Wake-promoting agents with different mechanisms of action: comparison of effects of modafinil and amphetamine on food intake and cardiovascular activity
Introduction
Despite efforts to achieve a desirable weight, two-thirds of the population has an elevated body weight (Flegal, Carroll, Ogden, & Johnson, 2002). The prevalence of obesity has been steadily rising over time across genders, ages, races, education levels, and geographical regions and has reached epidemic proportions (Wickelgren, 1998, Taubes, 1998, Mokdad et al., 2001). It has become increasingly apparent that safe and effective interventions are necessary to improve current conditions and promote lasting, healthy lifestyles. Medications have been successful in supporting weight loss but many of them have been withdrawn from the market or are not recommended for weight loss due to adverse effects such as hemorrhagic stroke (phenylpropanolamine), heart valve disease and pulmonary hypertension (fenfluramine, dexfenfluramine), and abuse liability (amphetamine).
Modafinil has recently been approved for use in the treatment of narcolepsy in the United States. Although its mechanism of action remains unclear, studies suggest that modafinil requires an intact adrenergic system to produce wakefulness (Duteil et al., 1990, Rambert et al., 1990, Hermant et al., 1991). Other studies also suggest that modafinil produces arousal by indirectly decreasing γ-aminobutyric acid (GABA) levels via serotonergic, adrenergic, and/or glutamatergic systems (Tanganelli, 1995, Ferraro et al., 2000, Ferraro et al., 2001). These systems are also actively involved in the regulation of appetite (Leibowitz and Hoebel, 1986).
A limited number of studies have examined the effects of modafinil on food intake in nonhumans and humans. Nonhuman studies suggest that modafinil decreases appetite and food intake and reduces frequency of eating (Nicolaidis & Saint Hilaire, 1993, Shelton et al., 1995). Two human studies evaluating the efficacy of modafinil for the treatment of attention deficit hyperactivity disorder (ADHD) in adults reported reductions in energy intake or appetite suppression following acute administration of modafinil, while no changes in appetite were observed in another study evaluating the effects of modafinil in children with ADHD (Jasinski & Kovacevic-Ristanovic, 2000, Taylor and Russo, 2000, Rugino and Copley, 2001). Taken together, these findings suggest that modafinil might be effective for the management of food intake.
An examination of the profile of effects produced by modafinil supports its potential utility for appetite regulation and weight loss. Unlike most adrenergic agonists, modafinil displays a low incidence of sympathetic side effects (Lyons et al., 1991, Boivin et al., 1993, Billiard et al., 1994, Laffont et al., 1994, Wong et al., 1998). Modafinil is classified as a schedule IV medication. Studies suggest that modafinil has less abuse liability and produces fewer adverse behavioral effects than stimulant drugs (Modafinil, 2000, Warot et al., 1993, Gold and Balster, 1996, Jasinski, 2000, Rush et al., 2002, Deroche-Gamonet et al., 2002). These characteristics may make modafinil a uniquely efficacious agent for the long-term treatment of obesity.
The overall aim of this study was to investigate the effects of the novel wake promoting compound, modafinil, on nutritional (i.e. energy and macronutrient intake) and physiological (i.e. cardiovascular activity) parameters in non-obese, healthy men and women. These effects were compared with those of d-amphetamine, an adrenergic anorectic with well-documented sympathetic side effects and abuse liability.
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Subjects
Eleven healthy, adult, nonsmoking males and females between the ages of 21 and 35 participated in the study. Participants were recruited by local and campus newspaper advertisements, posters, and word-of-mouth. Potential participants were informed that the purpose of the study was to determine the behavioral and subjective effects of medications and that a range of behaviors would be monitored and videotaped during the course of the study. Each volunteer completed a medical and psychological
Characteristics of participants
Five healthy adult nonsmoking males (one Caucasian, three Hispanic, one African-American) and six healthy adult nonsmoking females (three Caucasian, one Pacific Islander, one Asian/Native American, one Asian/Caucasian) between the ages of 21 and 35 (26.3±1.4) recruited from the local community completed the study. All participants had completed a minimum of 14 years of education. Participants reported occasional alcohol (1.0±0.3 occasions per month) and caffeine use (35±10.6, 8-oz servings of
Discussion
Findings from this study suggest that modafinil, like amphetamine, reduces the amount of food consumed and decreases energy intake, without altering the proportion of macronutrients consumed. The findings also indicate that neither medication substatially alters the topography of eating behavior. Although both medications significantly increased heart rate and blood pressure at higher doses, the dose of modafinil that was efficacious in decreasing food intake did not significantly increase
Acknowledgements
This work was supported by NIDA grant #: R03 DA13484-01 and an NIH Training Grant Fellowship.
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