Seizures have been reported in people taking modafinil, but the available human evidence does not show a consistent increase in seizure risk or establish that modafinil lowers seizure threshold.
The strongest direct evidence comes from people with epilepsy. Those findings are broadly reassuring, but most of the evidence is observational rather than prospective. For people already taking antiseizure medications, concomitant drug therapy also matters because modafinil can alter the metabolism of some medications.
Key Takeaways
- Most of the human evidence is observational rather than prospective.
- Modafinil has not been shown to consistently lower seizure threshold in humans.
- Animal findings vary by dose and seizure model and cannot be directly translated into human epilepsy risk.
- People taking antiseizure medications may need additional attention to potential medication interactions.
Does Modafinil Increase Seizure Risk in Humans?
Artsy and colleagues reviewed 10 years of clinical records and identified 205 patients with epilepsy who had received modafinil.
Ninety-one patients experienced seizures while taking modafinil, while 114 did not. That does not mean modafinil caused seizures in 91 of 205 patients. These patients already had epilepsy, and many also had neurological conditions associated with seizure risk.
There was no relationship between modafinil dose and whether seizures occurred. Six patients stopped modafinil because clinicians were concerned that it might be worsening their seizures. In four of those six, seizures continued after modafinil was discontinued.
Among 29 patients whose epilepsy was not accompanied by another neurological disorder, no major seizure exacerbation was observed. The authors described modafinil as potentially safe in epilepsy based on the available data (Artsy et al., 2012).
The Four New-Onset Seizure Cases
Four patients in the Artsy study experienced their first known seizure after modafinil had been started.
One was a 61-year-old woman with glioblastoma who experienced a seizure approximately one week after beginning modafinil at 200 mg per day. She was subsequently treated with levetiracetam. Modafinil was continued and later increased to 400 mg per day without another reported seizure before her death six months later.
The other three new-onset seizures occurred approximately five to seven years after modafinil initiation. The investigators did not consider modafinil contributory in those cases.
The underlying neurological disease and the long delay before three of the events make direct attribution difficult. These cases do not establish that modafinil caused the seizures, but they also cannot exclude individual susceptibility.
Clinical Reviews of Seizure Risk
Andrade (2016) reviewed animal data, overdose reports, clinical studies and experience in populations with increased seizure susceptibility. The review did not identify a convincing human proconvulsant signal from modafinil or armodafinil, although the available evidence was limited and largely uncontrolled.
A later review of treatments for excessive daytime sleepiness in people with epilepsy similarly found no established proconvulsant effect from modafinil and related wake-promoting agents (Zaccara et al., 2021).
Can Modafinil Interact With Antiseizure Medications?
Modafinil can induce CYP3A4 and inhibit CYP2C19, creating the potential for changes in medications that depend on these metabolic pathways.
Modafinil-induced CYP3A4 activity may increase carbamazepine metabolism and reduce drug exposure.
Conversely, modafinil inhibits CYP2C19, which may reduce phenytoin metabolism and increase phenytoin exposure.
Clobazam is harder to predict because the parent drug is converted partly through CYP3A4 to the active metabolite N-desmethylclobazam, while CYP2C19 plays an important role in clearing that metabolite.
A seizure occurring after modafinil is introduced cannot automatically be attributed to a direct effect on seizure threshold because changes in antiseizure-medication exposure, underlying epilepsy and other clinical factors may also need to be considered.
Does Modafinil Lower the Seizure Threshold?
Seizure threshold refers to how easily abnormal neuronal activity can progress to a seizure. A drug that lowers the threshold makes seizures easier to provoke in a susceptible person.
In the largest study involving people with epilepsy, seizure occurrence was not associated with higher modafinil doses, and subsequent clinical reviews have not identified a clear threshold-lowering effect.
There are no large prospective trials specifically designed to measure how modafinil affects seizure frequency or seizure threshold in people with epilepsy, so the available conclusion remains limited by the quality of the evidence.
What Do Animal Studies Show?
Zolkowska and colleagues tested modafinil and its metabolites in mouse models of electrically induced seizures. At 75 mg/kg, modafinil increased the threshold required to produce electroconvulsions.
At lower experimental doses, modafinil also enhanced the anticonvulsant activity of carbamazepine, phenytoin and valproate in the maximal electroshock seizure model. Some effects were accompanied by changes in brain concentrations of carbamazepine or phenytoin, while the enhancement of valproate activity occurred without a corresponding increase in brain valproate levels (Zolkowska et al., 2015).
Bahramnjead and colleagues found a different dose-dependent pattern in a pentylenetetrazole model. Modafinil at 80 mg/kg produced an anticonvulsant effect, whereas 150 mg/kg produced a proconvulsant effect (Bahramnjead et al., 2018).
Maximal electroshock and pentylenetetrazole models represent artificially induced seizure states and do not reproduce the full biology of chronic human epilepsy. The doses used in mice should not be treated as direct equivalents of therapeutic human doses.
