L. C. Bidwell, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): The applicant proposes a study aimed at delineating associations between executive processes, genes, and frontalstriatal brain structure in attention deficit hyperactivity disorder (ADHD). ADHD is associated with well- documented weaknesses in executive processing, including deficits in response inhibition (Rl) and working memory (WM). Evidence suggests that these deficits may be heritable and sensitive to genetic control. In addition, research has begun to characterize the specific neural substrates that mediate these executive processes. Given promising evidence for mediation of Rl and WM through genetic influences and neural pathways, these executive processes may be useful intermediate phenotypes for determining genetic and neural etiologies of ADHD. The proposed study involves collecting neuropsychological data in the domains of Rl and WM, genetic material, and anatomical brain images (as part of an ongoing functional magnetic resonance imaging study) from adults with ADHD and control participants. Specific associations between task performance, genotypes, volumes of putatively involved brain regions, and ADHD symptoms will be investigated. Findings will characterize the contributions of genetic variations and neural structures on executive processing in ADHD, as well as identify potentially useful genetic and neural intermediate phenotypes for future genetic studies of ADHD. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This K23 award advances the Candidate's long term goal of integrating pharmacogenetic and psychiatric genetic approaches in the study of smoking/nicotine dependence (ND) and its co-occurrence with Attention Deficit Hyperactivity Disorder (ADHD). The proposed training will enable the PI to develop the skills needed for an independent interdisciplinary research career in this field. Risk for smoking behaviors in adolescents, including earlier age of initiation and likelihood of regular smoking, has been associated with both a clinical diagnosis of ADHD and non-clinical levels of ADHD symptoms. Several converging lines of work suggest that the high rates of smoking in the presence of ADHD symptoms may be related to common genetic vulnerabilities that increase risk for both ND and ADHD. In addition, increased risk for smoking in this population may be related to the effects of nicotine and nicotine abstinence on ADHD-related deficits in executive function (EF) and delay discounting (DD). The research plan focuses on elucidating a neurobiological pathway to ND by examining the genetic and cognitive correlates of smoking in adolescents with ADHD. First, secondary analysis of extant genetically-informative samples will be conducted to address gaps in the literature related to 1) the latent genetic, environmental, and gene by environmental influences on the overlap between smoking/ND and ADHD and 2) associations with measured genetic variation related to the neuropharmacology of nicotine (i.e. dopaminergic, nicotinic acetylcholinergic, and nicotine metabolism genes) and the ND/ADHD comorbidity. This work will assist in characterizing phenotypes most relevant to genetic studies of adolescent smoking, especially in the presence of ADHD symptoms, and in selecting measured genes specific to this etiological pathway. Second, new data will be collected using laboratory pharmacology methods to probe the cognitive and genetic mechanisms underlying increased risk for smoking in adolescents with ADHD by assessing the effects of nicotine abstinence on EF and DD in adolescent smokers with and without ADHD. EF and DD performance will be compared in adolescent smokers with (n=32) and without (n=32) ADHD after 24-hour biochemically verified smoking abstinence in the following conditions: 1) placebo patch (nicotine abstinence) and 2) 14 mg nicotine patch (nicotine replacement). DNA will also be collected in order to test the moderating role of genetic variation related to nicotine neuro-pharmacology on EF and DD processes. Results will inform a critical vulnerability for nicotine use in a high risk population, i.e. adolescents with ADHD, and advance the understanding of etiological factors in ND more broadly. This research will lead to subsequent grant applications to further probe genetic and neuropharmacological mechanisms associated with smoking risk in the presence of ADHD as well as clinical projects to develop more effective interventions for ND in this high-risk group. To enable the PI to pursue this long-term research agenda, she will work with experienced mentors to build upon her current expertise in neurocognitive phenotypes of ADHD with five areas of training: (1) nicotine psychopharmacology, 2) laboratory methods in behavioral pharmacology, 3) phenomenology of adolescent smoking, 4) advanced behavioral genetic analytic approaches, and 5) pharmacogenetics of ND. Taken together, the proposed research and training plans address a key priority of integrating genetic and pharmacological methodologies to advance the understanding of etiological and treatment factors in ND, and it will fully prepare the PI for an independent clinical research career in the field.

