http://orcid.org/0000-0001-8496-8518
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Abstract
Cannabidiol (CBD) is the major non-psychotropic phytocannabinoid present in Cannabis sativa. In 2018, Congress designated certain C. sativa plant material as “hemp,” thus removing it from the DEA’s list of controlled substances. As a result, CBD-containing hemp extracts and other CBD products are now widely available and heavily marketed, yet their FDA regulatory status is still hotly debated. The goal of this study was to investigate the effects of a cannabidiol-rich cannabis extract (CRCE) on the gut microbiome and associated histomorphological and molecular changes in the mouse gut mucosa. Male C57BL6/J mice were gavaged with either 0, 61.5, 184.5, or 615 mg/kg/bw of CRCE in sesame oil for 2 weeks (Mon–Fri). Substantial CRCE-induced increases in the relative abundance of A. muciniphila, a bacterial species currently accepted as probiotic, was observed in fecal samples at all doses. This was paralleled by decreases in the relative abundance of other gut bacterial species. Coincident with the observed changes in gut ecology were multiple pro-inflammatory responses, including increased expression of cytokines and chemokines—Il1ß, Cxcl1, and Cxcl2 in the colon tissue. Furthermore, dramatic increases in the relative abundance of A. muciniphila significantly decreased expression of Muc2—a gene intimately associated with gut integrity. Taken together, these findings raise concerns about the safety of long-term CBD usage and underline the need for additional well-designed studies into its tolerability and efficacy.
Acknowledgments
The authors would like to thank Robin Mulkey and Bianca Schutte for providing excellent animal care at the UAMS Animal Facility.
Declaration of interest
The authors declare no conflicts of interest. The authors alone are responsible for the content and writing of the article.
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Notes on contributors
Charles M. Skinner
Charles M. Skinner, BS, is a Senior Research Associate at the Center for Dietary Supplements Research, Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences. His research has been mainly focused on the field of dietary supplements and the effects of CRCEs on the tissues and organs of mice and humans. The recent addition of Emulate’s organ-on-chip technology to the Koturbash lab, allows him to look at the effects of dietary supplements and CBD on human tissues.
Intawat Nookaew
Intawat Nookaew, PhD, is an Associate Professor in the Department of Biomedical Informatics at the College of Medicine, University of Arkansas for Medical Sciences. He received his PhD degree from King’s Mongkut’s University of Technology Thonburi, Thailand. (2008). Intawat completed his training as of postdoctoral fellow in Chalmers University of Technology in Sweden in the area of systems biology. He has published over 115 peer-reviewed articles and book chapters. Intawat’s research has been focus on development bioinformatics & computational biology frameworks to uncover secrets of life from large-scale data in the area of biotechnology and clinical/biomedical research. His research is also focused on microbiome analysis using whole genome shotgun sequencing to understand impact of microbiome on health and diseases.
Laura E. Ewing
Laura E. Ewing, MSc, is a senior PhD Student at the Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences. She received a MS degree in zoology from the University of Oklahoma. Her thesis involves the evaluation of the combinatorial effects of methionine and radiation exposure on gastrointestinal health and the microbiome. During her tenure with Dr. Koturbash, Ms. Ewing was also highly involved in studies on the cannabidiol-rich cannabis extract-induced liver toxicity.
Thidathip Wongsurawat
Thidathip Wongsurawat, PhD, is an Instructor in the Department of Biomedical Informatics (DBMI), University of Arkansas for Medical Sciences (UAMS). She received her PhD degree from Nanyang Technological University, Singapore (2015). Thidathip completed her training as postdoctoral fellow at Bioinformatics Institute, A*STAR, Singapore and also DBMI, UAMS, USA. Thidathip focuses on utilizing next-generation sequencing and long-read sequencing technology to answer biological questions faster and better than previous. Thidathip implements sequencing technology across a number of projects, including microbial genomes, metagenome, human genomics, cancer research and environmental research.
