Narcolepsy is a neurological disorder typified by excessive daytime sleepiness. The symptoms of the disorder can be disabling, and for years treatment relied on amphetamines and related stimulants to help patients stay awake. For nearly 2 decades now, modafinil (Provigil) has been available to treat the symptoms of narcolepsy; modafinil has been the preferred wake-promoting drug due to its mechanism of action and safety profile that is distinct from traditional stimulants. It was long believed that modafinil could produce the benefits of the stimulants without the dangerous and unwanted side effects. However, a new study conducted by the National Institutes of Health (NIH), reported in the Journal of the American Medical Association, has shown that it might not be as different from traditional stimulants as once believed.

The National Institute on Drug Abuse, part of the NIH, studied the effects of therapeutic doses of modafinil on the dopamine levels in the brain. Dopamine is a neurotransmitter that influences reward pathways in the brain and mediates euphoria, pleasure, and addiction. Cocaine and amphetamines dramatically increase dopamine levels in the brain, and it was largely believed that modafinil did not have the same effect on dopamine levels. However, the new study reports that modafinil does, in fact, increase dopamine levels in regions of the brain that are critical to the rewarding effects of drug abuse. The researchers concluded that dopamine does play a role in the mechanism of modafinil, and that its abuse potential could be higher than initially considered.

The abuse potential of modafinil might not be worrisome if its use was restricted to patients with significant or debilitating symptoms associated with excessive daytime sleepiness. But, modafinil’s off-label use has increased dramatically in the last few years, and is frequently used for psychiatric indications, including treatment-resistant depression, attention-deficit/hyperactivity disorder, schizophrenia, and cognitive dysfunction. It is also quickly becoming a lifestyle drug for people with various undefined fatigue syndromes, as well as college students, truck drivers, workaholics, and others wanting to find a substitute for sleep. Currently, the United States Food and Drug Administration approves the use of modafinil for shift work sleep disorder and obstructive sleep apnea/hypopnea syndrome, in addition to the excessive daytime sleepiness associated with narcolepsy.

Modafinil has always been viewed as an innocent alternative to traditional stimulants and amphetamines. It was believed to boost the performance of the central nervous system without the cardiovascular side effects and euphoria associated with amphetamines. (The most common side effects of modafinil are mild headache and nausea, and are only reported by about 1% of people who use the drug.) Now it is clear that the more silent effects involving dopamine may have significant consequences. Modafinil’s effects on the brain are similar to other stimulants and drugs of abuse and this may lead to abuse of modafinil in otherwise healthy individuals.

The NIH study was notably small in size, evaluating only 10 healthy male adults, but it highlights the need for further investigation of the true mechanism of modafinil. The potential for abuse and risk of undiagnosed causes of fatigue and sleepiness increase as the off-label use of modafinil grows.

References

Didato, G., & Nobili, L. (2009). Treatment of narcolepsy Expert Review of Neurotherapeutics, 9 (6), 897-910 DOI: 10.1586/ern.09.29

Minzenberg, M., & Carter, C. (2007). Modafinil: A Review of Neurochemical Actions and Effects on Cognition Neuropsychopharmacology, 33 (7), 1477-1502 DOI: 10.1038/sj.npp.1301534

Teitelman E. Off-label uses of modafinil. Am J Psychiatry. Aug 2001;158(8):1341.

Volkow, N., Fowler, J., Logan, J., Alexoff, D., Zhu, W., Telang, F., Wang, G., Jayne, M., Hooker, J., Wong, C., Hubbard, B., Carter, P., Warner, D., King, P., Shea, C., Xu, Y., Muench, L., & Apelskog-Torres, K. (2009). Effects of Modafinil on Dopamine and Dopamine Transporters in the Male Human Brain: Clinical Implications JAMA: The Journal of the American Medical Association, 301 (11), 1148-1154 DOI: 10.1001/jama.2009.351

Winder-Rhodes, S., Chamberlain, S., Idris, M., Robbins, T., Sahakian, B., & Muller, U. (2009). Effects of modafinil and prazosin on cognitive and physiological functions in healthy volunteers Journal of Psychopharmacology DOI: 10.1177/0269881109105899