Chronic pain effects 76 million Americans and is the most commonly cited reason for use of medical marijuana. Marijuana and its constituent cannabinoids, including 9-delta-tetrahydrocannabinol (THC), are thought to be involved in reducing pain and associated inflammation. However, THC also is associated with harmful cognitive side effects. Synergistic interactions of cannabinoids are believed to produce different effects on pain and inflammation, as well as on cognitive function as compared to THC alone. For example, cannabidiol (CBD) is another primary cannabinoid that may work synergistically with THC in a multi-target analgesic and antiinflammatory approach. In addition, CBD does not have psychoactive properties and is thought to attenuate the negative cognitive side effects of THC. Despite limited data on their effects, there is a vast array of widely used marijuana products available for pain treatment across dispensaries throughout the US. These marijuana products contain a range cannabinoid potencies and ratios, which may have a large impact on their effects in chronic pain patients, including cognitive side effects. We propose an observational study to examine the effects of cannabinoid levels in blood on pain relief, inflammation, and cognitive dysfunction in chronic low back pain patients who choose to use edible cannabis in the context of a short-term (2 weeks) mechanistic study using a patient-oriented approach and a mobile pharmacology lab that solves many of the logistical problems with marijuana research. Our global hypothesis is that our observations of self-report and objective measures of the effects of marijuana edible products by pain patients who choose to use these products will vary as a function of the ratio of THC to CBD in their blood. Further, we hypothesize that cognitive impacts observed will differ by the THC/CBD ratio in blood. To that end, we will measure the association of pain, inflammation, and cognitive impairment with the levels of THC and CBD in the blood of pain patients who wish to use edible cannabis to treat their pain. This approach is ecologically valid and timely given that marijuana edibles of various cannabinoid potencies and ratios are widely used medically by patients in our state and across the US, yet absolutely no research has been done on these products to date. Blood levels of THC and CBD will be measured before, during, and after the exposure period (when participants in the observational study ingest a product they have purchased and choose to ingest) to determine whether there are associations with pain, inflammation, and cognitive dysfunction. Results from this study will provide critical and timely data to the public and health professionals regarding the effects of self-directed marijuana use, including the associations of various cannabinoids, on pain and related processes.

Project Summary Marijuana use is not only increasing, but gaining traction for use as an ?off-label? add-on therapy for treatment-resistant anxiety. Paradoxically, however, while data suggest that marijuana, in particular ?9- tetrahydrocannabinol (THC), increases anxiety acutely, cross sectional and longitudinal data suggest possible links between chronic marijuana use and lower risk for anxiety disorders. Research is critically needed to understand the effects of marijuana these outcomes. In light of considerable evidence that marijuana has anti- inflammatory properties and, further evidence suggesting that inflammation plays a pivotal role in the etiology of anxiety disorders, we propose that the anti-inflammatory properties of marijuana are linked with its anxiolytic effects. Importantly, prior work has not considered that the psychotropic and anti-inflammatory effects of marijuana are the compound action of different cannabinoids, which vary in their pharmacology and effects. Specifically, cannabidiol (CBD), a non-psychotomimetic component of marijuana (doesn?t produce a ?high?), is thought to have anxiolytic properties and may mitigate some of the harmful effects of tetrahydrocannabinol (THC). Further, preliminary data, including our own, suggest that THC and CBD render differential effects on anxiety-related processes, such as effects on inflammatory markers and stress response. Critically, there is huge diversity in the amounts and ratio of THC and CBD commercially available and widely used in states like Colorado. Therefore, the ratio of CBD to THC may have a pivotal impact on the anxiolytic and anti- inflammatory effects of various strains of