Annual Report 2022-2023 - The Consortium for Medical Marijuana Clinical Outcomes Research

ANNUAL REPORT | 2022-2023

February 2023

Prepared by the Consortium for Medical Marijuana Clinical Outcomes Research

For more information about the Consortium visit: www.mmjoutcomes.org For questions or comments, contact: Almut G. Winterstein, RPh, PhD, FISPE Director, Consortium for Medical Marijuana Clinical Outcomes Research Email: mmj.outcomes@cop.ufl.edu Phone: 352-273-6984

TABLE OF CONTENTS EXECUTIVE SUMMARY.................................................................................................... 3 CONSORTIUM RESEARCH PROGRAM...........................................................................3 Grants Program........................................................................................................ 4 MEMORY.................................................................................................................... 4 Clinical Research Core............................................................................................. 4 Evidence Core............................................................................................................5 Outreach.....................................................................................................................5 HIGHLIGHTS OF 2022-2023 CONSORTIUM RESEARCH FINDINGS........................... 6 CONSORTIUM RESEARCH PLAN 2023-2024...............................................................7 Grants Program.........................................................................................................7 MEMORY.....................................................................................................................7 Clinical Research Core............................................................................................. 8 Evidence Core........................................................................................................... 8 Outreach.................................................................................................................... 8 INTRODUCTION...............................................................................................................9 HIGHLIGHTS OF CONSORTIUM RESEARCH FINDINGS................................................ 11 MEDICAL MARIJUANA UTILIZATION..........................................................................11 MMUR Analyses.......................................................................................................11 MECHANISTIC STUDIES................................................................................................13 Does Cannabidiol Cause Drug-Drug Interactions?..............................................13 Can CBD Reduce Chronic Inflammation in People Living with HIV?..................15 Health Outcomes Among Adults Initiating Medical Marijuana for Chronic Pain....................................................................... 17 Post Traumatic Stress Disorder Related Sleep Disturbances and Other Symptoms Among Patients on Medical Marijuana............................19 Long-Term Molecular, Metabolic and Behavioral Consequences of Perinatal Exposure to Cannabidiol — A Safety and Efficacy Study.............. 20 CONSORTIUM LEADERSHIP AND ADMINISTRATIVE STRUCTURE.............................. 21 BOARD MEETINGS........................................................................................................22 CONSORTIUM ACTIVITIES IN FY 2023.......................................................................... 23 GRANTS PROGRAM..................................................................................................... 23 Summaries of Studies Completed During the 2019–21 Grant Cycles............... 25 2019 Grant Awardees....................................................................................... 25 2020 Grant Awardees........................................................................................27 2021 Grant Awardees....................................................................................... 29 Ongoing Studies from the 2022 Grants Cycle..................................................... 32 MMJ CLINICAL OUTCOMES RESEARCH DATA REPOSITORY (MEMORY)................ 34 MEMORY Development — Progress Towards Core Milestones......................... 35 CLINICAL RESEARCH CORE........................................................................................ 36 MMJ Contact Registry........................................................................................... 36 Medical Marijuana & Me (M3).................................................................................37 CARMMA................................................................................................................. 39

EVIDENCE CORE.......................................................................................................... 39 Evidence in Context Series.................................................................................... 39 Evidence Synthesis for FDA................................................................................... 42 OUTREACH................................................................................................................... 42 Website.................................................................................................................... 43 Newsletter............................................................................................................... 43 Researcher Spotlight Series.................................................................................. 43 Cannabis Clinical Outcomes Research Conference (CCORC).............................44 SUMMARY OF CONSORTIUM RESEARCH PRODUCTIVITY..........................................45 BIBLIOGRAPHY — PEER-REVIEWED PUBLICATIONS............................................... 46 EXTRAMURAL GRANTS SUBMITTED BY CONSORTIUM FACULTY AND GRANT AWARDEES................................................... 49 MEDIA COVERAGE....................................................................................................... 50 CONSORTIUM RESEARCH PLAN 2023-2024............................................................... 51 GRANTS PROGRAM......................................................................................................51 MEMORY....................................................................................................................... 53 CLINICAL CORE............................................................................................................ 53 EVIDENCE CORE.......................................................................................................... 53 OUTREACH................................................................................................................... 53 APPENDICES..................................................................................................................54 THE CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH BOARD...................................................................................................... 54 CORE FACULTY AND STAFF OF THE CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH.............................. 58 LIST OF REVIEWERS OF THE 2022 RESEARCH GRANTS PROGRAM...................... 62 CCORC PROGRAM BROCHURE.................................................................................. 63

EXECUTIVE SUMMARY Since passing of the Compassionate Use Act in 2014, Florida citizens have had access to marijuana and marijuana products for the treatment of certain debilitating conditions.

While medical marijuana (MMJ) may improve health outcomes, evidence to support its effectiveness for the treatment of most conditions is scarce and there are significant safety concerns related to cognitive effects, risk of accidents, interactions with other medications, psychosis, and addiction. Moreover, cannabis products vary in terms of components and mode of administration, but there is limited research to elude which plant types, doses and delivery methods provide the optimal risk-benefit. This substantial need for research stands in stark contrast to the available infrastructure to support such work and to the rapid uptake of medical marijuana. As of January 13, 2023, the number of Floridians licensed to use MMJ has grown by more than 18% compared to last year, to a total of 783,416 individuals.

Each week Florida dispensaries supply 280kg Tetrahydrocannabinol (THC) in non-smokable products and more than 530-790kg THC if smokable products contain between 10-20% THC. The following report details activities of the Consortium for Medical Marijuana Clinical Outcomes Research (Consortium) completed during the fourth year of its existence (July 2022–Feb 1, 2023). The first three annual reports were submitted on February 15th in 2020, 2021 and 2022 and are available at mmjoutcomes.org/our-consortium/annualreport/.

CONSORTIUM RESEARCH PROGRAM The Consortium research program rests on five pillars aimed at supporting the Consortium mission to foster medical marijuana clinical outcomes research including: A Grants Program, a unique research data repository known as the MEdical Marijuana Clinical Outcomes RepositorY (MEMORY), a Clinical Research Core, an Evidence Core and an Outreach Program. Following is a brief overview of the purpose and accomplishments for each pillar.

2023 ANNUAL REPORT | 3

Grants Program Launched in September 2019, the Consortium grants program has since completed four award cycles and initiated its fifth cycle with releasing its Request for Proposals (RFP).

During the first four grant cycles, 100 research proposals were received and ~$2.55M were awarded to 38 researchers from seven Consortium member institutions. Research outcomes and health conditions addressed in these proposals include neuropathy and pain of various origins, anxiety, cancer, PTSD, assessing drug interactions, pattern and motivation for MMJ use and access to MMJ, and adverse events.

Despite setbacks caused by the COVID-19 pandemic, grant awardees have generated important evidence, resulting in 41 peer-reviewed publications, one book chapter and one patent and 22 new extramural grant applications, seven of which have been awarded. In addition, UF Core Faculty has secured federal funding for cannabis research addressing cannabis outcomes from the National Institutes of Health (NIH) and the Food and Drug Administration (FDA). Noteworthy, 86 trainees including 18 from under-represented minorities have been involved in the funded research grants and two new courses have been developed, one of which is approved by the state university system, supporting the development of research capacity in cannabis outcomes in the state.

MEMORY The growing use of MMJ in Florida offers a unique opportunity for real-world evaluations of cannabis clinical outcomes that can help overcome the lack of randomized clinical trials and greatly accelerate the availability of evidence on clinical outcomes. MEMORY has been conceived to establish the infrastructure for real-world MMJ clinical outcomes evaluations similar to those employed by the FDA to evaluate and monitor the risk-benefit of approved prescription medications. To ensure comprehensive longitudinal follow-up and capture of relevant health outcomes, the Consortium aims to link the Office of Medical Marijuana Use (OMMU) Medical Marijuana Use Registry (MMUR) with other clinical databases commonly used for outcomes research. The Consortium plans to make a de-identified version of the repository accessible to Consortium researchers, thus providing state-wide infrastructure for real-world clinical outcomes research.

In the past years, the Consortium has obtained IRB approval and established Data User Agreements with the Agency for Healthcare Administration (AHCA), the Centers for Medicaid and Medicare Services (CMS) and the Department of Health Vital Statistics Office for databases that will be linked to the MMUR. The Data User Agreement with the Department of Health OMMU to access the MMUR was signed on Jan 30th, 2023. The MEMORY data science team, which has completed development of the data architecture, is awaiting release of the data to begin development of MEMORY.

Clinical Research Core The Clinical Research Core was established to complement MEMORY and provide infrastructure support for prospective studies including randomized controlled trials. To facilitate such studies, an MMJ patient contact registry to support recruitment has been rolled out statewide, with a registry portal on the consortium website. To date, over 1,300 individuals who are using or are planning to use MMJ have registered in the contact registry.

Clinical and industry partners are now listed in the online Connect and Advance Research for Medical Marijuana Analysis (CARMMA) database.

In May 2022, the Consortium launched Medical Marijuana and Me (M3), the first large prospective MMJ patient cohort in Florida, and one of the first in the United States. Enrollees complete a sequence of surveys about their general health, use and experiences with medical

4 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

marijuana and related health outcomes. M3 design has been guided by a scientific planning committee consisting of 11 members, including six researchers from consortium member universities, four MMJ physicians, and one MMJ patient representative. To date, 1001 patients have been enrolled and data curation and analysis has commenced.

Evidence Core The evidence core focuses on the synthesis and dissemination of scientific evidence regarding MMJ clinical outcomes for researchers, providers, and community members.

Evidence core activities include publication of its Evidence in Context series, provision of scientific expertise on an ad hoc basis to the scientific, clinical and patient community, and development of evidence reviews to inform the research priorities in the Consortium Research Plan.

The Evidence in Context series addresses needs for rapid distillation and appraisal of emerging evidence in the form of brief, plain-language commentaries on new studies or developments in cannabis clinical outcomes research and how this research translates to patient care. These articles are available in the scientific journal Medical Cannabis and Cannabinoids and on the Consortium website at mmjoutcomes.org/evidence/evidence-incontext/. No such resource was previously available specifically for MMJ. On Jan 27, 2023, UF finalized a contract with the United States Food and Drug Administration (FDA) to support a project titled, “Medical Literature and Data on Cannabis Use.” The results from this project will be used by the FDA as supporting evidence as they draft their recommendations for either maintaining or revising the current Schedule I classification for cannabis, which will be presented to federal lawmakers in 2023. The Consortium research team will accomplish the assessment of clinical riskbenefit through the conduct of large-scale systematic literature reviews. Project 1 will examine a series of harms outcomes described in studies that examined cannabis use for medical, nonmedical, and for unknown purposes. Project 2 will examine the effectiveness of cannabis for pain, PTSD, anxiety disorders, epilepsy, nausea, anorexia, HIV/AIDS, and Crohn’s disease. The team consists of members from the Consortium, led by Amie Goodin, assistant director for the Consortium Evidence Core, the Harvard Pilgrim-based Sentinel Initiative and the FDA.

Outreach The Consortium’s outreach activities are directed towards health care providers, researchers, patients and industry, to maximize participation in research, and keep these stakeholders abreast of the latest research findings. In addition to its website and quarterly newsletter, the Consortium has enhanced its outreach activities with a new researcher spotlight video series.

The first Cannabis Clinical Outcomes Research Conference (CCORC) was hosted virtually on April 8th and 9th, 2021 and drew over 225 registrants from across 31 U.S. states and five countries. The second CCORC conference, was held in person and with virtual options, on May 19–20, 2022, at the UF Research and Academic Center at Lake Nona, Orlando, FL. CCORC 2022 attracted more than 125 attendees. The conference’s program featured keynote addresses by three national level experts in cannabis research, panel discussions, workshops, a poster session for scientific abstracts selected following peer review, and oral presentations of top scientific abstracts.

The third annual CCORC is planned for May 18–19, 2023. CCORC 2023 will also be held in Orlando, Florida, and the conference will again be delivered in a hybrid format to promote inclusivity and broad outreach.

2023 ANNUAL REPORT | 5

HIGHLIGHTS OF 2022-2023 CONSORTIUM RESEARCH FINDINGS • For non-smokable products, the weekly dispensed amount of THC per total number of MMJ cardholders remained stable over the past four years. When including smokable products, there was a 2.4-fold increase in weekly dispensed THC over the same period, from 279mg to 662mg (assuming 10% THC content in smokables).

• When comparing the distribution of conditions in MMJ certifications across time, there is a remarkable increase in certifications associated with treatment of PTSD (23.9% to 38.7% of all certifications in 2020 versus 2022) and multiple sclerosis (1.3% to 11.0%). In turn, the representation of especially chronic nonmalignant pain has dropped from 36.2% to 13.6%. Compared to prevalence estimates of these conditions among all Floridians, especially PTSD, ALS and MS are overrepresented among MMJ certified patients while glaucoma and AIDS are underrepresented.

• The first clinical study to assess Drug-Drug Interactions (DDIs) with any cannabinoid using FDA-recommended probe drug methodology, revealed concomitant ingestion of CBD is not likely to result in a significant interaction with methylphenidate (MPH; Ritalin®), both of which rely on the same liver enzyme for metabolism and could therefore increase each other’s plasma concentrations.

• Using blood cells from people living with HIV revealed a specific group of genes that are mainly responsible for inflammation were less active after CBD treatment.

This is a first step towards the understanding of how CBD may be used for antiinflammatory therapeutic strategies.

• In a 3-month prospective study incorporating ecological momentary assessment (EMA) and patient surveys, the cohort of middle-aged and older adults with chronic pain who initiated MMJ reported reduced pain intensity/inference, lower anxiety/depression, and improved sleep and quality of life.

• A similar study in a small sample of patients with post-traumatic stress disorder (PTSD) suggested significant reductions in PTSD symptom severity and nightmares with corresponding improvements in sleep (increased duration of sleep hours, sleep quality, sleep efficiency).

• An animal study on the molecular, metabolic, and behavioral consequences of perinatal exposure to CBD observed reduced pup survival when compared to the offspring of dams not exposed to CBD during pregnancy or lactation.

6 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

CONSORTIUM RESEARCH PLAN 2023-2024 In the coming year, the Consortium will continue its efforts towards facilitating and conducting research that informs clinical care and policy within the five original Consortium research program pillars: the Grants program, MEMORY, the Clinical Core, the Evidence Core, and Outreach activities. Two recent developments will play an important role in the coming year: Receipt of MMUR data will allow development of MEMORY, which will accelerate the ability to generate evidence on MMJ clinical outcomes. The new contract with the FDA will allow a new focus on evidence synthesis to support regulatory decision making. The 2023-2024 Consortium research plan, focuses on the following research priorities: • Generation of conclusive evidence on clinical outcomes of MMJ use including both risk and benefit • Evaluations of route and dosing, in particular research on high potency THC • Interactions of MMJ with other drugs/medications • Epidemiologic studies on utilization pattern and accessibility of MMJ across diverse groups • Research on the effects of MMJ use in reducing opioid dependency • Evaluating Components of Medical Marijuana/Cannabis The following describes the Consortium Research Plan for fiscal year 2024.

Grants Program The Consortium has launched its fifth grants cycle in October 2022 with release of its Request for Proposals (RFP). The RFP announcement has been expedited to encourage broader and increased researcher participation. The intent continues to be to complete the application reviews by the end of the fiscal year to expedite funding of prioritized proposals, upon approval of the FY 2024 Consortium budget. Consortium research priorities are emphasized in the RFP.

MEMORY

Clinical outcomes

Route & dose

Interactions

Impact on pain and opioid use

Epidemiology

MMJ Components

With the release of the MMUR data, the Consortium will implement its longstanding plan to develop MEMORY. This will include MMUR data curation, linkage to 2023 Research Priorities other health databases and development of analytical cohorts for access by Consortium researchers. As envisioned, MEMORY will then serve to support studies on MMJ effectiveness and safety, and utilization and access. Consortium core faculty plans to have a first set of safety and effectiveness studies completed by the end of the new fiscal year.

2023 ANNUAL REPORT | 7

Clinical Research Core Goals for the Clinical Core include continued expansion of the Consortium infrastructure to support patient recruitment into prospective research studies via its patient contact registry and CARMMA database of collaborating physicians, researchers, and industry partners. The Consortium is set to finish enrollment into M3, finalize data curation for access

by Consortium researchers and complete a first set of analyses and publications over the coming year.

The Clinical Core will also continue to work on guidance for investigators on regulatory issues involving use of MMJ in research studies. This will include guidance on DEA licensure and other relevant state and federal regulations.

Evidence Core In the coming year, the Evidence Core will have completed its evidence review for the FDA to support the 8-factor analysis requested by congress and begin publications and other dissemination of related findings. The Consortium will also continue to publish its Evidence in context series, and survey and evaluate emerging evidence to inform the Consortium research priorities.

Outreach Building on the success of our first two Cannabis Clinical Outcomes Research Conference (CCORC), the Consortium plans to hold its third annual CCORC in May 2023. Other outreach activities through the Consortium website, its quarterly newsletter and participation in scientific conferences will continue. The newly added Researcher Spotlight Series will be developed further to promote Consortium activities and disseminate research outcomes.

The Consortium board, core faculty and staff look forward to continuing this critical work to support the Florida Medical Marijuana program’s primary goal to improve the health of Florida citizens. The Consortium addresses an urgent and critical need in this regard in providing patients, providers and regulators the necessary evidence on the safe and effective use of MMJ.

8 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

INTRODUCTION Beginning with the Compassionate Use Act passed in 2014 and followed by several amendments, Florida law allows the use of marijuana for the treatment of certain debilitating conditions. Persons seeking medical marijuana (MMJ) may suffer from serious health conditions and symptoms, which may not be completely alleviated with approved medications. While there is some promise that MMJ may improve certain health outcomes, evidence in support of its effectiveness for treatment of most conditions is lacking and there are significant safety concerns related to cognitive effects, risk of accidents, interactions with other medications, psychosis, and addiction. Moreover, marijuana products vary in terms of specific components and mode of administration, but little is known about what components, doses and delivery methods provide the optimal risk-benefit. There is a substantial and urgent need to understand how MMJ impacts health to guide both policy and clinical decision-making. But due to the complex legal restrictions, the research infrastructure to support MMJ evaluations is lagging far behind the rapid uptake of MMJ in the state.

The number of Floridians licensed to use medical marijuana has continued to increase, with a growth of 19% comparing December 31st, 2022 to Dec 2021, reaching a total of 778,781 individuals.

Increase in certified medical marijuana patients in Florida, 2018–2022

To address the need for rigorous evidence on the safety and effectiveness of MMJ for the various patient populations who are seeking certification for use, the state legislature introduced Section 1004.4351, Florida Statutes, to establish the Consortium of Medical Marijuana Clinical Outcomes Research. The statutory-defined mission of the Consortium is to conduct, disseminate and support rigorous scientific research on the clinical outcomes of medical marijuana use. In July 2019, the Florida State University System Board of Governors, following a competitive request for proposals, designated the University of Florida as the lead university of the Consortium. Eight additional universities have joined the Consortium to-date.

2023 ANNUAL REPORT | 9

Consortium member universities

Consortium responsibilities as defined in the charter and consistent with statute include: • Conduct rigorous scientific research • Disseminate research • Guide statewide policy on ordering and dosing practices for the medical use of marijuana.

The Consortium of Medical Marijuana Clinical Outcomes Research presents its fourth Annual Report on its accomplishments in research and outreach, and its Research Plan for 2023-2024.

10 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

HIGHLIGHTS OF CONSORTIUM RESEARCH FINDINGS Over the last four years, the Consortium has generated research on the use, mechanisms of action, and clinical outcomes of MMJ. The following highlights key findings with relevance to regulatory and clinical decisions involving the use of MMJ for the treatment of debilitating conditions.

