Atomoxetine does not alter cocaine use in cocaine dependent individuals: A double blind randomized trial

Abstract

Background Cocaine abuse continues to be a significant public health problem associated with morbidity and mortality. To date, no pharmacotherapeutic approach has proven effective for treating cocaine use disorders. Preclinical and clinical evidence suggests that noradrenergic activity may play a role in mediating some effects of cocaine and may be a rational target for treatment. Methods This double blind, placebo-controlled randomized, parallel group, 12-week outpatient clinical trial enrolled cocaine dependent individuals seeking treatment to examine the potential efficacy of the selective norepinephrine reuptake inhibitor, atomoxetine (80 mg/day; p.o.; n=25), compared to placebo (n=25). Subjects were initially stratified on cocaine use (<15 days or ≥15 days of the last 30), age and race using urn randomization. Attendance, medication adherence and study compliance were reinforced with contingency management, and weekly counseling was offered. An array of measures (vital signs, laboratory chemistries, cognitive and psychomotor tests, cocaine craving and urine samples for drug testing) was collected throughout the study and at follow-up. Results Survival analysis revealed no differences in study retention between the two groups, with approximately 56% of subjects completing the 12-week study (Cox analysis X2=.72; p=.40; Hazard Ratio 1.48 [CI 0.62–3.39]). GEE analysis of the proportion of urine samples positive for benzoylecgonine, a cocaine metabolite, revealed no differences between the atomoxetine and placebo groups (X2=0.2, p=.66; OR=0.89 [95% CI 0.41 – 1.74). Atomoxetine was generally well tolerated in this population. Conclusions These data provide no support for the utility of atomoxetine in the treatment of cocaine dependence.

Sex differences in reinstatement of cocaine-seeking with combination treatments of progesterone and atomoxetine

“…The lack of therapeutic effects solely by ATO in the present study is not uncommon, as ATO has shown mixed effects on decreasing stimulant use (Levin et al, 2009; Walsh et al, 2013; Rush et al, 2011). A previous study indicated that ATO alone decreased reinstatement (Zlebnik and Carroll, 2015), but Broos and colleagues (2015) showed no effect on reinstatement if rats had received extinction training.…”

“…In humans, ATO decreased both physiological (e.g., blood pressure increases) and subjective (e.g., pleasurable ratings) responses to d-amphetamine (Sofouglu et al, 2009). However, in some studies, no effects of ATO on stimulant use have been found (Levin et al, 2009; Walsh et al, 2013; Rush et al, 2011). …”

Effects of the combination of wheel running and atomoxetine on cue- and cocaine-primed reinstatement in rats selected for high or low impulsivity

“…Using ATO, studies have demonstrated reduced impulsivity across a range of behavioral tasks such as the 5-choice serial reaction time (Baarendse and Vanderschuren 2012, Robinson et al 2008), stop-signal reaction time (Robinson et al 2008), and delay-discounting (Bizot et al 2011, Robinson et al 2008) tasks (but see Baarendse & Vanderschuren, 2012, Broos et al 2012, Sun et al 2012). Regarding atomoxetine’s effects on stimulant addiction, some clinical investigations have found no therapeutic effect on cocaine use (Levin et al 2009, Walsh et al 2013) and the subjective effects of methamphetamine (Rush et al 2011), while others found reduced physiological and subjective effects of d-amphetamine (Sofuoglu et al 2009), significant attenuation of alcohol cravings (Wilens et al 2011), longer abstinence from alcohol use (Benegal et al 2013), and fewer days of heavy alcohol drinking (Wilens et al 2008). Similarly equivocal findings were demonstrated in rodents.…”

Cocaine-like discriminative stimulus effects of “norepinephrine-preferring” monoamine releasers: time course and interaction studies in rhesus monkeys

“…Although further work is needed to clarify species-related differences in the neurochemical and behavioral effects of DβH inhibition, it seems evident that modulating NE neuronal activity can directly influence the behavioral effects of cocaine (see also Kohut et al 2013). Moreover, increased or decreased noradrenergic activity alone is not associated with reinforcement, consistent with the low abuse liability of directly- or indirectly-acting NE-related drugs (Wee and Woolverton 2004; Wee et al 2006; Walsh et al 2013) and supporting the further investigation of candidate medications with prominent noradrenergic actions for cocaine use disorder.…”