Piroon Jenjaroenpun
Piroon Jenjaroenpun, PhD, is an Instructor in the Department of Biomedical Informatics at the University of Arkansas for Medical Sciences College of Medicine. He is a bioinformatician with more than ten years of experience working in Next-generation sequencing (NGS) data analysis at the Bioinformatic Institute of Singapore. He completed his training as a postdoctoral fellow at UAMS in Third-generation sequencing data analysis, such as Pacific Biosciences and Oxford Nanopore Technology. He has published more than 30 peer-reviewed articles related to NGS. Piroon’s research has been focused on developing and applying bioinformatics pipelines and tools to integrate and make sense of biological data, for example, microbial genomes, transcriptome, metagenome, human genomics, and cancer research
Charles M. Quick
Charles M. Quick, MD, is an Associate Professor of Pathology at the University of Arkansas for Medical Sciences. He has completed fellowships in both Surgical/Gastrointestinal Pathology and Women’s and Perinatal Pathology and serves as the Director of Anatomic Pathology Subspecialty Practice and Director of Gynecologic Pathology for the Department of Pathology at UAMS.
Eric U. Yee
Eric U. Yee, MD, is an Assistant Professor of Pathology at the University of Arkansas for Medical Sciences. He has completed a fellowship in Gastrointestinal and Hepatobiliary Pathology and serves as the Director of Gastrointestinal Pathology Subspecialty Service at UAMS.
Brian D. Piccolo
Brian D. Piccolo, PhD, is an Assistant Professor at the USDA-ARS-Arkansas Children’s Nutrition Center (ACNC), located at the Arkansas Children’s Hospital in Little Rock, AR. He also has a joint appointment in the Department of Pediatrics at the University of Arkansas for Medical Sciences. His research is focused on exploring host-microbe intestinal cross-talk mechanisms associated with host energy regulation.
Mahmoud ElSohly
Mahmoud A. ElSohly, PhD, is a Research Professor at The National Center for Natural Products Research, and Professor of Pharmaceutics and Drug Delivery, School of Pharmacy, University of Mississippi (UM) and is the Director of the National Institute on Drug Abuse (NIDA) Marijuana Project at UM. He is also the President and Laboratory Director of ElSohly Laboratories Incorporated, an analytical forensic drug testing and product development laboratory. He received his undergraduate and Masters from Cairo University, Cairo, Egypt and his Ph.D. in 1975 from the University of Pittsburgh, School of Pharmacy, Pittsburgh, PA. He has been with the University of Mississippi since 1975 and has been Director of the NIDA Marijuana Project since 1981. He has over 40 years’ experience working with the isolation of natural products (notably cannabis secondary metabolites), synthetic, analytical and forensic chemistry. He has more than 30 patents and over 300 publications in these areas of science. Dr. ElSohly is also a member of many professional organizations, such as American Society of Pharmacognosy, American Chemical Society, American Academy of Forensic Sciences, Society of Forensic Toxicology, International Cannabinoids Research Society, International Association of Cannabinoid Medicines, to name a few and have received numerous awards.
Larry A. Walker
Larry A. Walker, PhD, is Director Emeritus of the National Center for Natural Products Research (NCNPR) at the University of Mississippi. He was trained in pharmacy and pharmacology, and has worked for much of his 38 yr career on natural products drug discovery, pharmacology, toxicology and metabolism. He has been integrally involved in the design and execution of preclinical and early clinical development studies on drugs and natural products.
Bill Gurley
Bill J. Gurley, PhD, is a Principal Scientist at the National Center for Natural Products Research at the University of Mississippi, Oxford. His research interests include mechanisms of herb-drug interactions, toxicity of multiple-component herbal dietary supplements, phytochemical modulation of human drug-metabolizing enzymes and drug transport proteins, pharmacokinetics of phytochemicals in humans and botanical supplement use in special populations. Gurley has been conducting pre-clinical and clinical research on botanical dietary supplements for more than 20 years.
Igor Koturbash
Igor Koturbash, MD, PhD, is an Associate Professor at the Department of Environmental and Occupational Health and Co-Director of the Center for Dietary Supplements Research at the University of Arkansas for Medical Sciences (UAMS) Fay W. Boozman College of Public Health. Being both MD and PhD, Igor has a long-lasting interest in diet and dietary supplements and their impact on human health. Therefore, the major focus of his research is safety, efficacy and mechanisms of action of dietary supplements and understanding how diet and dietary supplements can modulate tissue response to cancer therapy. Igor is heavily involved in a number of safety and efficacy studies on various dietary supplements and herbs, including methionine supplementation, green tea extract and cannabidiol (CBD), to name a few. Igor has published 90+ peer-reviewed articles and book chapters and his research has received uninterrupted extramural funding from various sources since the beginning of his independent career.