Evaluating Modafinil as a Smart Drug, 20 Years On

modafinil box of 100mg tablets

Modafinil (Provigil) first entered the U.S. markets in 1998 after FDA approval. Although it was originally intended for narcolepsy and related sleep disorders, it quickly garnered a reputation as an off-label ‘smart drug’. Using more than two decades of scientific data, we review modafinil’s effectiveness in this grey area and the future of cognitive enhancers.

What is Modafinil (Provigil)?

Modafinil was discovered in the 1970s by French neurophysiologist Michel Jouvet, then working for Lafon Laboratories. Like caffeine and methamphetamine, modafinil belongs to a class of drugs known as stimulants. In 1998, the U.S. Food and Drug Administration (FDA) approved its use as a wakefulness-promoting agent for treating narcolepsy, under the brand name Provigil.

Modafinil’s mechanism of action is not well understood despite its effectiveness in treating narcolepsy, a condition in which the individual experiences excessive daytime sleepiness. There is some evidence that it works through increasing dopamine in the brain, albeit through a different pathway to other stimulants1.

Modafinil has a half-life of around 11-14 hours, with the cytochrome P450 family of enzymes primarily responsible for its inactivation and excretion2. Unlike amphetamines, modafinil doesn’t appear to promote reinforcing behavior and hence has a low potential for addiction and abuse.



Studies on Cognitive Enhancement

Cognitive enhancers or ‘smart drugs’ fall into the category of nootropics, substances which may improve memory, creativity or motivation in individuals. Many supplements can claim to have nootropic properties as U.S. law does not restrict such marketing, although few have been properly evaluated. After its introduction into the market in 1998, modafinil quickly gained a reputation as an effective off-label nootropic, prompting independent studies into its effectiveness that continue to this day.

Early Clinical Trials

From a medical and scientific standpoint, it made sense for modafinil to be evaluated as a nootropic as it is already an approved drug. Phase IV (post-approval) trials to determine if the drug was useful for other applications could be conducted. In this case, researchers could evaluate modafinil’s effectiveness as a ‘smart drug’ on healthy individuals.

However, it is important to note that relatively few human studies exist that directly evaluate modafinil’s effects on cognitive enhancement. Furthermore, sample sizes used in these studies are generally small and hence may not accurately reflect the population.

The first report of modafinil providing benefits to cognition is from a paper published in 2003. The participants who took the drug fared better in short-term memory tasks but exhibited significant delays in completing others3.

However, another study also published in 2003 found no changes in cognitive performance across a range of standardized tests4. Another double-blind crossover study in 2004 also found no significant effect of modafinil on the outcome of other cognitive tests5.

Modafinil in Low and High IQ Individuals

In 2005, a study was conducted by a group that previously reported no effects, this time using a much larger sample size (n = 89)6. Again, no significant cognitive improvement was detected despite better statistical power, lending more credibility to the claim. Interestingly, the study showed evidence that modafinil might have a greater effect on individuals with low to average IQ. In higher-performing individuals, modafinil did not offer cognitive benefits.

Several other studies performed later also showed that modafinil worked better in low baseline individuals. One study published in 2010 went further to show that while the drug led to greater improvement in low-performing participants, it was detrimental to higher-performing participants in visual processing speed and short-term memory tests7.

Additional Cognitive Effects

In many of these studies, participants were also assessed on their creativity. There is a consensus that problem-solving or ‘convergent’ creativity is not affected by modafinil. However, some studies report that the drug impairs ‘divergent’ creativity – creativity in which multiple associations are generated from a given subject8.

Although modafinil may not be the go-to ‘smart drug’ to take before problem-solving or brainstorming tasks, it may benefit other cognitive abilities. Specifically, attentional tasks that some individuals might consider lengthy or ‘boring’ may be easier to overcome under the effects of modafinil. Further clinical trials might shed more light on this and may even uncover additional cognitive effects.

A 2017 double-blind crossover study pitted chess players under the effects of modafinil against a computer program9. It was found that players on modafinil lost an abnormally large number of games due to running out of time. Removing these timed games from consideration showed marked improvement in the scores compared to placebo, suggesting that modafinil may improve performance in complex cognitive tasks but only in the absence of time pressures.



