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ICR State Fiscal Year 2022

ICR – Research Projects:

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

Lead PI: Jarrod Ellingson

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.

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

Lead PI: Ken Olejar

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. 

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

Lead PI:  Nichole Reisdorph

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. 

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

Lead PI: Emily Bates

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.

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

Lead PI: Drs. Cinnamon Bidwell and Tyrell Towle, University of Colorado Boulder and MX, LLC

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.

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

Lead PI: Hollis Karoly

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. 

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

Lead PI:  Stephanie McGrath

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. 

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

Lead PI: Camille Stewart, MD, Assistant Professor of Surgery, Division of Surgical Oncology, at the University of Colorado Anschutz Medical Campus.

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. 

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

Lead PI: Ashley Brooks-Russell

Ashley Brooks-Russell 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.

Dissecting the Genetic Basis of Sex and Dioecy in Cannabis Sativa

Lead PI:  Nolan Kane

Project Summary Coming Soon

 

Research Projects:

Understanding Genomic Constituents of Cannabis and Genetic Regulation Underlying Cannabinoid Production

Dr. Sang Hyuck Park, ICR

The objective of the ICR research projects is to provide in-depth scientific evidence for better understanding the biology, chemistry, and physiology of Cannabis sativa L. to improve its agronomic values, as well as to extend the scope of the use of phytocannabinoids as a potential therapeutical agent. In order to achieve this goal, multi-tiered research projects have been initiated.

The main focus has been on the reference-level genome sequencing of commercial hemp varieties and has now reached to the chromosomal level sequencing. Our ongoing genomic comparative analyses will provide clues to unraveling the genomic structure and genetic regulations underlying cannabinoid biosynthesis and other agronomically important traits.

In addition, the effects of environmental cues (e.g., light spectra, UV radiation) were of great interest and a greenhouse test was set to identify the potential impacts of various wavelengths of light on cannabinoid synthesis and compositional profiles. As a continuation of cannabidiol (CBD) study on the ethanol-intoxicated tobacco hornworm, another insect model species, a fruitfly (Drosophila melanogaster) has been selected to further explore the long-term effects of CBD on their growth, development, and fecundity. More ecological impacts of CBD-enriched hemp are currently being investigated through multiple collaborations.

Anti-Cancer Potential of Fermented Dietary Hempseed (CANNABIS SATIVA L.) Metabolites and the Role of CB Receptors in Human Colon Cancer Cell CACO2 Viability, Proliferation, and Energy Metabolism

Dr. Annette Gabaldón, Biology

The objective of this study is to determine whether metabolites generated through probiotic fermentation of dietary hempseed (Cannabis sativa L.) exert anti-cancer effects. Specifically, we will culture human colorectal carcinoma cells Caco-2 in growth media supplemented with hempseed fermentation supernatant and test for alterations in cell viability, proliferation, and energy metabolism.

Previously, we investigated the ability of two lactic acid producing probiotics (L. plantarum and L. fermentum) to ferment whole hempseed. Our question of interest was whether hempseed could serve as a prebiotic to support probiotic growth and metabolism. In results that will be reported at the 2019 ICR Conference, we discovered that both probiotic organisms grow very well in media prepared with 5% hempseed powder(HS-5).

From colony forming unit (CFU) assays, we observed the characteristic phases of a bacterial growth curve (i.e., lag, log, stationary). From pH measurements of the fermentation media, we observed significant acidification, indicative of acidic secondary metabolite synthesis. Acidic metabolites yielded from carbohydrate fermentation include lactic acid and short chain fatty acids (SCFAs), notably acetate, butyrate, and propionate. These SCFAs provide protective effects against colorectal cancer.

If hempseed fermentation is found to yield high levels of SCFAs, then perhaps this nutrient-rich seed can be developed as a novel dietary anti-cancer therapeutic. We are finalizing SCFA and lactic acid analysis on the HS-5 fermented samples and if this new proposal is funded, we will grow Caco-2 cells in a cell culture system and test for anti-cancer activity using HS-5 fermentation samples that were collected in the study described.

In the event that chemical analyses of the HS-5 fermentation media shows low SCFA levels, the Caco-2 study is still worth pursuing because the HS-5 fermented media is expected to be complex. Whole hempseed is a rich nutrient that is high in protein, lipid, digestible and indigestible carbohydrate, vitamins, and phytochemicals.

The HS-5 fermented product that we have generated may also contain protein fermentation metabolites and there is much interest in identifying bioactive fermentation peptides related to human health. In a second study, we are proposing to investigate the role of CB receptors in modulating the viability, proliferation, and cellular energy metabolism of cultured colon cancer cells.

Effects of dietary hempseed (Cannabis sativa L.) on growth patterns, body composition, bone mineral density, and gut microbiota diversity in female C57BL/6J mice

Principal Investigator: Dr. Annette Gabaldon, Biology 

The objective of this study is to understand the effects of dietary hempseed (Cannabis sativa L.) ingestion on growth patterns, body composition, bone mineral density, and gut microbiota diversity in female C57BL/6J mice. Hempseed is a nutrient-dense food which contains high amounts of protein, carbohydrate, fiber, lipids, vitamins, minerals, and phytochemicals, but its use as a dietary aide is controversial in the U.S. due to the presence of cannabinoids present in small amounts. The oil from cold-pressed hempseed is mostly polyunsaturated and 

rich in Omega-3 and Omega-6 fatty acids. The pressed cake is rich in proteins and carbohydrate. Hempseed oil and seeds are beginning to appear in the U.S. market for human consumption, but its use in agricultural animal feed has not gained approval from the FDA. Most of the research on hempseed nutritional properties and health benefits to animals has come from regions where it is a major gran, such as China, Canada, Australia, Italy, and France. Here, we will investigate the influence that dietary hempseed has on growth parameters and intestinal microbiota diversity in young female mice. Forty mice will be randomly divided into four groups: control diet (CON, no hempseed), 5% hempseed in deity (HS5), 10% hempseed in diet (HS10), and 20% hempseed in diet (HS20).