MEDICAL MARIJUANA UTILIZATION MMUR Analyses As the number of certified medical marijuana users in the state has grown, so has the total dispensed amount of THC. Currently, over 280kg of THC is dispensed per week in non-smokable products. Adding smokable products, the amount THC dispensed per week increases to 530 kg assuming a THC content of 10%, and to 790 kg assuming a THC content of 20%.

Weekly dispensed amount of THC in medical marijuana including or excluding smokable products in Florida, February 2018–December 2022

The average weekly dispensed amount of THC per cardholder for non-smokable products remained fairly consistent across 2018 to 2022, with a 1.2-fold increase from 279mg to 342mg. However, when including smokable products, and assuming a THC content of 10%, there was a 2.4-fold increase from 279mg to 662mg over the same period. With 20% THC content in smokables, the increase was 3.5-fold. In 2022, the average weekly dispensed amount of THC per cardholder remained stable compared to 2021.

2023 ANNUAL REPORT | 11

Weekly dispensed amount of THC in medical marijuana including or excluding smokables per total number of cardholders in Florida, February 2018–December 2022

Between 2018 and 2022, among non-smokable products, the quarterly amount of THC dispensed consistently exceeded the quarterly amount of CBD dispensed. While the dispensed amount of THC increased significantly from 2018 to 2022, the dispensed amount of CBD did not show a visible increase after Q1 2021. As a result, the difference in dispensed THC and CBD grew consistently throughout this period. At the last quarter of 2022, the amount of dispensed THC in medical marijuana was more than 80 times the amount of dispensed CBD in low-THC non-smokable products.

Dispensed mg THC in medical marijuana products excluding smokables (orange) and CBD in low-THC products (blue)

12 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

With the steady growth of the number of patients certified for MMJ, a change in the representation of qualifying conditions among certified users has occurred. Reviewing the distribution of qualifying conditions across certifications published in the Physician Certification Pattern Review, Annual Report, by the Florida Board of Medicine and Board of Osteopathic Medicine, in 2020 and 2022, there is a remarkable increase in the representation of certifications associated with treatment of PTSD (23.9% in 2020 to 38.7% in 2022) and multiple sclerosis (1.3% to 11.0%). In turn, the representation of especially chronic nonmalignant pain has dropped from 36.2% to 13.6%. Compared to prevalence estimates of these conditions among all Floridians obtained from public health surveillance data and the published literature, especially PTSD, ALS and MS are overrepresented among MMJ certified patients while glaucoma and AIDS are underrepresented.

Qualifying condition Cancer Epilepsy Glaucoma HIV AIDS PTSD ALS Crohn’s disease Parkinson’s disease Multiple sclerosis Chronic nonmalignant pain Medical conditions of the same kind

2020 Report (535,717 conditions, 291,885 patients)

2022 Report (1,620,991 conditions, 653,190 patients)

Estimated % of Floridians with condition in 2020

6.9% 1.6% 1.5% 0.7% 0.1% 23.9% 0.1% 1.5% 0.9% 1.3% 36.2% 25.2%

3.8% 1.1% 0.8% 0.6% 0.1% 38.7% 0.6% 1.9% 0.5% 11.0% 13.6% 27.1%

0.58% 1.70% 2.11% 0.62% 0.32% 4.70% 0.004% 0.22% 0.35% 0.27% 20.40%

Comparison of prevalences of qualifying conditions across MMJ certifications versus among all Floridians

This work was completed by Consortium core faculty and the Consortium MEMORY data science team.

Mechanistic Studies Does Cannabidiol Cause Drug-Drug Interactions?

The chronicity and types of illnesses treated with MMJ often require concomitant use of prescription or over-the-counter medications, which may result in potential interactions, commonly referred to as drug-drug interaction (DDI). The DDI potential of cannabis and its major constituents has not been systematically evaluated. This study assessed whether cannabidiol (CBD) inhibits the activity of the major hepatic enzyme carboxylesterase 1 (CES1), potentially resulting in significant plasma level increases of drugs dependent on CES1 for clearance. This IRB-approved study, assessed the influence of CBD (administered as Epidiolex®) on the disposition of the known CES1 substrate methylphenidate (MPH; Ritalin®).

In a randomized, placebo-controlled, crossover study, 12 research participants (6 male, 6 female) ingested 750 mg of CBD (Epidiolex®) solution, or alternatively, a placebo solution twice daily for a 3-day run-in period followed by an additional CBD dose (or placebo), and a single 10 mg dose of MPH, and completed serial blood sampling for pharmacokinetic analysis. MPH and CBD concentrations were measured by liquid chromatography with tandem mass spectrometry.

2023 ANNUAL REPORT | 13

CBD-MPH DDI Clinical Study Design

When compared to MPH only, the geometric mean ratio (CBD/control, 90% CI) for AUCinf and Cmax with CBD co-administration was 1.09 (0.89, 1.32) and 1.08 (0.85, 1.37), respectively.

Although the upper bound of bioequivalence was not met, the mean estimates of AUC and Cmax ratios were generally small and unlikely to be of clinical significance.

Pharmacokinetic parameters of MPH with and without CBD co-administration

14 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

Mean MPH (a) and CBD (b) plasma concentration versus time curves for all subjects (n = 12).

Error bars represent SD.

The findings demonstrate that short-term co-administration of CBD at a clinically relevant dose has minimal effect on the pharmacokinetics of MPH. Thus, concomitant ingestion of CBD at the dose evaluated is not likely to result in significant increases in plasma concentrations of MPH and, potentially, other CES1 substrates.

Markowitz JS, De Faria L, Zhang Q, Melchert PW, Frye RF, Klee BO, Qian Y. The Influence of Cannabidiol on the Pharmacokinetics of Methylphenidate in Healthy Subjects. Med Cannabis Cannabinoids. 2022 Nov 4;5(1):199-206. DOI: 10.1159/000527189 . PMID: 36467779; PMCID: PMC9710314.

This work was completed by 2020 Consortium grants awardee John Markowitz, PhD, University of Florida.

Can CBD Reduce Chronic Inflammation in People Living with HIV? Chronic inflammation is a common condition for people living with HIV (PLWH). Cannabis sativa (marijuana) and its cannabinoid derivatives, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are largely used by PLWH to stimulate appetite, prevent weight loss, or manage chronic pain. Importantly, while THC exhibits psychotropic effects, CBD does not and its effect on inflammation among PLWH is unclear.

This study was designed to investigate cellular type/state alterations associated with CBD. Human peripheral blood mononuclear cells (PBMCs) obtained from PLWH following a CBD oral treatment (67 mg/day for 27 to 60 consecutive days) were used for single-cell RNA sequencing to measure gene expression in PBMCs of PLWH that started a CBD treatment for at least one month. Gene expression was compared as baseline (before CBD) and after CBD treatment. Importantly, the gene expression of single PBMCs (~41,000 cells) was measured.

2023 ANNUAL REPORT | 15

Uniform Manifold Approximation and Projection (UMAP) of the collected dataset Each dot is a single cell. The relative position of each cell depends on its gene expression pattern, i.e., cells expressing similar genes are closer than cells expressing different genes. (Top, left) Unsupervised clustering finds 10 cell communities, numbered 0 to 9. (Top, right) Per-subject projections. (Bottom, left) Per-condition projections. Baseline, i.e. before-CBD, and after-CBD cells are overlapped in all clusters, with the exception of clusters 5 and 7, where they appear to be separated. (Bottom, right) Cell populations are labeled based on overexpressed genes in the clusters. Clusters 5 and 7 are myeloid cells.

The data suggests that a group of genes is under-expressed after CBD treatment (i.e., significantly less active when compared to baseline) in myeloid cells, including monocytes and granulocytes. Both monocytes and granulocytes play a pivotal role in the inflammatory process, and the great majority of the genes emerging from the analysis play a well-known pro-inflammatory role. As chronic inflammation is a condition common to a plethora of different diseases, this study is a first step towards the understanding of how CBD may be used for anti-inflammatory therapeutic strategies for PLWH. This work was completed by 2021 Consortium grant awardee Simone Marini, PhD, from the University of Florida.

16 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

Health Outcomes Among Adults Initiating Medical Marijuana for Chronic Pain In response to the need for more rigorous data on medical cannabis and chronic pain, Consortium researchers conducted a 3-month prospective study using ecological momentary assessments (EMA) to examine the effects of medical cannabis on pain, anxiety/ depression, sleep, and quality of life.

Data were collected from 46 adults (Mean age 55.7±11.9, 52.2% male) newly initiating medical cannabis treatment for chronic pain. Participants completed a baseline survey, EMA for approximately one week pre- and up to three weeks post-medical cannabis treatment, and a 3-month follow-up survey. Forty-two (91.3%) participants completed the 3-month follow up, and five out of the 42 stopped using medical marijuana use. The self-reported EMA data (2535 random and 705 daily assessments) indicated significant reductions in momentary pain intensity (b = -16.5, p < 0.001, 16.5 points reduction on 0-100 visual analog scale) and anxiety (b = -0.89, p < .05), and significant increase in daily sleep duration (b = 0.34, p < .01) and sleep quality (b = 0.32, p <.001) after participants initiated medical cannabis. At three months, self-reported survey data suggested improvements in pain, pain interference, depression, sleep duration and quality, and quality of life.

Measures with respective score range or measuring unit Pain No more than minor pain (%)* At its worst (0-10)* On average (0-10)* Pain interference (1-5)* Anxiety (1-21) Depression (1-24)* Sleep Time to fall asleep (minutes) Hours of sleep (hours)*** Sleep quality (1-5)** Quality of life (1-5)***

Baseline (N = 46)

3 months (N = 42)

Statistical inference (chi-square or t value)

13.0% 8.15(1.51) 6.05(1.91) 3.64(1.09) 6.50(6.10) 8.50(6.10)

33.3% 7.25(2.25) 5.21(2.35) 2.90(1.11) 4.69(5.64) 5.67(5.42)

χ2 = 6.59 t = -2.38 t = -2.31 t = -3.82 t = -1.51 t = -3.43

65.7(54.9) 5.31(1.83) 1.17(0.93) 2.72(0.68)

50.8(45.8) 6.17(1.79) 1.64(0.85) 3.27(0.78)

t = -1.05 t = 3.95 t = 3.04 t = 4.48

*p < .05, **p < .01, ***p < .001

Main Outcomes Based on Survey Data at Baseline and 3-Month Follow Up, Mean (SD)

2023 ANNUAL REPORT | 17

Pain intensity trajectory of 37 adults pre- and post-medical marijuana treatment.

The individual lines represent the real-time pain intensity ratings for each participant over time. The red dash line represents the overall trend among the 37 participants. Data from all participants were aligned so that Day 0 was the first day of starting MMJ for each participant. The time axis therefore indicates how many days before (negative numbers) or after (positive numbers) MMJ treatment. The overall trend curve was constructed using LOWESS with bandwidth of 0.3. The overall trend curve was constructed from data up to 15 days before and 20 days after Day 0, given that this was the period where most participants had available data.

Real-time pain reduction of 37 adults by MMJ product type n = number of occasions reporting using this specific type of MMJ product. The reduction of realtime pain level was calculated by contrasting the real-time pain level shortly after using each type of product with baseline real-time pain level.

In the study sample of primarily middle-aged and older adults with chronic pain we observed self-reported improvements in pain intensity/inference, lower anxiety/depression, and improved sleep and quality of life. Patients who reported more pronounced reductions in pain intensity tended to use sublingual dosage forms or flower.

18 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

Wang Y, Jean Jacques J, Li Z, Sibille KT, Cook RL. Health Outcomes among Adults Initiating Medical Cannabis for Chronic Pain: A 3-month Prospective Study Incorporating Ecological Momentary Assessment (EMA). Cannabis. 2021 Oct;4(2):69-83. DOI: 10.26828/ cannabis/2021.02.006 PMID: 34671723; PMCID: PMC8525881.

This work was completed by Consortium researcher Yan Wang, PhD, from the University of Florida.

Post Traumatic Stress Disorder Related Sleep Disturbances and Other Symptoms Among Patients on MMJ Post Traumatic Stress Disorder (PTSD) is a debilitating disorder experienced by a subgroup of individuals following a life-threatening trauma. This prospective study of adults with confirmed PTSD investigated whether PTSD symptoms, sleep quality, affect, and general physical and mental health well-being improved post-initiation of MMJ treatment.

Fifteen participants were recruited from two medical marijuana clinics in Gainesville and Jacksonville, FL. Participants were positive for PTSD, were 18 years or older, not currently on MMJ, and were willing to abstain from recreational marijuana if using any, until the State Medical Cannabis Card was obtained. Participants were assessed at baseline (pre-MMJ initiation), 30- and 70- days post MMJ initiation using the Pittsburgh Sleep Quality Index (PSQI), PTSD Checklist for DSM-5 (PCL-5), Positive and Negative Affect Schedule (PANAS), PROMISGlobal Health V1.2, and a semi-structured marijuana and other substance use assessment.

Variables PCL-5 Total Nightmares (PCL-5)* Sleep Duration-hours Sleep Quality * Sleep Efficiency * PSQI – Total PANAS – Neg. Affect PANAS – Pos. Affect Global Health – Physical Health Global Health – Mental Health

Baseline (T1) 49.60 (13.2) 2.00 (1.1) 5.03 (1.0) 2.27 (0.5) 47.2 (25.8) 13.79 (3.5) 31.64 (8.1) 28.86 (9.3) 12.87 (3.3) 8.73 (2.8)

Mean (SD) 30 – Day (T2) 30.33 (13.2) 1.57 (1.2) 6.64 (1.7) 1.21 (0.5) 52.26 (22.2) 10.62 (4.8) 24.14 (10.6) 29.64 (12.4) 13.00 (3.4) 10.36 (3.9)

70 -Day (T3) 29.0 (15.2) 0.87 (1.2) 6.83 (1.9) 1.07 (0.8) 49.79 (18.0) 9.13 (2.9) 22.93 (9.0) 32.53 (8.6) 14.40 (3.0) 12.13 (2.47)

p Value ** 0.0015 <.0001 0.0381 <.0001 0.0007 0.4618 0.1097 0.0014

Post-Hoc p Value ac ac ac a ac ac NA NA c

* Friedman’s test was used since the normality assumption for ANOVA was not met.

PSQI-Pittsburgh Sleep Quality Index PTSD Checklist for DSM-5 (PCL-5) PANAS-Positive and Negative Affect Schedule **Post-Hoc p Value: a indicates a significant change between baseline (T1) and 30-day (T2) b indicates a significant change between 30-day (T2) and 70-day (T3) c indicates a significant change between baseline (T1) and 70-day (T3) NA: Not applicable since the omnibus test was not statistically significant.

Changes in measures of sleep, PTSD symptoms, positive and negative affect and quality of life after medical marijuana initiation (N=15)

PTSD symptom severity as measured by total PCL-5 score improved significantly at 30- and 70-day follow-up. Similarly, statistically significant reductions in nightmares were reported at 30- and 70-day follow-ups. Corresponding improvements in sleep were noticed with participants reporting increased duration of sleep hours, sleep quality, sleep efficiency and total PSQI score. Likewise, negative affect and global mental health improved significantly at follow-up. According to the post-hoc analyses, the most statistically significant changes occurred between baseline and 30-day follow-up. The exception to this pattern was nightmares, which did not show significant improvement until day 70.

2023 ANNUAL REPORT | 19

PTSD patients who initiated MMJ reported improvements in symptoms, particularly concerning sleep disturbances, which often do not respond to currently available treatments.

This work was completed by 2019 Consortium grant awardee Krishna Vaddiparti, PhD, from the University of Florida.

Long-Term Molecular, Metabolic and Behavioral Consequences of Perinatal Exposure to Cannabidiol (CBD) — A Safety and Efficacy Study Researchers at Florida State University are exploring the efficacy and safety of cannabidiol (CBD) during pregnancy and early postnatal development (during lactation) in mice. The hypothesis is that CBD treatment during gestation results in increased mortality due to changes in maternal behavior, rather than placentation problems, and that transcriptome alterations (gene changes) result in long-term metabolic or psychiatric changes.

Dams were dosed daily for two weeks with strawberry jam laced with CBD or control solvent prior to mating and during the 20 days of gestation. At birth, pups with prenatal exposure to CBD were cross-fostered to untreated dams to separate any maternal behavioral effects from that of prenatal exposure. The behavior of the CBD treated vs. untreated dam towards their original or foster pups was determined using pup-retrieval assays. Perinatally-exposed male and female mice were then raised to three-months (adults) and were physiologically screened for locomotion and energy use (CLAMS home cage metabolic system) as well as their ability to clear a glucose challenge. Anxiety-like behavior (light-dark box; LDB), obsessive compulsive-like behavior (marble burying test), and 1 h and 24 h object memory tests were performed while extracting mRNA subsequent to the task. Among 10 cohorts of 5-8 pregnant dams that have been cross fostered results thus far indicate that CBD may not be safe during pregnancy. Fetal exposure to CBD significantly decreased survival of the pups — 62% of CBD-treated pups died before weaning age (23 days) whereas only 9.5% of jamtreated pups died prior to weaning, although cross-fostering a CBD-treated pup to a drugfree dam allowed survival rates not significantly different than those of jam-treated pups (13% died prior to weaning). Pup birth weight was not significantly different between CBD vs. jam-treated animals, however, by postnatal day 10 and 21, CBD-exposed mice weighed significantly more. Cohorts 1 to 7 (approximately 130 offspring) have been video recorded and metabolically profiled and data are analyzed.

Mortality rates among 1) pups exposed to jam during pregnancy and lactation (black filled circle), 2) pups exposed in utero and during lactation to CBD (solid red squares), 3) pups exposed to CBD in utero but not during lactation (CBD to Jam), and 4) pups exposed to CBD only during lactation but not during pregnancy (Jam to CBD).

Results suggest that administration of CBD in utero results in reduced pup survival and accelerated growth rate.

This work is being conducted by 2021-22 Consortium grant awardee Debra Fadool, PhD, from the Florida State University.

20 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

CONSORTIUM LEADERSHIP AND ADMINISTRATIVE STRUCTURE The Consortium of Medical Marijuana Clinical Outcomes Research is open to all public and private universities in Florida. The Consortium is directed by the Medical Marijuana Research Board, which is composed of representatives from each participating university. Board members represent a variety of scientific and medical fields as required per statute. Profiles of the Consortium Board members are available in the Appendix.

CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH BOARD BOARD MEMBER

INSTITUTION

William Anderson, PhD (Chair)

Florida International University

Martha S. Rosenthal, PhD (Vice Chair)

Florida Gulf Coast University

Peter Holland, PhD

Florida Atlantic University

Roger B. Fillingim, PhD

University of Florida

Jacqueline Sagen, PhD

University of Miami

Dinender Singla, PhD

University of Central Florida

Eric H. Holmes, PhD

Florida State University

Charles Weatherford. PhD

Florida A&M University

Max. C. E. Orezzoli, PhD

Florida Memorial University

Pursuant to statute, the board appointed Almut G. Winterstein, RPh, PhD, FISPE, Distinguished Professor in Pharmaceutical Outcomes and Policy and Director of the Center for Drug Evaluations and Safety (CoDES) at UF as its director. She is supported by Dr. Robert Cook, MD, MPH, professor of Epidemiology and Internal Medicine and director of the Southern HIV and Alcohol Research Consortium (SHARC) Center for Translational HIV Research. They are supported by Assistant Directors for MEMORY, the Clinical Research Core, and the Evidence Core. Program staff include an Assistant Director for Research Administration, who manages the Consortium operations, a communication expert who leads outreach activities, a research coordinator who assists with participant recruitment, study operations, database management, and teams of analysts and research assistants that support the cores. Taking advantage of its academic base, Consortium leadership involves several trainees in Consortium activities. Profiles of the Consortium leadership and staff are available in the Appendix.

