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NCI-NIH Complementary and Integrative Medicine Training Course (IM)

IM Course NCI, CCT Website: https://www.cancer.gov/grants-training/training/resources-trainees/courses-fellowships/integrative-medicine

Cannabis and Cancer Speaker Series

Sponsored By:
The Trans-NIH Integrative Medicine Course Committee:
Ann Berger, MD NIH Clinical Center; Terry Moody, Ph.D NCI; David Shurtleff, Ph.D NCCIH; Dan Xi, Ph.D NCI & Farah Zia, MD NCI
(December 10th, 2020)

• Cannabis is a genus of flowering plants in the family Cannabaceae. The term (“cannabis”) often refers to the various products or compounds derived from the dried leaves, flowers, stems, and seeds of the Cannabis sativa plant, and may be used for either recreational or medicinal purposes. Other species from this genus include Cannabis indica and Cannabis ruderalis.
• Cannabis is made up of more than 400 chemical substances, of which, to date, greater than 100 have been identified as having psychoactive properties, and are termed “cannabinoids.” Other non-psychoactive components include terpenes and flavonoids. Although medical research has not yet elucidated the specific effects of each component of cannabis, the majority of research is focused on two of them, cannabidiol (CBD) (traditionally non-psychoactive) and delta-9 Tetrahydrocannabinol [THC] (psychoactive & euphoric, producing the feeling of the “high”).
• Hemp, also known as industrial hemp is a variety of the Cannabis sativa plant species that is grown specifically for industrial use, such as the production of hemp fiber, hemp seeds and their oils. In the U.S. “industrial hemp” is classified by the federal government as cannabis containing no more than 0.3% THC by dry weight.
• The term “marijuana” is most appropriately used to describe products from Cannabis sativa that contain substantial amounts of tetrahydrocannabinol (THC), the component primarily responsible for producing the sense of the “high.”
• Cannabis is most often consumed recreationally for its relaxing and calming effects.
• Although the U.S. Food and Drug Administration (FDA) has not approved the cannabis plant for medicinal use, it has approved several drugs that contain individual cannabinoids. These drugs may be helpful in treating certain conditions, including, for example: chronic pain, glaucoma, poor appetite, anxiety, movement disorders due to Tourette Syndrome, epilespsy, and neuro-muscular spasticity due to Multiple Sclerosis (MS). Epidiolex is an example of a drug that contains a purified form of CBD, approved for the treatment of seizures associated with 2 rare forms of epilepsy.
• Cannabis and its related products are increasingly being used by some cancer patients for management of associated symptoms, such as pain, chemotherapy induced nausea and vomiting, and loss of appetite. Marinol and Syndros are examples of 2 FDA approved drugs that contain dronabinol, a synthetic THC, often prescribed to cancer patients with resistant chemotherapy induced nausea and vomiting. Dronabinol is also effective as an appetite stimulant in those patients with chronic disease. Another example of an FDA approved drug is Cesamet, which contains nabilone, a synthetic substance similar to THC, and is also used for chemotherapy related nausea and vomiting. In addition to this FDA approved indication, physicians will often prescribe Cesamet for off-label uses, such as alleviation of fibromyalgia pain, anorexia, and neuropathic pain syndromes.
• Preclinical research of cannabis-based drug development and early phase clinical trials have been slowly emerging over the past decades; however, interest and use of cannabis has been growing at a pace much faster than research; therefore, there exists an urgent need for objective assessment of mechanism of action of all components of Cannabis sativa, and rigorous evaluation for clinical safety and efficacy in various medical conditions, as well as different subsets of patients.
• The Cannabis & Cancer Speaker Series was conceptualized in 2017 by The Trans-NIH Integrative Medicine Course Committee, based on a new report from the National Academies of Sciences, Engineering, and Medicine that described the health effects of cannabis and cannabinoids, and reported the current state of evidence and recommendations for research. The report acknowledged a changing landscape for cannabis. At the time of the release of the report (January 2017), 28 states and the District of Columbia had legalized cannabis for the treatment of certain medical conditions. Also, eight of these states and the District of Columbia had legalized its use for recreational purposes. In addition to the expanding availability of legalized cannabis products, there was also greater acceptance to its use, raising public health concerns. Upon the 2017 release of this report, the Trans-NIH Integrative Medicine Course Committee worked to identify a platform for the time-sensitive education of NIH fellow, NIH staff, and the public, along with assessment of research needs, in this rapidly expanding area of interest. Our work came to fruition, and this comprehensive series, a first-ever topic for the NIH and NCI, was presented from March to May 2020, in a virtual format, open to NIH staff as well as to the public. It was organized by the Trans-NIH Integrative Medicine Course Committee and co-sponsored by the Integrative Oncology Working Group. Given the time-sensitive and rapidly evolving topic, this speaker series will continue into 2021.Through our initial needs assessment analysis, we were able to identify the following goals:

Goals of the Cannabis & Cancer Speaker Series:

• Education: provide time-sensitive and evidence-based scientific information, utilizing expert speakers from academia, government, and the community.
• Research: describe the current state of the science, identify research gaps, and stimulate collaborations within the NIH intramural and extramural communities, as well as through public-private partnerships.
• Product: produce a white paper summary of the lecture series, ultimately informing NIH research strategies.

