rsfMRIeffects of KB220Z™ on neural pathways in reward circuitry of abstinent genotyped heroin addicts

Abstract

Recently Willuhn et al. reported that cocaine use and even non-substance related addictive behavior, increases, as dopaminergic function is reduced. Chronic cocaine exposure has been associated with decreases in D2/D3 receptors, also associated with lower activation to cues in occipital cortex and cerebellum in a recent PET study from Volkow’s group. Therefore, treatment strategies, like dopamine agonist therapy, that might conserve dopamine function may be an interesting approach to relapse prevention in psychoactive drug and behavioral addictions. To this aim, we evaluated the effect of KB220Z™ on reward circuitry of ten heroin addicts undergoing protracted abstinence, an average 16.9 months. In a randomized placebo-controlled crossover study of KB220Z™ five subjects completed a triple blinded–experiment in which the subject, the person administering the treatment and the person evaluating the response to treatment were blinded as to which treatment any particular subject was receiving. In addition, nine subjects total were genotyped utilizing the GARSRX™ test. We preliminarily report that KB220Z ™ induced an increase in BOLD activation in caudate-accumbens-dopaminergic pathways compared to placebo following one-hour acute administration. Furthermore, KB220Z™ also reduced resting state activity in the putamen of abstinent heroin addicts. In the second phase of this pilot study of all ten abstinent heroin-dependent subjects, three brain regions of interest (ROIs) we observed to be significantly activated from resting state by KB220Z compared to placebo (P < 0.05). Increased functional connectivity was observed in a putative network that included the dorsal anterior cingulate, medial frontal gyrus, nucleus accumbens, posterior cingulate, occipital cortical areas and cerebellum. These results and other qEEG study results suggest a putative anti-craving/anti-relapse role for KB220Z in addiction by direct or indirect dopaminergic interaction. Due to small sample size, we caution definitive interpretation of these preliminary results and confirmation with additional research and ongoing rodent and human studies of KB220Z, is required.

Do We Really Need to Continue Pharmacotherapy for Opioid Use Disorder (OUD) Indefinitely?

“…We think that the stress of long term therapy should be restricted only to a small subset of individuals who are resistant to short-term treatment. For some of these individuals pharmacotherapy or other forms of dopamine agonistic therapy [23,24] may be effective for some but not all, while others may benefit from psychological and social interventions, which should be used to maximize benefits of the short-term treatment. We can achieve better outcome with this approach without adverse consequences of long-term use.…”

Neurogenetic and Epigenetic Correlates of Adolescent Predisposition to and Risk for Addictive Behaviors as a Function of Prefrontal Cortex Dysregulation

“…Quantitative electroencephalographic (qEEG) studies in humans have found that KB220Z modulates theta power in the anterior cingulate cortex. In abstinent heroin addicts, a single dose of KB220Z compared with placebo in a pilot study (Blum et al 2014b) resulted in activation of the NAc as well as activation and improvement of the prefrontal-cerebellar-occipital neural network. In addition, it was found that carriers with the DRD2 A1 allele showed a significant Pearson correlation in terms of enhanced compliance to KB220Z treatment relative to carriers of the normal compliment of DRD2 receptors in known obese patients (Blum et al 2014b).…”

Molecular Genetic Testing in Pain and Addiction: Facts, Fiction and Clinical Utility

“…potentially play important roles in heroin addiction. Most recently Blum's laboratory along with Zhang's group [23] in abstinent heroin addicts showed that KB220Z™ a complex putative dopamine D2 agonist, induced an increase in BOLD activation in caudate-accumbens-dopaminergic pathways compared to placebo following one-hour acute administration. Furthermore, KB220Z™ also reduced resting state activity in the putamen of abstinent heroin addicts.…”