HT Drugs Food Intake and Feeding Behavior in Humans

As stated previously the effects of 5-HT drugs on human appetite expression are also well documented. Rogers and Blundell (Rogers and Blundell 1979) demonstrated that a single dose of fenfluramine (60 mg), when given to lean healthy males, could reduce food intake of a lunchtime meal by 789 kJ (26%), an effect accompanied by significant decreases in eating rate and desire to eat. These changes in eating behavior contrasted with the effects of amphetamine, which increased eating rate instead, despite reducing overall intake. It was later shown that both d-fenfluramine and fluoxetine produced similar changes to human appetite expression as fenfluramine (Goodall and Silverstone 1988; McGuirk and Silverstone 1990). In addition acute doses of sibutramine, a 5-HT and noradrenaline reuptake inhibitor, have been shown to reduce food intake and appetite in lean male participants (Hansen et al. 1998; Chapelot et al. 2000). Fenfluramine, d-fenfluramine, fluoxetine, and sibutramine also bring about similar changes in appetite in the obese (Blundell and Hill 1990; Drent et al. 1995; Pijl et al. 1991; Lawton et al. 1995; Ward et al. 1999; Rolls et al. 1998; Halford et al. 2010). With regard to sibutramine, it should also be noted that Barkeling et al. (2003) have demonstrated a link between sibutramine-induced hypo-phagia and subsequent sibutramine-induced weight loss in humans.

With regard to the direct agonism of 5-HT receptors, mCPP (a 5-HT 1B/2C receptor preferential agonist) has been shown to reliably reduce food intake in humans. The effect of an acute dose of mCPP (0.4 mg/kg) was initially investigated in a double blind, placebo controlled, crossover design, study conducted with lean healthy female volunteers (Walsh et al. 1994). Each participant was dosed orally with either mCPP or a placebo 150 m prior to the presentation of a buffet lunch. At this ad libitum meal, food intake in those receiving mCPP treatments was reduced by 30% (approximately 1,000 kJ). This study also showed that the effect of mCPP on food intake was significantly associated with premeal hunger ratings being reduced. The study was replicated in a larger group of both male and female lean and healthy volunteers (Cowen et al. 1995). The drug was again effective at reducing food intake in women (28% reduction, 1,205 kJ), but also in men (20% reduction, 1,219 kJ). The drug produced significantly reduced hunger ratings prior to the meal in both men and women (150 min post dosing). This effect occurred marginally after peak plasma levels of mCPP (120 min post dosing), and just prior to the lunch.

The effects of mCPP on appetite and body weight have also been examined in the obese (Sargent et al. 1997). In this placebo controlled, double-blinded crossover trial; participants were treated for 14 days with mCPP (20 mg twice daily for women, 25 mg twice daily for men). Significantly more weight (0.8 kg) was lost from baseline with mCPP compared with placebo (0.04 kg). Participants were invited to the laboratory on the penultimate day of dosing and blood samples were taken to assess mCPP level and prolactin response. During this procedure, hunger-rating scales were also completed by the participants. Analysis of the scales subsequently showed that drug treatment produced a significant decrease in hunger ratings. It is important to note that mCPP can also produce transient but significant increases in the self-reported subjective ratings of light-headedness, anxiety, and nausea (Walsh et al. 1994; Cowen et al. 1995). It has also been observed that in response to acute doses of mCPP, transient increases in blood pressure and heart rate can occur (Ghaziuddin et al. 2003).

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