Speakers & Topics:

“Integrating Cannabis Into Clinical Cancer Care” Donald Abrams, M.D.; “Mechanisms of Cannabinoids Anticancer Action” Manuel Guzman, Ph.D.; “Cannabidiol Targeting Cancer” Sean McAllister, Ph.D.; “Targeting Cannabinoid Signaling in the Immune System: A “High”-way to Heal?”” Attila Oláh, M.D., Ph.D.; “Overview: NIH Cannabis Research”, Susan Weiss, Ph.D.; “Cannabis and Pain”, David Shurtleff, Ph.D.; “Cannabinoids Promote Progression of HPV Positive Head and Neck Squamous Cell Carcinoma via p38 MAPK Activation” Joseph Califano, M.D.; “Practitioner Experience” Sunil K. Aggarwal, M.D., Ph.D, FAAPMR; “Practitioner Experience” Jeffrey Y. Hergenrather, M.D.

Brief Highlights:

Research Highlights & Identified Gaps:

• The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based neurotransmitters that bind to cannabinoid receptors (CBD-R), CB-1R mainly located in the central nervous system, and CB-2R, in the peripheral nervous system and on immune cells. It is a complex cell signalling system, identified in the early 1990’s by researchers exploring the physiological effects of THC, and plays an important role in human physiology. Our current understanding is that the ECS plays a role in regulating a range of functions including sleep, mood, appetite, memory, pain-sensation and reproduction and fertility. Continued investigation is needed to further define the intricacies, interplay, and clinical importance of this system in regulating human physiologic functions via endogenous cannabinoids, as well as those administered exogenously. For example, its role role in immune fuction is a current area of investigation. This represents a research gap that would enhance the understanding of the role and effect of cannabinoids in the human body.
• Some published epidemiological, preclinical, and clinical research has shown potential therapeutic benefit of cannabis or cannabinoids on certain areas of disease management. For example, there is a role for the medicinal use of cannabis in the prevention and management of chemotherapy induced nausea and vomiting in adults. With regard to chronic pain, those adults who were treated with cannabis or cannabinoids were more likely to experience a clinically significant reduction in symptoms. Also, for those adult patients with neuro-muscular spasticity related to multiple sclerosis (chronic and progressive neuro-degenerative disorder), short-term use of oral cannabinoids improved patient-reported spasticity syndromes. For these conditions, the effects of cannabinoids have been shown to be modest; for all other conditions evaluated by the National Academies, there was inadequate information to assess their effects. As such, this represents a research gap, and more rigorous study is needed, both in cancer and other disease states, to better understand the potential benefits of cannabis or cannabinoids for disease management.
• Interestingly, a 2019 retrospective study showed that concurrent use of cannabis during anti-cancer PDL-1 immunotherapy reduced response rates, without ultimately having an effect on overall survival; therefore, cannabinoids may be immune suppressive. Dr. Attila Oláh, a speaker in this lecture series, discussed his research on the potential immunosupressve effect of cannabinoids. In this changing landscape of increased use of immunotherapy for the management of cancer and other diseases, along with an increased acceptance and use of cannabis, the interplay of cannabis with the immune system represents a research gap that is intriguing and needs investigation.
• Marijuana use has been shown to be associated with the acceleration of growth of human papilloma virus (HPV) mediated oropharyngeal cancer (OPC). University of California San Diego (UCSD) School of Medicine rsearchers, led by Joseph Califano, M.D., have identified the molecular mechanism activated by tetrahydrocannibiol (THC). Prescence of THC in the bloodstream activates the p38 MAPK pathway, which controls programmed cell death. When activated, p38 MAPK prevents apoptosis from occurring, allowing cancer cells to grow uncotrollably. The UCSD research team used human cell lines and animal models to demonstrate that THC activates the p38 MAPK pathway, resulting in enhanced HPVOPC growth, which could be inhibited by blocking activation of the pathway. A preclinical model showed that CB1 and CB2 agonists induced proliferation, migration, and reduced apoptosis of HPVOPC cells, consistent with the clinical observation of accelerated growth of HPV associated oropharyngeal cancer with use of cannabis (marijuana). The research team also analyzed blood and tumor samples from patients with HPV related throat cancer who had their genomes comprehensively mapped to delineate activated gene pathways. Results indicated that similar to the cell lines, tumor specimens obtained from patients whose blood samples indicated detectable THC, showed p38 MAPK activation and loss of apoptosis. Califano and team are now exploring whether cannabidiol (CBD) has a similar effect to THC. They are also investigating whether p38 MAPK can be targeted with drugs to inhibit the growth of HPV related head and neck cancers. Cannabinoids may also be immune suppressive in the context of HPVOPC and thus may reduce efficacy of cytotoxic and immunotherapy. Given that HPV-related head and neck cancer is one of the fastest growing cancers in the U.S. and the fact that use and acceptance of cannabis (marijuana) and related products are rapidly expanding, further defining these pathways represents a research gap that should continue to be explored and understood. Probing possible immunesuppressive characteristics of cannabinoids represents another critical research gap in this era of immunotherapy.