Consortium Administrative Structure

2023 ANNUAL REPORT | 21

BOARD MEETINGS Since its inception, the board has met 14 times between August 2019 and Feb 1, 2023.

Key accomplishments and decisions at the board meetings in the previous year are summarized below and complete meeting minutes are available on the Consortium website at mmjoutcomes.org/our-consortium/board-meetings/ MAY 20, 2022 • Dr. Dinender Singla was welcomed as the new Board Member from UCF and Dr. Timothy Gilbertson was thanked for his service.

• During this in-person meeting immediately at the end of CCORC, the success of the Consortium’s second conference was recognized and the board approved continuation of this outreach activity with CCORD 2023.

JUNE 27, 2022 • The board was informed about the continued funding by the State.

• The board finalized selection of research proposals to be awarded for the 2022 grants funding cycle.

SEPTEMBER 16, 2022 • Dr. Peter Holland from FAU was introduced as the new board member replacing Dr. Ximena Levy.

• The board approved the FY23 budget including support for Medical Marijuana and Me (M3), and approved the plans for the third conference of the consortium to be held in May 2023 in Orlando.

22 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

CONSORTIUM ACTIVITIES IN FY 2023 Central to the Consortium is its mission to foster clinical outcomes research on MMJ across the state. Five pillars constitute the Consortium Research Program: A Grants Program, the MEdical Marijuana Clinical Outcomes RepositorY (MEMORY), a Clinical Research Core, an Evidence Core and Outreach activities. Consistent with its charter, the Consortium has engaged scientists with relevant research programs to participate in the Consortium and foster research collaborations to accelerate the development of evidence on MMJ clinical outcomes. The following sections provide a description of each of the Consortium functions and a detailed progress report.

Consortium Structure and Functions

GRANTS PROGRAM Each year, the Consortium offers a Research Grants Program, open to all members of the Consortium and teaching nursing homes as stipulated by statute. The research focus of the grants program is prioritized based on statutory guidance and the annual Consortium research plan to ensure optimal fund utilization. Applications are reviewed by external reviewers, recruited from out-of-state, using NIH review criteria. Final grant awards are made by the Medical Marijuana Research board based on study quality, impact and relevance to the Consortium research priorities. Calls for proposals are disseminated by each board member within their university and through the Consortium website, newsletter, and listservs. We have completed the 2019, 2020 and 2021 grants program cycles, are mid-way through the 2022 grants program cycle and have launched the 2023 grants cycle.

2023 ANNUAL REPORT | 23

Between 2019 and 2022, the Consortium Grants Program has received 100 research proposals and after review, awarded 38 of these to researchers of seven of its member institutions.

These awards, totaling more than $2.5 million, cover a broad range of focus areas consistent with Consortium research priorities.

Consortium Grants Program: >$2.5 Million Awarded

A summary of findings of the completed studies of the 2019, 2020 and 2021 grant cycles and an overview of ongoing studies from the 2022 grants cycle are presented as follows.

24 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

Summaries for Studies Completed During the 2019–21 Grant Cycles benzodiazepines than non-authorized physicians of the same specialty. Overlay of physician prescribing, PI: PAUL BORSA, PHD practice location, dispensary locations, and other University of Florida community-level measures revealed that, during the Study Title: Efficacy of a controlled short- study period, there was lack of medical cannabis access term trial of CBD ingestion on reducing in rural areas as compared with more densely populated symptomatic response and facilitating areas in Florida. Additionally, we documented a strong recovery after induced muscle injury correlation between cannabis access and utilization of opioids.

Study Summary: Many physically active Americans have reported pain-relieving effects of cannabidiol (CBD) that can reduce or eliminate use of nonsteroidal PI: ANDREA CIPPITELLI, PHD anti-inflammatory drugs (NSAIDs). Currently, rigorous Florida Atlantic University clinical research in humans regarding CBD effectiveness Study Title: Cannabidiol: A potential is lacking. We have secured Investigational New Drug treatment for migraine- like pain, (IND) status for our investigational product from the US negative emotion and Photophobia Food & Drug Administration (FDA). Our IND approved investigational product has been manufactured and Study Summary: Migraine is a complex condition processed through a Florida-based CBD company, which characterized by the tendency to have headache has agreed to source our hemp-derived CBD for the with sensory disturbances and comorbid anxiety project as well as for future studies. Patient recruitment and depression. Our calcitonin gene-related peptide has commenced after initial delays due to the pandemic. (CGRP) migraine model) in mice revealed that CGRPData from this study will contribute to evidence on induced cephalic allodynia is successfully blocked CBD effectiveness and help shape future studies on

by CBD treatment (30 mg/kg, ip) both in male and identifying an efficacious dose range of CBD, as well as female C57BL/6J mice. We also observed reliable determining the cellular and molecular mechanisms that photosensitivity both in male and female mice, but contribute to symptom resolution and recovery.

CBD pretreatment was not effective in blocking CGRP-

2019 Grant Awardees

PI: HELEN BRAMLETT, PHD University of Miami Study Title: Therapeutic dosing of a cannabinoid (CBD) after mild and moderate brain injury for translation to the clinic Study Summary: Cannabidiol (CBD) has been shown to have anti-inflammatory, neuroprotective effects and its administration may be a therapeutic strategy in the treatment of traumatic brain injury (TBI). We observed several interesting trends with CBD treatment after TBI. We found that oral consumption of CBD may have reduced inflammation, protected vulnerable brain regions, and reversed certain memory and sensorimotor deficits that are observed after brain injury. The appearance of reduced microglia reactivity led us to believe that a higher oral dose may be more efficacious in reversing neuropathological sequelae.

Further investigation is needed to fully evaluate CBD as a therapeutic avenue in TBI. PI: JOSHUA BROWN, PHARMD, MS, PHD University of Florida Study Title: Characterizing community and physician-level factors associated with medical marijuana prescriber registration and patient access

induced photophobia. CGRP produced anxiogenic-like activity only in male mice, an effect reversed by CBD. Collectively, our results suggest that CBD is effective in relieving migraine-like pain and anxiety comorbid to headache pain but fails in providing protection from other symptoms experienced by migraineurs such as photophobia.

PI: GREGORY MCMANUS, PHD Florida Golf Coast University Study Title: Rapid identification and quantification of heavy metals and microplastics in CBD oil Study Summary: The goal of this project was to develop reliable, rapid, inexpensive techniques for the determination of key contaminants within the cannabis plant. For the purposes of this study we collected 25 different CBD oil samples from 15 different vendors across the country. Analysis showed that heavy metals were not present in the samples within the detection limits of the WDXRF instrument. However, analysis did identify the presence of trace amounts of silicon in at least 12 of the 25 samples measured. Presumably, due to the low concentrations of microplastics in the samples, no characteristic endothermic phase transition temperatures were observed for the samples.

Study Summary: This project created a dynamic data visualization tool and linkable database to crossreference cannabis-licensed physician practices, cannabis dispensary locations, and community-level and physician-level indicators of access and health.

We found that authorized physicians, overall and for select specialties, prescribed more opioids and more

2023 ANNUAL REPORT | 25

PI: MANDIP SINGH SACHDEVA, PHD Florida Agricultural & Mechanical University

distress, using Ecological Momentary Assessment (EMA) delivered via smartphone and surveys. To test our hypothesis, we recruited 15 patients with confirmed PTSD seeking to start MMJ for their PTSD symptoms Study Title: Hyaluronic acid from cannabis clinics in North-Central Florida and functionalized, Cannabidiol-loaded Mesenchymal Stem Cells (MSC)-Derived assessed them at different phases of MMJ treatment.

This pilot study confirmed that patients with PTSD on Exosomes for Drug Resistant Cancers MMJ could be recruited and retained in longitudinal Study Summary: About 10-14 % of all breast cancers are real-time monitoring research. Our preliminary analysis triple negative (TNBC), which represents an important also suggests that there might be improvements in sleep clinical challenge, as these tumors often develop and mental health well-being, and decreases in PTSD resistance to conventional chemotherapeutics. While symptoms and nightmares. cannabidiol (CBD) may have favorable effects, poor solubility and increased metabolism by cytochromes PI: JENNY L WILKERSON, PHD P450 enzymes limit the bioavailability of CBD. We University of Florida formulated exosomes derived from hUCMSCs with CBD. CBD Exosomes significantly decreased the proliferation Study Title: Marijuana- derived terpenes of MDA-MB-231 and MDA-MB-468 cells. We further for the treatment of chemotherapyfunctionalized these exosomes by using Hyaluronic induced pain acid (HA) and it was observed that these exosomes significantly decreased the proliferation of MDA-MB-468 Study Summary: Paclitaxel, commonly used to treat breast, lung and other cancers, can also produce cells with significant increase in G1 phase cell cycle persistent and debilitating side effects such as arrest when compared to CBD alone at similar doses. chemotherapy induced peripheral neuropathy (CIPN).

Anecdotal reports suggest marijuana may be an PI: JACQUELINE SAGEN, MBA, PHD effective analgesic. We examined the ability of a subset University of Miami of terpenes found in marijuana and found that each Study Title: Evaluation of medical terpene reversed pain-related behavior in paclitaxelmarijuana for the treatment of chronic treated mice. Cannabis-based terpenes possess a spinal cord injury pain using a rat central pharmacological profile that may yield new efficacious neuropathic pain model analgesics.

Study Summary: Although the most frequently reported use of MMJ is for pain relief, there has been a paucity of preclinical studies evaluating the effects of cannabis in chronic pain models. Chronic pain following spinal cord injury (SCI) occurs in a majority of patients and can be so severe that it is their top quality of life concern. The chronic SCI pain-reducing effects of CBD and beta-caryophyllen (BCP) were evaluated using a battery of behavioral tests for neuropathic SCI pain in both male and female rats with clip compression spinal injury. Results showed that the CBD/BCP combination synergistically reduced cold allodynia in both male and female rats with chronic SCI neuropathic pain. The combination produced additive effects in reducing tactile allodynia.

PI: KRISHNA VADDIPARTI, MSW, MPE, PHD University of Florida Study Title: A feasibility study of realtime monitoring of post traumatic stress disorder related sleep disturbances and other symptoms among patients on medical marijuana Study Title: The goal of this pilot grant was to evaluate the feasibility of recruiting and retaining patients with PTSD on MMJ in a prospective study and examine in real-time how MMJ affects PTSD related sleep disturbances and recovery from PTSD symptoms and

PI: ALI M. YURASEK, PHD University of Florida tudy Title: The Relationship between S State Medical Marijuana Laws, Substance Use and Mental Health Disorder Diagnoses, and Associated Health Care Costs Study Summary: Despite the potential of MMJ to assist with mental health conditions, marijuana use is also associated with increased participation in substance use treatment and risk for the development of psychosis and mood-related disorders. Yet, whether the passage of MMJ laws is associated with changes in substance use, mental health diagnoses or healthcare costs remains unclear. Our preliminary analyses examined the treatment costs associated with eight different mental health disorder diagnosis in 2012, including Opioid Use Disorder (OUD), Cannabis Use Disorder (CUD), Alcohol Use Disorder (AUD), Post-Traumatic Stress (PTSD) related disorders, Anxiety Disorders (AD), Depressive Disorders (DD), Psychosis related disorders (PD), and Sleep Disorders (SD). In 2012, states that passed MMJ laws had higher rates of OUD, CUD, AUD, PTSD, DD, and PD than those that did not yet pass MMJ laws. Similarly, the healthcare costs were significantly higher across all disorders examined in states with MMJ laws compared to those without MMJ laws.

26 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

Summaries for Studies Completed During the 2019–21 Grant Cycle continued 2020 Grant Awardees PI: HASSAN AZARI, PHD University of Florida Study Title: Hemp derived extracellular vesicles (EVs) for the treatment of glioblastoma Study Summary: Hemp EVs are nanoparticles that are naturally available in the hemp plant. We isolated and analyzed their cannabinoid content and potential therapeutic benefits in controlling tumor cell proliferation, death and invasion in human and murine glioblastoma (GBM) in tissue culture and in animal models. Hemp EVs effectively reduced GBM cell proliferation and invasion in tissue culture. Interestingly, intranasal delivery of hemp EVs into the brain tumor bed significantly delayed tumor growth and increased animal survival in an immunocompetent murine glioma model (KR-158-luc) but not in human L0 GBM xenotransplant (immunocompromised) model. With respect to the effects of hemp EVs on temozolomide (TMZ) chemotherapy, our results showed that hemp EVs might increase TMZ cytotoxic effects. Using hemp EVs together with TMZ therapy in animal model of GBM did not show any further benefits in reducing tumor growth or increasing animal survival. Measuring the amount of CBD-A in tumor bed showed that CBD-A concentration delivered via hemp EVs was much lower than the amount required to have a direct anti-tumor effect. Moreover, we found that cannabigerloic acid (CBG-A, the least abundant cannabinoid in our hemp EVs) accumulates in brain tumor tissue overtime. Overall, feasibility for large scale production, efficacious delivery of hemp EVs to the brain via the non-invasive intranasal route, possible anti-inflammatory effects of hemp EVs, and the increase in the survival of GBM tumor bearing animals, hold a great promise for future clinical utility of the hemp EVs. Patent Filed — US Provisional application for: Cannabinoid containing plant derived extracellular vesicles and therapeutic methods using the same

wheel activity) and metabolic energy expenditure. We were surprised to find that THC did not increase food intake in rats with ABA, but believe this may be related to the short duration of food access in the current study.

PI: DEBRA FADOOL, PHD Florida State University Study Title: Mechanisms of Action for Cannabidiol in a Mouse Model of Anxiety Study Summary: Given the over-thecounter accessibility of CBD and the fact that anxiety disorders are the most common type of mental illness in the United States, our objective was to assess the therapeutic potential of CBD for the treatment of anxiety, attention deficit, and ingestive disorders.

Our data demonstrate that acutely administered CBD decreases obsessive compulsive-like behaviors in male mice but has no effect in female mice. In terms of anxiety, wildtype female mice are responsive to a low dose of 10 mg/kg CBD and unresponsive to a high dose (20 mg/kg), whereas males required a higher dose to observe a significant reduction in anxiety-like behaviors.

Interestingly, in the Kv1.3-/- mice that are naturally more anxious, acutely administered CBD was anxiogenic (anxiety generating or producing) — it caused the mice to increase their anxiety-like behaviors rather than mitigating them.

PI: JASON FORD, PHD University of Central Florida tudy Title: Patterns, Motives, and S Risks Associated with Marijuana Use: A Comparison of Medical Marijuana Patients and Non-Patient Marijuana Users in Florida

Study Summary: The Florida Young Adult Cannabis Study (FYACS) is a study of young adult cannabis users, aged 18 to 34, in the state of Florida. Our findings show PI: LISA ECKEL, PHD that MMJ patients are older, more likely to be male, and Florida State University more likely to be a college graduate, employed, and have health insurance. Non-patient cannabis users (NPUs) Study Title: Cannabinoid medication reported initiating regular cannabis use at a younger age for treatment of a pre-clinical model of and consuming cannabis products more frequently. MMJ anorexia nervosa users used edible forms of cannabis more often and were also more likely to indicate micro-dosing or CBDStudy Summary: Anorexia nervosa (AN) is a serious psychiatric illness that disproportionately affects young dominant use. MMJ users were also more likely to report women during adolescence and early adulthood. Clinical health-related problems (e.g., pain, suicidal ideation), had higher rates of other substance use and were more practice shows that this eating disorder is treatment resistant, relapse rates are high, and full recovery occurs likely to indicate cannabis substitution (i.e., stopping/ reducing use of another drug and using cannabis in in less than half of AN patients. While various forms of its place). MMJ users were more likely to indicate they THC, including medical marijuana, have been shown operated a watercraft under the influence of cannabis. to improve appetite in patients with cancer and HIV Finally, we found evidence of cannabis diversion from infection, the therapeutic potential of THC in alleviating dispensaries as both MMJ users and non-patient users AN symptoms has received relatively little attention. reported buying/receiving cannabis from someone (e.g., In our rodent model of AN called activity-based anorexia dealer, friend, or family) who originally obtained the (ABA), we found that female rats receiving THC lost cannabis at a dispensary. less body weight and displayed increased survivability Interestingly, about 30% of NPU identify using cannabis in the ABA paradigm, relative to vehicle-treated rats. for exclusively or primarily medical reasons.

Interestingly, THC’s ability to attenuate weight loss in rats with ABA was due to decreases in exercise (running

2023 ANNUAL REPORT | 27

PI: JOHN MARKOWITZ, PHD University of Florida tudy Title: An Assessment of the S Drug Interaction Potential Between Oral Cannabidiol (Epidiolex®) and the CES1 Substrate Methylphenidate in Healthy Volunteers Study Summary: The use of MMJ includes the potential risk for potential drug-drug interactions (DDIs). This study assessed whether cannabidiol (CBD) could significantly inhibit the activity of the major hepatic enzyme carboxylesterase 1 (CES1), potentially resulting in significant interactions with drugs dependent on CES1 for clearance. In our open-label, placebo-controlled, crossover study in 12 healthy subjects, we assessed the influence of CBD (administered as Epidiolex®) on the disposition of the known CES1 substrate methylphenidate (MPH; Ritalin®). We noted an increase in area under the plasma concentration curve (AUCtotal) of MPH in eight of the 12 subjects. However, when the mean MPH values for all 12 subjects were examined with and without CBD concurrent use, the two conditions were approximately bioequivalent i.e., suggesting a significant DDI did not occur.

PI: DAVID NEWMAN, PHD Florida Atlantic University

PI: MANDIP SACHDEVA, PHD Florida Agricultural & Mechanical University tudy Title: Preclinical evaluation of S exosomal cannabinoid formulations in chemotherapy induced peripheral Neuropathy Study Summary: Paclitaxel (PTX) is widely used for Triple negative breast cancer (TNBC) and PTX-induced peripheral neuropathy (PIPN) is a major clinical concern for patients. We evaluated the effects of CBD exosomes in PTX induced neuropathic mice. CBD and CBD-exosomes treatments significantly displayed improvement in neurobehavior of paclitaxel induced neuropathic animals. In our animal model, thermal and mechanical sensitivity was considerably reduced after six weeks in PTX induced neuropathic animals when compared to control animals. The decrease in tail flick and paw withdrawal latencies (parameters to assess neuropathy) with hot stimulus and IR radiation respectively were significantly reversed when treated with CBD and CBD-exosomes.

PI: DOUGLAS STORACE, PHD Florida State University Study Title: The influence of cannabinoid receptors on olfactory function

Study Title: Assessing and Supporting Effective and Safe Use of Medical Marijuana for Older Adults with Chronic Pain

Study Summary: Cannabinoids play an important therapeutic role in the stimulation of appetite.

One potential mechanism underlying these changes in food-seeking behavior is the modulation of sensory Study Summary: This study recruited 131 MMJ input. We determined the impact of both exogenous participants to obtain information on patterns of use, and endogenous cannabinoids on olfactory sensitivity in safety concerns, education, and MMJ’s effectiveness in mice. The infusion of WIN 55212 (CB1 receptor agonist) reducing pain. The overall finding indicated that there directly to the olfactory bulb caused a decrease in were some side effects, with the largest side effect being sensitivity while an intraperitoneal injection of the same an in increased appetite (22.3%). This was followed by drug caused no change in sensitivity. We also found that lethargy (14.0%), elevated mood changes (12.4%), lack the infusion of a CB1 receptor antagonist directly into of concentration (11.6%) and dizziness (9.1%). There the olfactory bulb had no effect on sensitivity. This result was a statistically significant decrease in reported pain challenges the current theory regarding the effect of from prior to after MMJ use, with an average decrease cannabinoids on olfactory perception in the mouse and of 52.7% in total pain. Participants reported that most highlight some potential similarities with humans. of the information about MMJ use comes from the MMJ provider (52%) with an average time lasting less than PI: ROBERTO VINCIS, PHD 20 minutes.

