Cannabidiol is a non-intoxicating cannabinoid that has been suggested to reduce features relevant to opioid addiction. The current project will test a new CBD formulation that increases CBD’s bioavailability to assess the reduction of craving and anxiety associated with opioid addiction. Three studies will be conducted to investigate the effects of Cannabidiol (CBD) on opioid use disorder. The first study is an open cross-over design study in healthy individuals to confirm the safety and pharmacokinetic effects of CBD. The second is a randomized, double-blinded, placebo-controlled study of CBD, we will determine the pharmacokinetic and pharmacodynamic effects in participants with an opioid use disorder and obtain knowledge about the concentration range of CBD that reduces craving studied over a 4- to 8-week period (Study 2 and 3). The third phase of this project will study various CBD dose effects on opioid abstinent individuals not maintained on medication assisted therapy (but supported with behavioral therapy) (Study 2) as well as on those managed on opioid agonists (Study 3). Study participants will be evaluated for measures of craving, anxiety, depression, elements of cognitive function, and psychiatric history.

This study will investigate the neurobiological effects of Cannabidiol (CBD) a non-intoxicating cannabinoid that is being investigated as a potential treatment for opioid addiction. The study will utilize neuroimaging techniques to determine the neural circuits and transmitters associated with the effects of CBD on craving and anxiety. This is a randomized, double-blinded placebo-controlled study in abstinent subjects with a heroin use disorder. The neuroimaging will be conducted in participants immediately following their first administration of CBD or placebo and one week after the last administration (3 daily doses). Study participation duration is 2 weeks and includes MRI imaging; CBD/placebo administration; MRI tasks such as the resting-state functional MRI; and questionnaire measuring craving, anxiety, depression, elements of cognitive function, and psychiatric history.

Opioid addiction is a national epidemic contributing to the deadliest drug overdose crisis in US history and accompanied by excessive healthcare burdens due to the misuse of heroin and opioid prescription medications. There continues to be a lack of neurobiological knowledge about opioid use disorder to drive novel therapies critically needed to provide options to the current medications that are predominantly opioid-based and thus of abuse liability themselves. A fundamental core of our reverse translational research efforts has been to fill critical gaps of knowledge by direct investigation of the brains of human heroin abusers. Through such strategies we recently discovered a previously unrecognized neurobiological impact of opioids suggesting opioid-induced epigenetic alteration linked to the FYN which mediates glutamatergic signaling and phosphorylates tau (pTau); we also detected significant glutamatergic alterations and hyper-pTau pathology in heroin abusers. FYN is a Src family tyrosine kinase within the postsynaptic density that phosphorylates tau, involved in microtubule stability and dynamics, and thus a regulator of cytoskeletal remodeling which is a key feature of addiction. We verified elevation of FYN-targeted Tau phosphorylation in rats that self-administered heroin and in our chronic opioid in vitro cell culture model. Moreover, we were able to inhibit heroin self-administration (SA) and seeking behaviors in animals treated with a Fyn inhibitor and Fyn knockdown. These multidisciplinary and integrative data provides a strong foundation on which to interrogate FYN in opioid abuse with the goal of therapeutic development. We hypothesize that upregulation of Fyn and its resulting downstream target impairments in mesocorticolimbic brain areas contribute to heroin addiction behavior and can be targeted for treatment interventions. We propose to (1) determine the molecular signature of FYN-related networks in mesocorticolimbic regions associated with heroin abuse by RNA-sequencing in a cell-specific manner in human and the rat heroin SA model and to (2) characterize cell-specific downstream alterations mediated by Fyn underlying heroin SA and seeking behaviors. The downstream mechanisms leverage viral mediated cell-specific effects of Fyn on intracellular signaling cascades and pTau as well as cytoskeletal organization. Results gained from our integrative multidisciplinary study will advance knowledge of Fyn-related abnormalities underlying opioid abuse and provide science-based pharmacotherapeutic targets to expand treatment options for opioid addiction.

The objective of this project is to elucidate transcriptional and epigenetic mechanisms underlying glutamatergic dysregulation in mesocorticolimbic circuits in heroin abuse, a chronic relapsing disorder. Aberrant glutamatergic transmission in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) is central to drug-seeking behavior and addiction vulnerability. Our research focuses on studies of the human brain for which limited molecular insights are available. Preliminary data from microarray analysis already revealed distinct impairments of NAc glutamate-related gene expression in heroin abusers. The majority of these genes are upregulated, indicating that transcriptional change may be predominantly activation. Bioinformatic prediction of potential transcriptional regulators of these gene alterations identified DNA-binding factors SP1 and CREB1 as most likely regulators. SP1 and CREB1 are known to interact with various molecules involved in histone modification, such as histone acetyltransferases (e.g., Ncoa1, Ncoa3) that were also affected in the heroin population, which is mechanistically consistent with the observed predominance of upregulated glutamatergic genes. We will validate these findings using a comprehensive view of the genome by RNA-seq next-generation sequencing (Program Core) in the NAc of another subset of heroin abusers and control subjects, and will also examine the transcriptome in the mPFC, which provides glutamatergic innervation to the NAc. Specific glutamatergic disturbances will be assessed within discrete striatal output pathways using laser capture microdissection. To interrogate the molecular mechanisms by which glutamatergic aberrations are maintained, we will perform parallel studies in the rat heroin self-administration model in which viral-mediated gene manipulation strategies will be used to evaluate causal relationship of gene targets to heroin-seeking and intake. ChIP-Seq will be conducted (Program Core) to map genome-wide binding of a select number of target transcription factors, chromatin modifiers and histone marks in the NAc and mPFC. Overall, the novel research in this Project, which is fully integrative with the Core and other Projects of the PPG, will advance molecular knowledge about the pathophysiology of addiction disorders.

The cannabis sociopolitical landscape has dramatically shifted in recent years leading to the decriminalization, medicalization, and legalization of cannabis use, which has contributed to the reduced risk perception of its harm. This transformational time, however, has health implications particularly for vulnerable populations related to neurodevelopment since cannabis is commonly used by pregnant women and women of childbearing age. Accumulating evidence from our long-standing research has clearly demonstrated that prenatal exposure to D9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis, has long-term effects on behaviors — relevant to reward, motivation, negative affect and decision-making, and molecular disturbances linked to synaptic plasticity with profound epigenetic dysregulation that are exacerbated by stress. We have also identified specific epigenetic modifications linked to synaptic plasticity and behaviors associated with the protracted effects of developmental THC exposure. Recent results have highlighted the immune system as relevant to developmental cannabis/THC since preliminary gene expression analysis of the placenta from women who used cannabis during pregnancy revealed marked reorganization of the immune transcriptome that correlated with later childhood behavior. Immune-related genes were also altered in mesocorticolimbic structures of adult rats with developmental THC exposure, which enhances the correlation between immune- and synaptic-related genes. To gain neurobiological and mechanistic insights, we will conduct integrative and translational studies (human and rat models) to: (1) Determine the impact of prenatal cannabis/THC exposure on immune-related disturbances (placenta and brain); (2) Delineate molecular networks within distinct mesocorticolimbic cell populations through high resolution single-cell strategies altered by developmental cannabis/THC exposure relevant to immune function; and (3) Identify early biological disturbances (sustained into adulthood) predictive of long-term effects on brain and causally mediate behavior due to prenatal cannabis/THC exposure. The translational knowledge gained and the human and rodent databases generated from this project will significantly advance our understanding of psychopathology risk that often has its genesis during development.

Sarah Gund Award
Sarah Gund Prize for Research and Mentorship in Child Mental Health

https://childmind.org/bio/yasmin-hurd-phd/