT activity are of fundamental importance to reduce/restore physiological levels of extracellular DA and DA neurotransmission. Most CNS stimulants fall into these categories and have shown dependence producing actions in both human subjects and experimental animals. However, even though initial studies suggested that drugs able to inhibit DAT would be behavioral reinforcers (M. Kuhar, M. Ritz, & J. Boja, 1991; M. C. Ritz, R. Lamb, S. R. Goldberg, & M. J. Kuhar, 1987), and possess abuse liability, several DAT inhibitors (reviewed in Reith et al., 2015; Gianluigi Tanda, Newman, & Katz, 2009) do not show the same behavioral and neurochemical actions of cocaine and cocaine-like, typical DAT inhibitors.

In particular, modafinil binds to DAT and blocks its biological function similar to other cocaine-like DAT inhibitors. However, it is suggested that modafinil may act as an atypical inhibitor of the DAT protein. Specifically, studies suggest when modafinil is bound to DAT it promotes an occluded/closed, inward facing conformation of the transporter (Loland et al., 2012; Schmitt & Reith, 2011), at variance with cocaine and other typical DAT blockers that promote an open, outward facing conformation of DAT (Abramyan et al., 2017; Loland et al., 2008). Distinct conformations of DAT are related to divergent behavioral and neurochemical actions of typical and atypical DAT blockers (Abramyan et al., 2017; Kohut et al., 2014; Loland et al., 2012; A. H. Newman et al., 2019; Schmitt & Reith, 2011). On the behavioral level, modafinil and its enantiomers have not consistently shown the reinforcing actions of cocaine or cocaine-like DAT inhibitors (reviewed in Melinda Hersey, Bacon, et al., 2021; Gianluigi Tanda, Hersey, Hempel, Xi, & Newman, 2021). For example, in contrast with most psychostimulants, modafinil elicited only a few instances of cocaine-like behavioral activities in preclinical tests (Deroche-Gamonet et al., 2002; Quisenberry, Prisinzano, & Baker, 2013; Tahsili-Fahadan et al., 2010). A few studies reported modafinil-induced conditioned place preference (Nguyen, Tian, You, Lee, & Jang, 2011; Shuman, Cai, Sage, & Anagnostaras, 2012; Wuo-Silva et al., 2011). Interestingly, modafinil did not maintain self-administration behavior in rodents (Deroche-Gamonet et al., 2002; M. Mereu et al., 2020), but one study showed that modafinil substitution for intravenous self-administration of cocaine in monkeys could maintain the self-administration behavior (Gold & Balster, 1996). Generalization of modafinil with the subjective stimulus of cocaine was shown in drug-discrimination tests in rodents (Gold & Balster, 1996; Maddalena Mereu et al., 2017; J. L. Newman, Negus, Lozama, Prisinzano, & Mello, 2010). It is worth noting that modafinil generalized with the subjective effects of cocaine in mice (Maddalena Mereu et al., 2017) at doses and times after administration that suggested little involvement of DA levels. Moreover, in contrast with methylphenidate, modafinil did not potentiate cocaine-induced stimulation of nucleus accumbens shell (NAS) DA levels in rats. However, it potentiated cocaine self-administration behavior, an effect reversed by pretreatment with an inhibitor of electrotonic coupling (M. Mereu et al., 2020). On the neurochemical level, modafinil inhibition of DAT in rodents does not seem to produce changes in DA extracellular concentration comparable to those obtained by administration of cocaine or cocaine-like stimulants (Loland et al., 2012; Maddalena Mereu et al., 2017; M. Mereu et al., 2020). In recent voltammetry studies, modafinil, and other atypical DAT blockers, did not elicit cocaine-like increases in stimulus-evoked NAS DA release in rodents. The limited modafinil-induced increases in DA levels may resemble a kind of “ceiling” effect (Maddalena Mereu et al., 2017), suggesting that even larger doses of the drug would not produce larger stimulation of DA levels (Maddalena Mereu et al., 2017; M. Mereu et al., 2020), which may explain its reduced ability to stimulate behavioral activity in rodents, as compared to other CNS stimulants.