Florida State University Study Title: Endocannabinoid mechanism in the neural processing of foodpredicting sensory cues Study Summary: In recent years, the endocannabinoid system (ECS) has emerged as one of the most important neuromodulatory systems involved in the regulation of food intake, gathering significant attention as a promising therapeutic target in eating disorders. We investigated the role of cannabinoid modulation of the mouse Insular Cortex (IC), a cortical area known to process motivationally salient stimuli associated with food reward cues and driving food-oriented behaviors.

Due to the COVID-19 pandemic and the complicated nature of the experiments, experiments are not yet completed.

28 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

Summaries for Studies Completed During the 2019–21 Grant Cycle continued including physician and patient education, case series to identify high risk and common adverse drug events, and PI: JENNIFER ATTONITO, PHD an initial tool to build a drug interaction checking tool. This Florida Atlantic University work will impact patients and providers by providing a Study Title: Acceptance of and access to resource for informed decision-making on potential risks medical marijuana and CBD as a palliative specific to adverse drug events and drug interactions. care and hospice treatments for nursing home patients PI: ANDREA CIPPITELLI, PHD

2021 Grant Awardees

Study Summary: We examined associations between Florida long-term care (LTC) providers’ knowledge of MMJ effects, contraindications, dosing, and prescribing/ procuring processes; attitudes, and beliefs surrounding use of MMJ for their patients; barriers to accessing MMJ to treat patient symptomatology; and regional, institutional, and economic factors that may be linked to barriers to accessing MMJ in LTC. We surveyed 126 clinicians and interviewed 25 patients in nursing homes and assisted living facilities. Respondents expressed that major barriers to utilization existed, such as lack of education/training and clinical guidelines. Some participants considered MMJ and recreational MJ use to be similar. Patients interviewed reported that they have not been offered MMJ by their providers and are unfamiliar with the procedures for obtaining a MMJ card. Still a schedule 1 drug at the federal level, providers in long-term care settings rely on Medicare dollars for patient care, and are leery of losing reimbursement.

Further, evidence on MMJ clinical research outcomes and guidelines are not effectively disseminated to care providers.

PI: JOSHUA BROWN, PHARMD, PHD, MS University of Florida Study Title: Characterizing adverse drug events reports involving cannabis and cannabinoids Study Summary: This project utilized an untapped resource in cannabis research, the U.S. Food and Drug Administration’s (FDA) Adverse Event Reporting System (FAERS). FAERS is the FDA’s primary pharmacovigilance tool to detect medication safety and conduct causality assessments. We evaluated over 15,000 adverse event reports from FAERS that included cannabis or cannabinoids used for medical purposes or recreationally.

Over 500 adverse drug events (“reactions”) were represented among 200 different product names. The ultimate objective of this work was to produce a data product that is a comprehensive reference of possible adverse drug events with these products. Toward this goal, our team: 1) Identified adverse drug reports involving cannabis or cannabinoids; 2) Characterized report attributes including patient information, reporter type, concomitant medications, reactions, and outcomes; and 3) Identified implicated drug interactions and other pharmacological mechanisms contributing to the reactions. Our final data product is the most comprehensive reference for cannabis and cannabinoid drug interactions that can be leveraged for multiple uses

Florida Atlantic University Study Title: Investigating cannabidiol anti-headache actions through PPAR signaling Study Summary: Current therapeutics for migraine include preventive approaches, which help prevent attacks from happening, and acute treatments, used to help get rid of the attack. By modeling a migraine-like state in mice, we demonstrate that cannabidiol blocks head sensitivity when injected prior to or after the migraine-triggering substance Calcitonin gene-related peptide (CGRP), suggesting that cannabidiol can be effective both as a preventive tool and as a treatment for headaches. CBD also reduced head sensitivity in female mice, in a chronic migraine model, indicating that CBD could be effective in preventing chronic migraine, which represents approximately 2% of the population.

PI: LISA ECKEL, PHD Florida State University Study Title: Cannabinoid modulation of neuroinflammation in a pre-clinical animal model of anorexia nervosa Study Summary: Our group is interested in the endogenous cannabinoid system as a novel therapeutic target for anorexia, based on its involvement in regulating food intake, energy expenditure, and immune function, all of which are dysregulated in anorexic patients. We found that THC treatment slowed the weight loss associated with activity-based anorexia, in a pre-clinical animal model of anorexia, called activitybased anorexia, and that this improved outcome was mediated primarily by a decrease in exercise (running wheel activity), rather than an improvement in appetite.

We also demonstrated that rats with activity-based anorexia develop inflammation in brain areas that control food intake and regulate body weight, and that THC can attenuate this neuroinflammatory response.

This pre-clinical study investigating the therapeutic potential of THC in alleviating inflammation and other core symptoms of activity-based anorexia in female rats offers a translational model for the development of new cannabinoid-based pharmacotherapies, including the use of medical marijuana.

2023 ANNUAL REPORT | 29

PI: MARIOLA EDELMANN, PHD University of Florida Study Title: The role of endocannabinoids and cannabinoids in the clearance of bacterial infections and macrophage polarization Study Summary: This study aimed to determine if synthetic cannabinoids (CBs) can modify innate immune responses directed against Salmonella typhimurium and maintain homeostasis during this highly inflammatory infection. We aimed to demonstrate that synthetic cannabinoids prime macrophages towards a more phagocytic and less inflammatory M2 phenotype to support bacterial clearance and reduce inflammation.

We tested multiple CB compounds in murine bone marrow-derived macrophages in ability to suppress the TNF-alpha upon infection with S. typhimurium, where THC-mimicking WIN 55,212-2 completely reduced proinflammatory cytokines during Salmonella infection. To validate the data, we infected RAW264.7 macrophages with S. typhimurium, followed by exposure to several concentrations of WIN55,212-2, and this CB completely blocked proinflammatory TNF-alpha responses. We evaluated the effect of CBs on bacterial clearance, where WIN55,212-2 increased bacterial clearance. However, there was no direct suppression of Salmonella’s growth by WIN 55,212-2. Overall, our results suggest that CBs decreases inflammation and promote pro-phagocytic functions during Salmonella infection.

PI: DEBRA FADOOL, PHD Florida State University Study Title: Early Developmental Mechanisms of Action for Cannabidiol (CBD) in a Mouse Model of Anxiety Study Summary: Given the over-the-counter accessibility of CBD and the fact that anxiety disorders are the most common type of mental illness in the United States, we assessed the therapeutic potential and safety of perinatal CBD use for the treatment of anxiety, attention deficit, and ingestive disorders in the offspring as adults. We hypothesized that CBD might be anxiolytic (lessening anxiety) for adult offspring when orally administered to pregnant dams in a newly found mouse model having trait anxiety and attention deficits (Kv1.3-/- mice). We also hypothesized that exposure to CBD during pregnancy could result in anatomical restructuring of neuronal circuits and their communication networks, called synapses, and that these networks would show an increase in electrical excitability when mice were raised to adults. We have discovered that CBD may not be safe during pregnancy.

Fetal exposure to CBD significantly decreased survival of the pups — 62% of CBD-treated pups die before weaning age (23 days) whereas only 9% of jam-treated pups die prior to weaning. When the offspring were raised to adults, CBD exposure in utero turned out to be anxiolytic in females — the adult mice were less anxious even though they remained drug free as adults. This did not occur for males. However, for both females and males, the mice exhibit increased obsessive compulsivelike (OCD) behaviors, and this behavior was not lessoned

by cross-fostering in the males. While ADHD behaviors are not affected by in utero CBD exposure, female mice had a reduction in long-term object memory.

Developmental changes in the brain were also observed in response to CBD exposure.

PI: SIMONE MARINI, PHD University of Florida Study Title: CBD-induced biomarkers of inflammation reduction in people living with HIV at the single cell level Study Summary: Chronic inflammation is a common condition for People living with HIV (PLWH). Cannabis sativa (marijuana) and its cannabinoid derivatives, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are largely used by PLWH to stimulate appetite, prevent weight loss (FDA approved Marinol or Dronabinol), or manage chronic pain. While THC exhibits psychotropic effects, CBD does not, though its impact on health outcomes in PLWH remains understudied. This study was designed to investigate cellular type/state alterations associated with CBD. We used human peripheral blood mononuclear cells (PBMCs) obtained from PLWH following a CBD oral treatment (67 mg/day for 27 to 60 consecutive days). We compared the gene expression as baseline (before CBD) and after CBD treatment. Our data suggests that a group of genes is under-expressed after CBD treatment in myeloid cells, including monocytes and granulocytes. Both monocytes and granulocytes play a pivotal role in the inflammatory process, and the great majority of the genes emerging from our analysis plays a well-known pro-inflammatory role, such as JUN and FOS. Gene network analysis indicates that the genes associated with CBD treatment, differently from randomly selected genes, show statistically significant interactions.

These interactions further confirm the coherent nature of the gene group, indicating how they may act in concert in reducing the inflammatory processes after CBD treatment. As chronic inflammation is a condition common to a plethora of different diseases, this study is a first step towards the understanding of how CBD can be used for anti-inflammatory therapeutic strategies in general, not just for PLWH. PI: MANDIP SACHDEVA, PHD Florida A&M University Study Title: Evaluation of Minor Cannabinoids loaded Exosomes in Chronic Diabetic Neuropathy Study Summary: Diabetic peripheral neuropathy (DPN) is one of the most common causes of neuropathy in the United States, affecting 60-70 percent of diabetic patients. Nonpsychoactive phytocannabinoids like cannabidiol (CBD), Tetrahydrocannabivarin (THCV), and cannabigerol (CBG) have recently received a lot of attention for reducing pain associated with a variety of conditions, but their stability and bioavailability issues have limited their research in human subjects. We previously optimized cannabidiol loading in extracellular vesicles derived from human umbilical cord derived stem cells/stromal cells (hUCMSCs-EVs) grown in

30 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

PBS-vertical wheel (PBS-VW) bioreactors, and our formulations demonstrated excellent neuroprotection against chemotherapy-induced neuropathy. Little research has been done on the effects of these drugs on diabetic neuropathic pain. Therefore, we sought to investigate the effects of these drugs in hUCMSCs-EVs formulations on STZ-induced diabetic neuropathy in rats and DRG primary neuronal cells exposed to high glucose concentrations. We developed a STZ-induced diabetic neuropathic model in rats and used neurobehavioral and nerve functional parameters to screen these drugs against diabetes-induced pain in rats. These drugs were administered (i.p) to neuropathic rats for four weeks after six weeks of diabetes induction at two different doses (10 and 20 mg/kg) based on the published literature, and these drugs significantly improved mechanical and thermal hyperalgesia and nerve blood flow in diabetic rats. The results from our laboratory demonstrate the role of phytocannabinoids, cannabidiol (CBD), Tetrahydrocannabivarin (THCV), and cannabigerol (CBG) in alleviating diabetic induced neuropathic pain via various anti-inflammatory and mitochondrial pathways.

PI: JACQUELINE SAGEN, PHD, MBA University of Miami Study Title: Alleviation of phantom limb pain in a rat model by treatment with components of Cannabis Study Summary: The study evaluates the potential for Cannabis components to manage intractable phantom limb pain using a preclinical phantom limb pain model.

Results of this study indicated that both prevention of phantom limb pain onset following a traumatic complete sciatic nerve transection, and reversal of phantom limb pain progression once initiated, can be amenable to daily treatment with a combination of cannabis components.

In particular, a low dose of ∆9-tetrahydrocannabinol (THC) together with a synergistic combination of cannabidiol (CBD) and terpene β-caryophyllene (BCP), can significantly block the onset of phantom limb pain symptoms. The combination of all three of these components can also significantly attenuate further progression of phantom limb pain severity once it has begun. These findings support the clinical potential for MMJ use for alleviation of debilitating phantom limb pains.

PI: JENNY WILKERSON, PHD AND JOSHUA BROWN, PHARMD, MS, PHD University of Florida Study Title: Translational examination of the pharmacological interactions of medical marijuana with neuropathic pain analgesics in both young and older adults Study Summary: Paclitaxel, commonly used to treat breast, lung and other cancers, can also produce persistent and debilitating side effects such as chemotherapy induced peripheral neuropathy (CIPN). Anecdotal reports suggest marijuana may be an effective analgesic. The primary constituent of marijuana, Δ-9 tetrahydrocannabinol (THC), produces

most of its physiological actions via cannabinoid type 1 receptors (CB1R), predominately distributed on neurons, and cannabinoid type 2 receptors (CB2R), predominately distributed on immune cells. Our study examined the impact of two major variables, sex and age, on the potency of cannabis to relieve pain-related behaviors caused by CIPN, as well as analgesic drugTHC interactions. Results from our studies show that in both young and aged female mice, when compared to their aged matched male cohort, THC, morphine, and gabapentin all have small but significant increased potency to attenuate CIPN-related behaviors. Likewise, in younger mice of both sexes’ THC, morphine, and gabapentin have increased potency to attenuate CIPNrelated behaviors. Current studies are examining the impact that this change in potency may have on the interactive effects of THC when combined with CBD, morphine, and gabapentin. These data confirm the original hypothesis that age and sex both likely play important roles in the translational use of medical marijuana for pain as well as other standard analgesics.

PI: ELLEN ZIMMERMANN, MD University of Florida Study Title: The Effect of Delta9-tetrahydrocannabinol (THC) on Intestinal Inflammation and Fibrosis in Experimental Crohn’s disease Study Summary: Cannabis has been shown to improve quality of life and reduce the negative symptoms of Inflammatory Bowel Disease (IBD) however, clinical research also finds a strong correlation between cannabis use and the need for intestinal surgery in Crohn’s Disease (CD) patients. One explanation could be the psychoactive effects of cannabis might be masking symptoms of CD without improving, or potentially even worsening, the underlying intestinal inflammation and fibrosis. To separate perceived symptom improvement from objective biological effects, we chose to test the most abundant psychoactive cannabinoid found in cannabis, delta-9-tetrahydrocannabinol (THC). Our preliminary data using isolated human cells showed THC to have differential effects with the potential to either improve or worsen fibrosis. In order to obtain data most relevant to our translational goal of guiding patients and clinicians, we used a well-established animal model of IBD to test the effectiveness of THC-treatment, which was able to recapitulate many of the indicators of human disease (weight loss, reduced red-blood cell volume, increased expression of inflammatory and fibrotic genes). Any effective treatment would prevent or reverse these disease indicators. THC treatment had mixed efficacy with little to no effect on hematocrit and colon length, but altered gene expression consistent with previous data in human cells. Surprisingly, THC was found to have a suppressive effect on normal weight gain in healthy mice, and exacerbated colitis-associated weight loss in treated mice. This surprising result raises new questions and potentially new research paths as research continues.

2023 ANNUAL REPORT | 31

Ongoing Studies from the 2022 Grants Cycle PI: NAUEEN CHAUDHRY, MD University of Florida

PI: ROBERT DVORAK, PHD University of Central Florida

Study Title: Cannabinoid use in young adults with Crohn’s Disease

Study Title: Event-level changes in psychiatric and physical symptoms following medicinal cannabis use in older adults

Project Narrative: College-aged patients with Inflammatory Bowel Disease (IBD) are a vulnerable population with unique needs during their transition from their home town to college with changes in their support system, medical care and new academic and social challenges. In this study, we are using a mixed methods approach to study how college-aged students will differ in their attitudes and cannabinoid use patterns than an older cohort, and hence may also experience different outcomes.

Anticipated Impact: Emerging adults, although physically developed, remain in an emotional, cerebral and psychological developmental phase during this crucial part of their life. A sharp increase in marijuana use has been reported in this age group. Our study, with the additional layer of qualitative data will provide valuable insights into the patterns and outcomes of marijuana use in young college-aged adults with Crohn’s Disease.

PI: RODRIGO CRISTOFOLETTI, PHD University of Florida Study Title: Quantitative assessment of complex drug-drug interaction networks involving medical cannabis products in special populations Project Narrative: 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, 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.

Anticipated Impact: Qualifying conditions to get access to medical cannabis in Florida are 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 these complex patients.

Project Narrative: Little is known about the immediate effects of medical cannabis use on clinical symptoms in real time. This study will examine the changes in both physical and mental health symptoms after medical cannabis use in older adults. Participants will use their mobile phones to report on symptoms throughout the day to determine the magnitude of changes in symptoms from pre- to post-medical cannabis use.

Anticipated Impact: Results from the current study will provide guidance on symptoms that are, or are not, amenable to medical cannabis use, and help guide prescription recommendations for providers to reduce polypharmacy related issues.

PI: DEBRA FADOOL, PHD Florida State University Study Title: Long-term molecular, metabolic and behavioral consequences of perinatal exposure to cannabidiol (CBD) — a safety and efficacy study Project Narrative: Individuals seek CBD during pregnancy to reduce stress, nausea, and anxiety but the impact of CBD on cognitive development and longterm health/mental health consequences is not known.

We want to understand the effects of perinatallyadministered CBD in mice in terms of offspring health, growth, and pup/dam interactions. We have designed experiments that will monitor long-term health consequences of fetal-exposed pups once raised to adults, that will measure glucose metabolism, energy homeostasis, and memory and attention behaviors, and whether modifications in gene expression are associated with long-term metabolic or psychiatric changes.

Anticipated Impact: Cannabis products cross placental membranes to enter fetal circulation, in fact, postpartum sampling of umbilical cords in women have indicated higher cannabis use than reported by survey — upwards to 22% for pregnant mothers in the USA. Our study will examine health outcomes of offspring exposed to CBD in utero, where we will examine how gestational exposure produces molecular changes in brain-region specific gene transcription that may increase obsessivecompulsive behavior and decrease long-term memory as adults.

32 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

PI: VARAN GOVIND, PHD University of Miami Study Title: 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 Project Narrative: 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.

Anticipated Impact: 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.

PI: WALTER STEIGLEMAN, MD University of Florida Study Title: Randomized, controlled cross-over comparison of cannabidiol to oral opioid for postoperative photorefractive keratectomy pain control Project Narrative: Photorefractive keratectomy (PRK) is a refractive eye surgery like LASIK with excellent outcomes and long-term stability. However, PRK involves longer healing and more pain than LASIK, often requiring treatment such as oral opioid medications to control. A substantial fraction of patients who develop addiction to opioid medications start with a legitimate prescription for postoperative pain. In this study, we will evaluate if an oral CBD product can offer similar pain relief to current standard therapy with an opioid medication.

Anticipated Impact: The impact of our study will inform the ophthalmology community about cannabidiol influence on postoperative PRK pain control. If we find similar efficacy, we should be able to reduce future opioid use for this surgery. This will be among the first reported studies evaluating CBD for eye/ocular pain.

PI: EVA WIDERSTROM-NOGA, PHD University of Miami Study Title: Effects of cannabidiol on resting state EEG and neuropathic pain severity in people with spinal cord injury

PI: LORI KNACKSTEDT, PHD University of Florida

Project Narrative: Although some individuals with spinal cord injury (SCI) who experience neuropathic pain Study Title: A translational animal model report beneficial effects of marijuana, there is limited research regarding the analgesic impact of Cannabidiol to study neurobehavioral consequences of THC and oxycodone polysubstance use (CBD) after SCI. Endocannabinoid receptors are common in areas of the brain that are involved in the pain experience and therefore it is likely that CBD modulates Project Narrative: Our proposed research will use a brain activity. However, the effect of CBD on neuropathic rodent model of sequential oxycodone and cannabis pain symptoms and its relationship with brain intake to investigate the effects of opioid-cannabis electrocortical activity in people with SCI is incompletely polysubstance use on opioid-seeking, anxiety and the potential effects of the route of cannabis administration known. We will investigate the analgesic effects of a single CBD dose and associated brain changes using (inhaled smoke or ingested “edibles”) on these electroencephalography. measures.

