Agenda and Abstracts | Evaluating the Therapeutic Potential of Cannabinoids: How to conduct research within the current regulatory framework

Section 1 – Evaluating the Risks and Potential Benefits of Cannabinoids: The State of the Science

Cannabinoids for Medical Use: A Systematic Review and Meta-Analysis
Penny Whiting, Ph.D.
University of Bristol

In June 2018 we published our systematic review “Cannabinoids for Medical Use: A Systematic Review and Meta-Analysis.” We reviewed randomized trials that had evaluated medicinal cannabinoids for the treatment of one of the following indications: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette’s syndrome. We included 79 trials (6,462 participants) and found moderate quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV, sleep disorders, and Tourette’s syndrome. Cannabinoids were associated with an increased risk of short-term adverse events. I will discuss the findings of our review and touch on developments following our review, including a brief summary of reviews published since our review was published.

Therapeutic Cannabis Use in 2018: Where Do We Stand?
Kevin Hill, M.D., M.H.S.
Harvard Medical School

As of November 2018, 33 states and the District of Columbia have initiated policies that allow the use of cannabis or cannabinoids for the treatment of specific medical conditions. Despite promising new research, the evidence base for the therapeutic use of cannabis has not grown as quickly as the interest in the topic. With the recent FDA approval of Epidiolex, physicians now have three cannabinoids at their disposal that are approved for cancer-induced nausea and vomiting, appetite stimulation in wasting conditions like HIV, and two pediatric epilepsies (Dravet syndrome and Lennox-Gastaut syndrome). Beyond these conditions, the best evidence exists for chronic pain, neuropathic pain, and muscle spasticity associated with multiple sclerosis. While many of the adverse effects of acute and chronic use are well described, there is a distinct need for longitudinal studies of the impact of cannabis and cannabinoids upon physical and mental health. Although international organizations such as the World Health Organization have made strides in promoting progress in the research of cannabis and cannabinoids, much work remains in order for the United States to play a leading role in this area.

Section 2 – Supporting Cannabinoid Research: Balancing the Need for Federal Regulations and Knowledge

The NIH Perspective: The National Center for Complementary and Integrative Health (NCCIH)
Emmeline Edwards, Ph.D.
The National Center for Complementary and Integrative Health, NIH

NCCIH supports rigorous scientific investigation of natural products such as the cannabis plant and its components (e.g., cannabinoids and terpenes). This talk will discuss NCCIH research interests and available funding opportunities.

NIDA Research Priorities: Cannabis, Cannabinoids, and the Endocannabinoid System
Susan Weiss, Ph.D.
National Institute on Drug Abuse, NIH

NIDA has a substantial investment in cannabis research: >$88 M in 2017 covering a variety of topic areas, including 1) epidemiology to track the prevalence, trends, and patterns of use; 2) prevention, focused especially on vulnerable populations, such as youth, pregnant or breastfeeding women, and individuals with mental illness; 3) treatment development for cannabis use disorders; and 4) policy research to assess the impact of the changing legal environment in the United States and globally. NIDA also supports basic neuroscience research to understand the function of the brain’s endocannabinoid system, including its role in pain, mental illness, and HIV, and to determine the impact of cannabis exposure, use, and addiction on brain structure and function, cognition, motivation, affect, adolescent and fetal development, among others. In 2017, NIDA funded ~$16M in therapeutic cannabinoid research. These studies focus on treatment of pain, substance use disorder (e.g., with cannabidiol), and HIV. Most use THC, CBD, or other chemical entities that modulate the activity of the endocannabinoid system to achieve a therapeutic effect. These are thought to be more likely than the plant or its crude extracts to result in an FDA-approved medication.

The NIH Perspective: The National Institute of Mental Health (NIMH)
Mi Hillefors, M.D., Ph.D.
National Institute of Mental Health, NIH

NIMH supports a small but important portfolio of research on cannabinoids. The major research areas of these efforts include furthering our understanding of mechanisms and underlying pathophysiology, modulation of adolescent maturation of the brain, adolescent use of cannabis, clinical risks with cannabinoid use, etc. Clinical areas of NIMH interest may include risk for psychotic disorders and cannabis, neuroinflammation and cannabinoid use, and mental health disorders such as PTSD and anxiety. For research on developing cannabis as a novel treatment, NIMH requires an experimental medicine approach, which focuses on demonstrating that the drug engages the target as assessed with PET, MRI, etc., that it changes brain function (e.g., brain waves), and that such target engagement and functional brain changes are linked to improvement in clinical outcome.

