Sex differences in guanfacine effects on drug craving and stress arousal in cocaine-dependent individuals

Abstract

Currently, no FDA-approved medication exists for the treatment of cocaine use disorder. Furthermore, as women become increasingly more at risk for the consequences of cocaine addiction, the need to establish better-tailored treatment medications is paramount. We examine the effects of the alpha2 adrenergic agonist, guanfacine HCl, on responses to stress and drug cue in a group of cocaine-dependent men and women who also abuse alcohol and nicotine. Forty early abstinent treatment-seeking cocaine-dependent males and females were randomly assigned to receive either daily placebo (12 M/7 F) or guanfacine (2 or 3 mg) (15 M/6 F) for 3 weeks. In week 4, they participated in a laboratory experiment and were exposed to three 10-min guided imagery conditions (stress/stress, cue/cue, and stress/cue), one per day, consecutively in a random, counterbalanced order. Craving, negative emotion, anxiety, and cardiovascular function were assessed at baseline, immediately following imagery exposure, and at various recovery time points. Guanfacine significantly attenuated cocaine craving, alcohol craving, anxiety, and negative emotion following exposure to all three imagery conditions in females, but not males. Guanfacine did, however, reduce sympathetic tone as well as stress and cue-induced nicotine craving and systolic blood pressure (SBP) in both males and females. These findings highlight sex-specific effects of guanfacine on drug craving, anxiety, and negative mood with significant effects in women and not men. The findings suggest further evaluation of guanfacine in the treatment of cocaine use disorder with a specific focus on sex differences in treatment response.

Trial registration: ClinicalTrials.gov NCT00585754.

Figures

Figure 1

(a) Basal heart rate. Bar graph shows a medication group × sex interaction (GUAN Fp<0.0001; GUAN M<PLA M, p=0.001; PLA F>PLA M, p=0.01). A main effect of medication group (GUAN<PLA, p<0.0001) and sex (F>M, p<0.04) were also observed. (b) Basal systolic blood pressure (SBP). Bar graph shows a main effect of medication group (GUAN<PLA, p=0.03) and sex (M>F, p<0.02). (c) Basal diastolic blood pressure (DBP). Bar graph shows a medication group × sex interaction (GUAN M<PLA M, p<0.0001; PLA M>PLA F, p=0.003). A main effect of medication group (GUAN<PLA, p<0.02) and sex (M>F, p=0.02) were also observed. ***p<0.0001; **p⩽0.01. F, females; GUAN, guanfacine; M, males; PLA, placebo.

Figure 2

(a) Cocaine craving. Line graphs show a medication group × sex × time-point interaction (GUAN Fp<0.0001 and +5 time points, p<0.02; PLA F>PLA M at 0 and +5 time points; GAUN M>PLA M at 0 time point, p<0.0001 in all cases). (b) Alcohol craving. Line graphs show a medication group × sex × time-point interaction (GUAN F<PLA F at 0 time point, p<0.0001 and +5 time point, p=0.003; PLA F>PLA M at 0 time point, p=0.001. (c) Nicotine craving. Line graphs show a main effect of medication group (GUAN<PLA, p=0.003). Data in all graphs are collapsed across all three imagery conditions, as no significant condition interactions were observed. All graphical data are adjusted for baseline and represent means and SE. ***p<0.0001; **p⩽0.01; *p⩽0.05. F, females; GUAN, guanfacine; M, males; PLA, placebo.

Figure 3

(a) Anxiety. Line graphs show a medication group × sex × time-point interaction (GUAN Fp<0.0001, +5 time point, p=0.002 and +20 time point, p<0.02; PLA F>PLA M at 0, p<0.0001 and +5 time points, p=0.001). (b) Negative emotion. Line graphs show a medication group × sex interaction (GAUN F<PLA F, p<0.04; PLAF>PLAM, p<0.02). Data in all graphs are collapsed across all three imagery conditions as no significant condition interactions were observed. All graphical data are adjusted for baseline and represent means and SE. ***p<0.0001; **p⩽0.01; *p⩽0.05. F, females; GUAN, guanfacine; M, males; PLA, placebo.