The Smart Drug Landscape

Popularity of Modafinil

From the evidence collected over the past 20 years, modafinil shows small but significant positive effects as a ‘smart drug’, especially in improving the attention span and memory of individuals with cognitive deficiencies. In students or adults working in a fast-paced environment however, taking modafinil has not been shown to improve general performance.

Even so, the drug appeals to healthy individuals who take the drug for its mood-enhancing or wakefulness-inducing properties. A 2014 survey suggested that 1 in 5 students in UK universities have used modafinil. Its minor side effects coupled with a low risk of addiction make it reasonably safe, at least from short to medium-term use. Despite its popularity, modafinil is unlikely to be granted regulatory approval as a cognitive enhancer anytime soon.

Regulatory Issues and Implications

For a drug to be approved for a particular use, it must be deemed safe and effective. While the consensus is that modafinil provides a positive influence toward mood and wakefulness, clinical trials have yet to build a strong case toward its cognitive enhancing capabilities. Furthermore, long term safety endpoints have yet to be conducted – and they likely never will.

This lends a peculiar balance to the consumer landscape of modafinil. On one hand, manufacturers know that it would be futile to appeal to regulatory agencies to sell the drug as a cognitive enhancer. On the other, the demand for modafinil from the general public means that illegal trade of the ‘smart drug’ is likely to flourish.

As markets emerge to satisfy this demand, it becomes more difficult for authorities to control the drugs’ use. Furthermore, the unregulated sale of the drug in this manner could increase the likelihood of counterfeits in the market, as manufacturers need not satisfy conventional regulatory requirements.

The dilemma facing regulatory agencies is approving a drug for use by individuals with no existing disease or impairment. How will its use be justified or controlled? If a true cognitive enhancing drug is indeed discovered one day, there will be no precedent. Just as with genetic engineering, it’s perhaps time for a wider discussion on the ethics of ‘smart drugs’.

Cover image by Doctor4U (Flickr)



Reference

  1. Ferraro, L., Tanganelli, S., O’Connor, W. T., Antonelli, T., Rambert, F., & Fuxe, K. (1996). The vigilance promoting drug modafinil increases dopamine release in the rat nucleus accumbens via the involvement of a local GABAergic mechanism. European journal of pharmacology306(1-3), 33-39.
  2. Ballas, C. A., Kim, D., Baldassano, C. F., & Hoeh, N. (2002). Modafinil: past, present and future. Expert review of neurotherapeutics2(4), 449-457.
  3. Turner, D. C., Robbins, T. W., Clark, L., Aron, A. R., Dowson, J., & Sahakian, B. J. (2003). Cognitive enhancing effects of modafinil in healthy volunteers. Psychopharmacology165(3), 260-269.
  4. Randall, D. C., Shneerson, J. M., Plaha, K. K., & File, S. E. (2003). Modafinil affects mood, but not cognitive function, in healthy young volunteers. Human Psychopharmacology: Clinical and Experimental18(3), 163-173.
  5. Liepert, J., Allstadt-Schmitz, J., & Weiller, C. (2004). Motor excitability and motor behaviour after modafinil ingestion–a double-blind placebo-controlled cross-over trial. Journal of neural transmission111(6), 703-711.
  6. Randall, D. C., Shneerson, J. M., & File, S. E. (2005). Cognitive effects of modafinil in student volunteers may depend on IQ. Pharmacology Biochemistry and Behavior82(1), 133-139.
  7. Finke, K., Dodds, C. M., Bublak, P., Regenthal, R., Baumann, F., Manly, T., & Müller, U. (2010). Effects of modafinil and methylphenidate on visual attention capacity: a TVA-based study. Psychopharmacology210(3), 317-329.
  8. Mohamed, A. D. (2016). The effects of modafinil on convergent and divergent thinking of creativity: a randomized controlled trial. The Journal of Creative Behavior50(4), 252-267.
  9. Franke, A. G., Gränsmark, P., Agricola, A., Schühle, K., Rommel, T., Sebastian, A., … & Ruckes, C. (2017). Methylphenidate, modafinil, and caffeine for cognitive enhancement in chess: A double-blind, randomised controlled trial. European Neuropsychopharmacology27(3), 248-260.

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