ICR State Fiscal Year 2022

Jarrod Ellingson, PhD

Assistant Professor, Psychiatry-Substance Dependence, University of Colorado School of Medicine

Short-term Effects of Cannabis use and Cannabinoids in Youth: A Sibling-Comparison Study

In the last 10 years, cannabis has become more accessible and more potent in tetrahydrocannabinol [THC] content. Prior studies have linked earlier cannabis use and greater THC potency to adverse mental health outcomes. However, these studies generally suffer from two important limitations. First, cannabis use has primarily been assessed in a pre-legalization environment, when THC potencies were lower. Second, most studies of adolescent cannabis use have not considered familial confounds, such as genetic or environmental factors. This study will recruit sibling pairs to examine the mental health effects of cannabis while controlling for important familial factors. Specifically, we will test whether participants with heavier cannabis use have worse mental health functioning, on average, compared to their sibling. Within this study design, we will also examine the short-term effects of adolescent cannabis use, such as whether school week functioning is affected by weekend cannabis use. Short-term effects are important because they can help to identify mechanisms of long-term effects. Thus, this study will help to understand the mental effects of cannabis in adolescents, while controlling for family background factors.

Ken Olejar, PhD

Colorado State University Pueblo

Cannabinoid Conversion to CBN During Hemp Extraction and Post-Extraction Fluorination of CBD and CBN for Increased Bioavailability

Large numbers of therapies originate from compounds originating in plants. Cannabinoids produced by industrial hemp are a group of compounds that are emerging for potential medical use. One problem that exists with all-natural compounds is their bioavailability. Studies have shown that when many of these compounds are given at therapeutic levels, the levels actually found in the bloodstream are below therapeutic levels. As such, mechanisms for increasing the availability of these compounds are required. Fluorination of a compound is a known method for increasing bioavailability. Using this technique this project aims to increase the bioavailability of cannabidiol (CBD) and cannabinol (CBN). The obtained analogues of these cannabinoids will be tested for efficacy against a Rheumatoid arthritis model and in breast cancer. These two disease models were chosen because of the purported benefits of the cannabinoids against inflammation and use in pain management. It is therefore expected that the derived analogues obtained through fluorination will provide therapeutic possibilities by increasing the bioavailability for treating Rheumatoid Arthritis and breast cancer.

Nichole Reisdorph, PhD

Professor Mass Spectrometry Facility Director, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus

Microbiome-Mediated Effects of Cannabis and CBD on Neurotransmitter-Related Molecular Networks and Anxiety

Orally consumed Cannabis and extracted cannabidiol (CBD) products are becoming widely used supplements for a range of health disorders, including depression and anxiety. However, there is limited understanding regarding how Cannabis and CBD affect those living with these and other psychiatric conditions. Personal reports and some early research studies suggest that the effects of orally consumed tetrahydrocannabinol (THC), CBD, and Cannabis are largely dependent on the individual. We hypothesize that some of this variability in a person’s response is due to differences in an individual’s gut microbiome composition. Therefore, our research will help determine if an individual’s gut microbiome plays a role in how he/she/they metabolize CBD, THC, and other Cannabis molecules when orally ingested. In addition, our research will help understand the effects of CBD and Cannabis on anxiety and depression by measuring important neurotransmitters known to be related to anxiety/depression. These include dopamine, serotonin, kynurenine, epinephrine, and several endocannabinoids. Results can be used to develop similar studies that focus on other conditions such as post-traumatic stress disorder (PTSD) and to determine if ingestion of a pro- or pre-biotic can influence an individual’s response to CBD or Cannabis.

Emily Bates, PhD

Associate Professor, Pediatrics-Developmental Biology, University of Colorado Anschutz Medical Campus

Defining the Effects of CBD Consumption During Pregnancy on Fetal Neurodevelopment and Postnatal Anxiety

Morning sickness during pregnancy can be debilitating for a significant portion of women. Because there are not good remedies easily available and marijuana can help with nausea, women are drawn to using it, or the non-psychoactive component cannabidiol (CBD), thinking it is safe for their unborn child. CBD passes from the placenta to the fetus and crosses the blood-brain barrier. Retrospective clinical studies suggest that fetal marijuana exposure is associated with decreased birth weight, poor birth outcomes, anxiety, and attention deficit, and hyperactivity disorder (ADHD). However, these studies do not include dosing information and there is no way to distinguish the impact of CBD from the psychoactive marijuana component, tetrahydrocannabinol (THC). Funding from the Institute of Cannabis Research will allow us to learn how fetal exposure to CBD affects brain development and anxiety behaviors.