Anticipated Impact: The ability of cannabis to influence opioid intake has not yet been assessed in either humans or animals, and thus the use of experimental models to do so will have the advantage of careful control of drug availability, route of administration and the timing of seeking and anxiety assessments. This work will potentially impact policy regarding the use of medical marijuana for the treatment of opioid use disorder, as is currently legal in several U.S. states.

Anticipated Impact: As far as we know, no studies have examined changes in neuropathic pain symptoms and resting state electrocortical activity following oral full-spectrum CBD oil administration. This study will provide important information regarding if a single CBD dose produces analgesic effects in those who experience neuropathic pain after their SCI and if these are associated with electrical changes in the brain. It will also serve as a basis for a larger, high-quality clinical trial to evaluate the effects of long-term CBD treatments in people who experience neuropathic pain after their SCI.

2023 ANNUAL REPORT | 33

MMJ CLINICAL OUTCOMES RESEARCH DATA REPOSITORY (MEMORY) The growing uptake of MMJ in Florida offers a unique opportunity for real-world evaluations of MMJ outcomes that can help overcome the slow availability of randomized clinical trials and provide timely evidence on MMJ risk benefit. MEMORY has been conceived to establish the infrastructure for real-world MMJ clinical outcomes evaluations similar to those employed by the FDA to evaluate and monitor the risk-benefit of prescription medications after marketing MEMORY will support: • controlled studies on MMJ effectiveness and safety • active surveillance to capture emerging safety issues involving individual products or generalized effects among MMJ users • MMJ utilization studies on MMJ access and utilization pattern across Floridians To ensure comprehensive longitudinal follow-up to capture relevant health outcomes and availability of control groups, the Consortium aims to link the Office of Medical Marijuana Use (OMMU) Medical Marijuana Use Registry (MMUR) with other clinical databases commonly used for outcomes research to create a robust research-ready repository. The planned linkages will optimize detail on MMJ use (type, dose, route, from the MMUR) and detail on patient health history, other treatments and outcomes (from linked clinical encounter data), and facilitate controlled longitudinal studies on safety and effectiveness outcomes. Importantly, via linkage to other clinical databases including pharmacy dispensing records, we will be able to establish control groups to facilitate comparisons of outcomes among patients who have initiated MMJ and patients with similar conditions and health history who are relying on conventional therapeutic approaches alone.

MMJ Clinical Outcomes Research Repository: MEMORY

The Consortium plans to make a de-identified version of the repository available to Consortium researchers, thus providing state-wide infrastructure for real-world clinical outcomes research.

34 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

Memory Development — Progress Towards Core Milestones MEMORY development involves several milestones including: • Regulatory approvals • Data acquisition, curation and linkage, resulting in a well-documented longitudinal database of patients who initiated MMJ and adequate control groups who have not (yet) initiated MMJ, • Provision of adequate study cohort data for researchers along with analytical support, and • Policies and procedures to access and use the data.

Regulatory approvals for the access to identifiable claims data from the Agency for Healthcare Administration (AHCA) and the Centers for Medicare and Medicaid Services (CMS) and to vital statistics data from the Department of Health Vital Statistics Offices have been obtained. On January 30, 2023, the Consortium received approval by the Department of Health OMMU to access the MMUR. The University of Florida Institutional Review Board (IRB) has approved the development of MEMORY and related research aims. After receipt of the OMMU DUA, the same application has now been submitted to the Department of Health IRB and is pending approval.

UF IRB approved (2021)

DoH Vital DUA approved (2022)

AHCA & CMS Medicaid DUA approved; data received (2022)

Data curation & architecture plans drafted (2021-22)

OMMU DUA approved (2023)

DoH IRB under review

The MEMORY data science team has developed the data architecture and the data dictionary that will define variables after final data acquisition. The data dictionary contains specifications for all variables that are accessible to Consortium researchers within a deidentified longitudinal dataset. The data architecture has been specified to include cohorts of MMJ initiators whose MMJ utilization data is overlaid with healthcare utilization and outcomes data from claims and vital data. Control cohorts are customized and matched based on MMJ patients’ study entry.

With the final approval of MMUR data release, the Consortium is now in the position to expedite data linkages and launch studies on MMJ clinical outcomes. We expect that a first set of studies has been completed by the time of the next annual report in 2024.

2023 ANNUAL REPORT | 35

CLINICAL RESEARCH CORE The Clinical Research Core establishes infrastructure support for prospective studies including randomized controlled trials. Support services in collaboration with the Clinical and Translational Science Institutes (CTSIs) at UF, the University of Miami and Florida State University, include assistance with patient recruitment, data collection or analysis, clinical research study design, support with regulatory issues (with FDA or DEA), and access to laboratory experts for product analysis. The Clinical Core also provides three specific resources to support clinical outcomes research: its Patient Contact Registry, the “Medical Marijuana & Me (M3)” Patient Cohort, and a database of research collaborators (CARMMA).

MMJ Contact Registry The MMJ contact registry facilitates patient recruitment for future research on MMJ clinical outcomes. The registry was approved by the University of Florida IRB in November 2020. As of January 2023, 1,393 current or prospective MMJ users across the state are enrolled in the contact registry. Clinics participating in recruitment and the geographic location of enrolled patients is similar to the current geographic distribution of MMJ clinics and dispensaries.

36 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

Medical Marijuana & Me (M3) In May 2022, the Consortium launched Medical Marijuana & Me (M3) (mmjoutcomes.org/m3study/), the first large MMJ patient cohort in Florida, and one of the first in the United States. M3 will provide detailed patient-reported data on MMJ utilization and outcomes to enhance our understanding of patient experiences with MMJ. The strategic goals for Medical Marijuana & Me are to: • collect patient-centered data, focusing on the most common health conditions, to characterize the experiences and clinical outcomes among a diverse and representative group of MMJ users in Florida.

M3 data domains

• provide access to data and recruitment infrastructure for consortium researchers to support pilot studies, papers, and grant proposals.

• support high-quality, impactful research that can inform state policy, clinician practice and patients.

Participants complete a sequence of surveys assessing the M3 data domains including general health, use and experiences with MMJ, and related health outcomes. As of January 2023, M3 has recruited a total of 1001 patients: 369 new MMJ users and 632 current users.

M3 participants cover a broad range of ages and racial/ethnic groups. Top patient-reported reasons for MMJ use include anxiety, depression, insomnia, chronic pain and PTSD. Mean Age (SD)

43 (14)

Sex at Birth Female

63%

Male

37%

Ethnicity/Race White

78%

Black/African American

13%

Hispanic

12%

Other

9%

M3 Participant Demographics (N=966)

Main Reasons for MMJ Use (75% of respondents selected multiple reasons for using)

Recruitment of the current user cohort has finished, and data are currently curated.

Researchers will soon have the opportunity to access cross-sectional data from M3. The Data access request application has been opened for submissions. More information, and a summary of research studies that has already been approved, is available at mmjoutcomes.org/m3study/

2023 ANNUAL REPORT | 37

M3 design has been guided by a scientific planning committee consisting of 11 members, including six researchers from consortium member universities, four MMJ physicians, and one MMJ patient representative.

SCIENTIFIC PLANNING COMMITTEE MEMBERS — M3 (MMJ PATIENT COHORT) PARTICIPANT

INSTITUTION

ROLE ON PLANNING GROUP

George Burgess

University of Florida

MMJ Patient Liaison

John Crump, MD

Releafe Now

Certified MMJ Provider

Justin Davis, MD

Florida Marijuana Doctors

Certified MMJ Provider

Jason Ford, PhD

University of Central Florida

MMJ Researcher

Raul Gonzalez, PhD

Florida International University

MMJ Researcher

Patricia Green-Powell, PhD

Florida A&M University

MMJ Researcher

Dushyantha Jayaweera, MD

University of Miami

MMJ Researcher

Jonathon Quinonez, DO

CannaMD

Certified MMJ Provider

Martha Rosenthal, PhD

Florida Gulf Coast University

MMJ Researcher

Denise Vidot, PhD

University of Miami

MMJ Researcher

Michelle Weiner, DO, MPH

Spine Wellness America

Certified MMJ Provider

The following clinics and practitioners have served as participant recruitment sites for M3: Affordable Marijuana Licenses, Dr. Bob’s Compassion Clinic, Dr. Justin Davis, MD, Dr. Melanie Bone, MD, CannaMD, Green Health & Wellness, Releafe Now, ReliefMD, and Spine & Wellness Centers of South Florida.

38 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

CARMMA The Consortium launched the Connect and Advance Research for Medical Marijuana Analysis (CARMMA) Database to connect researchers, physicians, and industry collaborators with the goal to increase and accelerate MMJ research. Researchers, physicians, and industry collaborators can add their contact information and connect with other researchers, physicians, and industry collaborators at any time. As of January, 2023, CARMMA has 26 researchers, nine physicians, and six industry collaborators and can be accessed at mmjoutcomes.org/collaborate/carmma/.

EVIDENCE CORE The evidence core focuses on the synthesis and dissemination of scientific evidence for researchers, providers and patients.

Evidence core activities include publication of its Evidence in Context series, provision of scientific expertise as needed by Consortium researchers, clinicians, policy-makers and other stakeholders and development of evidence reviews to inform the Consortium research priorities. A new and prominent activity of the Evidence Core that has recently started includes the provision of an evidence synthesis on cannabis riskbenefit to the FDA to support the agency’s recommendations for either maintaining or revising the current Schedule I classification for cannabis.

Evidence in Context Series The evidence base for medical cannabis and cannabinoids continues to evolve rapidly while researchers, healthcare providers, and patient communities remain in need of clear translation of study findings to future or current implications for clinical practice. The “Evidence in Context” series addresses these needs for rapid distillation and appraisal in the form of brief, plain-language commentaries. These articles are available in the scientific journal Medical Cannabis and Cannabinoids and on the Consortium websites and both of these publication platforms are fully accessible to all members of the public, as the journal uses an open-access publishing format. To date, the journal has published seven articles within this series accessible at mmjoutcomes.org/evidence/evidence-in-context/ and linked to in the Bibliography section. No such resource was previously available specifically for MMJ.

2023 ANNUAL REPORT | 39

The three new articles since the last report are as follows:

Cannabis Effects on Driving Performance: Clinical Considerations Brianna Costalesa,b Shanna L. Babalonisc Joshua D. Browna,b, Amie J. Goodina,b a Consortium for Medical Marijuana Clinical Outcomes Research, University of Florida, Gainesville, FL, USA; bCenter for Drug Evaluation and Safety (CoDES), Department of Pharmaceutical Outcomes and Policy, University of Florida, Gainesville, FL, USA; cDepartment of Behavioral Science, College of Medicine, University of Kentucky, Lexington, KY, USA

Key Points • Driving under the influence of cannabis has been identified as a public health concern as medical and recreational cannabis availability increases in some countries.

• A recent randomized clinical trial found similar levels of acute driving impairment with THC-dominant cannabis and with a combination of THC-CBD equivalent cannabis using on-road driving tests that provided real-world conditions; however, CBD-dominant cannabis did not produce significant cognitive or psychomotor impairment compared with placebo in this trial.

• Media coverage of this study conveyed the findings as CBD-dominant cannabis not causing driving impairment while THC-dominant cannabis does, with the latter lasting up to 4 h post-dose.

• It is recommended that clinicians counsel about the risks of driving impairment when patients disclose use of cannabis products containing THC.

Clinical Considerations for Cannabis Use and Cardiovascular Health Ruba Sajdeyaa,b Sebastian Jugla,c Robert Cooka,b Joshua D. Browna,c Amie Goodina,c Consortium for Medical Marijuana Clinical Outcomes Research, University of Florida, Gainesville, FL, USA; Department of Epidemiology, University of Florida, Gainesville, FL, USA; cCenter for Drug Evaluation and Safety (CoDES), Department of Pharmaceutical Outcomes & Policy, University of Florida, Gainesville, FL, USA

a b

Key Points • The American Heart Association (AHA) released a scientific statement critically reviewing the evidence available on cannabis safety and efficacy profile related to cardiovascular health and provided a guide for clinicians regarding the current legal status, health implications, therapeutic possibilities, and clinical interventions among patients who use cannabis.

• The cardiovascular effects of cannabis can vary based on the dose and timing of exposure, potency, and formulations of products, route of administration, and concurrent use of other drugs. Clinical assessment of patients who use cannabis should include a comprehensive evaluation of cannabis use or

40 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

exposure and determination of the risk for adverse cardiovascular effects and potential drug-drug interactions, especially among patients with underlying cardiovascular comorbidities.

• Clinical interventions among patients with a higher risk of cannabis-related cardiovascular adverse events include, but are not limited to, patient counseling to modify cannabis use patterns when heavy use or cannabis use disorder is identified, patient education about dose titration to reduce severe side effects, eliminating or reducing THC-containing products among patients with underlying cardiovascular diseases who may have a higher risk of adverse cardiovascular events, and assessing the risk of drug-drug interactions.

• The complexity and variability of cannabis products, the presence of other cannabinoids and chemicals, intraindividual and interindividual use pattern variations, and lack of sufficient information disclosed by patients due to legal and social concerns can stand as barriers to clinical interventions to reduce the potential for drug-drug interactions, even when guidelines are available

Will Cannabis or Cannabinoids Protect You from SARS-CoV-2 Infection or Treat COVID-19?

Joshua D. Browna,b Amie J. Goodina,b a Consortium for Medical Marijuana Clinical Outcomes Research, University of Florida, Gainesville, FL, USA; bCenter for Drug Evaluation and Safety (CoDES), Department of Pharmaceutical Outcomes & Policy, University of Florida, Gainesville, FL, USA

Key Points • A recent study reported that two cannabinoids, cannabidiolic acid (CBDA) and cannabigerolic acid (CBGA), could block cellular entry of the virus that causes COVID-19 during in vitro experiments using cell cultures in a laboratory • There is a low likelihood of translating these preclinical research findings to cannabinoid-based therapies due to clinical and pragmatic concerns with dosing that render CBDA and CBGA (as well as other cannabinoids) to be unlikely candidates for further drug development. These include, for example, a short half-life of CBDA, requiring frequent dosing intervals; high doses required at each interval to match the inhibitory concentrations studied; and high cost and lack of availability of CBDA and CBGA. • Replicating the observed effects in the complex human body is unlikely due to the interplay of these compounds within the endocannabinoid system, and there are known and hypothesized safety concerns for the doses required.

• Cannabinoids, including CBDA and CBGA, are not recommended for the treatment or prevention of SARS-CoV-2 infection.

• Recreational or medical use of currently available cannabis-derived products are at doses much lower than those studied and are unlikely to provide any benefit against SARS-CoV-2 infection.

2023 ANNUAL REPORT | 41

Evidence Synthesis for FDA In January 2023, members of Consortium leadership received funding from the United States Food and Drug Administration (FDA) for a project titled, “Medical Literature and Data on Cannabis Use.” The purpose of this project is to synthesize the literature to support a comprehensive assessment of the clinical risk-benefit of cannabis.

The results from this project will be used by the FDA as supporting evidence as they draft their recommendations for either maintaining or revising the current Schedule I classification for cannabis, which will be presented to federal lawmakers in 2023. In December 2022, an administrative order was put forward by President Biden to the Secretary of Health and Human Services and to the Attorney General to trigger the review of marijuana’s current Schedule I classification status. This triggered review responsibilities within both the FDA and the Drug Enforcement Agency (DEA), where the FDA is responsible for contributing to an ‘8 Factor Analysis’ (8FA) for this Scheduling status review of cannabis. The 8FA requires consideration of eight ‘factors’ (contributors to risk or benefit), as outlined within the Controlled Substance Act, to justify classification of any substance.

The Consortium research team will accomplish the assessment of clinical risk-benefit through the conduct of large-scale systematic literature reviews and meta-analyses. Project 1 will examine a series of harms outcomes, also known as adverse events, as described in studies that examined cannabis use for medical, nonmedical, and for unknown purposes.

Project 2 will examine the effectiveness of cannabis for the following therapeutic indications: Pain, PTSD, Anxiety Disorders, Epilepsy, Nausea, Anorexia, HIV/AIDS, and Crohn’s Disease.

The team consists of members from the Consortium at the University of Florida, the Harvard Pilgrim-based Sentinel Initiative, and the FDA. The Consortium will be acknowledged during reports to federal lawmakers and Consortium leaders are strongly represented in this highprofile project, as Amie Goodin serves as Principal Investigator, Almut Winterstein and Yan Wang as co-Investigators, and Robert Cook as a Subject Matter Expert. The significant effort, which requires a rapid turnaround time of less than four months, is also joined by nine UF graduate students, three research interns, and several ad hoc UF pharmacy students, in addition to UF Health Sciences Specialist Librarian Lauren Adkins.

OUTREACH The Consortium’s outreach activities are directed towards community members, providers, researchers, and industry, to maximize participation in research and keep these stakeholders abreast of the latest research findings. The Consortium’s outreach platform includes a website and a quarterly newsletter. In this past year, the Consortium enhanced its outreach activities with addition of a new “Researcher Spotlight” video series and by hosting its annual Cannabis Clinical Outcomes Research Conference (CCORC). The Consortium also hosted a booth at the Florida Medical Cannabis Conference and Exhibition in Orlando, in June 2022, and presented at the Annual Research Society on Marijuana Conference in Boston, in July 2022.

42 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

Website The Consortium continues to expand its website (mmjoutcomes.org/) to disseminate information to researchers, member institutions, physicians/providers, patients, and the public. The website provides a comprehensive and interactive hub for the grants program, research updates and Consortium news. Since its launch in October 2019, more than 10,805 web-users have visited the website. The Consortium has optimized the website to be fully mobileresponsive. Further improvements continue to increase website performance across all devices.

Newsletter As part of the communication and outreach plan, the Consortium distributes a quarterly newsletter via email to researchers, physicians/providers, and individuals interested in MMJ research. The newsletter includes updates on Consortium activities and ongoing research. For recognition, the Consortium branded the newsletter as MEDICAMENT, which stands for MEDICAl Marijuana rEsearch NewsleTter. A total of 789 individuals have signed up for the newsletter as of December 2022.

The Consortium has published 13 issues of MEDICAMENT, one every quarter, available at mmjoutcomes.org/newsletter.

Researcher Spotlight Series In Fall 2022, the Consortium commenced the Researcher Spotlight Series, a video series showcasing Consortium researchers. The spotlight series intends to disseminate Consortium research and raise awareness about Consortium work and the importance of the scientific process in evaluating MMJ outcomes.

Each video includes an overview of the researcher’s study, methodological approaches, clinical relevance, and current/expected results. The first two spotlight videos featuring Dr. John Markowitz and Dr. Paul Borsa, two Consortium funded researchers, were released in Jan 2023 (mmjoutcomes.org/researcher-spotlight/).

2023 ANNUAL REPORT | 43

Cannabis Clinical Outcomes Research Conference (CCORC) The Consortium for Medical Marijuana Clinical Outcomes Research launched its annual Cannabis Clinical Outcomes Research Conference (CCORC) in 2021. This research-centric meeting, open to patients and providers, offers a venue for sharing research findings, disseminating the latest evidence on the health impacts of marijuana, and catalyzing research collaborations both state-wide and nationally. Specific objectives of CCORC are: • Dissemination of research findings on medical cannabis use, efficacy and safety • Provide a venue for clinical and research educational opportunities related to medical cannabis • Foster research collaboration, and stakeholder engagement, between Consortium member institutions and beyond Adapting to conditions created by COVID-19, the Consortium’s held its inaugural CCORC conference virtually on April 8–9, 2021. Last year, CCORC 2022 was held using a hybrid attendance model; the conference was held in-person at UF’s satellite campus in Lake Nona, FL with select presentations available to stream online.

A summary of CCORC 2022 capturing the highlights of the conference is available in the Appendix.

The Consortium is planning its third Cannabis Clinical Outcomes Research Conference (CCORC) to be held on May 18–19, 2023 in Orlando, Florida. A scientific program committee with participation from consortium member institutions advises the organizing committee on conference themes and scientific content. The CCORC save-the-date announcements and call for abstracts have been widely disseminated.

