2023 Project Narratives and Anticipated Impacts
Cannabinoid Treatment for Reducing Chemotherapy-Induced Cachexia and Neuropathic Pain in a Pre-Clinical Rodent Model
Lisa Eckel, PhD
Professor of Psychology and Neuroscience
Director, Program in Neuroscience
Dept. of Psychology
Florida State University
Cachexia is a multi-faceted wasting syndrome characterized by anorexia, weight loss, and skeletal muscle atrophy. It is a common side effect in advanced cancer patients receiving chemotherapy. In addition to exacerbating cachexia, cytotoxic chemotherapies can damage sensory fibers through inflammatory processes, resulting in peripheral neuropathies and chronic pain. Our research will examine the effects of multiple cannabinoids, including cannabidiol (CBD) and cannabigerol (CBG), in alleviating anorexia, loss of adipose and lean tissue mass, inflammation, and allodynia in a rodent model of cisplatin-induced cachexia.
Chemotherapy-induced cachexia and neuropathic pain are not well managed under current treatment protocols, which are typically limited to managing nausea. Cannabinoid based treatments, including CBD and CGD offer a novel therapeutic option for chemotherapy-induced cachexia and represent a viable alternative to opioids for chronic, neuropathic pain management with less dependence liability. Outcomes of the proposed studies have significant implications for informing medical practice related to treating cachexia and chronic neuropathic pain and thus improving the quality of life for patients with advanced cancer diagnoses.
Impacts of Medical Marijuana Use on Inflammasome Activation and Breast Cancer Clinical Outcomes
Jennifer J. Hu, PhD
Professor and Division Director, Dept. of Public Health Sciences
Sylvester Comprehensive Cancer Center
University of Miami
Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer death in American women. A recent survey reported that 42% of breast cancer patients used Medical Marijuana (MMJ) to manage treatment-related symptoms. Although MMJ is generally considered safe and well-tolerated in cancer patients, there are potential adverse effects and conflicting reports of interactions with cancer therapies on clinical outcomes. Therefore, we propose a prospective cohort study of a diverse breast cancer population (50% minorities) to assess the impacts of MMJ on clinical outcomes and quality of life.
Our research will bridge critical scientific knowledge gaps regarding the benefits and harms of MMJ in breast cancer patients during and after treatments, whether inflammasome/inflammatory biomarkers mediate the benefits and harms of MMJ in breast cancer therapies and other medications used, and the impact of MMJ characteristics on the benefits and harms and biomarkers. The outcomes will support future validation studies and ultimately impact decision-making when physicians/patients consider MMJ for improving QOL and enhancing clinical outcomes.
Development of Cannabinoid Treatments to Ameliorate Methamphetamine Use Disorder
Habibeh Khoshbouei, PhD, PharmD
Professor
Associate Chair for Research, Dept. of Neuroscience
College of Medicine
University of Florida
Increasing efforts are made to develop treatments for methamphetamine use disorder. For instance, agonist replacement medications such as oral dosage forms of d-amphetamine and methylphenidate have shown promise in reducing methamphetamine relapse by increasing basal dopamine levels, but they have abuse potential. Alternatively, the endocannabinoid system modulates the activity of dopaminergic neurons through other mechanism(s). The CB1R agonist Δ9-Tetrahydrocannabinol (THC) increases firing activity of dopamine neurons and enhances dopamine synthesis. Although interactions between cannabinoid receptors and increased dopamine transmission are reported, their properties for methamphetamine relapse have been scarcely investigated. This study assesses the hypothesis that in freely behaving mice, THC reduces methamphetamine regulation of VTA dopamine neurons and striatal dopamine transmission.
The results are two-fold: revealing THC regulation of VTA dopamine neuronal activity, striatal dopamine release, their correlation with behavioral responses, and their contribution to methamphetamine reinstatement. We predict THC could increase VTA dopamine neuronal activity that increases striatal dopamine levels that potentially facilitate drug extinction and reduce drug reinstatement.