The individual groups of mice will be fed their respective diets daily from ages five to 30 weeks and growth parameters will be evaluated at monthly intervals. Body composition analysis will be performed using dual energy x-ray absorptiometry (DEXA) scanning, which reports lean mass, fat mass, bone area, bone mineral content, and bone mineral density. Somatometric measurements will include body mass, length, and surface area. At bi-weekly intervals, the mice will be placed singly into metabolic cages for measurement of food intake and collection of feces for microbiota diversity testing by colony forming unit (CFU) assay. Endpoint measurements at 30 weeks of age will include blood plasma total antioxidant capacity, visceral organ component analysis, and DEXA scan on selected individual skeletal bones which will then be tested for mechanical strength properties.

This is a new area of ICR research, but it complements well two ongoing ICR pilot projects. Study 1 is investigating the influence of hempseed supplementation on probiotic growth and synthesis of secondary metabolites in cultured Lactobacillus strains. Study 2 is evaluating new bone formation by cultured human osteoblast (HOB) cells in the presence of estrogen and endocannabinoids (2-AG and anandamide). These studies will help us to gain a better understanding of the functional significance of industrial hempseed and cannabinoids to human nutrition and health.

Applications of Industrial Hemp 

Dr. Brian Vanden Heuvel, Biology

This project enables an inter-departmental, multi-faculty collaborative workflow that builds on 18 months of previous achievements by the principal investigator and co-principal investigators and established infrastructure through previous ICR funding. We believe that it is time to extend our work to applied projects.

Specifically, this proposal asks: 1) Can industrial hemp be used as a remediation tool for metals and metalloids from soil and municipal sewage sludge?; 2) Can cannabinoid extraction methods developed in previous ICR projects be scaled up to industrial volumes?; 3) Can waste products from industrial hemp production (stems/leaves) be a reliable source of important biopolymers?; and 4) Can the recently sequenced genomes for industrial hemp be a framework for continued research into what genes are turned on and off during different growth stages, affecting important traits like disease resistance, drought intolerance, yield, specific concentrations of CBCs, THC, or other secondary chemicals?

An ongoing investigation into the effects of medicinal cannabis on seizures in adults with medically refractory epilepsy 

Dr. Barbara Brett-Green, Psychology 

The primary objective for this project is to continue an ongoing study into the effects of medicinal cannabis on seizures in adults with medically refractory epilepsy. The Principal Investigator has established a partnership with Realm of Caring, a nonprofit organization, to provide support services for patients, and iC42, a bioanalytics company, to process participants’ biological samples (blood and urine) for antiepileptic medication and cannabinoid levels. Additional funding awarded by the ICR substantially improved the quality of the original study; however, it also lengthened the original study’s time frame.

Challenging aspects of conducting this research include the six-month length of the study and the expected length of the participant enrollment period. The Principal Investigator and research team are actively engaged in recruiting participants for this study. Recruitment is expected to continue for between six to 12 months until 34 participants are enrolled.

Data analysis and the production of articles for peer-review are expected to continue beyond 2019. Since the ICR initially awarded funding for this study, the Principal Investigator has been engaged in numerous research-related activities, including presenting a progress report at the first annual ICR conference, producing a technical report for the Pueblo County Commissioners, submitting multiple abstracts for presentations at upcoming regional and national conferences, accepting invitations to present at national cannabis conferences and other conferences, and preparing a review article for publication in the upcoming ICR journal.

The primary objective is to keep the Principal Investigator’s lab fully operational so that data collection for this study can be completed. Specific aims are to continue to support the costs of participant stipends, personnel, re-assigned time for the Principal Investigator, travel to present research results at scholarly conferences, and publishing. The Principal Investigator also plans to apply for funding external to the ICR.

Formation of Cannabinoids in Glandular Trichomes of Cannabis (Partnership Project) 

Dr. Sang Hyuck Park, Dr. Eun Soo Kim

This study will provide a base for a future thrust relating to a selection of hemp varieties. According to the morphological aspect, three types of glandular trichomes in Cannabis sativa are recognized: bulbous, capitate-sessile, and capitate-stalked trichomes. Capitate-stalked trichomes have garnered research interest, whereas the other two types of trichomes have almost not been investigated during the past twenty years.  

Our goal is to determine the functional activities of the three types of glandular trichomes related to the biosynthesis of cannabinoids. First, we will examine and compare the external features, distribution, and densities of these glandular trichomes using digital microscopy and scanning electron microscopy. Second, we will analyze secretory cavity contents of individual glandular trichomes removed through microcapillary procedures from hundreds trichomes of each type using gas chromatography. Third, we will examine localization and distribution of available antibody probe for CBD in chemically fixed and embedded tissues using transmission electron microscopy.

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