Typical and atypical stimulants also show different effects at the molecular level. Cocaine enhancement of evoked DA release has been suggested to be a result of increasing mobilization of a synapsin-dependent reserve pool of DA vesicles (Venton et al., 2006). Synapsin is a protein that controls neurotransmitter-filled vesicle release via exocytosis during neurotransmission (Chi, Greengard, & Ryan, 2001). Synapsins’ activities can be regulated by calcium-calmodulin-dependent protein kinase II (CaMKII) (Chi et al., 2001), which functionally interacts with DAT (Hadlock, Nelson, Baucum II, Hanson, & Fleckenstein, 2011; Padmanabhan, Lambert, & Prasad, 2008). We have hypothesized that distinct conformations of DAT, stabilized by binding with typical or atypical DA uptake inhibitors (Abramyan et al., 2017; Loland et al., 2008; A. H. Newman et al., 2019), would facilitate or hinder DAT interactions with CaMKII, thus regulating phosphorylation of synapsins, mobilization of the reserve pool of DA vesicles, and enhancement of DA release. We tested this hypothesis, injecting intracerebroventricularly an inhibitor of CaMKII activity, KN93, which significantly attenuated cocaine effects on evoked DA release, but not its effect on DA clearance rate. These results indicate that specific DAT conformations stabilized by cocaine-like or atypical DAT inhibitors could produce (or not) downstream secondary effects, independent from DAT inhibition, that may influence the extracellular levels of DA and, in turn, DA neurotransmission (Jacqueline D Keighron et al., 2023). Changes in DA neurotransmission might result in activation of behavioral events, including those related to misuse and addiction. Thus, it is possible that differences between modafinil and cocaine, or other typical stimulants, might be the result of differences in affinity for and blockade of DAT, but also to divergent effects of its binding to DAT (protein conformation preference, activation of neurotransmitter systems, downstream signaling, etc.). It is also important to note that modafinil, even when administered at high doses, selectively activates specific brain areas (Thomas M Engber, SA Dennis, et al., 1998; Thomas M Engber, Elizabeth J Koury, et al., 1998). This effect is in contrast with typical CNS stimulants, like amphetamine, which produce an unselective, broader activation of brain areas (Thomas M Engber, SA Dennis, et al., 1998; Thomas M Engber, Elizabeth J Koury, et al., 1998).

Another atypical CNS stimulant activity of modafinil comes from its ability to reduce neuroinflammation. This effect contrasts with addictive psychostimulants (Guo, Roodsari, Cheng, Dempsey, & Hu, 2023), which have been repeatedly shown to produce neuroinflammation after their administration in clinical (Moreira et al., 2016) and preclinical studies (Cui, Shurtleff, & Harris, 2014). Thus, the literature suggests that modafinil has a CNS stimulant profile that differs from that of typical stimulants. As we can see in the next sections, such a profile is likely responsible for some of the atypical features that are beneficial for the therapeutic efficacy of modafinil in several brain disorders.

3.0. Currently approved, and potential therapeutic uses of modafinil

3.1. Narcolepsy and sleep disorders

While the precise mechanism(s) of modafinil action have not yet been fully elucidated, modafinil has been approved by the FDA for the treatment of narcolepsy and sleep disorders (shift-work sleep disorder and obstructive sleep apnea)(FDA, 2015).