Cinnamon Bidwell, PhD, Institute of Cognitive Science Faculty, Assistant Professor, University of Colorado Boulder

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Duncan Mackie, PhD, Director of Pharmacology & Experimental Therapeutics, MedPharm Holdings 

Is What You See What You Get? A Systematic, Public Health-driven Analysis of Cannabis Product Label Claims VS. Actual Cannabinoid Content

This project constitutes an independent and comprehensive evaluation of cannabis product label claims and testing infrastructure in the State of Colorado. The primary aim is to determine the actual cannabinoid potency (via independent testing in authentic cannabis products found in the Colorado Retail Cannabis marketplace) and compare to the claimed potency found on the label. Over the course of 3 years, 480 authentic cannabis products will be randomly selected and purchased from state-licensed retail dispensaries from four basic categories: flower/joints, edible/ingestible, concentrate, and other/infused. Each product will be independently and blindly analyzed for cannabinoid content, and, in later years of the study, relevant contaminants will also be determined. Should systematic deviations be detected, secondary analyses will disentangle whether these deviations occur across specific product types and whether inaccurate testing stems from specific state-licensed laboratories. Results will be rapidly disseminated to state policymakers and the public. In addition, repeated product testing each year of the three-year study will allow the determination of whether the testing accuracy improves over the course of the study. The resulting information will be highly relevant to our state’s testing policies and procedures, as well as to our patient and user community. The proposed work represents a collaboration among leading cannabis scientists at the University of Colorado Boulder (UCB) and MX, LLC, a Denver-based company with Marijuana Enforcement Division (MED) Occupational and Research and Development licenses. This landmark proposal is the first of its kind in two ways: First, no prior study has systematically tested the full range of cannabis products sold in our state retail market. The proposed work will allow a direct comparison of product content to product labels, enabling an independent quantification of any systematic biases that may exist across product types or testing facilities. Second, the project represents a novel collaboration among scientists bridging academia and the cannabis industry. Only MX, LLC has the state licenses to handle and analyze cannabis products for research purposes. In turn, Dr. Bidwell at UCB will serve as an independent academic partner, with the expertise to inform an unbiased, rigorous design, complete skilled data management, and analysis, and lead the investigative team in rapidly publishing and disseminating these critical, public health-relevant findings.

Hollis Karoly, PhD

Assistant Professor, Department of Psychology, Colorado State University

Exploring Intoxication During Acute Alcohol and Cannabis Co-Administration: A Focus on Cannabinoid Content and Order Effects

Cannabis is the most commonly used drug among people who drink alcohol, yet evidence on the effects of using these substances together is quite limited. Two important factors that might impact the relationship between cannabis and alcohol use are the specific type of cannabis used (i.e., THC/CBD content) as well as the order of use (i.e., using alcohol before cannabis or cannabis before alcohol). Another issue relevant for understanding this relationship is the increasing popularity of cannabis products called "concentrates" which contain very high concentrations of THC. No research has been conducted exploring the effects of these concentrates when combined with alcohol. This study aims to address these issues. We will recruit a community sample of individuals who regularly use alcohol and cannabis to participate in study sessions in our mobile laboratory. The sessions will involve individuals consuming different cannabis concentrate products: (THC-dominant [5mg THC/0mg CBD], CBD-dominant [0mg THC/5mg CBD/], 1:1 THC/CBD [2.5mg THC/2.5mg CBD] and placebo [0mg THC/0mg CBD]) along with a moderate dose of alcohol. Half of the participants will use the alcohol before cannabis, and the other half will use the cannabis before alcohol. We will measure intoxication (e.g., balance performance, self-ratings of intoxication) and biological outcomes (e.g., breath alcohol level, heart rate) every 30 minutes for 4 hours after they use the cannabis and alcohol. We expect to see differences in these outcomes depending upon which cannabis concentrate product was consumed. We expect the greatest intoxication in those who used the THC-dominant concentrate and the least intoxication in the placebo group. We will also measure differences between those who used alcohol before cannabis and those who used cannabis before alcohol.