Challenges and Barriers in Conducting Cannabis Research:

• The federal government has not yet legalized cannabis ((marijuana) Schedule I) and continues to enforce restrictive policies and regulations;
• “Legal” cannabis for research purposes is available only through the NIDA Drug Supply Program;
• Products available through the federal system do not sufficiently reflect the variety of products used by consumers;
• Investigators must work with FDA (IND), NIDA (LOA), DEA (site licensure), State Boards (controlled substance certificate);
• Any cannabis product marketed with a therapeutic claim, derived from hemp or otherwise, must receive FDA approval (e.g. CBD);
• Product integrity (consistency) is a challenge that must be further addressed for public safety, health, and benefit.

Research Needs Based on Identified Gaps:

• Basic biological research of the endocannabinoid system:
  It is necessary to better understand the physiological importance of the endocannabinoid system and its interplay with exogenous cannabinoids. Central to this research are investigations to elucidate the molecular mechanisms related to agonistic and antagonistic effects on CBD receptors, as well as identifying those molecules (specific cannabinoids) with such effects (endogenous and exogenous).
• Translational therapeutic preclinical study (In vitro and animal models):
  In vitro identification of those specificic cannabinoids which engage with the CBD receptor, resulting in signal transduction and molecular and translational effects is necessary. Subsequent identification of synergistic combinations of cannabinoids should also be investigated. Single agents and those combinations identified as synergistic should be further investigated in animal models. In order to set the pre-clinical stage for subsequent clinical investigations, it would be important to study the most effective cannabinoid combinations along with various chemo and immunotherapies, both in vitro, and in animal models. Finally,the identification of molecular biomarkers aimed to predict response, is necessary in this era of personalized and targeted therapies. Pre-clinical research addressing these strategic questions, along with carefully designed mechanistic studies, would set the stage for subsequent clinical research and trials.
• Clinical research and trials:
  Subsequent to rigorous pre-clinical research, and identification of effective single cannabinoids and/or cannabinoid combinations, phase 1-3 clinical trials establishing dosage, safety and efficacy in those with cancer, as well as other disease states, including those on various standard chemo and immunotherapies is warranted. A better understanding of adverse effects and drug-drug interactions is vital, in this new landscape of widespread cannabis usage. Correlative studies may identify important variables such as effects of the host genetic, environment, age, sex, diet, and other lifestyle factors.
• Public health and epidemiological studies assessing the impact of cannabis on the population:
  This would include research to better understand physical, mental, emotional, and other long term health benefits or detriments to the overall population, as well as specific subsets of the population. For example, elucidation of the long-term benefits or detriments to patients receiving anti-PD-L1 immunotherapy for cancer or other diseases, would seem important, based on early signals reported in this speaker series. Epidemiological studies could help shed light on the correlative effects of age, sex, diet, and other lifestyle factors.

Education:

Given the increasing accessibility and usage of cannabis and its related producs, it is important to provide appropriate and time-sensitive information to the healthcare community and public, with an understanding that public health and safety are placed forefront and center of all processes of decision-making. Educational resources should be written to the level of understanding of the target audience, and based on current evidence, both positive and negative; furthermore, informational material must alert readers about potential unkown health risks, given that the use of cannabis (medicinal marijuana) is far ahead of current research and clinical evidence. Resources should also address other important issues, including the implications of medical marijuana laws. Finally, given the polarized nature of this topic, public discourse, such as the scientific platform organized by the Trans-NIH Integrative Medicine Course Committee, has proven to be an effective resource to set the stage for understanding the current situation, gaps that need to be filled, and roadblocks that must be passed, in order to create a path forward. Science and research is the key to knowledge and developing best practices for patient care and public health outcomes.

References:

• https://dctd.cancer.gov/NewsEvents/Newsletter_August_2020.pdf
• https://www.nap.edu/catalog/24625/the-health-effects-of-cannabis-and-cannabinoids-the-current-state
• FDA and Cannabis: Research and Drug Approval Process (10/01/2020): https://www.fda.gov/news-events/public-health-focus/fda-and-cannabis-research-and-drug-approval-process
• Abrams DI, Guzmán M., “Can Cannabis Cure Cancer?” JAMA Oncol. 2020 Mar 1;6(3):323-324.
• Tarek Taha, David Meiri, Samira Talhamy, Mira Wollner, Avivit Peer, Gil Bar-Sela. “Cannabis Impacts Tumor Response Rate to Nivolumab in Patients with Advanced Malignancies”, Oncologist. 2019 Apr;24(4):549-554.
• Gil Bar-Sela, Idan Cohen, and Salvatore Campisi-Pinto et al., “Cannabis Consumption Used by Cancer Patients during Immunotherapy Correlates with Poor Clinical Outcome”, Cancers (Basel). 2020 Aug 28;12(9):2447

Lecture Recording links:

Summary and Highlights

Dec 10, 2020                    https://nci.rev.vbrick.com/#/videos/a920be9c-8214-4ae9-96a1-b49d25ae84c2

Training Opportunities at NIH

NIH offers a variety of training opportunities across all of the Institutes.

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