marijuana, which in turn may have important implications for 1) effects on anxiety and 2) marijuana regulation policies aimed at harm reduction. In order to address this gap in understanding of the effects of cannabinoids, we propose to test the hypothesis that the anxiolytic effects and anti-inflammatory properties of marijuana vary as a function of the ratio of CBD to THC, and that these effects may shed light on the mixed data linking cannabis use and anxiety. We propose a unique observational study that employs real-world marijuana strains currently available to Colorado residents that vary in their CBD to THC ratios. We test the effects of specific strains of marijuana selected based on their differing CBD to THC ratios [i.e. a high CBD strain (+CBD/-THC), a 1:1 (+THC/+CBD) strain, and a typical THC-based strain +THC/-CBD)] on anxiety and inflammation, expecting that +CBD marijuana will mitigate anxiety, peripheral inflammatory responses (including cytokine levels with and without an ex-vivo immune challenge), and behavioral and biological responses to stress induction over the course of 4 weeks of observation. It is expected that the proposed research will generate information about which marijuana strains produce the most harmful effects on anxiety and inflammation and inform personal and policy decisions related to marijuana use and regulation.

Project Summary Previous research has documented acute harmful effects of cannabis use on verbal episodic memory, but prior work has not sufficiently considered that the memory effects of cannabis are the compound action of different cannabinoids acting on different memory processes. Specifically, cannabidiol (CBD), a non-psychotomimetic component of cannabis (doesn?t produce a ?high?), is thought to have cognitively protective properties and may mitigate some harmful effects of ?9-tetrahydrocannabinol (THC). Preliminary data, including our own, suggest that THC and CBD render differential effects on memory. Further, few prior studies have tested high potency strains that are commonly available. Our global hypothesis is that the effects of cannabis on memory vary as a function of the ratio of CBD to THC, with THC having adverse effects that may be counteracted by CBD. The goal of this study is to test the effects of three real-world commercially available cannabis strains that differ markedly in their ratio of CBD to THC. To that end, we will test the effects of -THC/+CBD (0% THC/16% CBD), +THC/-CBD (16% THC/0% CBD), and +THC/+CBD (16% THC/16% CBD) strains on recognition memory as well as event-related brain potentials (ERPs) that have previously been found to be related to different underlying memory processes. We use a naturalistic observational design in which each participant will complete the same memory task while intoxicated one day and not intoxicated another day (order counterbalanced). Aim 1 (Experiment 1) will assess recognition memory performance and memory-related ERP components in cannabis users after self-administration of one of three randomly assigned cannabis strains (+THC/-CBD vs. -THC/+CBD vs. +THC/+CBD) during both memory encoding (learning) and memory retrieval. Aims 2 and 3 will dissociate the effects of cannabis on memory encoding vs. retrieval processes. The effects of the three strains will be tested when users are acutely intoxicated only during memory retrieval (Aim 2, Experiment 2) or when users are intoxicated only during memory encoding (Aim 3, Experiment 3). We hypothesize a step wise effect of strain in each experiment such that the +THC/-CBD group will demonstrate the largest decrement in memory accuracy, as compared to the +THC/+CBD group, which will show a larger memory decrement than the -THC/+CBD group. In addition to strain assignment, CBD and THC blood levels will also be tested in relation to memory accuracy, with greater CBD/THC levels associated with higher/lower memory accuracy. We further predict that memory-related ERP components recorded during encoding and retrieval will show strain and blood level effects paralleling accuracy, with variations in these effects indicating the relative influences on different memory subprocesses (encoding, familiarity, recollection, post-retrieval monitoring). This study is critical in today?s climate of rapid legal changes and increased cannabis use for both recreational and medicinal purposes. Timely and accurate data on the impact of real-world cannabis on memory processes is critical in order to reduce the harms and identify the benefits of widespread legalization.