Two kinds of narcolepsy have been described: narcolepsy type 1, characterized by the presence of cataplexy symptoms (a sudden and transient loss of muscle tone), and narcolepsy type 2, when cataplexy symptoms are not present. Narcolepsy type 1 is highly related to reduced levels of brain orexins due to a loss of orexin neurons in the lateral hypothalamus in clinical and preclinical studies (E. Mignot, Zeitzer, Pizza, & Plazzi, 2021; Nishino, Ripley, Overeem, Lammers, & Mignot, 2000; Peyron et al., 2000). Indeed, release of orexin peptides promote wakefulness by activating orexin receptors in several brain areas (Chemelli et al., 1999; Lin et al., 1996; Scammell et al., 2000). Modafinil interaction with the brain orexin system indicates a mechanism of action related to its therapeutic efficacy for narcolepsy. Modafinil does not directly interact with orexin receptors, but it indirectly produces long-term potentiation of glutamatergic transmission, leading to stimulation of circulating levels of orexin over lateral hypothalamus orexin neurons (Rao et al., 2007). The orexin system modulates the stimulating effects of modafinil on extracellular levels of histamine (Ishizuka et al., 2010; Yamanaka et al., 2002), a neurotransmitter involved in the physiology of sleep (Kanbayashi et al., 2009; Nishino et al., 2001; Nishino et al., 2009; Parmentier et al., 2007; Thakkar, 2011). Thus, the wakefulness actions of modafinil could be the result of interactions with multiple neurotransmitter systems, mostly mediated by a combination of its indirect actions on the glutamate, orexin, and histamine systems.

Modafinil’s mechanism of action, related to its therapeutic effect on sleep disorders, was initially thought to be more closely related to activation of the adrenergic system than to its brain dopaminergic activities. However, similarly to other wakefulness stimulants like amphetamine and methylphenidate, modafinil interacts with DAT and the dopaminergic system, which play a significant role in its therapeutic effects (E Mignot et al., 1994; J. P. Wisor et al., 2001). For instance, DAT knockout mice showed increased wakefulness and decreased response to the wake-promoting effects of modafinil (Giros, Jaber, Jones, Wightman, & Caron, 1996; J. P. Wisor et al., 2001). Blunting of DA receptors, either by administration of pharmacological antagonists or by genetically engineering D2R knock outs, produces diminished responses to the wake-promoting effects of modafinil administration (Qu, Huang, Xu, Matsumoto, & Urade, 2008). It is likely that increased levels of extracellular DA resulting from modafinil blockade of DA uptake, as shown in preclinical studies, would activate both D1 and D2-like DA receptors (Korotkova et al., 2007; Qu et al., 2008), which mediate actions of modafinil related to wakefulness, together with its effects on the orexin system in the hypothalamus. Indeed, D1 receptors are expressed in the lateral hypothalamus and found to localize in orexin positive neurons (Yang et al., 2019). Moreover, these neurons are surrounded by dopaminergic neural fibers (Yang et al., 2019). Thus, an increase in D1 receptor activity, at the level of the lateral hypothalamus, suggests another potential mechanism for modafinil to modulate orexinergic activity and, likely, its therapeutic efficacy on sleep disorders. As suggested by Wisor (2013), modafinil actions on adrenergic, GABAergic, and glutamatergic systems, together with its orexinergic and histaminergic interactions, might be the result of increased dopaminergic neurotransmission subsequent to modafinil inhibition of DAT.

The wakefulness actions of modafinil could be beneficial during times of higher vigilance/attention resulting from sleep deprivation or shift-work sleep disorder (Batejat & Lagarde, 1999; Wesensten, 2006). For example, modafinil use is common in ambulance drivers, airplane pilots, and military operations (Buguet, Moroz, & Radomski, 2003; Whitmore et al., 2006). It is important to note that the typical medications available for these jobs/situations also include amphetamine and caffeine. The vigilance effects of caffeine (at 600 mg dosage) in sleep-deprived subjects, though similar to dexamphetamine (20 mg) and modafinil (400 mg), may not always provide a long-lasting level of efficacy. Additionally, it could produce more undesired side effects (nervousness, excitation, nausea, jitteriness) than modafinil, but similarly to dexamphetamine, compared to placebo (Killgore, Kahn-Greene, Grugle, Killgore, & Balkin, 2009; Killgore et al., 2008). Reports on misuse and dependence of stimulants in veterans returning home from combat operations, suggest that modafinil was the safest recommended therapeutic for maintaining vigilance/attention during sleep deprivation (Estrada, Kelley, Webb, Athy, & Crowley, 2012).

