Cannabis and Cannabinoids in Heart, Lung, Blood, and Sleep

Overview

The National Heart, Lung, and Blood Institute (NHLBI), of the National Institutes of Health (NIH), hosted a two-day, virtual workshop on June 21-22, 2023, entitled, Cannabis and Cannabinoids in Heart, Lung, Blood, and Sleep. This workshop aimed to summarize existing knowledge and identify research gaps surrounding the use of cannabis and cannabinoids and the resulting effects on heart, lung, blood, and sleep (HLBS) health. Additionally, participants sought to better understand the research community's challenges regarding resources, legal obstacles, and other barriers to cannabis and cannabinoid research. 

Background

The shifting legal landscapes governing medical and recreational uses have resulted in a new focus on cannabis as a drug of use, as opposed to a drug of abuse. Cannabis use has expanded across the country recreationally, medicinally, and for self-medication. Despite claims of providing health benefits, the full mechanisms and effect profiles of cannabis are not fully understood. There remains a lack of knowledge supporting therapeutic use for conditions such as sickle cell disease (SCD), chronic pain, insomnia, and anxiety. The increasing usage rates of cannabis products have highlighted the need for greater research on the potential short-term and long-term impacts of cannabis, cannabinoids, additives, and by-products on HLBS health. However, various legal challenges and barriers still affect cannabis research at the federal and state levels within the United States. This workshop aimed to discuss the current state of cannabis research, identify critical gaps and challenges, and provide strategies and resources to facilitate further research on both therapeutic and recreational uses of cannabis.

Discussion

Basics Science and Pharmacology of Cannabinoids

Cannabis, or “marijuana” (as defined under U.S. law), is a term used to describe varieties of the cannabis plant, which contains a class of compounds known as phytocannabinoids (plant-based cannabinoids).  Humans and all other mammals produce structurally distinct forms of endogenous cannabinoids, known as endocannabinoids, as well as endogenous cannabinoid receptors that have a variety of physiological functions, mainly homeostasis.  Panelists provided an overview of the endocannabinoid system and the cannabinoid receptors that, when activated by endogenous ligands or exogenous cannabinoids from cannabis, interact with the endocannabinoid system. The endocannabinoid system is a stress-responsive system that is generally considered to mediate homeostatic responses affecting the central nervous system as well as the cardiovascular, immune systems, sleep, pain, and metabolic systems. This is due to the presence of type1 and 2 cannabinoid receptors that are expressed throughout the central nervous systems, as well as the peripheral nerves and tissues.

Patterns of Cannabinoid Use and Epidemiology

Cannabis containing greater than 0.3% delta-9 tetrahydrocannabinol (THC) by dry weight is currently under federal control as a Schedule 1 substance under the Controlled Substances Act (CSA). However, dozens of states, territories, and the District of Columbia have legalized marijuana for medicinal and/or recreational purposes. Workshop participants discussed current use patterns in legalized and non-legalized states, noting that smoking of dried cannabis flower remains the dominant form of use, but the use of vaping liquids is on the rise.  Cannabis literacy, however, remains low as many consumers aren’t aware of true THC concentrations, abundance of other phytocannabinoids, or additives that are in the products they consume. This literacy challenge extends to physicians and healthcare providers due to the lack of standardization in the production and labeling of cannabis products and lack of research on the health effects of cannabis. In states where cannabis remains illegal, products containing cannabinoids derived from legal hemp, such as cannabidiol (CBD) and delta-8 THC, have exploded in popularity. As cannabinoid usage continues to rise and use patterns evolve, more research is needed to understand how these products affect human health. Implementing more community-based research protocols can help researchers understand why people use, the types of products used, and what social and structural factors influence their usage. Co-use of cannabis with other substances, such as tobacco, alcohol, opioids, and even other types of cannabis products (including synthetics), warrants further study to understand potential drug interactions and the effects on behavioral and physiological health. Barriers to conducting prospective research and potential strategies to navigate the current legal and regulatory policies regarding the study of cannabis in humans were discussed.