Do Modafinil Overdoses Commonly Cause Seizures?
Spiller and colleagues reviewed 137 single-substance modafinil exposures reported to poison centres. Tachycardia, insomnia, agitation, dizziness and anxiety were among the most frequently reported effects (Spiller et al., 2009).
Carstairs and colleagues later reviewed 87 supratherapeutic single-substance exposures. Tachycardia, agitation and anxiety were again common, with no major outcomes or deaths reported (Carstairs et al., 2010).
Poison-centre data cannot establish that seizures are impossible after overdose, but seizures were not a prominent signal in either series.
A Confounded Case Report: Modafinil and Kratom
Boyer and colleagues described a generalized tonic-clonic seizure in a man who had taken 100 mg of modafinil while also using kratom to self-manage opioid withdrawal and chronic pain (Boyer et al., 2008).
Because both substances were being used together, the report cannot determine whether modafinil caused the seizure, whether kratom contributed, or whether another factor was responsible.
Is Modafinil Safe for People With Epilepsy?
The decision depends on the individual rather than on epilepsy alone.
Existing seizure control, seizure type, the cause of the epilepsy, other neurological disease and concomitant medications can all affect the risk assessment. Medication interactions may also matter when modafinil is added to an existing antiseizure regimen.
Modafinil should not be started, stopped or adjusted solely on the assumption that it is either unsafe or harmless in epilepsy. A clinician can assess the person’s seizure history, current treatment and potential medication interactions before making a treatment decision.
When Does a Seizure During Modafinil Treatment Need Medical Review?
A first seizure requires medical assessment regardless of whether modafinil appears to be involved.
Someone with established epilepsy should also seek medical review if seizures become more frequent, change in character, or begin occurring after a medication or dose change.
A prolonged seizure, repeated seizures without normal recovery between them, significant injury or difficulty breathing requires emergency medical attention.
Conclusion
For people with epilepsy, modafinil is not a simple yes-or-no seizure-risk question. The available evidence does not support treating it as uniformly proconvulsant, but treatment decisions still depend on seizure control, the cause of the epilepsy, other neurological conditions, current antiseizure medications and possible drug interactions.
Those factors are more useful clinically than assuming that any seizure occurring during modafinil treatment was caused by the drug.
References
Artsy, E., McCarthy, D. C., Hurwitz, S., Pavlova, M. K., Dworetzky, B. A., & Lee, J. W. (2012). Use of modafinil in patients with epilepsy. Epilepsy & Behavior, 23(4), 405–408. https://doi.org/10.1016/j.yebeh.2012.02.011
Andrade, C. (2016). A method for deciding about the possible safety of modafinil and armodafinil in patients with seizure disorder. The Journal of Clinical Psychiatry, 77(1), e25–e28. https://doi.org/10.4088/JCP.15f10580
Bahramnjead, E., Kazemi Roodsari, S., Rahimi, N., Etemadi, P., Aghaei, I., & Dehpour, A. R. (2018). Effects of modafinil on clonic seizure threshold induced by pentylenetetrazole in mice: Involvement of glutamate, nitric oxide, GABA, and serotonin pathways. Neurochemical Research, 43(11), 2025–2037. https://doi.org/10.1007/s11064-018-2623-7
Boyer, E. W., Babu, K. M., Adkins, J. E., McCurdy, C. R., & Halpern, J. H. (2008). Self-treatment of opioid withdrawal using kratom (Mitragynia speciosa Korth). Addiction, 103(6), 1048–1050. https://doi.org/10.1111/j.1360-0443.2008.02209.x
Carstairs, S. D., Urquhart, A., Hoffman, J., Clark, R. F., & Cantrell, F. L. (2010). A retrospective review of supratherapeutic modafinil exposures. Journal of Medical Toxicology, 6(3), 307–310. https://doi.org/10.1007/s13181-010-0017-6
Spiller, H. A., Borys, D., Griffith, J. R. K., Klein-Schwartz, W., Aleguas, A., Sollee, D., Anderson, D. A., & Sawyer, T. S. (2009). Toxicity from modafinil ingestion. Clinical Toxicology, 47(2), 153–156. https://doi.org/10.1080/15563650802175595
Zaccara, G., Bartolini, E., Tramacere, L., & Lattanzi, S. (2021). Drugs for patients with epilepsy and excessive daytime sleepiness. Epilepsy & Behavior, 124, 108311. https://doi.org/10.1016/j.yebeh.2021.108311
Zolkowska, D., Andres-Mach, M., Prisinzano, T. E., Baumann, M. H., & Luszczki, J. J. (2015). Modafinil and its metabolites enhance the anticonvulsant action of classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model. Psychopharmacology, 232(14), 2463–2479. https://doi.org/10.1007/s00213-015-3884-3
