Neural Mechanisms of Cannabinoid-impaired Decision-Making in Emerging Adults

Emerging adults are a particularly vulnerable group for experiencing the immediate and potentially lifelong negative impacts of habitual cannabis use, and trends suggest that cannabis use disorder (CUD) will soon escalate in this population. The proposed research will combine clinical pharmacology, non-invasive brain stimulation, and neuroimaging techniques to establish the brain mechanisms of cannabinoid-impaired decision-making processes in emerging adults with CUD. Results from this project will inform CUD prevention/treatment efforts in this high-risk group and address a growing public health concern.

This mentored career development award (K01) will enable Dr. Michael J. Wesley to achieve his long-term goal of becoming an independent investigator with a clinical research program examining cannabis use disorder (CUD) in emerging adults, which is a current NIDA funding priority. Dr. Wesley is a new Assistant Professor at the University of Kentucky (UK) College of Medicine. The activities proposed in this award build on Dr. Wesley's background in neuroimaging and drug abuse research and will allow him to accomplish these specific short-term objectives: Become an expert in (1) clinical pharmacology and (2) non-invasive brain stimulation research, and enhance/develop his (3) knowledge of the responsible conduct of research, (4) skills for scientific communication and grant writing, and (5) ability to manage an independent research program. UK has numerous faculty and projects focused on drug abuse research and is an ideal environment for Dr. Wesley to successfully complete this award. Dr. Wesley has assembled a stellar mentoring team consisting of Dr. Josh Lile (Mentor), who runs a successful NIH-funded clinical pharmacology research program at UK and Drs. Mark George (Co-Mentor) and Colleen A. Hanlon of the Brain Stimulation Laboratory at the Medical University of South Carolina, Together they will guide and oversee Dr. Wesley's training in clinical pharmacology, brain stimulation, and scientific communication and grant writing. Dr. Wesley has proposed to engage in a series of formal classes, lab exchanges, and research seminars/meetings that will assist him in accomplishing the objectives of this award. The proposed research project is novel, innovative, and rigorous. It will combine the acute administration of Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, with brain stimulation and neuroimaging to examine the role of the dorsal lateral prefrontal cortex (DLPFC) and connected brain areas in drug-impaired decision-making processes. Specifically, transcranial magnetic stimulation (TMS) will be used to raise or lower DLPFC functionality following the administration THC in randomized, double-blind, placebo- and sham-controlled experiments. Aim 1 will test the hypotheses that excitatory TMS (raising DLPFC functionality; Exp. 1) will attenuate, whereas inhibitory TMS (lowering DLPFC functionality; Exp.2) will enhance, the impairing effects of THC on study outcomes. Aim 2 will use neuroimaging to test the hypothesis that individual differences in brain structure and function predict the specific and/or combined effects of THC and TMS on study outcomes. Results from this project will improve the investigator's understanding of the mechanisms involved in cannabis-impaired decision-making, which will inform CUD management and address a growing public health concern.

All individuals will receive multiple doses of oral THC (0, 10 and 30mg). Additionally, group 1 will receive excitatory TMS and group 2 will receive inhibitory TMS (real and sham in each group).

Functionality will be tested following combinations of THC and TMS will be tested in randomized, double-blind, placebo- and sham-controlled experiments.

In a Probabilistic Reinforcement Learning Choice (PRLC) task, two stimuli are presented and choosing either could result in a monetary reinforcer, but the reinforcement probabilities of the stimuli differ, and change throughout the task. Individuals attempt to optimize choices according to learned probabilities and track changing probabilities over time. PRLC performance allows mathematical modeling of trial-by-trial data under "real-world" uncertainty and yields computational parameters, such as the learning rate. Learning rates should favor recent changes in the experience of rewards so that individuals may have up-do-date representations of the world and reduced influence of irrelevant information while problem solving. We expect excitatory transcranial magnetic stimulation of the dorsal lateral prefrontal cortex, a brain area engaged by problem solving, to reduce the negative impact of increasing doses of THC on learning rates.

A Visual Analogue Scale (VAS) is used to measure the acute subjective effects of drugs. Responses are made for VAS items along a 100-unit scale anchored on the extremes by "Not At All" (0) and "Extremely" (100) with a higher score meaning more of the effect.

Elasticity of Demand measured by the Cannabis Purchase Task (CPT) where participants are asked how many hits of cannabis they would consume at 16 different price points in ascending order. Higher values indicate more sensitivity and reduced demand of a substance when prices increase.

Measured by The N-Back task where participants are presented with a sequence of letters and must indicate when the letter currently being viewed matches the one from N steps earlier in the sequence. The load factor "N" is adjusted between 0, 1, and 2 to adjust the difficulty of the task (0-Back = no WM load, 1-Back = minimal WM load, 2-Back = greater WM load) where a higher score means better memory performance.

Inclusion Criteria: Habitual cannabis use problems Body Mass Index ≤30 Exclusion Criteria: Past or current serious physical or mental health Sesame seed oil allergy Irregular health issues identified by the Study Physician Standard magnetic resonance imaging and transcranial magnetic stimulation exclusion criteria (e.g., metal implants, history of epilepsy, etc.) Lack of affective form of birth control (females) Pregnancy (females)