Sleep disorders also occur as a consequence of other neurologic disorders. Sleep disturbances have been described in people affected by substance use disorder (see section 3.5, below), and excessive daytime sleepiness is a symptom often associated with Parkinson’s disease. Indeed, modafinil has been suggested as a medication for the treatment of sleep disorder and fatigue in Parkinson’s disease patients. However, both positive and limited effects have been reported for the efficacy of modafinil for these uses (Elbers, Berendse, & Kwakkel, 2016; Schutz, Sixel-Doring, & Hermann, 2022).

3.2. Off-label use of modafinil as a cognitive function enhancer

Cognitive functions include several brain activities that are often monitored in human and animal subjects to assess and evaluate attention, learning, memory, processing speed, etc. These functions are supported by and are under control of several brain neurotransmitter systems, including acetylcholine (Bentley, Driver, & Dolan, 2011; Bubser, Byun, Wood, & Jones, 2012), DA (Maddalena Mereu, Bonci, Newman, & Tanda, 2013), serotonin (Meneses, 1999; Perez-Garcia & Meneses, 2008), GABA (Xu & Wong, 2018), and histamine (Passani et al., 2017), which activate selected brain regions. The precise mechanism of action of modafinil underlying its efficacy as a cognitive enhancer is not fully understood. However, modafinil appears to modulate the activity of selected brain areas and neurotransmitter systems that play a role in cognitive functions (Thomas M Engber, SA Dennis, et al., 1998; T. M. Engber et al., 1998). For instance, modafinil modulates the activity of frontal-cortical areas (Burgos et al., 2010; Gozzi et al., 2012) involved in important cognitive and executive functions that are impaired in different psychiatric disorders, like schizophrenia (Chudasama & Robbins, 2006) (see section below). In a functional magnetic resonance imaging (fMRI) neuroimaging study in healthy human subjects, modafinil decreased the effects of fearful stimuli on the amygdala, suggesting reduced anxiety, thus enhancing the efficiency of prefrontal cortical cognitive information processing (Rasetti et al., 2010). In another human study, aiming to test the possibility that modafinil could modulate the default mode network (DMN), modafinil increased the speed of sensorimotor processing dependent on changes in ventral-medial prefrontal cortex activity (M. J. Minzenberg, Yoon, & Carter, 2011). This brain area receives projections from the main catecholamine systems, also providing outputs that can modulate activities of subcortical brain areas involved in cognitive functions (Gu, 2002). Taken together, these reports suggest that the therapeutic effects of modafinil in improving cognitive functions result from complex interactions of different neurotransmitters in select brain areas (Maddalena Mereu et al., 2013; Murillo-Rodríguez et al., 2018).

Notably, numerous clinical studies have reported the therapeutic efficacy of modafinil in subjects affected by neurologic or neuropsychiatric disorders that may also produce cognitive impairment. Initial clinical studies with modafinil in patients with schizophrenia provided a positive treatment outcome on fatigue and cognitive functioning score (Rosenthal & Bryant, 2004; Saavedra-Velez, Yusim, Anbarasan, & Lindenmayer, 2009; D. C. Turner et al., 2004). However, more recent reviews of the effects of modafinil in patients with schizophrenia reveal conflicting results, without fully positive outcomes (Andrade, Kisely, Monteiro, & Rao, 2015; Lees et al., 2017; Ortiz-Orendain et al., 2019). For example, small but significant effects of modafinil on negative symptoms have been reported (Sabe, Kirschner, & Kaiser, 2019), and the discrepancy in the results among different studies has been suggested to depend on several factors that include patient demographics (age, sex, race, etc.), current pharmacotherapy, the phase of disease (i.e., early stages or chronic), and the choice of appropriate tests/tasks to measure the potential improvements (Lees et al., 2017; Morein-Zamir, Turner, & Sahakian, 2007; Pringle, Browning, Parsons, Cowen, & Harmer, 2013). Also, we are far from elucidating the mechanism(s) of action associated to the potential therapeutic efficacy of modafinil in schizophrenia. While modafinil effects on GABA produce a reduction of its activity in most regions of the brain, catecholamine levels appear to increase in cortical and prefrontal cortical areas, and in striatal areas, providing potential support to modafinil actions as an enhancer of cognitive function, attention, and arousal (Scoriels, Jones, & Sahakian, 2013). Furthermore, in a placebo-controlled, within-subject case-control, crossover fMRI neuroimaging study (single-dose modafinil effects on changes in cognitive-related brain area activities in 27 patients treated for schizophrenia and 21 healthy controls), it was found that alteration of locus coeruleus and VTA activities were significantly related to the pharmacologic effects of the antipsychotic treatments, mainly antagonists of alpha-2 adrenergic and DA-D2 receptors. The authors suggest that these interactions might lead us to consider medications with less catecholamine antagonist activity, in combination with pro-cognitive medications, like modafinil, in order to obtain significant improvements in the cognitive deficits that characterize schizophrenic patients (M. J. Minzenberg, Yoon, Soosman, & Carter, 2018).

