The serotonin-2C agonist Lorcaserin delays intravenous choice and modifies the subjective and cardiovascular effects of cocaine: A randomized, controlled human laboratory study

Abstract

Background: Lorcaserin is a modestly selective agonist for 2C serotonin receptors (5-HT2CR) approved for weight-loss therapy. This class can attenuate cue-induced responding and drug taking in preclinical studies, but effects in humans have not been reported.

Methods and participants: We evaluated effects of single 10 mg doses of lorcaserin on the subjective and reinforcing effects of cocaine, using a randomized, double-blind, within-subject, cross-over design. Male, non-treatment-seeking, regular cocaine users received either single doses of oral placebo (n = 9) or lorcaserin (n = 9), followed by low- or high- doses of intravenous cocaine (0.23 or 0.46 mg/kg-injection). They were then allowed to self-administer the lower dose of cocaine.

Results: Cocaine was well tolerated after lorcaserin pretreatment. Oral lorcaserin did not modify the number of cocaine injections self-administered. However, it prolonged the time over which participants made intravenous choices relative to the duration of monetary (cash) decisions. Lorcaserin increased ratings of 'high' and 'stimulated' after low-dose cocaine or vehicle, but decreased craving for cocaine after intravenous vehicle. It also caused small but significant increases in heart rate following noncontingent injections of intravenous placebo or cocaine. When active cocaine was self-administered, lorcaserin decreased heart rate after selection of a monetary choice, but increased it following an intravenous choice.

Conclusions: Combined treatment with cocaine and lorcaserin was safe in a limited number of subjects, but did not diminish cocaine-motivated behavior or drug-induced 'high'. Some positive subjective effects of cocaine were enhanced by lorcaserin, and it delayed intravenous choices and decreased craving under some conditions. Effects on heart rate depended on the type of reinforcer being self-administered.

Trial registration: clinicaltrials.gov Identifier, NCT02680288.

Keywords: Cocaine-related disorders; Dose-response relationship; Drug interactions; Infusions; Intravenous; Self-administration; Serotonin receptor agonists.

Conflict of interest statement

All authors declare that they have no conflict of interest pertaining to this manuscript.

Published by Elsevier Inc.

Figures

Figure 1.

Response Latency during Cocaine Self-Administration. Latency is shown on vertical axes both as overall values to complete five clicks on a computer mouse, and values associated with each individual mouse click, plotted horizontally. Responding during monetary and intravenous reinforcement is shown on the upper and lower graphs, respectively. Group means with standard error are shown for 5 to 9 participants per condition. * indicates a significant simple main effect of lorcaserin, with one and two symbols corresponding to p < 0.03 and p < 0.01, respectively.

Figure 2.

Lorcaserin modifies Visual-Analogue Measures. Participants used a computer mouse to endorse cocaine-induced ‘High’ or other subjective effects, shown on vertical axes. Time after intravenous injection is plotted horizontally. Group means with standard error are shown after treatment with oral placebo (n = 9) or 10 mg of lorcaserin (n = 9). For either oral treatment, each participant received two injections of intravenous placebo and a single injection of low- and high- dose cocaine. * indicates a significant effect of lorcaserin, with 1 and 2 symbols corresponding to p < 0.05 and p < 0.001 by simple main effects.

Figure 3.

Cardiovascular Measures after Treatment with Noncontingent Cocaine and Lorcaserin. Group means with standard error for absolute change in blood pressure (mm Hg) and heart rate (beats per minute) after noncontingent cocaine are shown following treatment with oral placebo (n = 9) or lorcaserin (n = 9). * indicates a significant effect of lorcaserin, with 1 and 2 symbols corresponding to p < 0.05 and p < 0.001 by simple main effects.

Figure 4.

Effects of Lorcaserin and Cocaine on Heart during Self-Administration. Values after monetary and intravenous choices are shown on the left- and right- graphs, respectively. Group means with standard error for absolute change in heart rate (beats per minute) after cocaine self-administration are shown for 5 to 9 participants per condition. * indicates a significant effect of lorcaserin corresponding to p < 0.001.