44 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

SUMMARY OF CONSORTIUM RESEARCH PRODUCTIVITY Over the 3.5 years of its existence, Consortium core faculty and Consortium grant awardees have generated 41 published manuscripts in peer-reviewed journals, a book chapter and the new data has served as the basis for one patent and 22 new extramural grant applications, seven of which were awarded. Noteworthy, more than 86 new trainees including 18 from underrepresented minorities have been involved in the funded research grants and two new courses have been developed, one of which is SUS approved, supporting the development of MMJ research capacity in the state.

51

conference abstracts

1

patent filed

86

undergraduates, post-doctoral, fellows & staff trained in research (18 from URM)

22

20

extramural grants submitted; 7 funded

invited talks and media interviews

41 1

1

peer reviewed publications

IND obtained

book chapter New college course developed SUS-approved

Dynamic data visualization tool and linkable database created

Outputs of the Consortium Research Program

2023 ANNUAL REPORT | 45

BIBLIOGRAPHY — PEER-REVIEWED PUBLICATIONS 1. Algarin AB, Plazarte GN, Sovich KR, Seeger SD, Li Y, Cohen RA, Striley CW, Goldberger BA, Wang Y, Somboonwit C, Ibañez GE, Spencer EC, Cook RL. Marijuana Use and Health Outcomes in Persons Living With HIV: Protocol for the Marijuana Associated Planning and Long-term Effects (MAPLE) Longitudinal Cohort Study. JMIR Res Protoc. 2022 Aug 30;11(8):e37153. DOI: 10.2196/37153. PMID: 36040775; PMCID: PMC9472048.

2. Alipour Haris G, Sarayani A, Winterstein AG. Letter by Alipour Haris et al Regarding Article, “Marijuana Use Among Young Adults (18-44 Years of Age) and Risk of Stroke: A Behavioral Risk Factor Surveillance System Survey Analysis”. Stroke. 2020 May;51(5): e91. DOI: 10.1161/STROKEAHA.120.029273. Epub 2020 Apr 7. PMID: 32252600.

3. Bilbrey JA, Ortiz YT, Felix JS, McMahon LR, Wilkerson JL. Evaluation of the terpenes β-caryophyllene, α-terpineol, and γ-terpinene in the mouse chronic constriction injury model of neuropathic pain: possible cannabinoid receptor involvement.

Psychopharmacology (Berl). 2022 May;239(5):1475-1486. DOI: 10.1007/s00213-02106031-2. Epub 2021 Nov 30. PMID: 34846548.

4. Bilbrey, J. A., Ortiz, Y. T., Felix, J. S., McMahon, L. R., & Wilkerson, J. L. (2022).

Evaluation of the terpenes β-caryophyllene, α-terpineol, and γ-terpinene in the mouse chronic constriction injury model of neuropathic pain: possible cannabinoid receptor involvement. Psychopharmacology, 239(5), 1475–1486. doi.org/10.1007/s00213-02106031-2 PMID: 34846548 5. Blanton HL, Barnes RC, McHann MC, Bilbrey JA, Wilkerson JL, Guindon J. Sex differences and the endocannabinoid system in pain. Pharmacol Biochem Behav. 2021 Mar;202:173107. DOI: 10.1016/j.pbb.2021.173107. Epub 2021 Jan 12. PMID: 33444598; PMCID: PMC8216879.

6. Blanton HL, Barnes RC, McHann MC, Bilbrey JA, Wilkerson JL, Guindon J. Sex differences and the endocannabinoid system in pain. Pharmacol Biochem Behav. 2021 Mar;202:173107. DOI: 10.1016/j.pbb.2021.173107 Epub 2021 Jan 12. PMID: 33444598; PMCID: PMC8216879.

7. Brown JD and AJ Goodin. Will cannabis or cannabinoids protect from SARS-CoV-2 infection or treat COVID-19? Med Cannabis Cannabinoids 2022;5(1):1-4. doi. org/10.1159/000522472 PMID: 35702401 PMCID: PMC9149510 8. Brown JD, Costales B, van Boemmel-Wegmann S, Goodin AJ, Segal R, Winterstein AG. Characteristics of Older Adults Who Were Early Adopters of Medical Cannabis in the Florida Medical Marijuana Use Registry. J Clin Med. 2020 Apr 18;9(4):1166. DOI: 10.3390/jcm9041166 PMID: 32325769; PMCID: PMC7230351 9. Brown JD, Goodin AJ. High risk of bias in medical cannabis and cannabinoid clinical trials dictates the need for cautious interpretation. Med Cannabis Cannabinoids. 2021; 4:63-66. PMID: 34676351 PMCID: PMC8525149 DOI: 10.1159/000514732 10. Brown JD, Goodin AJ. The prevalence of drivers under the influence of medical cannabis must be considered within proper context. Res Social Adm Pharm. 2019 Nov;15(11):1372-1373. DOI: 10.1016/j.sapharm.2019.01.015 Epub 2019 Jan 28. PMID: 30709730.

11. Brown JD, Rivera KJ, Crespo-Hernandez LY, Doenges MR, Auchey I, Pharm T and AJ Goodin. Natural and Synthetic Cannabinoids: Pharmacology, Uses, and Adverse Drug Events. J Clin Pharmacol. 2021; Aug; 61 Suppl 2:S37-S52. doi.org/10.1002/jcph.1871.

PMID: 34396558.

46 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

12. Brown JD, Winterstein AG. Potential Adverse Drug Events and Drug-Drug Interactions with Medical and Consumer Cannabidiol (CBD) Use. J Clin Med. 2019 Jul 8;8(7):989.

DOI: 10.3390/jcm8070989 PMID: 31288397; PMCID: PMC6678684 13. Brown JD. Potential Adverse Drug Events with Tetrahydrocannabinol (THC) Due to Drug-Drug Interactions. J Clin Med. 2020 Mar 27; 9(4):919. DOI: 10.3390/jcm9040919.

PMID: 32230864; PMCID: PMC7231229.

14. Costales B, Babalonis S, Brown JD and AJ Goodin. Cannabis effects on driving performance: clinical considerations. Med Cannabis Cannabinoids. 2023;6:8-14. DOI: doi.org/10.1159/000528714 15. Costales B, van Boemmel-Wegmann S, Winterstein A, Segal R. Clinical Conditions and Prescription Drug Utilization among Early Medical Marijuana Registrants in Florida. J Psychoactive Drugs. 2021 Jul-Aug;53(3):185-194.DOI: 10.1080/02791072.2020.1864069 Epub 2021 Jan 4. PMID: 33393877.

16. Crump C, Vaddiparti K, Lopez-Quintero C, Varma D, Cook R. Clinical decision making by medical marijuana physicians in Florida: A qualitative assessment. Accepted, Substance Use and Misuse, 2022.

17. Goodin A, J, Wilson D, L, Cook R, L, Wang Y, Brown J, Winterstein A, G: Proceedings of the 2021 Cannabis Clinical Outcomes Research Conference. Med Cannabis Cannabinoids 2021. Sep 10;4(2):143-146 doi.org/10.1159/000519037 PMID: 35224433; PMCID: PMC8832197.

18. Goodin AJ, Winterstein AG, Cook R, Wang Y and JD Brown. Introducing Commentary Series: “Evidence in Context.” Med Cannabis Cannabinoids 2021 Feb 23;4(1):61-62 DOI: 10.1159/000512684 PMID: 34676350; PMCID: PMC8525212.

19. Huffstetler CM, Cochran B, May CA, Maykut N, Silver CR, Cedeno C, Franck E, Cox A, Fadool DA. Single cannabidiol administration affects anxiety-, obsessive compulsive-, object memory-, and attention-like behaviors in mice in a sex and concentration dependent manner. Pharmacol Biochem Behav. 2022 Nov 29;222:173498. DOI: 10.1016/j.pbb.2022.173498. Epub ahead of print. PMID: 36455670.

20. Jugl S, Okpeku A, Costales B, Morris E, J, Alipour-Haris G, Hincapie-Castillo J, M, Stetten N, E, Sajdeya R, Keshwani S, Joseph V, Zhang Y, Shen Y, Adkins L, Winterstein A, G, Goodin A: A Mapping Literature Review of Medical Cannabis Clinical Outcomes and Quality of Evidence in Approved Conditions in the USA from 2016 to 2019. Med Cannabis Cannabinoids 2021; 4:21-42. DOI: 10.1159/000515069 PMID: 34676348; PMCID: PMC8525213.

21. Jugl S, Sajdeya R, Morris E, J, Goodin A, J, Brown J, D: Much Ado about Dosing: The Needs and Challenges of Defining a Standardized Cannabis Unit. Med Cannabis Cannabinoids 2021 Jun 17;4(2):121-124. DOI: 10.1159/000517154 PMID: 35224432; PMCID: PMC8832202 22. Kalvala AK, Nimma R, Bagde A, Surapaneni SK, Patel N, Arthur P, Sun L, Singh R, Kommineni N, Nathani A, Li Y, Singh M. The role of Cannabidiol and tetrahydrocannabivarin to overcome doxorubicin resistance in MDA-MB-231 xenografts in athymic nude mice. Biochimie. 2022 Dec 17;208:19-30. DOI: 10.1016/j. biochi.2022.12.008 Epub ahead of print. PMID: 36535544.

23. Kumar Kalvala A, Bagde A, Arthur P, Kumar Surapaneni S, Ramesh N, Nathani A, Singh M. Role of Cannabidiol and Tetrahydrocannabivarin on Paclitaxel-induced neuropathic pain in rodents. Int Immunopharmacol. 2022 Jun;107:108693. DOI: 10.1016/j. intimp.2022.108693. Epub 2022 Mar 15. PMID: 35303507.

2023 ANNUAL REPORT | 47

24. Markowitz JS, De Faria L, Zhang Q, Melchert PW, Frye RF, Klee BO, Qian Y. The Influence of Cannabidiol on the Pharmacokinetics of Methylphenidate in Healthy Subjects. Med Cannabis Cannabinoids. 2022 Nov 4;5(1):199-206. DOI: 10.1159/000527189. PMID: 36467779; PMCID: PMC9710314.

25. Ortiz, Y. T., McMahon, L. R., & Wilkerson, J. L. (2022). Medicinal Cannabis and Central Nervous System Disorders. Frontiers in pharmacology, 13, 881810. doi.org/10.3389/ fphar.2022.881810 PMID: 35529444; PMCID: PMC9070567.

26. Patel N, Kommineni N, Surapaneni SK, Kalvala A, Yaun X, Gebeyehu A, Arthur P, Duke LC, York SB, Bagde A, Meckes DG Jr, Singh M. Cannabidiol loaded extracellular vesicles sensitize triple-negative breast cancer to doxorubicin in both in-vitro and in vivo models. Int J Pharm. 2021 Sep 25;607:120943. DOI: 10.1016/j.ijpharm.2021.120943.

Epub 2021 Jul 27. PMID: 34324983; PMCID: PMC8528640.

27. Rosenthal M., Pipitone N. Demographics, Perceptions, and Use of Medical Marijuana among Patients in Florida. Med Cannabis Cannabinoids 2021;.4:13-20. DOI: 10.1159/000512342 PMID: 34676347; PMCID: PMC8525215 28. Roussos-Ross K, Dukharan V, Goodin A. Is In-Utero Marijuana Exposure Associated with Childhood Developmental Delay? [20K], Obstetrics & Gynecology: 135():p 118S-119S, May 2020. DOI: 10.1097/01.AOG.0000664476.72398.7c 29. Sagen J, Konin J, Paikoff S, Ford J, Newman D, Jyot J and AJ Goodin. Abstracts of the 2022 Cannabis Clinical Outcomes Research Conference (CCORC), on behalf of the Scientific Program Committee. Med Cannabis Cannabinoids 2022;5:142-158. doi. org/10.1159/000527081 30. Sajdeya R, Brown JD, Goodin AJ: Perinatal Cannabis Exposures and Autism Spectrum Disorders. Med Cannabis Cannabinoids 2021, 4:67-71. DOI: 10.1159/000515871 PMID: 34676352; PMCID: PMC8525188.

31. Sajdeya R, Cook RL. Need to Improve Dose Measurements in Studies of Marijuana Use for Pain. J Acquir Immune Defic Syndr. 2020 Mar 1; 83(3):e23. DOI: 10.1097/ QAI.0000000000002238 PMID: 32032280.

32. Sajdeya R, Goodin AJ, Tighe PJ. Cannabis use assessment and documentation in healthcare: Priorities for closing the gap. Prev Med. Dec;153:106798. DOI: 10.1016/j. ypmed.2021.106798 Epub 2021 Sep 8 PMID: 34506820.

33. Sajdeya R, Joseph V, Stetten N, Ibañez G, Wang Y, Powell L, Somboonwit C, Corsi K, Cook R. Reasons for Marijuana Use and Its Perceived Effectiveness in Therapeutic and Recreational Marijuana Users Among People Living with HIV in Florida. Cannabis.

2021, Volume 4 (1). DOI: 10.26828/cannabis/2021.01.002 34. Sajdeya R, Jugl S, Cook RL, Brown JD and AJ Goodin. Clinical considerations for cannabis use and cardiovascular health. Med Cannabis Cannabinoids 2022;Sept 28;5(1):120-127. doi.org/10.1159/000526731 PMID: 36467784; PMCID: PMC9710318.

35. Sajdeya R, Shavers A, Jean-Jacques J, Costales B, Jugl S, Crump C, Wang Y, Manfio L, Pipitone RN, Rosenthal MS, Winterstein AG, Cook RL. Practice Patterns and Training Needs Among Physicians Certifying Patients for Medical Marijuana in Florida. J Prim Care Community Health. 2021 Jan-Dec; 12: 21501327211042790. DOI: 10.1177/21501327211042790. PMID: 34452585; PMCID: PMC8404623.

36. Smolinksi N, Sajdeya R, Cook RL, Wang Y, Winterstein AG and AJ Goodin.

Proceedings of the 2022 Cannabis Clinical Outcomes Research Conference. Med Cannabis Cannabinoids 2022;5:138-141. doi.org/10.1159/000527080 PMID: 36467782; PMCID: PMC9710315.

48 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

37. Surapaneni SK, Patel N, Sun L, Kommineni N, Kalvala AK, Gebeyehu A, Arthur P, Duke LC, Nimma R, G Meckes D Jr, Singh M. Anticancer and chemosensitization effects of cannabidiol in 2D and 3D cultures of TNBC: involvement of GADD45α, integrin-α5, -β5, -β1, and autophagy. Drug Deliv Transl Res. 2022 Nov;12(11):2762-2777. DOI: 10.1007/ s13346-022-01137-2. Epub 2022 Feb 25. PMID: 35217991; PMCID: PMC9811521.

38. Wang Y, Jean Jacques J, Li Z, Sibille KT, Cook RL. Health Outcomes among Adults Initiating Medical Cannabis for Chronic Pain: A 3-month Prospective Study Incorporating Ecological Momentary Assessment (EMA). Cannabis. 2021 Oct;4(2):6983. DOI: 10.26828/cannabis/2021.02.006 PMID: 34671723; PMCID: PMC8525881 39. Wilkerson JL, Alberti LB, Thakur GA, Makriyannis A, Milligan ED. Peripherally administered cannabinoid receptor 2 (CB2R) agonists lose anti-allodynic effects in TRPV1 knockout mice, while intrathecal administration leads to anti-allodynia and reduced GFAP, CCL2 and TRPV1 expression in the dorsal spinal cord and DRG. Brain Res. 2022 Jan 1;1774:147721. DOI: 10.1016/j.brainres.2021.147721. Epub 2021 Nov 10.

PMID: 34774500.

40. Wilkerson JL, Bilbrey JA, Felix JS, Makriyannis A, McMahon LR. Untapped endocannabinoid pharmacological targets: Pipe dream or pipeline? Pharmacol Biochem Behav. 2021 Jul;206:173192. DOI: 10.1016/j.pbb.2021.173192. Epub 2021 Apr 29. PMID: 33932409.

41. Wilkerson, J. L., Alberti, L. B., Thakur, G. A., Makriyannis, A., & Milligan, E. D. (2022).

Peripherally administered cannabinoid receptor 2 (CB2R) agonists lose anti-allodynic effects in TRPV1 knockout mice, while intrathecal administration leads to anti-allodynia and reduced GFAP, CCL2 and TRPV1 expression in the dorsal spinal cord and DRG. Brain Res. 2022 Jan 1;1774:147721. DOI: 0.1016/j.brainres.2021.147721 Epub 2021 Nov 10.

PMID: 34774500.

Book Chapter: Muschett M, Brown JD. Profile of Older Users of Medical Cannabis and Cannabinoids. In: Martin, Patel, & Preedy (editors). Medicinal Usage of Cannabis and Cannabinoids. 1st ed. Elsevier. 2022 (In press).

EXTRAMURAL GRANTS SUBMITTED BY CONSORTIUM FACULTY AND GRANT AWARDEES Lead principal investigator, funding agency, title • Amie Goodin (co-Is: A Winterstein, Y Wang, S Guo), United States Food and Drug Administration via Sentinel Initiative. Medical Literature and Data on Cannabis Use. Funded from January 2023-May 2023 for $328,281.

• Amie Goodin (MPIs: D Roussos-Ross, D Varma, B Goldberger), University of Florida Research Opportunity Seed Fund. Assessing Prevalence, Maternal Perceptions, and Fetal Development Outcomes of Perinatal Marijuana Use. Funded from June 2022-May 2024 for $90,000 • Amie Goodin, NIDA, Medication use trajectories for opioid use disorders among pregnant women and resulting neonatal outcomes • Debra Fadool and Mandip Sachdeva, James and Esther King Foundation, Role of Exosomal Formulations of CDB for Treatment of Cancer-related Peripheral Neuropathy • Debra Fadool, Council on Research and Creativity (CRC), Does cannabidiol (CBD) really lessen anxiety behavior and is it safe to use during pregnancy, Funded June 2022June 2023 for $25,000

2023 ANNUAL REPORT | 49

• Debra Fadool, HEERF III (Federal Government), Higher Education Emergency Relief Fund, Funded from Sept 2021-Sept 2022 for $42,091 • Douglas Storace, NIDCD, Defining the role(s) of the olfactory bulb in adaptation • Douglas Storace, NIDCD, Defining the role(s) of the olfactory bulb in adaptation • Hassan Azari, DOD, Cannabinoids Acidic for the treatment of Glioblastoma • Hassan Azari, NIH, Acidic cannabinoids for the treatment of high-grade glioma • Hassan Azari, The Florida Center for Brain Tumor research (FCBTR), Effects of cannabigerolic acid containing hemp NPs on glioma tumor progression • Jacqueline Sagen, NCCIH, Combination analgesic evaluation of minor cannabinoids and terpenes with exercise in chronic spinal cord injury pain • Jenny Wilkerson, NCCIH, Terpenes and minor cannabinoids as novel analgesics • Jenny Wilkerson, NIDA, Terpenes and minor cannabinoids as novel analgesics • Joshua Brown, NIA, Cannabis use and adverse drug events in older adults • Mandip Sachdeva, James and Esther King Foundation, Role of Exosomal Formulations of CDB for Treatment of Cancer-related Peripheral Neuropathy • Mandip Sachdeva, NIH, Preclinical evaluation of minor cannabinoids in chemotherapy induced peripheral Neuropathy • Mandip Sachdeva, NIH, Tetrahydrocannabivarin (THCV) and cannabidiol (CBD) combination treatment for paclitaxel induced neuropathy.

• Mariola Edelmann, NIH, The regulatory functions of the endocannabinoid system in the innate immune responses against Gram-negative pathogens • Nicole Ennis, Sherrilene Classen, NIDA, Medical Marijuana Use and Driving Performance: A Test of Psychomotor Functioning in Adults 50 and Older Funded for $205,662 from 09/15/2020 – 09/14/2022.