Off-label, modafinil has also been tested as a therapy or adjunct therapy for depressive disorders, showing promising therapeutic efficacy on several symptoms, including improvement in cognitive functions (Colwell et al., 2022; DeBattista, Lembke, Solvason, Ghebremichael, & Poirier, 2004; Nunez et al., 2020; Szmulewicz et al., 2017). Modafinil’s mechanism of action related to its therapeutic efficacy on selected depressive symptoms has not been elucidated yet. However, modafinil inhibition of DAT is shared with antidepressant drugs like bupropion. Thus, DAT inhibition would likely contribute to modafinil efficacy, as well as its ability to stimulate and interact with catecholamine systems in brain areas that play a role in reward, cognitive, and executive functions.

3.3. Modafinil as a potential treatment for ADHD in children and adults

Attention deficit hyperactivity disorder (ADHD) is a complex psychiatric condition that is characterized by symptoms that fall into the attention or hyperactivity domains, or by a combination of those symptoms, which are used to diagnose the disease (American-Psychiatric-Association, 2013).

Currently, available pharmacotherapies for ADHD (CHADD, 2022) include psychostimulants (methylphenidate or amphetamine) and non-psychostimulants, like norepinephrine reuptake inhibitors (atomoxetine and viloxazine) or alpha-2 adrenergic receptor agonists (clonidine and guanfacine). These drugs interact with DA and norepinephrine brain systems to improve impaired attention, cognition, and executive function in ADHD patients. Other than these currently approved medications, modafinil has been clinically tested and proposed for children and adult ADHD patients (reviewed in: Lindsay, Gudelsky, & Heaton, 2006; D. Turner, 2006). Reports about the potential efficacy of modafinil as an ADHD medication show a more significant reduction of ADHD symptoms in children (Cortese et al., 2018; Rugino & Samsock, 2003; S. M. Wang et al., 2017; Zahed, Roozbakhsh, Davari Ashtiani, & Razjouyan, 2022) than adults patients (Arnold, Feifel, Earl, Yang, & Adler, 2014; Cortese et al., 2018; Elliott et al., 2020; Taylor & Russo, 2000; Wilens, Morrison, & Prince, 2011). Mechanistically, modafinil might produce therapeutic benefits in ADHD patients by interacting with DAT, thus, similarly to methylphenidate, modulating brain catecholamine levels (Madras et al., 2006; Maddalena Mereu et al., 2017; Michael J Minzenberg & Carter, 2008; Scoriels et al., 2013). The beneficial effects of modafinil on ADHD may also be the result of its modulatory effects on specific brain areas that are involved in arousal, attention, and cognitive functions (M. J. Minzenberg et al., 2011; M. J. Minzenberg et al., 2018), which might be impaired in ADHD patients (Smith, Jusko, Fosco, Musser, & Raiker, 2023). In addition, it has recently been suggested that neuroinflammation might be an increasing risk factor for developing ADHD (Vazquez-Gonzalez et al., 2023). It is of interest to notice that potential modulation of immune response by modafinil could be a mechanism of action to take into consideration for neurological disorders that include neuroinflammation (Zager, 2020).