A Pilot Double-Blind Placebo-Controlled, Randomized, Safety, Efficacy, and Acceptability Trial of a Hemp-Derived Cannabidiol Extract for the treatment of Anxiety
Catalina Lopez-Quintero, MD, PhD
Assistant Professor, Dept. of Epidemiology
College of Medicine
University of Florida
Approximately one-third of Americans will experience an anxiety disorder at some point in their lifetime. Anxiety is primarily treated with antidepressants or benzodiazepines, but unfortunately, many patients report a partial response or cannot tolerate the side effects of these medications. The therapeutic potential of various compounds derived from the Cannabis sativa plant has generated considerable interest, particularly for managing neuropsychiatric disorders that have limited treatment options. Animal and small-scale human studies have demonstrated CBD’s anxiolytic, antidepressant, panicolytic, and anticompulsive actions, however, more research is needed to investigate the mechanisms of action and determine whether these products represent a safe and effective option for the treatment of anxiety. To close this research gap, we will conduct a 1:1 randomized, double-blind, 4-week pilot clinical trial to investigate the dosing, safety, tolerability, efficacy, and acceptability of a hemp-derived CBD extract compared with placebo among 30 study participants (15 per treatment group).
As the use of medical cannabis for anxiety continues to increase in Florida and the US, without sufficient research supporting its use, there is a pressing need to elucidate the mechanisms of action for CBD and other minor cannabinoid products and determine their potential as a therapeutic resource for anxiety treatment. CBD has demonstrated a promising profile for the treatment of anxiety, exhibiting anxiolytic, panicolytic, and anticompulsive effects. CBD may offer an alternative option for the approximately 30% of individuals with anxiety who are unresponsive to conventional treatments.
The Influence of Cannabis Smoke Condensate on Drug Metabolizing Enzymes in the Human Lung
John S. Markowitz, PharmD
Professor, Dept. of Pharmacotherapy & Translational Research
College of Pharmacy
University of Florida
Drug-drug interactions (DDIs) are a major cause of medication-associated morbidity and mortality. Conventional medications undergo a rigorous assessment for DDI liability per specific FDA guidelines while medical cannabis (MC) has undergone no systematic DDI evaluation and information is highly limited. Cannabis flower, the most widely utilized form of MC in Florida and the US, contains > 400 phytoconstituents including > 100 cannabinoids. However, following combustion (i.e., smoking) hundreds of additional compounds are formed such that ultimately the lungs are exposed to thousands of compounds in MC smoke. Importantly, the lung contains many of the same drug-metabolizing enzymes as the liver, and their disruption is anticipated to impair the metabolism of inhaled therapeutics and the normal physiological functioning of lung drug-metabolizing enzymes (DMEs) in detoxification from environmental exposures. The influence of smoked MC on drug metabolism occurring in the lung is essentially unknown. Current regulatory and legal constraints highly limit research studies of smoked cannabis. We are incorporating a highly novel in vitro approach to assessing this issue via the production and use of cannabis smoke condensate (CSC) as a highly representative mixture to assess the influence of MC smoking on DMEs utilizing human lung microsomes. Furthermore, we will assess the influence of CSC on the metabolism of the commonly used inhaled corticosteroid for asthma, beclomethasone.
Qualifying conditions and disorders for medical cannabis in Florida are chronic in nature and multiple conventional medications are often prescribed concurrently with cannabis posing risks for the occurrence of detrimental drug interactions. The vast majority of dispensed MC in FL is in the form of smoked cannabis flower. There is essentially no information on the influence of cannabis smoke on drug-metabolizing enzymes in the human lung. Inhibition of their activity could significantly impair the effectiveness of pulmonary therapeutics. Study results could have direct implications for presently marketed inhaled therapeutics such as the steroid beclomethasone and potential and COVID-19 therapeutics presently under clinical development. Results from these studies will provide the first information, and perhaps guidance on the influence of smoked medical cannabis on drug metabolism, and help guide the selection of MC formulations and administration routes (e.g. oral vs smoking) in individual patients.
