Modafinil for Chronic Fatigue Syndrome: What the Evidence Shows

Chronic Fatigue Syndrome, also called Myalgic Encephalomyelitis (CFS or ME), is a long-term illness marked by severe fatigue, post-exertional malaise, unrefreshing sleep, and often cognitive issues like memory and attention problems. Standard options help some people, but many still struggle. Modafinil is a prescription medicine that promotes wakefulness. It is approved for narcolepsy, obstructive sleep apnea related sleepiness, and shift work disorder. Using it for CFS is considered off-label and should be guided by a clinician who understands your history and medicines (U.S. Food and Drug Administration, 2015; Greenblatt & Adams, 2023).

What is modafinil

Modafinil is a central nervous system stimulant that promotes wakefulness. It likely works by weakly blocking dopamine reuptake and by affecting orexin and histamine pathways in the brain. These pathways help regulate alertness. It may also influence norepinephrine and glutamate signaling (Greenblatt & Adams, 2023).

In the United States, modafinil is approved for narcolepsy, obstructive sleep apnea related sleepiness, and shift work sleep disorder. It is not approved for treating CFS. Any use for CFS is off-label (U.S. Food and Drug Administration, 2015).

Why do people consider modafinil for CFS

People with CFS often report daytime sleepiness, brain fog, and reduced ability to concentrate. Because modafinil can improve wakefulness in other conditions, clinicians and patients sometimes explore whether it can help select CFS symptoms. CFS is a biological condition with immune, neurologic, and autonomic features, which can include cognitive issues, orthostatic intolerance, and nonrestorative sleep. These may contribute to daytime fatigue and reduced function (Sapra & Bhandari, 2023).

What does the evidence show

Case reports and a small series

• A published case described a man with long-standing CFS who improved after starting modafinil 200 mg daily. He returned to part-time work and reported higher energy within months (Turkington et al., 2004).
• A 2021 case series reviewed three people with treatment-resistant CFS who received modafinil with cognitive behavioral therapy. Two had meaningful improvement in fatigue and concentration, and all three achieved social recovery such as returning to work or full-time training (Garg et al., 2021).

These reports show what can happen for individuals. They do not prove that most people with CFS will benefit.

Controlled trial with mixed findings

A double-blind, placebo-controlled crossover study in 14 adults with CFS tested modafinil at 200 mg and 400 mg daily, each for 20 days. Modafinil did not significantly improve self-reported fatigue or quality of life compared with placebo. There were mixed effects on some cognitive tests, with dose-related differences. Some participants experienced adverse effects that led to withdrawal during the study (Randall et al., 2005).

Bottom line on evidence: Results are inconsistent. Some people may feel more alert or think more clearly, but reliable improvements in fatigue or life quality have not been shown across studies. Benefits, if any, may be limited to subgroups, for example those with marked daytime sleepiness or coexisting sleep problems, but this needs better research (Randall et al., 2005; Sapra & Bhandari, 2023).

Who might benefit

Based on limited data and clinical reasoning, clinicians may consider a trial in carefully selected people who have:

• prominent daytime sleepiness despite good sleep hygiene,
• treated sleep apnea with persistent residual sleepiness,
• significant cognitive fatigue that limits function,
• a plan to pair medication with non-drug strategies such as pacing and cognitive behavioral therapy.

This is a clinical judgment call. It should include clear goals and a stop plan if there is no meaningful benefit (Garg et al., 2021; Sapra & Bhandari, 2023).

Risks and side effects

Common side effects include headache, nausea, decreased appetite, anxiety, dizziness, and insomnia. Serious but rare skin reactions can occur. Psychiatric symptoms such as agitation or mood changes are possible. People with heart conditions may need closer monitoring. Modafinil can impair the effectiveness of hormonal contraceptives. Always review contraception and other medicines with your clinician before starting modafinil (U.S. Food and Drug Administration, 2015; Greenblatt & Adams, 2023).

Seek medical care promptly for rash, swelling of the face or throat, trouble breathing, severe anxiety, chest pain, or unusual thoughts or behavior (U.S. Food and Drug Administration, 2015).