3.4. Modafinil as a “smart drug”

The effects of modafinil in healthy populations, with or without sleep deprivation, to improve learning, memory, and executive functions, have been repeatedly reported (Baranski, Pigeau, Dinich, & Jacobs, 2004; Randall, Shneerson, Plaha, & File, 2003; Danielle C Turner et al., 2003) (reviewed in: Battleday & Brem, 2015). However, there have been numerous reports of non-medical use of modafinil in healthy individuals as a “smart drug”, to increase attention, learning, and memory, in order to improve cognitive function for better performance and accomplishments in school, college, and professional-work settings (Cakic, 2009; Partridge, Bell, Lucke, Yeates, & Hall, 2011). The prevalence in the misuse of modafinil has raised health questions about its safety and potential for dependence, and it has opened an “ethical” and social/moral debate about taking substances as a short-cut for “brain-doping” or “cosmetic” neurology to improve brain function or cognitive abilities (Carton et al., 2018; Goodman, 2010; Ram et al., 2020). While this debate is still open (Aikins, 2019; Pavarini, McKeown, & Singh, 2018; Schifano et al., 2022), non-medical use of modafinil, and other nootropic drugs, has become popular among students worldwide, albeit with significant differences in prevalence levels among various countries (de Oliveira Cata Preta, Miranda, & Bertoldi, 2020; Maier, Liechti, Herzig, & Schaub, 2013; Miranda & Barbosa, 2022; Pighi et al., 2018; S. Sharif, Fergus, Guirguis, Smeeton, & Schifano, 2022; Safia Sharif, Guirguis, Fergus, & Schifano, 2021).

Modafinil may increase vigilance, alertness, attention, and memory processes in healthy individuals by altering catecholamine levels in selected brain areas. For example, in the frontal cortex, modafinil likely promotes a faster processing of information (M. J. Minzenberg et al., 2011; M. J. Minzenberg et al., 2018). Also, in non-sleep deprived, healthy volunteers, modafinil has stimulating effects on maintenance and manipulation processes in relatively difficult and monotonous working memory tasks. This effect was particularly relevant in subjects with lower performing baselines (Müller, Steffenhagen, Regenthal, & Bublak, 2004).

3.5. Modafinil as a potential medication for psychostimulant use disorder

Clinical use of modafinil has been approved longer than 25 years. It has also been used, without medical advice, as a cognitive enhancer by healthy subjects, young students, and professionals (Cakic, 2009; Dance, 2016; Partridge et al., 2011). Thus, it is of interest to note that, to date, there are no systematic reports of modafinil dependence, but only a few case reports on this topic (Melinda Hersey, Bacon, et al., 2021). Among the published reports about adverse effects of modafinil with potential addictive outcomes, we found two cases of patients with schizoaffective disorder who became dependent on modafinil at supratherapeutic doses, 1,200–1,500 mg/day (Kate, Grover, & Ghormode, 2012; Krishnan & Chary, 2015). Further, one patient with a history of depressive disorder and concurrent alcohol dependence, who escalated the modafinil dose from an initial 200 mg/day to 3,500 mg/day (Cengiz Mete, Senormanci, Saracli, Atasoy, & Atik, 2015). Another patient that started modafinil as an adjunct treatment for daytime somnolence and fatigue as a result of withdrawal from methamphetamine, and increased modafinil doses up to 400 mg/day (Dhillon, Wu, Bastiampillai, & Tibrewal, 2015). One final patient was diagnosed with ADHD, but not treated for the disease, started taking low, 50 mg/daily doses of modafinil and increased the dosage up to an estimated 1,000–5,000 mg/daily (Alacam, Basay, Tumkaya, Mart, & Kar, 2018). Apart from these case reports, in clinical studies modafinil does not seem to produce rewarding or euphoric effects commonly seen with addictive psychostimulants (Jasinski, 2000; Rush, Kelly, Hays, Baker, & Wooten, 2002; Rush, Kelly, Hays, & Wooten, 2002a; Warot, Corruble, Payan, Weil, & Puech, 1993). It is of interest to note that in people exposed to different study conditions, one characterized by a relaxing environment and another by performance requirements, modafinil worked as a reinforcer only during the performance requiring sessions. These results suggest that modafinil effects might be influenced by higher behavioral/mental fitness requirements (Stoops, Lile, Fillmore, Glaser, & Rush, 2005).