• Yan Wang, NIA, Real-Time and Long-Term Effects of Medical Marijuana on Older Adults: A Prospective Cohort Study. Funded from 2/15/2022-11/30/2026 for $2,940,426 • Yan Wang, NIH/NIA, R01 AG071729-01A1S1 Administrative Supplement, “Real-time and long-term effects of medical marijuana on older adults: A prospective cohort study” Funded 02/2022-11/2026. Total: $375,000

MEDIA COVERAGE • Dr. Jenny Wilkerson, How Cannabis- Based Therapeutics Could Help Fight COVID Inflammation, Medscape, www.medscape.com/viewarticle/940265 • Dr. Joshua Brown, Can weed protect you from COVID? (slate.com) • Dr. Joshua Brown, Are THC and CBD actually safe for everyone? Renee Consorte, July 27, 2021. Medium. perma.cc/LCD7-PAHA • Dr. Almut Winterstein, UF From Florida podcast, What is Florida’s medical marijuana research consortium studying – and what has it found so far?

50 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

CONSORTIUM RESEARCH PLAN 2023-2024 Since its inception in July 2019, the Consortium has made great strides towards facilitating and conducting research that informs clinical care and policy about the medical use of marijuana. In the coming year, the Consortium will continue these efforts within the five original Consortium research program pillars: the Grants program, MEMORY, the Clinical Core, the Evidence Core, and outreach activities. The specific goals and plans for each pillar have been updated and are described below.

In the coming year, the Consortium will continue its efforts towards facilitating and conducting research that informs clinical care and policy within the five original Consortium research program pillars: the Grants program, MEMORY, the Clinical Core, the Evidence Core, and outreach activities. Two recent developments will play an important role in the coming year: Receipt of MMUR data will allow development of MEMORY, which will accelerate the ability to generate evidence on MMJ clinical outcomes. The new contract with the FDA will allow a new focus on evidence synthesis to support regulatory decision making. The 20232024 Consortium research plan, focuses on the following research priorities: • Generation of conclusive evidence on clinical outcomes of MMJ use including both risk and benefit • Evaluations of route and dosing, in particular research on high potency THC • Interactions of MMJ with other drugs/medications • Epidemiologic studies on utilization pattern and accessibility of MMJ across diverse groups • Research on the effects of MMJ use in reducing opioid dependency • Evaluating Components of Medical Marijuana/Cannabis The following describes the Consortium Research Plan for fiscal year 2024.

GRANTS PROGRAM The Consortium grant funding program was restructured in 2022 to support two studies at $130,000 over a total of two years, where the second-year funding is committed if intermediate research goals for the first year have been accomplishment and adequate funding is available. An additional fund for one-year projects as offered previously has been retained. We will continue with these funding structure changes in the coming year.

The Consortium will also continue with the Consortium Board revised research priorities to emphasize the focus on clinical research, the impact of MMJ on pain management and opioid use, and an expanded scope on epidemiologic research.

2023 ANNUAL REPORT | 51

Consortium Research Priorities 2023 1. C linical Outcomes of Medical Marijuana Use: with particular emphasis on human subject research, with priority granted to studies investigating efficacy and safety, for the treatment of qualifying conditions listed for medical marijuana use in Florida knowthefactsmmj.com/patients/ 2. E ffect of Medical Marijuana Use in Reducing Opioid Dependence: human subjects research on the effectiveness of MMJ as an analgesic/adjuvant in pain management and reduction in opioid use.

3. R outes of Administration: effect of dosing and routes of medical marijuana use on efficacy and safety; of particular interest are studies that evaluate effects of smoking and vaping.

4. I nteractions of Medical Marijuana with Other Drugs/Medications: a. with particular focus on medications that are commonly used by patients who seek medical marijuana treatment b. impact of polysubstance, including interactions with alcohol, tobacco, benzodiazepines, and prescription and nonprescription opioids 5. Epidemiology Research to study trends for cannabis use and cannabis use disorder (CUD), including new products, patterns of use, and reasons for use in different populations, and medical, sociological and/or economic disparities in the access to and outcomes of medical marijuana across diverse communities.

6. E valuating Components of Medical Marijuana/Cannabis and contrast their clinical outcomes: a. comparing different components of medical marijuana (e.g. different terpenes) b. research on different potency levels of THC products (e.g. >10% vs <10% THC) c. standards for measuring cannabis dose, intoxication, and impairment The Consortium has launched its fourth grants cycle in October 2022 with release of its Request for Proposals and updated research priorities. The intent is to complete the application reviews by the end of the fiscal year to expedite funding of prioritized proposals, upon approval of the FY 2024 Consortium budget.

52 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

MEMORY With imminent release of the MMUR data, the Consortium will implement its long-standing plan to develop MEMORY. This will include MMUR data curation, linkage to other health databases and development of analytical cohorts for access by Consortium researchers. As envisioned, MEMORY will then serve to support studies on MMJ effectiveness and safety, and utilization and access. Consortium core faculty plans to have a first set of safety and effectiveness studies completed by the end of the new fiscal year.

CLINICAL CORE Goals for the Clinical Core include continued expansion of the Consortium infrastructure to support patient recruitment into prospective research studies via its patient contact registry and CARMMA database of collaborating physicians, researchers and industry.

The Consortium is set to finish enrollment into M3 by summer 2023, and will then finalize data curation for access by Consortium researchers and complete a first set of analyses and publications over the coming year. The Consortium hopes that established patient recruitment mechanism that have proven effective for M3 can be provided to investigators from all Consortium institutions to accelerate and enhance conduct of clinical outcomes studies. A proven patient recruitment platform is also critical for extramural grant applications (e.g., to NIH) to further expand the consortium’s research program. Data sharing policies and procedures are posted on the Consortium website (mmjoutcomes.org/ m3study/) to provide to access to M3 data to researchers interested in performing analyses that will inform policy and clinical guidelines. The Clinical Core will also continue to work on guidance for investigators on regulatory issues involving use of MMJ in research studies.

This will include guidance on DEA licensure and other relevant state and federal regulations.

EVIDENCE CORE In the coming year, the Evidence Core will have completed its evidence review for the FDA to support the 8-factor analysis requested by congress and begin publications and other dissemination of related findings. The Consortium will also continue to publish its Evidence in context series, and survey and evaluate emerging evidence to inform the Consortium research priorities.

OUTREACH Building on the success of our first two Cannabis Clinical Outcomes Research Conference (CCORC), the Consortium plans to hold its third annual CCORC in May 2023. Other outreach activities through the Consortium website, its quarterly newsletter and participation in scientific conferences will continue. The newly added Researcher Spotlight Series will be developed further to promote Consortium activities and disseminate research outcomes.

The board and Consortium faculty and staff would like to conclude this report by expressing strong continuing support and enthusiasm to advance the Consortium research program. The Consortium addresses an urgent and critical need to provide patients, providers and regulators the necessary evidence on the safe and effective use of MMJ. The medical use of marijuana must be guided by the same level of scientific evidence that is available for prescription medications and MMJ products should be monitored with similar surveillance methods. The Consortium is devoted to establishing both.

2023 ANNUAL REPORT | 53

APPENDICES THE CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH BOARD WILLIAM (BILL) ANDERSON, PH.D. Chair of the Consortium Board Associate Vice President of Research; Florida International University

Associate Vice President William (Bill) Anderson leads initiatives that expand FIU’s efforts in research development for faculty, doctoral students and postdoctoral scholars. Additional areas of leadership focus include research labs, core facilities, research integrity, and laboratory safety, among others. Dr. Anderson joined FIU in 2000 as Assistant Professor and has risen to the rank of Professor.

Administratively, he has served as Chair of the Department of Earth & Environment and Associate Dean of Faculty in the College of Arts, Sciences & Education where he most recently served as the Vice Dean.

He received a doctorate of Natural Sciences from the Swiss Federal Institute of Technology (ETH-Zentrum), a M.S. in Geology from Syracuse University and a B.A. in Geology from the University of Kansas. His research has been published in top tier journals; he has presented in national and international conferences; and he has received funding from the NSF, the American Chemical Society, and the U.S. Department of the Interior, among others.

MARTHA S. ROSENTHAL, PH.D. Vice-Chair of the Consortium Board Professor of Neuroscience/Physiology; Director of the Cannabis Research, Education, and Workforce initiative; Florida Gulf Coast University

Dr. Martha Rosenthal is a Professor of Neuroscience & Physiology at Florida Gulf Coast University, where she teaches courses in cannabis, drugs and society, neuroscience, human physiology, and human sexuality. Dr. Rosenthal received her bachelor’s degree in biology from the University of Virginia, her master’s degree in neuropharmacology from Brown University, and her Ph.D. in neuroscience from UCLA. She began her career teaching in the College of Pharmacy at the University of Florida, and then moved to Fort Myers to be one of the founding faculty members of FGCU. Dr. Rosenthal is the Director of the Cannabis Research, Education, and Workforce initiative (CREW) at FGCU, and runs the cannabis professional certificate program. She is the author of a number of textbooks, including Drugs: Mind, Body, and Society. Dr. Rosenthal has been honored to receive the Teacher of the Year award at both the University of Florida and at FGCU and to have presented a TED talk about sex and gender.

54 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

ROGER B. FILLINGIM, PH.D. Distinguished Professor; Director, University of Florida, Pain Research and Intervention Center of Excellence (PRICE); University of Florida

Roger B. Fillingim, PhD is a Distinguished Professor and Director of the Pain Research & Intervention Center of Excellence at the University of Florida (UF). His research investigates biopsychosocial contributions to individual differences in pain, including the influences of sex/gender, race/ethnicity and aging on the experience of pain. Dr. Fillingim’s research has been continuously funded by the NIH since 1994, including a current MERIT award from the National Institute on Aging. He has published more than 400 peer-reviewed papers and has delivered plenary and keynote addresses at numerous international conferences. Dr. Fillingim has received numerous honors and awards, including the Wilbert E. Fordyce Clinical Investigator Award and the Public Service Award (both from the American Pain Society), and a UF Foundation Preeminence Term Professorship (2019).

Regarding mentoring efforts, in 2013 Dr. Fillingim established the University of Florida Clinical and Translational Science Institute’s (CTSI) Mentor Academy, which provides training for UF faculty in best mentoring practices. Dr. Fillingim has a longstanding commitment to mentoring and has successfully mentored numerous postdoctoral fellows, and early-stage faculty members. He also directs an institutional training grant that supports postdoctoral training in pain and aging research and leads the UF Center for Advancing Minority Pain and Aging Science, which supports career development for early career investigators from underrepresented backgrounds conducting pain and aging research. In 2016, he was recognized for his mentoring contributions when he received the UF Office of Postdoctoral Affairs, Postdoc Mentoring Award. He currently serves as Secretary/Treasurer of the International Mentoring Association.

DINENDER K. SINGLA, PH.D., FAHA, FIACS, FAPS Professor of Medicine, Cardiovascular Division Leader, Florida Hospital Chair in Cardiovascular Science; University of Central Florida

Dr. Dinender Singla is a translational scientist. His team investigates the role of stem cells and its derivative exosomes in anti-cancer drug induced cardiac toxicities and diabetes-induced muscle myopathy and cardiomyopathy.

He is continuously serving to review the grants for various NIH, AHA, ministry of Italian health, and Hong Kong study sections. He is an Academic Editor for PLOS one, Associate Editor for the Canadian Journal of Physiology and Pharmacology, as well as an editorial board member for different journals such as American Journal of Physiology: Heart and Circulatory. He has served as a chair for the TPIG committee and the American Physiology Society, and a general secretary for the North American section of the International Academy of Cardiovascular Sciences. He is President of the International Society for Adaptive Medicine. He is a fellow at the International Academy of Cardiovascular Sciences, American Physiological Society and American Heart Association. Dr. Singla has served as a chair for various scientific sessions throughout the world with experience in organizing scientific conferences. He has published a book on stem cells and is an author/coauthor for more than 100 peer-reviewed papers.

2023 ANNUAL REPORT | 55

ERIC H. HOLMES, PH.D. Assistant Vice President for Research, Florida State University

Eric Holmes has a PhD in Biochemistry from the University of California, Davis. Since 2013 he has been an Assistant Vice President for Research in the FSU Office of the Vice President for Research. He currently also serves as the Interim Director for the FSU Office of Human Subjects. Prior to joining FSU, he was Director of Research at the University of Hawaii’s John A. Burns School of Medicine.

Dr. Holmes has a long track record of directing NIH-funded research in biochemical oncology. He is an author of approximately 100 research publications and is an inventor on over 30 issued US and foreign patents. Dr. Holmes has also worked in the Biotech industry in development-stage pharmaceutical companies located in the Pacific Northwest focused on antibody therapy and drug delivery technologies, and has designed and managed clinical trials related to the development of these technologies.

PETER J. HOLLAND, MD, FACOEM, DLFAPA Director of Clinical Research, Florida Atlantic University

Prior to joining FAU in 2003, Peter Holland founded Boca Raton Psychiatric Group and Boca Raton Medical Research — a clinical trial organization with a national reputation. Since joining FAU, he has been the principal investigator of numerous, double-blind, placebo-controlled clinical trials. He is currently the medical director of the FAU Clinical Research Unit. Dr. Holland is also a founding faculty member of FAU’s Schmidt College of Medicine where he directs medical student education in psychiatry.

Dr. Holland earned his medical degree at the University of South Florida College of Medicine. He completed his internship in Medicine and Psychiatry at the University of South Florida and continued his residency training and fellowship in Psychiatry at the University of North Carolina-Chapel Hill. Dr. Holland is board-certified in Psychiatry with additional qualifications in Geriatric Psychiatry. He is a Distinguished Life Fellow of the American Psychiatric Association and a Fellow of the American College of Occupational and Environmental Medicine.

MAX C. E. OREZZOLI, PH.D .

Associate Professor of Healthcare, School of Arts & Sciences, Florida Memorial University

Max C. E. Orezzoli, Ph.D. is an Associate Professor of Healthcare in the Department of Health & Natural Sciences at Florida Memorial University. He holds a doctorate in Sociology (Medical) with an emphasis on quantitative analysis from Florida International University. His expertise and research focus are centered on community-based interventions that positively impact the health of underrepresented communities. Dr. Orezzoli has over 15 years of experience in minority health disparities research, including substance use disorder (SUD), marijuana use, nutrition, violence, and HIV research. Additionally, Dr. Orezzoli has provided experimental and instrument design, data collection trainings, evaluation, statistical and methodological consulting and assistance to institutions, biomedical, educational, and healthcare organizations.

Dr. Orezzoli is bilingual and fluent in Spanish. He has extensive experience in formative and summative program evaluation using quantitative and qualitative methods which are regionally and culturally appropriate. Additionally, due to his research/evaluation experience, including SAMHSA projects, Dr. Orezzoli is well equipped to conduct research involving

56 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

human participants and, addressing sensitive issues/topics of focus (medical marijuana, diet research, HIV, SUD, violence, etc.) while adhering to all confidentiality and privacy requirements. Dr. Orezzoli served as the Co-chair of the Institutional Review Board (IRB) at Florida Memorial University from 2018-2022.

JACQUELINE SAGEN, PHD Professor of Neurological Surgery, University of Miami

Dr. Jacqueline Sagen is a Professor of Neurological Surgery at the Miami Project to Cure Paralysis, University of Miami Miller School of Medicine.

She received her B.A. in Neuroscience from Northwestern University, Ph.D. in Pharmacology from the University of Illinois College of Medicine in 1984 and an M.B.A. in Entrepreneurship from University of Illinois at Chicago in 1994. She completed a postdoctoral fellowship in 1986 and joined the faculty at University of Illinois College of Medicine in the Department of Anatomy and Cell Biology as Assistant/Associate Professor through 1995. From 1995-1998 she was Associate Director, Pharmacology and Behavioral Research, CytoTherapeutics, Inc and Adjunct Associate Professor of Cellular Technology, Brown University, prior to her current position at University of Miami.

Research in Dr. Sagen’s laboratory over the past 35 years has been focused on exploring novel therapeutic strategies for chronic pain management that have the potential to provide sustained relief on a long-term or permanent basis. As chronic pain syndromes are often resistant to traditional pain interventions and/or limited by untoward side effects and possible analgesic dependence, the long term goal of work in her lab is to identify and develop more potent interventive approaches to improve the quality of life of these patients.

A primary initiative in her lab is the generation of gene therapies and cell transplantation that can provide a continually renewable source of pain-reducing substances. The identification of superior alternatives to opioids, such as cannabinoids, is a current focus of her research. She has published over 150 articles and book chapters and holds six patents in the field of novel pain therapies. She serves on numerous scientific review panels for NIH, DoD, VA, CIRM, and private foundations, and is faculty representative on the FDP.

CHARLES A. WEATHERFORD, PHD Vice President for Research, Florida A&M University

Charles Weatherford is the Vice President for Research at Florida A&M University (FAMU). Dr. Weatherford is also the Director of the FAMU Industrial Hemp Pilot Project, Principal Investigator on the FAMU Medical Marijuana Education and Research Initiative, Director of the FAMU Center for Plasma Science and Technology, as well as a Professor in the FAMU Department of Physics.

He received his Ph.D. in Atomic and Molecular Physics from Louisiana State University in 1974. Dr. Weatherford is a Fellow of the American Physical Society and a Fellow of the National Society of Back Physicists. Dr. Weatherford has a Patent Disclosure 2018: “FieldAssisted Muon-Catalyzed Fusion,” 224 journal publications, five book articles and two books. He was PI or Co-PI on $60.5 million in Research Grants and Contracts. His research interests include Materials and Energy for National Security, Correlation in Many-Body Quantum Chemistry, Laser-Matter Interactions, High-Energy Density Science, Field-Assisted Muon-Catalyzed Fusion, and Computational Science.

2023 ANNUAL REPORT | 57

CORE FACULTY AND STAFF OF THE CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH ALMUT G. WINTERSTEIN, RPH, PHD, FISPE Consortium Director Distinguished Professor, Pharmaceutical Outcomes & Policy; Dr. Robert and Barbara Crisafi Chair in Medication Safety; College of Pharmacy, Director, Center for Drug Evaluation and Safety, University of Florida

Almut Winterstein is Distinguished Professor in the Department of Pharmaceutical Outcomes and Policy at the College of Pharmacy, the founding Director of the Center for Drug Evaluation and Safety, and affiliate professor in epidemiology at the University of Florida. In 2017, she was named the Dr. Robert and Barbara Crisafi Chair for Medication Safety in recognition of her research on drug safety and on devising ways to improve medication use. Since 2019 she serves as director of the Consortium.

She received her pharmacy degree from Friedrich Wilhelm University in Bonn, Germany and her PhD in Pharmacoepidemiology from Humboldt University in Berlin. Since joining the University of Florida in 2000, Winterstein has served as principal investigator on more than 25 extramurally funded grants and contracts and published more than 400 manuscripts and conference abstracts. Her research interests center on the post-marketing evaluation of drugs in pediatrics and pregnancy, infectious disease and psychiatry and the evaluation and improvement of quality surrounding medication use using real-world data. As expert in drug safety, she has chaired the Food and Drug Administration’s Drug Safety and Risk Management Advisory Committee from 2012-2018. Recognizing her contributions in pharmacoepidemiology, Dr. Winterstein was inducted as a fellow of the International Society of Pharmacoepidemiology in 2013 and served as president of the society from 2019-2020.

In 2022 she was inducted in the Academy of Science, Engineering and Medicine in Florida.

She has chaired more than two dozen PhD committees and was awarded the UF-wide Dissertation Advisor/Mentoring award for her excellence in graduate training.

