Modafinil: A Review and Its Potential Use in the Treatment of Long COVID Fatigue and Neurocognitive Deficits

Modafinil administration has resulted in cognitive improvement in patients with attention-deficit hyperactivity disorder, major depression, and schizophrenia and in healthy populations (9), as well as decreased fatigue in patients with other medical conditions. Table 1 presents results of studies in which the effects of modafinil on fatigue and cognition were examined (10–14). Modafinil is well tolerated; the most common side effects are headache, nausea, nervousness, anxiety, and insomnia (8). Although it is a Schedule IV drug, it has a low potential for abuse because of its insolubility in water and instability at high temperatures, thus preventing its use in intravenous or inhalation forms (9). Modafinil has the potential for drug-drug interactions; it has shown reversible inhibition of CYP2C19 in human liver microsomes (8). Because selective serotonin reuptake inhibitors (SSRIs) are metabolized by CYP2C19, modafinil may increase the serum levels of escitalopram. However, there was no difference in side effects in a controlled study when either placebo or modafinil was added to an SSRI in patients with major depressive disorder and persistent fatigue (15). Modafinil has no known drug interactions with remdesivir, an antiviral approved by the Food and Drug Administration to treat COVID-19.

Mizenberg and Carter (9) reviewed modafinil’s actions on neurotransmitters that likely mediate its effects on wakefulness. These consist of elevated synaptic/extracellular dopamine (DA) through inhibition of the DA active transporter; elevated synaptic/extracellular norepinephrine (NE) through interactions with alpha 1 and alpha 2 receptors; elevated extracellular glutamate in the thalamus, hypothalamus, striatum, and hippocampus through adrenergic mechanisms or through increasing the cerebral glutamate-glutamine pool; reduction of cortical GABA, possibly through adrenergic modulation of serotonergic (5HT) activity; and indirect elevation of synaptic/extracellular histamine localized to brain regions involved in wakefulness through its interactions with the NE, 5HT, and GABA systems. Modafinil has a diverse immunomodulatory profile in its therapeutic effects on preclinical models of neuroinflammatory disease states, with actions such as cytokine production impairment, T-cell recruitment and differentiation, and microglial activation (16).

Inflammation-induced reactive oxygen species damage mitochondrial membranes, allowing protons to leak and reducing ATP yield (17). Deficits in neural mitochondrial ATP production can lead to neuronal atrophy and dysfunction of neural networks involved in learning, memory, and executive function, resulting in neurocognitive symptoms, such as fatigue and executive dysfunction (17). Modafinil’s inhibition of this inflammatory chain reaction may account for its favorable effects in terms of wakefulness and cognitive function in populations with neurological and psychiatric diseases associated with neuroinflammation.

A recent meta-analysis identified fatigue as the most common and “attention disorder” as the third most common syndromes associated with long COVID (18). A positron emission tomography study of COVID-19 patients found hypometabolism in a cerebral network (including the frontal cortex, anterior cingulate, insula, and caudate nucleus) that was correlated with executive dysfunction and depressive symptoms (19).

There may be a link between acute COVID-19 infection and persistent post­infection neuropsychiatric symptoms. Excessive inflammatory cytokine release induced by initial viral infection and microglial activation disrupts neuronal mitochondrial energy metabolism, leaving neurons vulnerable to inflammatory excitotoxic factors. This process may culminate in neuronal atrophy and synaptic dysfunction. To support this, a parallel can be drawn with the findings of Rabkin et al. (13), in that persistent CNS inflammation, microglial activation, and mitochondrial toxicity are identified contributors to the development of HIV/AIDS-associated neurocognitive dysfunction (20). The evidence presented here suggests that modafinil can therapeutically act on these pathways, which possibly contributed to the symptomatic improvement shown in the trial conducted by Rabkin et al. (13). A registered clinical trial of modafinil to improve wakefulness in acutely ill COVID-19 patients is under way (NCT04751227). Used cautiously, modafinil may be an attractive candidate in treating long COVID–associated fatigue and neurocognitive deficits.