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Providgil Could Be Additive Study Says

Posted by Phillipa on March 23, 2009, at 19:22:15

According to this study providgil could be additive. Phillip

Study Flags Potential for Abuse and Dependence With Modafinil

March 20, 2009 A pilot study has found that modafinil (Provigil, Cephalon), a wake-promoting agent used to treat narcolepsy, blocks dopamine transporters and increases dopamine in the nucleus accumbens, actions that suggest the potential for abuse and dependence, researchers say.

The finding should highlight the need for heightened awareness of the potential for abuse in vulnerable individuals, the authors conclude.

"Modafinil is a very beneficial medication, and this particular finding in and of itself should not affect the way it is prescribed for the treatment of narcolepsy or even for the treatment in some instances off-label for [attention-deficit/hyperactivity disorder] ADHD or off-label for cognitive impairment in patients with schizophrenia, because under those conditions, the patient is being monitored properly," lead author Nora D. Volkow, MD, director of the National Institute on Drug Abuse, told Medscape Neurology & Neurosurgery.

"However," she added, "it is directly pertinent to the concept of the misuse of modafinil, which is increasingly being utilized by healthy individuals with the expectation of improved cognitive performance." In this unsupervised setting, the drug may not be as safe as previously thought, Dr. Volkow said.

The study, using positron emission tomography (PET) scanning, is published in the March 18 issue of the Journal of the American Medical Association.

Abuse Potential?

Unlike classical stimulant medications like methylphenidate (Ritalin, Novartis Pharmaceuticals), modafinil has been thought to produce its wake-promoting effects independent of dopaminergic actions, Dr. Volkow said. Although the Physician's Desk Reference does suggest there are some dopaminergic effects, including psychoactive and euphoric effects, she noted, "this was dismissed on the fact that the affinity of modafinil for the dopamine transporter was very low."

However, a series of animal studies, particularly in knockout mice, have suggested that the dopaminergic system might after all be crucial to the alerting properties of modafinil. For example, knockout mice for the dopamine transporter do not respond to modafinil, she noted.

To look more closely at the acute dopaminergic effects in humans of modafinil at doses used clinically, the researchers PET scanning to measure the effect of 200 mg and 400 mg of modafinil on extracellular dopamine and dopamine transporters in 10 healthy male subjects.

Scans were done over an 8-month period, using 2 tracers: [11C]raclopride, a D2/D3 ligand sensitive to changes in endogenous dopamine, and [11C]cocaine, a dopamine transporter radioligand, to measure changes in dopamine D2/D3 receptor and dopamine-transporter availability measured by changes in binding potential after modafinil or placebo.

They found that modafinil decreased the mean [11C]raclopride-binding potential in the caudate, putamen, and nucleus accumbens, reflecting increases in extracellular dopamine. "The magnitude of the change was actually equivalent to what we have previously reported for oral methylphenidate or Ritalin," Dr. Volkow said.

Mean (Standard Deviation) Decrease in [11C]raclopride Binding Potential With Modafinil Region Mean (SD) Decrease (%) 95% CI P
Caudate 6.1 (6.5) 1.5 10.8 .02
Putamen 6.7 (4.9) 3.2 10.3 .002
Nucleus accumbens 19.4 (20) 5 35 .02

Modafinil also acted to decrease [11C]cocaine-binding potential in the same brain structures, reflecting occupancy of dopamine transporters. "We showed that at the doses used clinically, you are occupying more than 50% of the dopamine transporters" with modafinil, Dr. Volkow noted. "Even though the medication may have, in an in vitro experiment, relatively low affinity, at the doses you are using, its availability which must be relatively high is producing a significant level of transporter blockade."