Interactions and precautions

• Birth control: Modafinil can reduce the effectiveness of pills, patches, rings, and some implants. Use a nonhormonal backup during treatment and for one month after stopping (U.S. Food and Drug Administration, 2015).
• Other medicines: Modafinil affects liver enzymes that process drugs. Levels of some medicines may rise or fall. Review antidepressants, anti-seizure medicines, blood thinners, and transplant medicines with your clinician or pharmacist (U.S. Food and Drug Administration, 2015; Greenblatt & Adams, 2023).
• Sleep disorders: If sleep apnea is present, address it first. Modafinil should not replace treatment for the underlying airway obstruction (U.S. Food and Drug Administration, 2015).
• Pregnancy and breastfeeding: Safety is uncertain. Discuss risks and alternatives with your clinician (Greenblatt & Adams, 2023).
• Substance use risk: Abuse potential is lower than traditional stimulants, but caution is advised in people with a history of substance misuse (Greenblatt & Adams, 2023).

How clinicians may approach a monitored trial

If a clinician and patient decide to try modafinil off-label for CFS, a careful plan helps protect safety and assess benefit.

1. Screening: Confirm CFS diagnosis, review sleep habits, screen for sleep apnea or circadian problems, and assess mood and anxiety. Treat underlying issues first when possible (Sapra & Bhandari, 2023).
2. Set goals: Choose 1 to 3 practical targets such as longer time on tasks, fewer daytime lapses, or improved attendance.
3. Start low, monitor often: Use the lowest effective dose and track sleep, energy, and side effects each week. If there is no meaningful improvement after a defined trial, stop the medicine.
4. Combine with non-drug care: Pacing, activity management, and cognitive behavioral strategies can help patients use any alertness gains without worsening post-exertional malaise (Garg et al., 2021).

Specific dosing should be individualized by a clinician. Do not start or change doses without medical guidance (U.S. Food and Drug Administration, 2015; Greenblatt & Adams, 2023).

How does modafinil compare with other options

There is no medicine approved to treat CFS. Programs often focus on pacing, sleep hygiene, management of orthostatic intolerance, pain control, and treatment of coexisting problems such as anxiety or depression. For a subset with marked daytime sleepiness, a short monitored trial of a wakefulness agent may be considered, but robust head-to-head data do not exist for CFS (Sapra & Bhandari, 2023). Choices should be individualized.

The bottom line

Modafinil can help with wakefulness. For CFS, the best study did not show consistent improvements in fatigue or quality of life, though some people report better alertness or thinking. If used, it should be part of a broader plan, with clinician supervision, clear goals, attention to safety, and a willingness to stop if it does not help you function in daily life (Randall et al., 2005; Garg et al., 2021; U.S. Food and Drug Administration, 2015).

FAQ

Can I take modafinil at night

This is usually not advised. Modafinil promotes wakefulness and can cause insomnia if taken late in the day. People with shift work sleep disorder may take it about one hour before the work shift under clinician guidance (U.S. Food and Drug Administration, 2015).

Does modafinil cure CFS

No. There is no cure for CFS. Modafinil may help alertness for some people, but evidence is mixed and it does not treat the underlying illness. It should be considered a supportive option, not a cure (Randall et al., 2005; Sapra & Bhandari, 2023).

Can I use modafinil if I have sleep apnea

Modafinil does not treat airway obstruction. If you have obstructive sleep apnea, treat it first, usually with continuous positive airway pressure when indicated. Modafinil may be used for residual daytime sleepiness under medical supervision (U.S. Food and Drug Administration, 2015).

What should I watch for when starting modafinil

Watch for headache, anxiety, reduced appetite, nausea, and trouble sleeping. Stop the medicine and seek care for any rash, swelling, trouble breathing, or severe mood changes. Discuss contraception and other medicines with your clinician before starting (U.S. Food and Drug Administration, 2015; Greenblatt & Adams, 2023).

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). Modafinil. In StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–. https://www.ncbi.nlm.nih.gov/books/NBK531476/
• Garg, H., Douglas, M., Turkington, G. D., & Turkington, D. (2021). Recovery from refractory chronic fatigue syndrome with CBT and modafinil. BMJ Case Reports, 14(3), e240283. https://doi.org/10.1136/bcr-2020-240283
• Randall, D. C., Cafferty, F. H., Shneerson, J. M., Smith, I. E., Llewelyn, M. B., & File, S. E. (2005). Chronic treatment with modafinil may not be beneficial in patients with chronic fatigue syndrome. Journal of Psychopharmacology, 19(6), 647–660. https://doi.org/10.1177/0269881105056531
• Turkington, D., Hedwat, D., Rider, I., & Young, A. H. (2004). Recovery from chronic fatigue syndrome with modafinil. Human Psychopharmacology: Clinical and Experimental, 19(1), 63–64. https://doi.org/10.1002/hup.554
• Sapra, A., & Bhandari, P. (2023). Chronic fatigue syndrome. In StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–. https://www.ncbi.nlm.nih.gov/books/NBK557676/