Cellular Level Effects of Cannabinoids on Heart, Lung, Blood, and Sleep-related Systems

Existing research studies on the effects of cannabis and cannabinoids on heart, lung, blood, and sleep were presented throughout the two-day workshop. Results and findings from both pre-clinical animal models and human clinical studies were discussed. There was mixed evidence on the overall safety of cannabis, but use was associated with higher risks of bleeding and decreased cerebral blood velocity, contributing to risk of stroke. Heart rates may spike after cannabis usage, and blood pressure may drop, further increasing the risk of adverse cardiovascular events, including myocardial infarctions. While clinical data is still incomplete about potential negative side effects, the mechanistic and pharmacological data show that cannabis use is not without health risks, even when used therapeutically. Additionally, no amount of cannabis use has been found to be safe during pregnancy. Prenatal exposure to cannabis can contribute to complications for maternal, fetal, and childhood health.  

Research was presented demonstrating that both direct and secondhand exposure to cannabis smoke affects the arterial dilation that controls blood flow volumes through flow-mediated dilation (FMD). Non-smokers exposed to secondhand smoke may have poor vascular function even when not active smokers themselves. This is due partially to the reduced release into the bloodstream of nitric oxide (NO), which is crucial to induce FMD, and smokers have blood serum that reduces NO release from cultured endothelial cells. Reduced FMD may also be observed in THC-edible consumers even though their serum does not reduce NO release from endothelial cells.  Multiple observational human subjects research studies reported associations between cannabis use and stroke, myocardial infarctions, and cardiac failure.  However, these studies have been limited by retrospective scopes, sample/population size, selection bias, recall bias, and lack of details on confounders. Cardiac function in rats progressively declined when exposed to cigarette, e-cigarette, cannabis, or even placebo smoke with no cannabinoids indicating that health dangers may be caused by toxins in the smoke or pyrolysis product generated from burning cannabis plant material rather than just from the cannabinoids they contain. Overall, speakers emphasized the need for more controlled human trials and high-quality observational studies with standardized protocols. Additionally, more research is needed on the effects of frequent secondhand cannabis smoke exposure in humans to determine the health differences between cumulative exposure and duration of exposure.

Cannabinoids and the Pulmonary System

The effects of cannabis on the pulmonary system are mainly attributed to the smoke or aerosols produced when smoking or vaping cannabinoids. In 2019, there was an epidemic of e-cigarette or vaping product use-associated lung injury (EVALI) amongst mostly young, male THC vapers. The epidemic highlighted that additives in cannabis products may also mediate adverse effects, particularly in the lungs. Speakers presented research findings that cannabis smoke and aerosols contain many of the same toxic, inflammatory, and carcinogenic components present in tobacco smoke and nicotine aerosols. One particular study noted that cannabis smokers were more likely to have impaired conductance in large airways and hyperinflation of the lungs versus non-smokers. The capacity for cannabis smoke to impair gas transfer of the lung or promote small airways disease and emphysema, key toxicities associated with chronic tobacco smoking, appears limited but not all studies agree on these findings. Respiratory symptoms frequently associated with cannabis smoking included cough, increased sputum production, bronchitis, and wheezing. Bronchoscopy and biopsy of the airway mucosa in habitual cannabis users frequently identify vascular hyperplasia, inflammation and swelling of airway epithelium along with cellular disorganization and molecular dysregulation. Several studies also indicated that exposure to direct or secondhand cannabis smoke can cause adverse effects in the pulmonary and cardiovascular systems. Despite the numerous risks to pulmonary and cardiovascular health, many cannabis users continue use for medicinal and self-medication purposes.

