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Addiction Risk Seen in Wakefulness Drug Provigil
By Daniel J. DeNoon
WebMD Health News
Reviewed by Louise Chang, MD
March 17, 2009 - Provigil promotes wakefulness without getting you hooked. But now it seems that addiction may very well be a Provigil risk.
Provigil (generic name, modafinil) is FDA approved for promoting wakefulness in people with narcolepsy, sleep apnea, and shift work sleep disorder. Because of its relatively benign safety profile, it's often prescribed "off label" for people complaining of fatigue.
Some prominent scientists have suggested that responsible, healthy adults should be allowed to use safer stimulant drugs such as Provigil and even Ritalin to boost intellectual creativity.
But now researchers led by Nora D. Volkow, MD, director of the National Institute on Drug Abuse (NIDA), report evidence that Provigil might be more addictive than thought.
"There is an increasing use of this medication, and people have promoted the off-label use of stimulants and Provigil as cognitive enhancers with the belief that these drugs are safe," Volkow tells WebMD. "But these drugs have side effects, and their use without proper medical oversight could lead to abuse and addiction."
In their pilot study, Volkow's team recruited 10 healthy men who underwent two sets of PET brain scans after taking either Provigil (200 milligrams or 400 milligrams) or an inactive placebo pill.
The brain scans showed that Provigil blocks dopamine transporters, the molecules that remove dopamine from brain synapses. This increases the amount of dopamine in the brain -- the brain's "reward" mechanism.
Addictive drugs such as cocaine and methamphetamine trigger the same mechanism, although they do it much faster and more powerfully than Provigil does.
"The changes we are observing in dopamine concentrations with modafinil are equivalent to those we have reported for [Ritalin] in the human brain," Volkow says. "So not only does [Provigil] increase dopamine in the human brain, but does it by similar mechanisms to Ritalin and cocaine, by directly blocking the dopamine transporter. It is not working by some distinct, different mechanism."
Volkow notes that Provigil has no effect on mice lacking dopamine transporters. This indicates that while the drug may have other effects in the brain, its dopamine-enhancing effect is crucial.
Provigil: How Addictive Is It?
David Weinshenker, PhD, associate professor of human genetics at Emory University, Atlanta, has performed some of the mouse studies Volkow cites.
Weinshenker agrees with Volkow that Provigil shares at least one brain receptor with cocaine, but he downplays the drug's addiction potential.
"What is Provigil's street value? It is zero. There are not addicts walking around buying and selling modafinil," Weinshenker tells WebMD. "Most people who take Provigil don't report euphoria or being high. They don't even report feeling particularly stimulated, like caffeine. In terms of addiction and withdrawal, it just doesn't do that."
Weinshenker notes that because of Provigil's relative safety, its possible benefits are being explored for a wide number of disorders, including ADHD, autism, and depression. He says the drug offers a major benefit over amphetamine-like stimulants in that it promotes wakefulness without the sleep rebound -- a need for extra sleep when the drug wears off.
Weinshenker and Vogel both note that because it blocks the brain receptors needed by cocaine and methamphetamine, researchers are exploring whether Provigil might help wean addicts from these life-threatening addictions.
But Volkow maintains that because drugs have very different effects in different people, Provigil may very well be dangerously addictive to vulnerable individuals.
"A vulnerable person would be anyone who has a present or past history of addiction, whether to alcohol, nicotine, or cocaine," Volkow says. "Or, your family history may indicate your risk, if you have close relatives with a history of addiction. But if you don't have this history, it does not mean you are completely safe."
Anecdotal evidence of Provigil addiction can be found on the non-judgmental Erowid web site, in a section where drug users report their experiences.
"It is now day 5 and I am back up to 1200 mg per day and cannot imagine not having this stuff," writes one user, who started off with one 200 milligram pill from her husband's Provigil prescription. "I guess I'm the one person out of a million that can actually get addicted to this miraculous 'non-addictive' drug."
Along with Xanax and Ambien, Provigil is classified by the Drug Enforcement Administration as a Schedule IV drug -- a controlled substance with low potential for abuse relative to Schedule III drugs such as codeine or anabolic steroids.
Provigil maker Cephalon agrees with the NIDA position that Provigil should not be taken by healthy individuals. But the company says the product's label accurately describes the drug's abuse potential.
"After 10 years on the market, millions of patients treated, as well as ongoing monitoring of abuse and diversion by Cephalon, the DEA, the FDA, and other international regulatory agencies, we believe that the potential risk of abuse and dependence is accurately reflected in the product labeling," Cephalon spokeswoman Candace Steele tells WebMD. "We believe that there is a low relative potential for abuse with modafinil, which is at least consistent with the DEA scheduling for Provigil."
The Volkow study appears in the March 18 issue of the Journal of the American Medical Association.
Volkow, N.D. Journal of the American Medical Association, March 18, 2009; vol 301: pp 1148-1154.
Erowid Experience Vaults: Modafinil, "Addicted Instantly" by Cparobbins.
Mitchell, H.A. Pharmacology Biochemistry and Behavior, December 2008; vol 91: pp 217-222.
FDA approved label for Provigil.
Candace Steele, senior director for product communications, Cephalon.
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