Modafinil Interactions with Common Medications, Foods, and Supplements

Modafinil is a wakefulness-promoting agent approved by the FDA for the treatment of narcolepsy, obstructive sleep apnea (OSA), and shift work disorder (FDA, 2015). It is also used off-label for cognitive enhancement and fatigue reduction. While generally well-tolerated, modafinil interacts with various medications, supplements, and physiological systems through its modulation of hepatic enzymes. Understanding these interactions is essential for avoiding reduced efficacy or heightened side effects when combining modafinil with other substances.

Overview of Modafinil

Modafinil’s wakefulness-promoting effects are believed to stem from its action on multiple neurotransmitter systems, including dopamine, orexin, histamine, and GABA (Salerno et al., 2019). The drug is a racemic compound, with both enantiomers exhibiting behavioral activity. It is lipophilic, protein-bound, and predominantly metabolized in the liver (Robertson & Hellriegel, 2003). A single dose reaches peak plasma levels in 2 to 4 hours and has a half-life ranging from 10 to 15 hours.

Enzyme Pathways and Metabolic Interactions

CYP3A4 Induction

Modafinil induces the cytochrome P450 3A4 (CYP3A4) enzyme, which can accelerate the metabolism of many drugs, potentially reducing their plasma concentrations and therapeutic effects. This interaction is particularly relevant for hormonal contraceptives and immunosuppressants (FDA, 2015).

CYP2C19 Inhibition

It also inhibits CYP2C19, increasing blood concentrations of drugs metabolized via this pathway, such as diazepam, phenytoin, and omeprazole (Robertson & Hellriegel, 2003; Greenblatt & Adams, 2025). This raises the risk of enhanced pharmacological effects and side effects from these medications.

Drug Interactions

Oral Contraceptives

Due to CYP3A4 induction, modafinil reduces the effectiveness of steroidal contraceptives, including pills, patches, rings, and implants. Women are advised to use additional or alternative non-hormonal contraceptive methods during and for one month after discontinuing modafinil (FDA, 2015).

Central Nervous System Stimulants

Modafinil shares overlapping mechanisms with other stimulants like methylphenidate and amphetamines. When used concurrently, these drugs can lead to additive stimulation, potentially resulting in anxiety, insomnia, or cardiovascular strain (Robertson & Hellriegel, 2003; Salerno et al., 2019).

Antiepileptic Medications

Caution is warranted when using modafinil with antiepileptic drugs. Through hepatic enzyme modulation, it may alter the plasma levels of medications like phenytoin and carbamazepine, necessitating careful dose monitoring (Robertson & Hellriegel, 2003).

Antidepressants and Anxiolytics

Modafinil may elevate serum concentrations of SSRIs, benzodiazepines, and other psychiatric medications via CYP2C19 inhibition. Clinicians should monitor for heightened therapeutic or adverse effects and adjust doses accordingly (Greenblatt & Adams, 2025).

Food and Supplement Interactions

Food

According to clinical data, food slightly delays the absorption of modafinil but does not significantly impact its bioavailability (Robertson & Hellriegel, 2003). No specific interactions with types of food are reported in the current literature.

Caffeine and Stimulant Supplements

Although not extensively documented in FDA labeling, research suggests that combining modafinil with other stimulants (including high-dose caffeine or certain nootropics) may lead to overstimulation, increased heart rate, and anxiety (Salerno et al., 2019). Patients should be advised to moderate intake.

Herbal Supplements

The reviewed documents do not include specific data on herbal interactions like St. John’s Wort. In the absence of such information, caution is advised with any substance known to affect liver enzymes.

Special Populations and Safety Considerations

Hepatic Impairment

In patients with severe hepatic dysfunction, modafinil’s clearance is reduced by approximately 50%. A lower starting dose—typically half the standard—is recommended (FDA, 2015).

Geriatric Patients

Older adults may have altered pharmacokinetics and increased susceptibility to side effects. Lower doses and close monitoring are recommended for this group (FDA, 2015).

Psychiatric Conditions

Modafinil may exacerbate underlying psychiatric disorders, including mania, anxiety, or psychosis. Caution is advised for patients with a history of such conditions (FDA, 2015).

Performance Use and Ethical Concerns

Off-label use of modafinil to enhance cognitive or physical performance in healthy individuals, such as athletes or students, is increasing. While studies suggest performance gains, ethical and medico-legal implications remain contentious (Salerno et al., 2019).

References

• U.S. Food and Drug Administration. (2015). PROVIGIL® (modafinil) tablets, for oral use, C-IV [prescribing information]. U.S. Department of Health and Human Services. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020717s037s038lbl.pdf
• Greenblatt, K., & Adams, N. (2023, February 6). Modafinil. In StatPearls [Internet]. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK531476/
• Robertson, P. Jr., & Hellriegel, E. T. (2003). Clinical pharmacokinetic profile of modafinil. Clinical Pharmacokinetics, 42(2), 123–137. https://doi.org/10.2165/00003088-200342020-00002
• Salerno, M., Villano, I., Nicolosi, D., Longhitano, L., Loreto, C., Lovino, A., et al. (2019). Modafinil and orexin system: Interactions and medico-legal considerations. Frontiers in Bioscience (Landmark Ed), 24(3), 564–575. https://doi.org/10.2741/4736