Potential Therapeutic Use in Pain and Sleep Disorders 

There are various pain pathways that exist in the body and chronic pain is one of the most common reasons cited for medicinal cannabis use. Speakers noted reductions in opioid overdose deaths in states with legalized medicinal cannabis and statistically significant drops in the number of opioid prescriptions for pain. In patients with sickle cell disease, ongoing research suggests that cannabis may help ease pain and possibly even modify the disease, but studies on this are not conclusive. More and better quality research is needed to explore the different types of pain and how cannabinoids and pharmaceutical grade cannabis affect specific pain types and pathways. Another potential therapeutic use for cannabis is to treat insomnia and other sleep challenges. Cannabis may help induce sleep, but chronic use can lead to poor sleep quality and other complications of sleep health. The endocannabinoid system is involved in the circadian rhythm, indicating that effects of cannabis on this system may induce and maintain sleep. However, studies have indicated that chronic use to the point of tolerance may cause a cyclic effect in which cannabis induces sleep but leads to unusual dreams, poor sleep quality, and relapse insomnia, resulting in more cannabis use to induce sleep. 

Research Resources

To guide investigators and facilitate further research, representatives from the National Institute on Drug Abuse (NIDA) and the National Center for Complementary and Integrative Health (NCCIH) presented information about the updated DEA registration process, identified suppliers for research cannabis, and provided various other resources for cannabis research. Under the CSA, researchers are required to obtain a special registration through the Drug Enforcement Administration (DEA), a process that historically has been challenging and even cost-prohibitive, particularly to newer investigators. However, newer legislation such as the 2018 Agricultural Improvement Act, also known as the “Farm Bill,” and the 2022 Medical Marijuana and Cannabidiol Research Expansion Act have loosened federal control of hemp-derived cannabinoids such as CBD and helped streamline the process to apply for and modify existing Schedule I DEA registrations. NIDA’s Drug Supply Program (DSP) supplies research grade cannabis at various concentrations of THC, CBD, and other cannabinoids to NIH grant recipients and researchers with valid DEA registrations. Additionally, the NCCIH hosts an NIH website (NIH-Funded Research) documenting the research interests of various NIH Institutes, existing cannabis research, funding opportunities, NIH contacts and program officers, links to approved suppliers, and other relevant information. While cannabis is still controlled as a Schedule I substance, there are an increasing number of resources available to facilitate much needed cannabis research.

Summary of Research Gaps and Opportunities

Throughout the workshop, participants identified important research gaps and opportunities, several of which are listed below: 

• Consider longer, multicenter-based studies with larger and more diverse sample populations in order to collect the data needed to advise policymaking and health guidelines.  Double blind clinical trials for specific pain conditions with specific products are required as different disease conditions may not have the same effect of cannabis due to differences in disease pathobiology.
• Improved research access to products with THC and CBD concentrations reflective of those found in real-world settings is important in order to better understand the potential for both therapeutic effects and toxicity.
• Further explore the complexity of smoke and various products using new models that can translate between preclinical and animal model research to human clinical studies. These effects must be examined in both integrated and organ-specific manners.
• Development of standardized units of measure for dosing and exposure, as well as terminology.
• Future research should include community-based studies with broader representation. By conducting collaborative research with communities, better research questions can be developed resulting in more useful data.
• There is a need for greater diversity and representation in sample populations. The social and structural influences of why and how these populations use cannabis, and the relationship between use and social determinants of health, should also be investigated.
• Delta-9-tetrahydrocannabinol (THC), the principal cannabinol1 receptor agonist in marijuana, is responsible for psychoactive and some of the cardiovascular and metabolic adverse effects. Over the past decades, the THC content in marijuana has increased from 2-4% to close to 20% and up to 50-90% in various extracts (used in dabbing and edibles).  As such, these products can introduce a more diverse and severe spectrum of cardiovascular and other side effects compared to those published in prior studies, and this needs to be studied.
• Further investigation to understand the mechanisms of action of the more potent synthetic cannabinoids.
• Further understanding of the long-term effects of vaping or inhalation of cannabis products through various routes is needed. The effects of cannabis and cannabinoids on HLBS health must also be examined in the context of varying routes of administration and product types.
• Examine the potential public health effects of people smoking cannabis in public as secondhand smoke and vaping aerosols may cause pulmonary and cardiovascular effects.
• Further work is needed to better understand simultaneous use patterns between cannabis and other substances. Significant work is also needed to investigate drug-drug interactions between cannabis and other prescription and recreational drugs.