Mean (Standard Deviation) Decrease in [11C]cocaine Binding Potential With Modafinil Region Mean (SD) Decrease (%) 95% CI P
Caudate 53.8 (13.8) 43.9 63.6 < .001
Putamen 47.2 (11.4) 39.1 55.4 < .001
Nucleus accumbens 39.3 (10) 30 49 .001

"Awareness of this as a potential complication should enable us to manage the utilization of this medication in a safer way," Dr. Volkow concluded. Although dependence on medications such as stimulants is rare, it does happen, she added. "By alerting the physician and the patient to this possibility, they can recognize the symptoms for addiction if they start to emerge."

Again, although these findings should not change how modafinil is used in the clinical setting under a physician's supervision, it does have implications for the possibility of diversion of the drug for nonmedical use as a cognitive-enhancement agent.

The belief has been that modafinil, because it does not have dopaminergic effects, is safe in this application, she said. "These findings suggest that we need to be cautious about the potential that modafinil has reinforcing effects in the human brain, and therefore one of the potential side effects could be its addictiveness," she added.

Cognitive Enhancement

A Commentary published online December 7, 2008 in Nature brought this issue of cognitive enhancement for healthy individuals to the forefront, Dr. Volkow pointed out. In the commentary, Henry Greely, from Stanford Law School, in California, and colleagues discussed the "responsible use of cognitive-enhancing drugs by the healthy," a trend brought forward first among students using drugs such as Adderall (Shire US) or Ritalin to achieve higher grades (Greely H et al. Nature. 2008;456:702-705). They propose a path toward helping society to "accept the benefits of enhancement, given appropriate research and evolved regulation."

They refer to modafinil in the article, suggesting that because prescriptions are not common, diversion is rare. However, anecdotal evidence suggests that adults "sometimes obtain modafinil from their physicians or online for enhancement purposes."

The concept of cognitive enhancement in healthy people "theoretically, in my view, is not negative, provided that the medications don't have any side effects," Dr. Volkow said. If modafinil had not had dopaminergic effects, it would have been "transformative, because it would have given us a medication that is wake-promoting without the potential negative effect of reinforcement and addiction. It didn't turn out like that, so as of now, cognitive-enhancing medications for healthy people should be viewed with a lot of caution."

Extent of Diversion Uncertain?

Asked about these new findings, Mark Mahowald, MD, a sleep expert at the University of Minnesota, in Minneapolis, commenting on behalf of the American Academy of Neurology, called this an "interesting and important article," because it provides more much-need information on the precise mechanism of action of modafinil.

However, he said, "I don't think there's good evidence that modafinil use frequently results in chemical dependence as we conventionally think of it." An informal poll of colleagues at his own institution since publication of this article, Dr. Mahowald added, showed that none have seen dependence in patients treated with modafinil. "I'm not saying it doesn't happen, but if it does, it certainly isn't often."

He also questioned how great the diversion of modafinil really is, since studies have suggested cognitive enhancement with this agent is not substantially different than that of caffeine, at a cost of about $10 per tablet.

"It does improve alertness, there's no question about that," Dr. Mahowald said. "How much it truly improves cognition, I think, remains to be seen."

Dr. Volkow agreed on the point that modafinil is expensive, which is likely to price it out of the hands of students in high school, for example. However, college students might be able to afford it, and the drug is expected to go off patent in 2012, which could substantially reduce the price.

The National Institute on Drug Abuse conducts a survey of high school students in the United States, asking them about their patterns of drug use, including illicit drugs and psychotherapeutics such as oxycodone (Oxycontin, Purdue Pharma) or Ritalin without a prescription.

"We've never had a question about modafinil, and as a result of this particular finding, I'm already speaking with my grantees to evaluate what it would take to start evaluating this question," Dr. Volkow said.

The study was carried out at Brookhaven National Laboratory under contract from the US Department of Energy, with infrastructure support from its Office of Biological and Environmental Research. Support was also provided by the National Institutes of Health, the National Institute on Alcohol Abuse and Alcoholism intramural research program, the National Institute of Biomedical Imaging and Bioengineering, and the General Research Clinical Centers. The authors report no relevant financial disclosures.




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