Evaluation of the dopamine β-hydroxylase (DβH) inhibitor nepicastat in participants who meet criteria for cocaine use disorder

Abstract

In the present study, we tested the hypothesis that the potent and selective dopamine-β-hydroxylase (DβH) inhibitor nepicastat would have minimal effects on cardiovascular and pharmacokinetic parameters associated with cocaine administration and would reduce the positive subjective effects produced by cocaine. We conducted a double-blind, placebo-controlled, inpatient study of oral nepicastat (0, 80 and 160 mg) concurrent with intravenous (IV) cocaine (0, 10, 20 and 40 mg) in non-treatment seeking participants who metcriteria for cocaine use disorder. Safety analyses revealed that nepicastat was well-tolerated and there were no differences in adverse events observed after nepicastat plus cocaine vs. cocaine alone. In addition, the pharmacokinetic properties of cocaine administration were not altered by nepicastat treatment. Cocaine-induced cardiovascular and subjective effects were evaluated for completers in the cohort randomized to nepicastat (n = 13) using a within-subjects statistical analysis strategy. Specifically, the cardiovascular and subjective effects of cocaine were assessed in the presence of placebo (0 mg), 80 mg of nepicastat or 160 mg of nepicastat on study Days 4, 8 and 12, respectively. Analyses revealed a main effect of nepicastat to reduce several cocaine-induced positive subjective effects. Taken together, these data indicate that nepicastat is safe when co-administered with cocaine and may suppress its positive subjective effects, and may be viable as a pharmacotherapy for treatment of cocaine use disorder.

Treatment With Nepicastat Decreases Contextual Traumatic Memories Persistence in Post-traumatic Stress Disorder

“…The effectiveness of drugs to treat PTSD is being challenged (Ipser and Stein, 2012) and there are evidence-based suggestions that psychotherapy decreases rather than remits PTSD symptoms (Steenkamp and Litz, 2013). In a previous study, safety analyses showed that nepicastat was well-tolerated in healthy adults and no differences in adverse events were observed (De La Garza et al, 2015). Our study showed that nepicastat treatment might be effective in reducing PTSD symptoms in a PTSD mice model with increased catecholamine levels (AD and NA; Martinho et al, 2020), and thus could be an efficient treatment at least in humans with PTSD that have increased catecholamine plasma levels.…”

Genetic moderation of cocaine subjective effects by variation in the TPH1, TPH2, and SLC6A4 serotonin genes

“…Thirdly, our sample size was small for a molecular genetic study; thus, replication of these findings will be needed to confirm these findings. Future studies could examine the subjective effects of several different doses a day (e.g., 0, 10, 20, and 40 mg; De La Garza et al , 2015). …”

The α-1 adrenoceptor (ADRA1A) genotype moderates the magnitude of acute cocaine-induced subjective effects in cocaine-dependent individuals

“…The 40 mg dose of cocaine was selected on the basis of several prior publications from our lab and others showing that it engenders significant increases in cardiovascular responses and subjective effects, yet the dose is well within the range of doses that can be safely administered to cocaine-dependent patients in a clinical setting. [35,36,37] Each individual participated in both conditions, one dose given at 9 AM and the second at ~1 PM. Subjective effects were recorded 15 minutes prior to and at 5, 10, 15, and 20 minutes after administration.…”