Stephanie McGrath, PhD

Associate Professor, Neurology, Colorado State University

Investigating the Effect of Cannabidiol and Cannabidiol-trazodone Combination Treatment on Naturally Occurring Canine Cognitive Dysfunction Syndrome as a Surrogate for Alzheimer’s Disease

The World Health Organization predicts that Alzheimer’s disease (AD) and other dementias will be the second leading cause of death in the United States within the next decade. Unfortunately, multimodal treatment efforts, with drugs, vaccines, and stem cell therapies, have yet to be successful. Neurodegenerative disorders are associated with the accumulation and aggregation of misfolded disease-specific proteins in the brain followed by the irreversible loss of neurons. Canine cognitive dysfunction syndrome (CCD) is a well-recognized neurodegenerative disease in older dogs and serves as an ideal naturally occurring surrogate for AD in humans. To date, there are no broadly effective treatment options for dogs or humans suffering from cognitive decline, partially due to the inferior animal models used in past research. Pathophysiologic changes associated with AD include increased amyloid- (A) deposition leading to senile plaques, increased tau hyperphosphorylation leading to neurofibrillary tangles, and significant neuroinflammation and oxidative stress leading to neurodegeneration and cognitive decline. Promising data have revealed that cannabidiol (CBD) and trazodone may have beneficial effects on various phases of the neurodegenerative process, which, given alone or in combination, could provide an effective preventive and therapeutic option in dogs, acting as a translational model for use in humans. We aim to enroll thirty client-owned dogs with naturally occurring cognitive dysfunction in a blinded, randomized, placebo-controlled clinical trial, with the objective of evaluating the effect and tolerability of CBD with and without trazodone on disease progression. The results of this in vivo study will set the foundation for human clinical trials.

Camille Stewart, MD

Assistant Professor of Surgery, Division of Surgical Oncology, University of Colorado Anschutz Medical Campus

Quantification of Endo- and Phytocannabinoids with Comparison to Pain Medication Requirements and Surgical Outcomes for Patients Undergoing Abdominal Surgery for Cancer

The use of cannabis is expanding in the United States. There is, however, a critical lacking in our understanding of how cannabis and its associated chemical compounds, called cannabinoids, affect patients after surgery. Patients undergoing abdominal surgery have substantial pain after surgery and often experience complications. Since we have found that cannabis is of interest to surgical patients diagnosed with cancer, they represent an ideal population to study. In our planned research, we will measure blood cannabinoid levels in daily cannabis users and non-users who undergo abdominal surgery for the treatment of cancer. Pain levels, pain medication requirements, and post-surgery complications will also be assessed. We think that patients with higher blood levels of cannabinoids will have more pain and need more pain medication after surgery, but that they will have similar rates of post-surgery complications. The information gained from this research will help doctors and patients understand how cannabis use affects patients after surgery and help determine if cannabis use is safe to use around the time of surgery.

Ashley Brooks-Russell, PhD, MPH

Associate Professor, Director (IVPC), Colorado School of Public Health, University of Colorado Anschutz Medical Campus

Observational Study of the Effects of Acute Cannabis Use on Ocular Activity Relevant to Driving

Police officers have long recognized that changes to the eyes, such as changes to the pupils or eye movements, can be a sign of recent drug use. Emerging research has found that changes to eye movement may indicate recent cannabis use and even impairment from cannabis. We will integrate eye-scanning technology into an existing driving simulator study to measures head position and eye movements while participants drive in a simulator after using cannabis. Successful completion of our research will inform future efforts to detect impairment related to cannabis while driving a vehicle or in an occupational setting.

Nolan Kane, PhD

Associate Professor, Ecology and Evolutionary Biology, University of Colorado Boulder

Dissecting the Genetic Basis of Sex and Dioecy in Cannabis Sativa

As hemp continues to become an ever more economically valuable/important crop, it becomes increasingly necessary to understand the mechanism of sex determination. Understanding these processes will help to develop new approaches, tools, and pipelines, which will propel Cannabis into the modern era as a legitimate crop species. Using crosses between dioecious and monoecious hemp varieties expressing variable levels of male to female flowering ratios, we propose to 1. understand the evolution and function of the X and Y chromosomes; 2. elucidate whether other genetic loci, autosomal and/or cytoplasmic, are important in sex determination; and 3. better characterize the effect of environment on sex expression plasticity. We will test the relative roles of cytoplasmic and nuclear factors in sex determination, quantitatively. The data collected from our crosses will be used to test the hypothesis that CMS mutations lead to gynodioecy in the absence of a Y chromosome, while the Y restores male fertility in a CMS background. This will aid breeders and growers in controlling the production of pollen-producing males and hermaphrodites, as well as understanding the early, ongoing evolution of a Y chromosome.