What Not to Mix with Modafinil: Interactions You Need to Know

Modafinil is a prescription medicine for narcolepsy, obstructive sleep apnea (OSA), and shift work disorder (SWD). It can also be used off label for other conditions. Modafinil affects liver enzymes that process many medicines and it has stimulant effects, so combining it with certain substances can create real risks (Greenblatt & Adams, 2023; U.S. Food and Drug Administration, 2015).

Why interactions matter

Modafinil is mainly metabolized in the liver. It induces cytochrome P450 3A4 (CYP3A4) and inhibits cytochrome P450 2C19 (CYP2C19). These enzyme changes can lower or raise levels of other medicines. Older adults and people with liver problems may clear modafinil more slowly, which can increase interaction risk (Greenblatt & Adams, 2023; U.S. Food and Drug Administration, 2015).

What not to mix with modafinil

Alcohol

Responses vary. Some people feel less drunk, while others have blackouts or poor coordination. The mix can mask intoxication and increase risk of injury. It also worsens insomnia (Greenblatt & Adams, 2023).

Practical advice

• Avoid alcohol, especially early in treatment and at higher doses.
• If you choose to drink, keep it minimal and not near bedtime.

Caffeine

Caffeine and modafinil both promote wakefulness. Together they can increase jitteriness, palpitations, anxiety, and sleep problems, especially in people with anxiety or heart risk factors (Greenblatt & Adams, 2023).

Practical advice

• Limit to low or moderate caffeine.
• Avoid energy drinks and late afternoon coffee.

Antidepressants, especially selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs)

Modafinil inhibits CYP2C19, which can raise levels of medicines like citalopram or diazepam. Higher serotonergic load may increase the chance of side effects such as agitation or, rarely, serotonin toxicity, particularly when multiple serotonergic drugs are combined. Pharmacodynamic interactions, where drug effects add up, also matter in practice (U.S. Food and Drug Administration, 2015; Cascorbi, 2012).

Practical advice

• Do not change doses on your own.
• Ask your clinician about dose adjustments or monitoring when starting or stopping modafinil.

Other stimulants, including amphetamine mixtures, methylphenidate, and cocaine

Combining stimulants raises blood pressure, heart rate, and insomnia risk. In a clinical study, modafinil reduced the pleasurable effects of cocaine but cardiovascular measures still increased, which supports avoiding stimulant stacking outside medical supervision (Malcolm et al., 2006). Modafinil’s action at the dopamine transporter differs from cocaine-like agents, which may reduce abuse liability, but this does not remove cardiovascular risk when combined with stimulants (Schmitt & Reith, 2011).

Practical advice

• Avoid combining with prescription stimulants or recreational stimulants.
• Seek medical guidance if you are already prescribed a stimulant for attention-deficit hyperactivity disorder.

Benzodiazepines and sedative hypnotics

Modafinil can counteract sedative effects, leading to trouble sleeping and reduced benefit from sleep medicines. It may also raise levels of diazepam through CYP2C19 inhibition, increasing side effect risk during the day (U.S. Food and Drug Administration, 2015).

Practical advice

• Discuss timing. Morning modafinil and careful evening sedative timing may help.
• Monitor for daytime drowsiness or paradoxical alertness and report issues.

Hormonal contraceptives

By inducing CYP3A4, modafinil can reduce the effectiveness of hormonal birth control methods such as pills, patches, rings, and some implants. The U.S. Food and Drug Administration advises using alternative or backup contraception while taking modafinil and for one month after stopping (U.S. Food and Drug Administration, 2015).

Practical advice

• Use a nonhormonal backup method during treatment and for one month after your last dose.

Immunosuppressants and other narrow therapeutic index drugs

Modafinil may lower cyclosporine concentrations, risking transplant rejection. Medicines highly sensitive to CYP changes warrant close monitoring or avoidance of the combination (U.S. Food and Drug Administration, 2015).

Practical advice

• If you take cyclosporine or similar medicines, your prescriber should check levels and adjust doses.

Strong enzyme inducers and inhibitors

Drugs that strongly induce CYP3A4, such as rifampin or certain anticonvulsants, can lower modafinil levels. Inhibitors of CYP3A4 can raise modafinil exposure. General principles of pharmacokinetic interactions apply, especially with multi drug regimens and in older adults (Kristensen, 1976; Cascorbi, 2012).