The NIH Perspective: The National Institute of Neurological Disorders and Stroke (NINDS)
Mohamed Hachicha, Ph.D.
National Institute of Neurological Disorders and Stroke, NIH

Delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the most abundant and investigated extracts from Cannabis sativa. Nabilone and dronabinol (synthetic analogs of Δ9-THC) have been approved by the FDA for chemotherapy-induced emesis in cancer patients. Most recently, the FDA also approved Epidiolex (CBD) for the treatment of rare and severe forms of epilepsy disorders (Lennox-Gastaut and Dravet syndromes) in patients 2 years of age and older. The accumulating pharmacological evidence of phytocannabinoids in a variety of therapeutic indications suggests that increased translational studies are required to establish proof-of-concept in humans for various therapeutic indications. In order to expedite translation from basic science to the clinic, NINDS proposes IGNITE, Blueprint Neurotherapeutics (BPN), and NeuroNext programs to help advance natural products into the clinic.

FDA Regulatory Roles Concerning Cannabis and New Drug Research
Dominic Chaipperino, Ph.D.
Center for Drug Evaluation and Research, FDA

This presentation will outline FDA’s regulatory roles with respect to cannabis and drug development, which includes our roles under the Federal Food Drug & Cosmetic Act (FDCA) and also under the Controlled Substances Act (CSA). Investigational drugs made from cannabis are controlled under the CSA in Schedule I, which is for drugs with a high potential for abuse and no currently accepted medical use. There are already some cannabis-related drug products approved by FDA and these have been rescheduled for placement in schedules under the CSA that allow appropriate controls to mitigate risks of abuse and diversion and are consistent with a drug’s approved medical use so that it may be prescribed and marketed. Rescheduling of drugs under the CSA involves FDA’s important role of conducting a scientific and medical analysis to support scheduling or rescheduling recommendations, transmitted to DEA to act upon. In the context of drug development, FDA will advise sponsors of data that should be collected to support our scheduling recommendations. FDA supports drug development of product formulations derived from the cannabis plant and has regulatory programs available to prioritize important drug development that may address an unmet medical need, which we have done for some cannabis-derived formulations. FDA’s primary regulatory role over investigational drug research is to regulate research in human subjects, which is conducted under an Investigational New Drug (IND) application. The primary focus in this regulatory role is to ensure the reasonable safety of subjects participating in research, but FDA also provides advice to sponsors as questions come up during their drug development under an IND. FDA also plays a role under DEA’s separate regulations under the CSA to assist DEA in their registration of research protocols that involve use of a Schedule I drug.

Marijuana, Research and the DEA
James Arnold
Diversion Control Division, DEA

Jim Arnold will discuss access to registration with the DEA as a Schedule I Researcher, the process by which registration with the DEA is obtained, and the DEA’s position on research with marihuana and other Schedule I controlled substances.

The Scientific Researchers’ Perspective: Insights on Establishing New Cannabis Research Programs
Emily Lindley, Ph.D.
University of Colorado, Denver

There is growing evidence for the efficacy of cannabis for the treatment of various health conditions. As such, there is a concomitant increase in the number of new investigators entering the realm of cannabis-based research. Implementing clinical trials of investigational cannabis products is a complex process, particularly for researchers at institutions without prior cannabis research experience. In addition to the arduous regulatory approvals required, there are various legal and infrastructural considerations that can be challenging to navigate. The goal of this presentation is to describe how we initiated a clinical trial of vaporized cannabis at the University of Colorado and to provide suggestions for avoiding obstacles when developing new cannabis research programs.

Novel Approaches to Research on Cannabis Products Available in State-Regulated Markets
Kent Hutchison, Ph.D.
University of Colorado, Boulder

More than two-thirds of the United States population have access to state-regulated cannabis markets, either medicinal or recreational. Despite the rapidly changing cultural, political, and legal landscape in the U.S. and around the globe, the scientific literature is inadequate and mostly uninformative with respect to public policy, public health, and personal decisions regarding the potential benefits and harms of cannabis. To address this gap, we recently launched several NIH-funded observational studies that involve collecting blood, subjective assessments of key outcomes such as mood and pain, cognitive assessments, and inflammatory biomarkers before and after the use of widely available cannabis products. In a little over 1 year, we have collected data on over 300 participants (both recreational and medical) and have gained some insight into the effects of high-potency flower, concentrates, and infused products. The presentation will briefly summarize the data and discuss the methodological approach.

