Fatigue by Walter Stuempfig, American 1914-1970
A large, positive trial, but don’t think amphetamines will do the job
STUDY: Frederiksen H et al, Journal of Clinical Oncology 2026
STUDY TYPE: Randomized controlled crossover trial
FUNDING: Danish Cancer Society, AP Moeller Foundation, and Danish academic sources
Background
Fatigue is a common unmet need in patients with hematologic (blood) cancers, and exercise isn’t feasible for many. Methylphenidate has given mixed results in solid tumors, and has few studies in blood cancers.
The Study
- 152 fatigued adults with blood cancers, off chemotherapy for at least 8 weeks and off psychiatric medication.
- Six weeks each of methylphenidate (up to 20 mg twice daily) and placebo, in random order.
- 130 of 152 completed both periods.
- Primary outcome: Fatigue scale (FACIT-F, 0 to 52, higher is better).
Results
Fatigue scores improved 8.9 points on methylphenidate versus 3.9 on placebo, a 5-point difference that cleared the trial’s 4.25-point threshold for a meaningful change. Both groups improved equally over the first two weeks; only methylphenidate kept improving after that.
Patients gained about 40 minutes of waking time daily, and sleep improved. Overall, 52% preferred the methylphenidate period, versus 23% placebo.
Side Effects
Adverse events were more common on methylphenidate (57% vs 40%), mostly mild headache, dizziness, tremor, nausea, and poor appetite. One patient stopped for agitation. Blood pressure was stable.
Limitations
- Treatment lasted only six weeks.
- Patients on active chemotherapy or antidepressants were excluded.
- Dry mouth and other effects may have unblinded some patients.
The Bigger Picture
There are approximately 50 randomized trials of stimulants for fatigue in medical disorders, and here’s how they stack up:
- Methylphenidate is the most studied, and comes out positive in meta-analyses
- The modafinils have the next-best evidence
- Amphetamines have only a few trials (around 4), most of which are negative
Most trials involved cancer, followed by multiple sclerosis and HIV.
Practice Implications
- For people with blood cancers and lingering fatigue, a methylphenidate trial is reasonable.
- Start immediate-release 5 mg at morning and noon and work up to 20 mg twice daily over two weeks.
- Wait at least three weeks before judging, since early placebo gains look identical.
- Trials of stimulants in medical fatigue largely use methylphenidate and modafinils. Avoid amphetamines, which are riskier and don’t clearly work.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
