Clonidine blocks stress-induced craving in cocaine users

Abstract

Rationale Reactivity to stressors and environmental cues, a putative cause of relapse in addiction, may be a useful target for relapse-prevention medication. In rodents, alpha-2 adrenergic agonists such as clonidine block stress-induced reinstatement of drug seeking, but not drug cue-induced reinstatement. Objective The objective of this study is to test the effect of clonidine on stress- and cue-induced craving in human cocaine users. Methods Healthy, non-treatment-seeking cocaine users (n = 59) were randomly assigned to three groups receiving clonidine 0, 0.1, or 0.2 mg orally under double-blind conditions. In a single test session, each participant received clonidine or placebo followed 3 h later by exposure to two pairs of standardized auditory-imagery scripts (neutral/stress and neutral/drug). Subjective measures of craving were collected. Results Subjective responsivity (“crave cocaine” Visual Analog Scale) to stress scripts was significantly attenuated in the 0.1- and 0.2-mg clonidine groups; for drug-cue scripts, this attenuation occurred only in the 0.2-mg group. Other subjective measures of craving showed similar patterns of effects but Dose × Script interactions were not significant. Conclusions Clonidine was effective in reducing stress-induced (and, at a higher dose, cue-induced) craving in a pattern consistent with preclinical findings, although this was significant on only one of several measures. Our results, though modest and preliminary, converge with other evidence to suggest that alpha-2 adrenergic agonists may help prevent relapse in drug abusers experiencing stress or situations that remind them of drug use.

Effects of the α2-Adrenergic Agonist Clonidine on the Pharmacodynamics and Pharmacokinetics of 3,4-Methylenedioxymethamphetamine in Healthy Volunteers

“…This result suggests that amphetamine acts primarily as a transporter-mediated NE releaser at higher doses (Florin et al, 1994). In contrast to our study, clonidine prevented behavior relevant to stimulant addiction, including amphetamine-induced psychomotor stimulation (Vanderschuren et al, 2003), cueinduced cocaine seeking in rats (Smith and Aston-Jones, 2011), and drug craving in cocaine users (Jobes et al, 2011). Altogether, the previous preclinical studies and our clinical findings indicate that amphetamines, including MDMA, do not increase NE impulse flow and their action in humans depends on transporter-mediated monoamine release that is not altered by clonidine.…”

“…Clonidine may therefore reduce stimulant-induced NE release and the associated behavioral effects of psychostimulants and may even be used in the treatment of stimulant addiction. In fact, clonidine prevented amphetamine-induced psychomotor stimulation (Vanderschuren et al, 2003), cue-induced cocaine seeking in rats (Smith and Aston-Jones, 2011), and drug craving in cocaine users (Jobes et al, 2011).…”

Memory of a drug lapse: Role of noradrenaline

“…The current results suggest that clonidine can be a useful pharmacotherapy in relapse prevention in at least three ways. First, it can attenuate the response to acute stressors (Samuels et al, 2007) and hence interfere with stress-induced reinstatement Jobes et al, 2011). Second, it could interfere with a process of stabilization of memories linking drugs to drug associated stimuli that occurs as a consequence of lapses.…”

β-Adrenergic Receptor Mediation of Stress-Induced Reinstatement of Extinguished Cocaine-Induced Conditioned Place Preference in Mice: Roles for β1 and β2 Adrenergic Receptors

“…In rodent and nonhuman primate models, central delivery of norepinephrine (Brown et al, 2011) or activation of central noradrenergic neurotransmission via antagonism of ␣ 2 adrenergic receptors (Lee et al, 2004;Feltenstein and See, 2006) reinstates extinguished cocaine seeking. Likewise, functional antagonism of noradrenergic neurotransmission through the administration of ␣ 2 adrenergic receptor agonists blocks stress-induced reinstatement in preclinical models (Erb et al, 2000) and attenuates stress-induced craving in human cocaine addicts (Jobes et al, 2011;Fox et al, 2012).…”