The Scientific Researchers’ Perspective: The Challenge of Conducting Clinical Trials of Cannabis and Cannabinoids in the Treatment of Human Conditions
Thomas D. Marcotte, Ph.D.
University of California, San Diego

Cannabis has shown beneficial effects for a number of conditions in short-term studies, yet there remains significant uncertainty regarding dosing, constituents, etc. and what conditions might benefit from treatment. While the opportunity for clinical trials using cannabis is expanding, there remain challenges in conducting this research. Drawing upon the Center for Medicinal Cannabis’s (CMCR) 15+ years of conducting such clinical trials, this presentation will 1) briefly discuss CMCR clinical trials utilizing cannabis plant material from NIDA, as well as other sources of plant-based and synthetic cannabinoids, 2) misperceptions regarding what can be undertaken in cannabis-related clinical trials, 3) the role that Centers can play in advancing cannabis/cannabinoid research, and 4) remaining challenges in understanding the effects of cannabis/cannabinoids in human health.

How Cannabis-Derived Medications Go Through the FDA Approval Process
Alice Mead, J.D.
Greenwich Bioscience

Securing approval from the Food and Drug Administration (FDA) is difficult for any investigational medication, but the challenges are even greater for products derived from botanical materials. In addition, there are additional hurdles and requirements for products containing substances that may affect the central nervous system (CNS). Strict control of the conditions of cultivation and harvest of the botanical starting material is the essential first step. Multiple quality control steps, specifications (agreed to by FDA), and batch-to-batch consistency are required at each point along the way as the botanical raw material moves through various stages into a finished drug product. Since cannabis is classified in Schedule I of the Controlled Substances Act, special Federal and state license and security requirements apply. Because cannabinoids have CNS activity, a full battery of abuse potential studies must be conducted. Upon FDA approval, a new cannabinoid product must be rescheduled under both state and Federal law before it can be dispensed by pharmacies.

Section 3 – Working Within the System: Advances in Cannabis-Related Production and Distribution

Resources Available From the NIDA Supply Catalog and How To Obtain Them
Richard Kline, Ph.D.
National Institute on Drug Abuse, NIH

The mission of the National Institute on Drug Abuse (NIDA) is to support and conduct research across a broad range of scientific disciplines to bring the power of science to bear on substance use disorders (SUDs). To facilitate research in basic and clinical science, NIDA established the Drug Supply and Analytical Services Program. It is the goal of this program to provide the drug abuse research community with a reliable source of authentic and quality assured drugs, compounds, and services to meet ever emerging and evolving needs in the field. This presentation will provide a brief introduction to the NIDA Drug Supply and Analytical Services Program, identify what types of drugs/compounds are contained in the program inventory, present some of the specific cannabis-related products available, and discuss procedures for applying to the program to obtain research materials.

A Cannabinoid Prodrug Approach to Treating Glaucoma
Brian Murphy, M.D., M.P.H.
Nemus Bioscience, Inc.

Glaucoma is one of the leading causes of irreversible vision loss globally. Therapies have focused on lowering intraocular pressure (IOP) to mitigate the loss of retinal ganglion cells (RGCs) secondary to the crush injury and hypoxia associated with elevated IOP. Tissues in the eye regulating IOP have a significant density of cannabinoid receptors, and delivering a cannabinoid receptor agonist directly to the eye could be a viable method to preserve vision by lowering IOP and via direct neuroprotection of the optic nerve by cannabinoids.

Pharmaceutical Technological Approaches for NIH Collaboration, Product Development, & Commercialization
Santos Murty, Ph.D.
Murty Pharmaceuticals, Inc. (MPI)

Murty Pharmaceuticals, Inc. (MPI) is a practical industrial-based research, development, and manufacturing organization. The company focuses on drug substance (DS) and drug product (DP) dossier activities in an FDA-approved facility with DEA Schedule I - V registrations for research, analytical, and manufacturing activities. Technical capabilities include synthetic API characterization, botanical extraction processes, preformulation, formulation development, analytical development, cGMP dosage form scale-up studies, and commercial-scale manufacturing. Furthermore, MPI possesses numerous intellectual property assignments in over a dozen countries worldwide for therapeutically delivering poorly water soluble drugs (PWSDs). Future organizational objectives include fostering collaborations for rapid development and commercialization of cannabinoid-based and other PWSD agents. With the United States currently lagging behind in cannabinoid product development, it is hoped a collaborative research, development, and manufacturing network could be established within the existing NIH scientific network.

Emerging Technologies: Using Yeast To Synthesize Cannabinoids
Anthony Farina, Ph.D.
Librede, Inc.

Librede, Inc. is a synthetic biology company focused on unlocking the therapeutically relevant natural products from cannabis. Librede, Inc. primarily focuses on developing a yeast-based biosynthetic production platform for CBD/CBDA. However, the cannabis plant has potentially many more compounds that could become pharmaceutically relevant thus creating a need to sustainably and economically produce them. This presentation will focus on the value of using recombinant microorganisms to study and produce the emerging therapeutic potential of the cannabis plant.