As detailed in section 2.2, preclinical studies have shown conflicting results when testing the potential reinforcing actions of modafinil (reviewed in: Melinda Hersey, Bacon, et al., 2021; Gianluigi Tanda et al., 2021). Inconsistent outcomes where also reported when testing the potential beneficial effects of modafinil as a medication in animal models of psychostimulant use disorder (PSUD). For example, chronic modafinil treatments significantly decreased cocaine self-administration behavior in monkeys (J. L. Newman et al., 2010), but acute pre-session administration of modafinil in rats potentiated cocaine behavioral effects (M. Mereu et al., 2020) or failed to alter cocaine effects (Deroche-Gamonet et al., 2002). In drug reinstatement studies, modafinil reinstated a previously reinforced cocaine drug taking behavior after extinction (Andersen et al., 2010; J. L. Newman et al., 2010). Modafinil decreased methamphetamine self-administration behavior, as well as cue-, drug-, and context-induced reinstatement in rats (Holtz, Lozama, Prisinzano, & Carroll, 2012; Reichel & See, 2010, 2012).

Off label, modafinil has been tested as a pharmacotherapy for substance use disorder (SUD), especially PSUD. Conflicting results on the clinical efficacy of modafinil to reduce psychostimulant use, especially cocaine or methamphetamine use, have been obtained in several studies with positive (Anderson et al., 2009; Dackis, Kampman, Lynch, Pettinati, & O’brien, 2005; Hart, Haney, Vosburg, Rubin, & Foltin, 2008; McElhiney, Rabkin, Rabkin, & Nunes, 2009) and negative outcomes (Dackis et al., 2012; De La Garza II, Zorick, London, & Newton, 2010; Malcolm et al., 2006). Of note, modafinil had a greater impact in subpopulations of patients with PSUD, but no other concurrent substance use disorder (reviewed in Melinda Hersey, Bacon, et al., 2021). Indeed, when compared to placebo, modafinil reduced methamphetamine use in a sub-group of patients with only methamphetamine dependence, even though there was no statistically significant difference between modafinil and placebo in the whole clinical sample (Shearer et al., 2009). Similar results were obtained in other studies in cocaine dependent subjects where modafinil efficacy in reducing the number of cocaine-use days, or cocaine craving, was greater than placebo only in the group of patients with PSUD without comorbid alcohol dependence (Anderson et al., 2009; Kampman et al., 2015).

PSUD is often associated with other comorbid health conditions like cognitive dysfunction (Sofuoglu, DeVito, Waters, & Carroll, 2016) and sleep disorders (Fragale et al., 2021; Valentino & Volkow, 2020). If left untreated, these conditions might reduce the likelihood of remission from PSUD. Thus, treating the cognitive impairment resulting from continuous use of psychostimulants may promote beneficial effects by enhancing executive functions and improving treatment compliance (Brady, Gray, & Tolliver, 2011; Sofuoglu, DeVito, Waters, & Carroll, 2013). Several studies in people with cocaine or methamphetamine dependence have shown that modafinil treatment can result in positive outcomes related to improved attention and working memory (Ghahremani et al., 2011; Hester, Lee, Pennay, Nielsen, & Ferris, 2010; A. Kalechstein, Mahoney III, Yoon, Bennett, & De La Garza II, 2013; A. D. Kalechstein, De La Garza, & Newton, 2010). Treating sleep disturbances in addiction may also be beneficial to promote drug abstinence and reduce craving (Angarita, Emadi, Hodges, & Morgan, 2016; Fragale et al., 2021; Valentino & Volkow, 2020). Modified sleep architecture has been related to chronic use of different addictive drugs (Angarita et al., 2016), regardless of drug class. Indeed, chronic exposure to alcohol, cocaine, cannabis, and opiates reduce sleep time, increase sleep latency, and wake time after sleep onset, and induce deficiency in slow-wave sleep generation (Angarita et al., 2016). Several studies have reported beneficial effects of modafinil in sleep disturbances elicited by psychostimulant use. (Mahoney III et al., 2012; Moosavi, Yazdani-Charati, & Amini, 2019; Morgan et al., 2016; Morgan, Pace-Schott, Pittman, Stickgold, & Malison, 2010).