Practical advice

• Share a full medication and supplement list with your clinician.
• Expect dose adjustments or monitoring if strong inducers or inhibitors are added or removed.

Herbal stimulants and nootropics

Data are limited. Stacks with caffeine, ginseng, yohimbine, or racetams can unpredictably increase anxiety, heart rate, or insomnia. Without robust evidence, caution is warranted (Greenblatt & Adams, 2023).

Practical advice

• If you experiment, add one supplement at a time, start low, and watch for side effects.
• Stop new additions if you notice heart, mood, or sleep problems.

How modafinil works and why that matters for interactions

Modafinil weakly inhibits dopamine reuptake and may influence norepinephrine and serotonin in parts of the brain that regulate wakefulness. It appears to interact with the dopamine transporter in a way that differs from cocaine-like stimulants, which may explain lower euphoric effects and lower abuse liability in typical use. These mechanistic differences do not remove the risk of additive cardiovascular or psychiatric side effects when combined with other stimulants (Schmitt & Reith, 2011; Greenblatt & Adams, 2023).

Safe use tips

• Start at the lowest effective dose, often 100 to 200 mg in the morning, as directed by your clinician (U.S. Food and Drug Administration, 2015; Greenblatt & Adams, 2023).
• Avoid late dosing to reduce insomnia.
• Check blood pressure and heart rate if you have cardiovascular risk.
• Share all medicines, supplements, and recreational substances with your clinician.
• Do not combine with other stimulants without medical advice.

Approved and off label use, in brief

• Approved uses include narcolepsy, OSA as an adjunct to continuous positive airway pressure, and SWD (U.S. Food and Drug Administration, 2015).
• Off label uses have been studied but have mixed evidence, such as attention-deficit hyperactivity disorder and fatigue in medical conditions. Discuss benefits and risks with your clinician and avoid self directed stacking to chase cognitive effects (Greenblatt & Adams, 2023).

When to contact a clinician urgently

• New rash, swelling of the face or tongue, or trouble breathing.
• Chest pain, sustained high blood pressure, severe anxiety, or confusion.
• Pregnancy planning while using hormonal contraception with modafinil (U.S. Food and Drug Administration, 2015).

FAQ

Can I take modafinil at night?

It is not recommended. Evening dosing increases the chance of insomnia. Most people take it in the morning or about one hour before a night shift if prescribed for shift work disorder (U.S. Food and Drug Administration, 2015).

Does modafinil reduce birth control effectiveness with all forms?

It can reduce effectiveness of many hormonal methods due to CYP3A4 induction. Use nonhormonal backup during treatment and for one month after stopping (U.S. Food and Drug Administration, 2015).

Is coffee completely off limits with modafinil?

No, but keep caffeine low. Many people tolerate a small morning coffee. Watch for jitteriness, racing heart, anxiety, or sleep trouble and cut back if these occur (Greenblatt & Adams, 2023).

If I already take a stimulant for attention-deficit hyperactivity disorder, can I add modafinil?

Do not add it on your own. The combination can raise blood pressure, heart rate, and insomnia risk. Your clinician can decide if benefits outweigh risks and set up monitoring if needed (Malcolm et al., 2006).

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/
• Malcolm, R., Swayngim, K., Donovan, J. L., DeVane, C. L., Elkashef, A., Chiang, N., Khan, R., Mojsiak, J., Myrick, D. L., Hedden, S., Cochran, K., & Woolson, R. F. (2006). Modafinil and cocaine interactions. The American Journal of Drug and Alcohol Abuse, 32(4), 577–587. https://doi.org/10.1080/00952990600920425
• Cascorbi, I. (2012). Drug interactions—principles, examples and clinical consequences. Deutsches Ärzteblatt International, 109(33–34), 546–555. https://doi.org/10.3238/arztebl.2012.0546
• Kristensen, M. B. (1976). Drug interactions and clinical pharmacokinetics. Clinical Pharmacokinetics, 1(5), 351–372. https://doi.org/10.2165/00003088-197601050-00003
• Schmitt, K. C., & Reith, M. E. (2011). The atypical stimulant and nootropic modafinil interacts with the dopamine transporter in a different manner than classical cocaine-like inhibitors. PLoS ONE, 6(10), e25790. https://doi.org/10.1371/journal.pone.0025790