ROBERT L. COOK, MD, MPH Consortium Associate Director Professor, Epidemiology, Medicine, Director, Southern HIV & Alcohol Research Consortium (SHARC), College of Public Health & Health Professions,University of Florida

Robert L. Cook, MD, MPH is a Professor of Epidemiology at the University of Florida, with a joint appointment in the Division of General Internal Medicine.

Dr. Cook has expertise and experience in a range of research methods, including randomized clinical trials, cohort studies, and qualitative research.

Over the past 20 years, Dr. Cook’s research has focused on strategies to improve health outcomes related to HIV and sexually transmitted diseases. He is the Director of the Southern HIV Alcohol Research Consortium (SHARC), which supports collaborative research and training related to alcohol and HIV infection across the state of Florida.

Dr. Cook’s research is translational, ranging from basic science to implementation science, and he is currently the PI or MPI of four major NIH grants with over $10 million in total research support. Dr. Cook has led an R01 project grant that is studying the effects of marijuana use on clinical outcomes in persons with HIV, including cognitive function and systemic inflammation.

Mentoring is also an important aspect of Dr. Cook’s academic career. He has served as PhD dissertation chair for eight students, PhD committee member for over 30 students, and mentor for numerous additional trainees, post-docs and junior faculty.

58 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

AMIE J. GOODIN, PHD, MPP Consortium Assistant Director, Evidence Assistant Professor, Pharmaceutical Outcomes & Policy; College of Pharmacy, University of Florida

Amie J. Goodin, PhD, MPP is an Assistant Professor within the Department of Pharmaceutical Outcomes and Policy (POP) at the University of Florida.

Dr. Goodin received her Master of Public Policy degree from the University of Kentucky (UK) and completed her Doctor of Philosophy degree at UK’s Martin School of Public Policy, with specialization in pharmaceutical outcomes and an additional Certificate in Informatics.

She completed a Postdoctoral Fellowship at University of Florida POP, specializing in pharmacoepidemiology methods while continuing her work in Pharmaceutical Health Services Research.

Dr. Goodin previously worked at the Institute for Pharmaceutical Outcomes and Policy as well as the Center for the Advancement of Pharmacy Practice, both of which were housed in the UK College of Pharmacy. Currently, Dr. Goodin’s research projects incorporate mixedmethod approaches to assess the impact of policy changes related to treatment access and utilization for Substance Use Disorders, particularly among persons enrolled in Medicaid and pregnant women.

JOSHUA D. BROWN, PHARMD, PHD, MS Consortium Assistant Director, Memory Associate Professor, Pharmaceutical Outcomes & Policy; College of Pharmacy, University of Florida

Joshua D. Brown, PharmD, PhD, MS joined the University of Florida in 2016.

Dr. Brown has training in clinical pharmacy and pharmacoepidemiology having received PharmD and MS degrees from the University of Arkansas for Medical Sciences and a PhD from the University of Kentucky. During his graduate training, Dr. Brown focused on research related to medication safety and effectiveness in high-risk populations, especially older adult and geriatric patient groups. He has also conducted research on medical devices, drug-drug interactions, and healthcare policy. As a graduate student, Dr. Brown was recognized as the Pfizer-Humana Research Fellow and received two Young Investigator Awards from the International Society for Thrombosis and Hemostasis.

Dr. Brown’s research program continues to evaluate the effectiveness and safety of medications used in real-world populations. He conducts research focusing on drug-drug interactions with hormonal contraceptives and anticoagulants and evaluates medication safety in older adult populations. His research has been funded by the U.S. Food and Drug Administration, the Bill & Melinda Gates Foundation, and the UF Institute on Aging. Dr. Brown has been recognized as a Claude D. Pepper Scholar in aging research, was invited to the National Academy of Medicine’s Emerging Leaders Symposium, and was awarded an early career recognition by the Academy of Managed Care Pharmacy.

2023 ANNUAL REPORT | 59

YAN WANG, PHD, Consortium Assistant Director, Clinical Core Assistant Professor, Epidemiology; College of Public Health & Health Professions, University of Florida

Yan Wang, PhD is an Assistant Professor of Epidemiology at the University of Florida. Dr. Wang has training and expertise in both psychology and epidemiology. She received her MS and PhD in Child and Family Studies from Syracuse University in 2013. She joined the Department of Epidemiology as a postdoctoral research associate in 2014, working on NIH funded projects on risk behaviors among rural-to-urban migrants in China.

Her research focuses on leveraging advanced methodology and new technology (e.g., wearable sensor) to improve health behavior monitoring and intervention. One of her current research projects focuses on improving alcohol use monitoring using a wearable alcohol biosensor and ecological momentary assessment. She is also working on a UF funded pilot project to investigate the real-time and long-term health effects of medical marijuana among patients with chronic pain. Dr. Wang has also worked on a number of NIH funded projects including those on mental health and risk behaviors among rural-to-urban migrants in China, alcohol use and marijuana use among persons living with HIV/AIDS in Florida, and advanced quantum modeling on sexual risk behaviors.

One of her research papers, “Stress and Alcohol Use in Rural Chinese Residents: A Moderated Mediation Model Examining the Roles of Resilience and Negative Emotions” published in the journal Drug and Alcohol Dependence has been recognized by the Matilda White Riley Early Stage Investigator Honor Program, sponsored by the National Institutes of Health Office of Behavioral and Social Sciences Research (NIH/OBSSR). Dr. Wang is leading a marijuana research working group at UF that includes other students and faculty. She has an R01 grant to study the effect of medical marijuana in older adults with chronic pain. She led a symposium at the National Society for Marijuana Research in Boston in 2022.

JEEVAN JYOT, PHD, PMP Consortium Assistant Director, Research Administration College of Pharmacy, University of Florida

Dr. Jyot received her PhD in Microbiology and Molecular Biology from the Institute of Microbial Technology (India) and completed her postdoctoral fellowship and was an Assistant Scientist at Division of Infectious Diseases and Global Medicine, Department of Medicine, University of Florida. In addition, she has Project Management Professional credentials.

Dr. Jyot has previously served as Research Program Coordinator at Division of Research Program Development (DRPD) at Office of Research at University of Florida.

Currently, Dr. Jyot is part of the Department of Pharmaceutical Outcomes and Policy (POP) at the University of Florida and serves the Medical Marijuana Clinical Outcomes Research Consortium.

60 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

SAMUEL MCKEE Consortium Communications Specialist College of Pharmacy, University of Florida

Sam is currently pursuing his master’s in mass communications from UF’s College of Journalism and Communications. His background includes various roles in marketing, communications, and community organizing. Before joining the Consortium for Medical Marijuana Clinical Outcomes Research, Sam worked for University of Florida Performing Arts.

HANNAH FECHTEL Research Coordinator Clinical Core Research Coordinator, Epidemiology; College of Public Health & Health Professions, University of Florida

Hannah assists with participant recruitment for the contact registry and M3 study, research operations, database management for the M3 dataset and CARMMA, and data analysis. Prior to joining the Consortium, Hannah obtained a Bachelor of the Arts in Statistics and a Bachelor of Public Health from the University of Florida. Outside her work with the Consortium, Hannah co-leads the Marijuana Working Group for the Southern HIV & Alcohol Research Consortium (SHARC) with Dr. Yan Wang.

2023 ANNUAL REPORT | 61

LIST OF REVIEWERS OF THE 2022 RESEARCH GRANTS PROGRAM *reviewers who reviewed more than one proposal Albert Thomas

University of California Los Angeles

Professor

Albert Wu

Stanford University

Assistant Professor

Aurelio Galli*

University of Alabama at Birmingham

Professor

Bradley Alger

University of Maryland

Professor Emeritus

Caroline Arout

Columbia University Irving Medical Center

Assistant Professor

Carrie Cuttler*

Washington State University

Assistant Professor

Charles Leonard

University of Pennsylvania

Assistant Professor

Claire Hulsebosch

University of Texas

Professor

Colleen Hegg*

Michigan State University

Associate Professor

Emmanuel Onaivi

William Patterson University

Professor

James White

Duke Molecular Physiology Institute

Assistant Professor

Jason Hockenberry*

Yale University

Professor

Julia Dilley

Washington State Department of Health

Research Scientist

Justin Strickland

Johns Hopkins University

Assistant Professor

Katrina Mark

University of Maryland

Associate Professor

Kelly Young-Wolff

Kaiser Permanente Division of Research

Research Scientist

Kevin Freeman

University of Mississippi Medical Center

Associate Professor

Mao Qingcheng

University of Washington

Associate Professor

Martin Kaczocha*

Stony Brook University

Assistant Professor

Matthew Coates

Pennsylvania State University

Associate Professor

Michael Hoane

Augusta University

Professor

Susan Ferguson*

University of Washington

Associate Professor

Tory Spindle

Johns Hopkins University

Assistant Professor

Xuan-Zheng Shi

University of Texas Medical Branch

Professor

62 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

CCORC PROGRAM BROCHURE

CCORC 2022 SUMMARY ccorc.mmjoutcomes.org

2023 ANNUAL REPORT | 63

CCORC PROGRAM BROCHURE

Cannabis Clinical Outcomes Research Conference (CCORC) INTRODUCTION The Consortium for Medical Marijuana Clinical Outcomes Research launched its annual Cannabis Clinical Outcomes Research Conference (CCORC) in 2021. This research-centric meeting, open to patients and providers, offers a venue for sharing research findings, disseminating the latest evidence on the health impacts of marijuana, and catalyzing research collaborations both state-wide and nationally.

The objectives of CCORC are: • Dissemination of research findings on medical cannabis use, efficacy, safety, and other relevant outcomes • Provide a venue for clinical and research educational opportunities related to medical cannabis • Foster research collaboration, and stakeholder engagement, between Consortium member institutions and beyond Adapting to conditions created by COVID-19, the Consortium’s held its inaugural CCORC conference virtually on April 8th and 9th, 2021. This year, CCORC 2022 was held using a hybrid attendance model; the conference was held in-person at UF’s satellite campus in Lake Nona, FL with select presentations available to stream online.

2

ccorc.mmjoutcomes.org

64 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

CCORC PROGRAM BROCHURE

CCORC 2022 OVERVIEW CCORC 2022 was a 1.5 day conference gathering medical marijuana researchers, providers, patients, and industry representatives.

The conference featured 3 keynote presentations, 6 oral presentations from top abstracts, 2 methods workshops, a poster session featuring 28 research abstracts selected following peer review, and 1 panel discussion with research, administrative, and industry collaborators on a successful MMJ study. Additionally, the conference hosted representatives from 6 exhibitors.

CCORC QUICK FACTS

55%

125

REGISTRANTS

7

US STATES

5

COUNTRIES

RESEARCHERS

17%

STUDENTS

28%

PROVIDERS

THREE THEMES FROM THE CONFERENCE Disentangling Research Findings Comparing Medical and Non-Medical Cannabis Use and Outcomes

+

Barriers and Facilitators for Conducting Clinical Cannabis Research

+

Resolving Uncertainties Around Cannabis Dosing

3

2023 ANNUAL REPORT | 65

CCORC PROGRAM BROCHURE

KEYNOTE SPEAKERS Staci Gruber, Ph.D.

Director, Cognitive and Clinical Neuroimaging Core, McLean Hospital Director, Marijuana Investigations for Neuroscience Discovery (MIND), McLean Hospital Assoc. Prof. of Psychiatry, Harvard Medical School Keynote Title: Clarifying Cannabis: Considering the impact of recreational and medical use on cognitive and clinical outcomes

Samer Narouze, M.D., Ph.D.

Assoc. Prof. of Surgery, Northeast Ohio Medical University Clinical Professor of Anesthesiology and Neurological Surgery, Ohio State University College of Medicine President, American Society of Regional Anesthesia and Pain Medicine Chairman, American Interventional Headache Society Keynote Title: Cannabis Use in Pain and as a Substitute for Opioid

Kent Hutchison, Ph.D.

Prof. of Psychiatry, Anschutz Medical Campus Adjunct Prof. of Psychology and Neuroscience, University of Colorado in Boulder Keynote Title: Effects of THC and CBD: Implications for Future Clinical Trials

Topics Covered: • Use patterns and observed clinical outcomes in medical/ non-medical cannabis users • Reframing research questions to focus on risk-benefit vs. solely on harm

• Shortage of translational research in cannabis research • Lack of consistency in definition of clinical outcomes, sample size constraints and difficulties with blinding and other methodological issues

4

66 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

CCORC PROGRAM BROCHURE

ORAL PRESENTATIONS|WORKSHOPS|PANEL DISCUSSION Attendees engaged with a wide range of topics related to cannabis research via oral presentations of top abstracts, method workshops, and a panel discussion. Each segment included a Q&A portion allowing audience members to further the conversation and contribute context from their perspectives within the world of medical marijuana.

Three of the six top abstracts selected for oral presentation were submitted by student researchers.

Erin Berthold

Ph.D. Candidate, Department of Pharmaceutics, University of Florida Abstract Title: Preclinical Herb-Herb Interaction of Cannabidiol and Kratom in Rats

Alexandra McMahon, MPH

Graduate Student, Department of Epidemiology, University of Florida Abstract Title: Perceived Effectiveness of Medical Marijuana Among Adults with Chronic Pain: Findings from Interview Data in a Three-Month Pilot Study

Alexis Noel Cox, B.Sc.

Undergraduate Scholar, Department of Biological Science and Program in Neuroscience, Florida State University Abstract Title: Perinatal Cannabidiol Exposure Decreases Survival in Mice, and Impacts Anxiety-like and Obsessive Compulsive-like Behavior and Object Memory in a Sexually Dimorphic Manner When Raised to Adult ccorc.mmjoutcomes.org

5

2023 ANNUAL REPORT | 67

CCORC PROGRAM BROCHURE

POSTER SESSION A poster session highlighting twenty eight abstracts selected following peer review provided an opportunity for research faculty and students from all nine Consortium-member institutions to present their work. A jury of experts scored each of the posters, awarding a prize to the top scoring poster presentation.

CCORC 2022 Best Poster Presentation:

Amanda Pacheco-Spiewak Research Associate, University of Miami

Poster Title: Mechanistic evaluation of combined Cannabis components cannabidiol and β-caryophyllene in reducing chronic pain in a rat SCI model

CONTINUING EDUCATION CREDITS OFFERED Starting in 2022, CCORC now offers Continuing Medical Education (CME) and Continuing Pharmacy Education (CPE) credits for physicians as well as pharmacists attending the conference. Stay tuned for next year’s Continuing Education offerings for clinicians.

6

ccorc.mmjoutcomes.org

68 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

CCORC PROGRAM BROCHURE

EXHIBITORS Representatives from industry and outreach-focused organizations were present to engage with attendees about their roles in cannabis research.

Exhibitors at CCORC 2022:

CONFERENCE PROCEEDINGS PUBLISHED The proceedings and abstracts for CCORC 2022 have been published in the official journal of the Consortium, Medical Cannabis and Cannabinoids. This peer-reviewed journal offers an international forum to present and discuss recent advances in the rapidly developing and challenging field surrounding the medical use of cannabis and cannabinoids. Inclusion in the journal expands the dissemination of the research presented at CCORC 2022 as well as increasing awareness for the conference at large.

Read CCORC 2022 proceedings here > Read CCORC 2022 abstracts here > For more information on Medical Cannabis and Cannabinoids, please visit karger.com/mca

7

2023 ANNUAL REPORT | 69

CCORC PROGRAM BROCHURE

PROGRAM AT A GLANCE May 19, 2022 TIME EDT 9:00-9:30am

EVENT Day 1 Welcome Address Δ

Δ=VIRTUAL OPTION AVAILABLE

Dr. Almut Winterstein Consortium for Medical Marijuana Clinical Outcomes Research University of Florida Agenda Overview and Introduction to Keynote Dr. Amie Goodin Consortium for Medical Marijuana Clinical Outcomes Research University of Florida

9:30-10:45am

Keynote: Clarifying Cannabis: Considering the impact of recreational and medical use on cognitive and clinical outcomes* Δ Dr. Staci Gruber McLean Hospital Harvard Medical School

10:45-11:00am Exhibitor Hall, Coffee Break 11:00-12:00pm Session: Methods Workshop for Measurement Techniques When Conducting Clinical Cannabis Research EMA Assessment Strategies for Medical Marijuana Use and Outcomes Dr. Yan Wang University of Florida Consortium for Medical Marijuana Clinical Outcomes Research

Self-Reported Use Measures and Instruments Dr. Catalina Lopez-Quintero University of Florida

Measuring Doses and Dosing Dr. John Markowitz University of Florida

12:00-1:00pm

Lunch

1:00-2:15pm

Keynote: Effects of THC and CBD: Implications for Future Clinical Trials* Δ Dr. Kent Hutchison Anschutz Medical Campus University of Colorado in Boulder

2:15-2:30pm

Exhibitor Hall, Coffee Break

2:30-3:30pm

Session: Presentations and Q&A of Top Abstracts

Dr. Dinender Singla, University of Central Florida, Moderator Dr. Karina Villalba University of Central Florida Dr. Amie Goodin University of Florida Dr. Andrea Cippitelli Florida Atlantic University

8

6 - CCORC 2022

70 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

CCORC PROGRAM BROCHURE

TIME EDT 3:30-4:15pm

EVENT Session: IRB Challenges and a Proposed Solution Dr. Jeff Konin Florida International University

4:15-5:00pm

Workshop: Extending Florida’s Adverse Event Reporting System Sebastian Jugl University of Florida

5:00-6:15pm

Poster Sessions and Exhibitor Hall, Networking Reception

May 20, 2022 TIME EDT 8:00-8:15am

EVENT Day 2 Welcome Address Δ Dr. Robert L. Cook Consortium for Medical Marijuana Clinical Outcomes Research University of Florida

8:15-9:30am

Keynote: Cannabis Use in Pain and as a Substitute for Opioids* Δ Dr. Samer Narouze Northeast Ohio Medical University Ohio State University College of Medicine American Society of Regional Anesthesia and Pain Medicine American Interventional Headache Society (AIHS)

9:30-10:30am

Session: Presentations and Q&A of Top Abstracts

Nicole Smolinski, PharmD, University of Florida, Moderator Erin Berthold University of Florida Alexis Cox Florida State University Alexandra McMahon University of Florida

10:30-10:45am Exhibitor Hall, Coffee Break 10:45-11:30am Session: Regulatory Challenges in Conducting Cannabis Research in Florida: A Panel Discussion Dr. Robert L. Cook Consortium for Medical Marijuana Clinical Outcomes Research University of Florida Panel Members: Sheila Austin, MS, ACRP-CP; Paul A. Borsa, Ph.D., ATC; Anthony Ferrari, Ph.D.; Paul R. Peluso, Ph.D.

11:30-12:00pm Closing and Reception, Awards Ceremony Δ Dr. Ximena Levy Consortium for Medical Marijuana Clinical Outcomes Research Florida Atlantic University

12:00-1:00pm

Board Meeting and Invited Lunch Reception

* Eligible for CME and CPE credits. Please check http://ccorc.mmjoutcomes.org/cme-credit/ and http:// ccorc.mmjoutcomes.org/agenda/cpe-credit-2022/ for details.

The University of Florida College of Medicine designates this live activity for a maximum of 3.75 AMA PRA Category 1 Credits™.

Physicians should claim only the credit commensurate with the extent of their participation in the activity.

The University of Florida College of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to ccorc.mmjoutcomes.org

provide continuing medical education for physicians. The University of Florida is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Each of the Keynote addresses is eligible for 1.25 CPE credits.

9

CANNABIS CLINICAL OUTCOMES RESEARCH CONFERENCE - 7

2023 ANNUAL REPORT | 71

CCORC PROGRAM BROCHURE

SAVE THE DATE FOR 2023

CONTACT US

mmj.outcomes@cop.ufl.edu 352-273-6984

ccorc.mmjoutcomes.org

72 | CONSORTIUM FOR MEDICAL MARIJUANA CLINICAL OUTCOMES RESEARCH

www.mmjoutcomes.org