Conclusion

The changing legal landscape surrounding cannabis and cannabinoids has resulted in an explosion of usage across the United States. Cannabis has historically been viewed as a drug of abuse, and now that the perspective is shifting to cannabis as a drug of use, there is a lot of ground to make up in the realm of understanding its potential for both therapeutic use and toxicity. The workshop participants presented the existing knowledge in their respective fields surrounding cannabis effects on HLBS health and usage patterns, but acknowledged that there remains much to learn. The smoke and aerosols generated by cannabis smoking and vaping are important contributors to adverse health effects, but the mechanisms of action of these pyrolysis products or the cannabinoids themselves are not fully understood. Additional resources were discussed by NIDA and NCCIH representatives to guide investigators and help facilitate much needed research. Cannabis and cannabinoids have the potential for both therapeutic and adverse health effects, but continuing research is needed to fully understand the mechanisms behind these effects as well as how they impact HLBS health.

Publication Plans

The workshop participants plan to prepare a manuscript that highlights the research gaps and opportunities for publication in a peer-reviewed journal.

Workshop Participants

Co-Chairs

• Murray A. Mittleman, M.D., DrPH Harvard T.H. Chan School of Public Health
• Robert Page II, PharmD, MSPH University of Colorado Schools of Pharmacy and Medicine
• Michael D. Roth, M.D. David Geffen School of Medicine at UCLA

Speakers and Moderators

• Gustavo Matute-Bello, M.D. Division of Lung Diseases, NHLBI
• Julie Panepinto, M.D., MSPH Division of Blood Diseases and Resources, NHLBI
• Angela M. Arensdorf, Ph.D. National Center for Complementary and Integrative Health
• Jacquelyn Bainbridge, PharmD University of Colorado
• Laura E. Crotty Alexander, M.D. University of California, San Diego and VA San Diego
• Susanna Curtis, M.D., Ph.D. Icahn School of Medicine, Mt. Sinai Hospital
• Patricia Goodhines, Ph.D. University of Maine
• Kalpna Gupta, Ph.D. University of California, Irvine
• David Hammond, Ph.D. University of Waterloo, Ontario, Canada
• Robert J. Hancox, M.D. University of Otago and Waikato Hospital, New Zealand
• Cecilia J. Hillard, Ph.D. Medical College of Wisconsin
• Jennifer A. Hobin, Ph.D. National Institute on Drug Abuse
• Andrew Kesner, Ph.D. National Institute on Alcohol Abuse and Alcoholism
• Christian Lehmann, M.D., Ph.D, FRCPC  Dalhousie University, Halifax, Nova Scotia, Canada 
• Jamie Lo, M.D., MCR Oregon Health & Science University
• David M. Lovinger, Ph.D. National Institute on Alcohol Abuse and Alcoholism
• Holly R. Middlekauff, M.D. David Geffen School of Medicine at UCLA
• Pal Pacher, M.D., Ph.D. National Institute on Alcohol Abuse and Alcoholism
• Sarah Pedersen, Ph.D. University of Pittsburgh
• Michael Shmilovich, M.S., Esq. National Heart, Lung, and Blood Institute
• Danielle Smith, Ph.D. Roswell Park Comprehensive Cancer Center
• Matthew Springer, Ph.D. University of California, San Francisco

NHLBI Workshop Planning Group

• Cheryl L. McDonald, M.D. 
• Lisa Postow, Ph.D. 
• Brian Bai, Ph.D.  
• Jining Lu, Ph.D.
• Jared Reis, Ph.D.
• Michael Shmilovich, M.S, Esq.
• Beena Sood, M.D., M.S.

Agenda

Day 1

Day 2