Brain scans showed that modafinil increased dopamine in areas that include nucleus accumbens, which gives drugs a rewarding effect, Nora D. Volkow, M.D., of the National Institute on Drug Abuse, and colleagues reported in the March 18 Journal of the American Medical Association.
"Because drugs that increase dopamine in the nucleus accumbens have the potential for abuse," they wrote, "these results highlight the need for heightened awareness for potential abuse of and dependence on modafinil in vulnerable populations."
The magnitude of the dopaminergic effect seen in the pilot study was similar to that of methylphenidate (Ritalin, Concerta), Dr. Volkow said. However, modafinil's abuse potential may be lower because it's five to 10 times more expensive and is not easily injected or snorted, she noted.
Researchers originally thought modafinil had less abuse potential than stimulants that target dopamine transporters, but mounting preclinical evidence implicated dopamine in modafinil's workings as well.
The drug, which promotes wakefulness through a poorly understood mechanism, is approved for treatment of sleep disorders.
But off-label use for cognitive enhancement in psychiatric disorders such as schizophrenia and attention-deficit hyperactivity disorder has led to increasing diversion by healthy individuals, they noted.
To evaluate the potential problem, researchers used positron emission tomography to map out the acute effects of modafinil on the brains of 10 healthy young men.
Carbon 11-tagged dopamine D2/D3 served as the radiotracer for changes in extracellular dopamine. Similarly tagged cocaine measured dopamine transporter availability -- and indicated whether modafinil binds to the same site as cocaine on the transporter molecules.
The men underwent PET scans after receiving placebo and then either the 200-mg dose of modafinil recommended for narcolepsy or the 400-mg dose shown to be beneficial for off-label treatment of ADHD.
The modafinil dose did not appear to impact dopamine transporter and receptor availability, or the rate at which the drug moved into the brain from the blood, although the researchers said this finding might have reflected the small sample size.
Combining the dose groups, modafinil significantly increased occupation of dopamine transporters and receptors as indicated by the following changes in binding potential:
- In the caudate, 6.1% reduction in dopamine D2/D3 receptor availability (P=0.02) and 53.8% lower cocaine transporter availability (P<0.001)
- In the putamen, 6.7% reduction in dopamine D2/D3 receptor availability (P=0.002) and 47.2% lower cocaine transporter availability (P<0.001)
- In the nucleus accumbens, 19.4% reduction in dopamine D2/D3 receptor availability (P=0.02) and 39.3% lower cocaine transporter availability (P=0.001)
Reports of modafinil abuse are rare, but this could be due to a relatively short clinical experience with the drug and the simple fact that physicians haven't looked for it, Dr. Volkow said.
Although the findings shouldn't hinder proper use of modafinil, she recommended that physicians follow these patients as they would any patient on stimulant medication -- with careful attention to risk factors such as personal or family history of substance abuse.
The authors noted several limitations of the study including the small sample size, which didn't provide sufficient statistical power to detect dose effects.
They also noted that because only healthy young men were tested, generalizability was limited.
Further studies are needed, they said, to measure a clinical outcome.
|The study was conducted under a contract with the Department of Energy, with infrastructure support from its Office of Biological and Environmental Research, and additional grants from the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Biomedical Imaging and Bioengineering, and General Research Clinical Centers.
Zalman S. Agus, MD Emeritus Professor
University of Pennsylvania School of Medicine
Journal of the American Medical AssociationSource Reference: Volkow ND, et al "Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications" JAMA 2009; 301: 1148-1154.