Comparative evaluation of cannabinoids and opioids for treating chronic pain in aged subjects
Niall Murphy, PhD
Research Associate Professor, Dept. of Orthodontics Research
College of Dentistry
University of Florida
Treating chronic pain in the elderly is challenging due to a poor understanding of how advanced age affects physiology and drug action. In this project, we will test the analgesic potency of marijuana constituents in aged animals, seeking evidence that cannabidiol (CBD) particularly may present itself as a safer alternative to other analgesics, e.g., opioids, for treating pain in the elderly.
Finding safe and efficacious analgesics for treating pain in the elderly is a high priority, particularly given the rise in aged populations. Results from the current study aim to address this need by seeking evidence to support using marijuana constituents as an alternative and safer pain treatment for the elderly.
2022 Level 2 Projects
The Consortium Grant Program offers two levels of funding options for researchers. Level 1 is a one-year award of up to $75,000; Level 2 is a two-year award of up to $130,000. Level 2 grants require a second review and approval by the Consortium Board in order to receive funding for the second year of the grant’s cycle.
The following projects received Level 2 funding grants in 2022 and subsequently received approval for second year funding in 2023:
Quantitative assessment of complex drug-drug interaction networks involving medical cannabis products in special populations
Rodrigo Cristofoletti, PhD
Assistant Professor
College of Pharmacy
University of Florida
Patients receiving medical cannabis are likely to be taking other concomitant drugs and thus, risks related to Drug-Drug Interactions (DDIs) should be carefully assessed. An emerging body of evidence from in vitro studies has predicted inhibitory effects of cannabinoids on several drug metabolizing enzymes. However, clinical studies designed to assess DDIs involving major cannabinoids are scarce in the literature, which is partially due to the small number of approved cannabinoid products by the Food and Drug Administration, the high costs associated with performance of confirmatory clinical DDI trials, and legal and ethical issues surrounding medical cannabis use. We will apply modern in silico modeling techniques to estimate DDI risks related to cannabinoids.
Qualifying conditions to get access to medical cannabis in Florida include cancer, epilepsy, glaucoma, positive status for human immunodeficiency virus, Crohn’s disease, and many others. What these conditions and disorders have in common is both their chronicity and the lack of fully effective therapeutics to treat them. Thus, multiple medications are frequently prescribed concurrently (i.e. polypharmacy), and many of these agents will continue to be used concomitantly with medical cannabis. Such practices pose unknown risks for potential DDIs. Our research project aims to identify and mitigate the risks of DDIs involving medical cannabis in complex patients meeting.
Evaluation of immunomodulatory effects of chronic medicinal marijuana use and its routes of administration (smoking versus vaping) on the cerebral metabolism, morphology, dopamine (via neuromelanin MRI), and neural circuits of the whole-brain, and pain in young adults living with- and without-HIV
Varan Govind, PhD
Associate Professor
University of Miami
More than 50% of HIV-positive individuals use marijuana for alleviating the adverse effects of HIV infection and its medication. Inhalation is the most widely used consumption method for marijuana products and these are available in many forms or formulations such as joints, blunts, vape oil cartridges, and other forms. The beneficial and harmful compounds in these marijuana-based products vary widely across the cannabis plant strains and the parts thereof used, forms/formulations used, routes of administration, and intake durations. Consequently, marijuana users experience conflicting or mixed health outcomes. This study proposes to evaluate the effects of chronic marijuana use and routes of its administration on the brain, inflammation, immune function, pain, and behavioral functionsin HIV+ individuals.
People living with HIV use medical or recreational marijuana for alleviating adverse effects of HIV infection and its medication such as neuropathic pain, anxiety, depression, and cognitive dysfunction among many others. Specifically, this proposal will evaluate effects of chronic marijuana use and its routes of administration on the brain, systemic inflammation, immune activation, neuropathic pain, and behavioral measures in HIV-positive individuals. We anticipate that this study will provide preliminary data for assessing the impact of the form, dose and route of cannabis administration on the systemic inflammation and immune activation, brain metabolism and tissue structure, and interactions between the systemic and central nervous system (CNS) measures. This will form an important first step for designing cannabis-based systematic interventional studies to ameliorate specific conditions in HIV-positive individuals.