Modafinil does enhance cognition, review finds

The statement that modafinil may be the world’s first safe “smart drug” [1] and could risk human health and life, bearing in mind that the drug may be purchased illegally over the internet without a prescription and because adverse effects have been reported widely. The review by Battleday and Brem [1] involved a systematic search using one search engine and produced results in narrative with no grading of the evidence that is expected of systematic reviews. The literature search included the terms ‘modafinil’ and ‘cognitive’ but not ‘safety’ or ‘side effects’. Included studies were controlled trials that often involved the administration of a single dose. These lack external validity or generalisability and it is fundamentally wrong to use these studies as a basis to say that ’modafinil appears safe for widespread use’.

Methodologically apt evidence for statements about the risk of side-effects would derive from case series, prospective cohort studies and adverse drug reaction reporting schemes. The authors of another systematic review of modafinil [2] noted that many studies (seven in common with the reported review) had no standardised method of assessing adverse reactions and attrition due to adverse effects; and refrained from commenting on drug tolerance. They reported numerous adverse effects including headache, dizziness, gastrointestinal complaints, tachycardia and palpitations and insomnia. A Cochrane review [3] reported incidences of 11% for nausea and 34% for headache, and noted that post-marketing surveys reported Stevens-Johnson syndrome. Another new review [4] reports that modafinil is associated with serious adverse drug reactions and that almost half of reported adverse events appear to be with use outside of the approved indications. In 2011, the European Medicines Agency’s Committee for Medicinal Products for Human Use concluded that the benefits of modafinil could only be considered to outweigh the risks when used to treat narcolepsy and concluded that the benefit/risk profile was not adequate for use for other indications [5].

The findings of recent systematic reviews and studies have been summarised4 and it is important to nuance the benefits that are reported. Many studies indicate that pharmacological cognitive enhancers, including modafinil, produce modest benefits that might be more significant in subgroups, such as those whose baseline performance is poorest or in individuals with a particular genotype. Currently available research suggests that these drugs improve cognition in people at the lower end of the spectrum but they may impair people who are already at the optimum level of cognitive function – ie healthy people, in some cases leading to over confidence. The conclusion is that in healthy individuals, functioning at an optimum level, it is difficult to improve their cognition.

Paul J Nicholson

1. Battleday RM, Brem AK. Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: a systematic review. European Neuropsychopharmacology, http://dx.doi.org/10.1016/j.euroneuro. 2015.07.028
2. Repantis D, Schlattmann P, Laisney, et al. Modafinil and methylphenidate for neuroenhancement in healthy individuals: a systematic review. Pharmacological Research. 2010; 62: 187-20
3. Liira J, Verbeek J & Ruotsalainen J. Pharmacological interventions for sleepiness and sleep disturbances caused by shift work. JAMA, 2015; 313: 961-962.
4. Nicholson PJ, Mayho G, Sharp C. Cognitive enhancing drugs and the workplace. British Medical Association, London, 2015.
5. European Medicines Agency. Patient health protection assessment report for modafinil containing medicinal products. Procedure number: EMEA/H/A-31/1186 London, 2011. EMA/4038/2011