The positive effects of modafinil as a treatment for PSUD could be related to its dopaminergic effects mediated by its interaction with DAT, a pharmacological target of addictive psychostimulants. This outcome suggests its potential “agonist” substitution therapy effects, which would promote patient compliance to this drug. Also, the efficacy of modafinil as a treatment for cognitive and sleep dysfunctions related to chronic use and dependence on psychostimulants may be the result of its interactions with pharmacologic targets different from, or in combination with, its dopaminergic effects (Fragale et al., 2021). Thus, it is likely that the interaction between modafinil and the orexin system, may restore sleep-equilibrium in individuals affected by PSUD, and in concert with known dopaminergic effects of modafinil, provide an improvement in cognitive/executive functions that can lead to a more positive outcome.

Neuroinflammation produced by addictive psychostimulants has been suggested as a target to provide novel therapeutic strategies for the treatment of PSUD (Namba, Leyrer-Jackson, Nagy, Olive, & Neisewander, 2021). In contrast with the effects of typical CNS stimulants (Karimi-Haghighi et al., 2023), modafinil reduces neuroinflammation (Zager, 2020). Thus, this atypical CNS stimulant action of modafinil might be part of those neurobiological effects that support its potential as a medication for PSUD.

4.0. Conclusion

Modafinil has been approved for the treatment of sleep disorders for decades. Clinical and preclinical studies on modafinil have elucidated the agent’s pharmacokinetics, but the complex and wide-spread mechanism(s) of action related to its therapeutic efficacy remains unresolved. However, research suggests that modafinil is different from classical, typical CNS stimulants. Modafinil actions as an atypical inhibitor of DAT and resulting actions on the dopaminergic system have been well documented. Modafinil also interacts (either directly or indirectly) with other neurotransmitter systems, including other monoamine neurotransmitters, GABA, glutamate, orexin, and histamine. Thus, while the neurochemical actions of modafinil have not been fully elucidated yet, these actions occur in specific brain areas that are known for their physiological and pathological roles in several neurologic and neuropsychiatric disorders. Taken all together, the “atypical” stimulant actions of modafinil and its overall safety profile support its approved use for treatment of sleep disorders, as well as support its potential use as a cognitive enhancer and a potential medication for psychostimulant use disorders.

Figure 2:

Modafinil has three main potential therapeutic uses, namely sleep disorders, cognition, and addiction. The biochemical actions of modafinil in certain brain regions are linked to distinct physiological effects that promote their therapeutic uses. Brain regions are abbreviated as follows: amygdala (AMG), hippocampus (HIPPO), hypothalamus (HT), nucleus accumbens (NAc), orbitofrontal cortex (OFC), prefrontal cortex (PFC), substantia nigra (SN), and ventral tegmental area (VTA).

Abbreviations

ADHD

Attention deficit hyperactive disorder

AMG

Amygdala

BDNF

Brain derived neurotrophic factor

DA

Dopamine

DAT

Dopamine transporter

CaMKII

Calcium-calmodulin-dependent protein kinase II

CNS

Central nervous system

FDA

U.S. Food and Drug Administration

fMRI

Functional magnetic resonance imaging

GABA

γ Aminobutyric acid

HIPPO

Hippocampus

HT

Hypothalamus

LC

Locus coeruleus

MOD

Modafinil

NAc

Nucleus accumbens

NAS

Nucleus accumbens shell

NET

Norepinephrine transporter

OCT

Organic cation transporter

OFC

Orbitofrontal cortex

PET

Positron emission tomography

PFC

Prefrontal cortex

PSUD

Psychostimulant use disorder

SERT

Serotonin transporter

SN

Substantia nigra

VTA

Ventral tegmental area

VMAT2

Vesicular monoamine transporter 2