viruses Review The Link between Cannabis Use, Immune System, and Viral Infections Sanjay B. Maggirwar 1,* and Jag H. Khalsa 1,2 1 Department of Microbiology, Immunology and Tropical Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20037, USA; [email protected] 2 Medical Consequences of Drug Abuse and Infections Branch, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD 20852, USA * Correspondence: [email protected] Abstract: Cannabis continues to be the most used drug in the world today. Research shows that cannabis use is associated with a wide range of adverse health consequences that may involve almost every physiological and biochemical system including respiratory/pulmonary complications such as chronic cough and emphysema, impairment of immune function, and increased risk of acquiring or transmitting viral infections such as HIV, HCV, and others. The review of published research shows that cannabis use may impair immune function in many instances and thereby exerts an impact on viral infections including human immune deficiency virus (HIV), hepatitis C infection (HCV), and human T-cell lymphotropic type I and II virus (HTLV-I/II). The need for more research is also highlighted in the areas of long-term effects of cannabis use on pulmonary/respiratory diseases, immune dysfunction and the risk of infection transmission, and the molecular/genetic basis of immune dysfunction in chronic cannabis users. Citation: Maggirwar, S.B.; Khalsa, Keywords: cannabis; marijuana; cannabinoids; immune system; infections; HIV; HCV; HTLV-I/II J.H. The Link between Cannabis Use, Immune System, and Viral Infections. Viruses 2021, 13, 1099. https:// doi.org/10.3390/v13061099 1. Introduction Today, marijuana (cannabis) is the most frequently used drug in the world, with over Academic Editors: Maria Cecilia 188 million users, or ~2.5% of the population that is 15–64 years of age [1]. In the United Garibaldi Marcondes and Marcus States, the percentage of people aged 12 or above who were past year marijuana users Kaul increased from 11.0 percent (or 25.8 million people) in 2002 to 17.5 percent (or 48.2 million people) in 2019 [2]. Approximately 2 to 3 million new users of marijuana are added each Received: 13 March 2021 year with about 1.1% becoming clinically dependent on it [3]. According to a recent annual Accepted: 3 June 2021 survey of high school students, known as Monitoring the Future (MTF), the total annual Published: 9 June 2021 marijuana prevalence rose by a significant 1.3% to 23.9% in 2017 with prevalence of 10%, 26%, and 37% in 8th, 10th and 12th graders, respectively, whereas daily marijuana use Publisher’s Note: MDPI stays neutral remained at 1%, 3%, and 6%, respectively [4]. In addition to problematic cannabis use, with regard to jurisdictional claims in an estimated 38 million people are living with human immune deficiency virus infection published maps and institutional affil- iations. (HIV [5]), 170 million people with hepatitis C virus (HCV [6]) infection, 10–20 million people with human T-lymphotropic virus type 1 (HTLV-1 [7]), and an estimated 161 million people have been infected with coronoavirus, SARS-Cov2 [8], in the world. Cannabis use is associated with a wide range of adverse economic, social, psychosocial and health consequences. The psychosocial consequences of marijuana use—such as dropping out of Copyright: © 2021 by the authors. school, poor school performance, and antisocial and other behaviors among youth—have Licensee MDPI, Basel, Switzerland. been the subjects of many reviews/publications. The health consequences of cannabis This article is an open access article use involve almost all physiological and biochemical systems including the immune, distributed under the terms and conditions of the Creative Commons cardiopulmonary/respiratory, hepatic, renal, endocrine, reproductive, and central nervous Attribution (CC BY) license (https:// systems, as well as genetics and general health [9–12]. This review presents current research creativecommons.org/licenses/by/ on the impact of cannabis use on the immune system which, in turn, may lead to increased 4.0/). Viruses 2021, 13, 1099. https://doi.org/10.3390/v13061099 https://www.mdpi.com/journal/viruses Viruses 2021, 13, 1099 2 of 13 risk of acquisition and transmission of viral infections including HIV, HCV, HTLV-I/II and SARS-CoV2. 2. Methods To prepare this review, we used the NIH PubMed database and Google Scholar, by using key words including cannabis, cannabinoids, tetrahydrocannabinol, THC, cannabid- iol, CBD, marijuana, immune system, viral infections, HIV, hepatitis C infection (HCV) and HTLV-I/II, and identified, retrieved and reviewed the papers published in the English language that are relevant to the topic of a link between cannabis, the immune system, and viral infections. 3. Cannabis and Immune System The cannabis sativa plant contains 560 chemicals, of which 104 are known as cannabi- noids [13]. The most studied cannabinoids are D9-tetrahydrocannabinol (THC), which produces the majority of its psychopharmacological and other effects through two cannabi- noid receptors, CB1 (localized mainly in the brain) and CB2 (localized mainly in the periphery), and cannabidiol (CBD), a non-psychoactive cannabinoid. The endogenous cannabinoids, known as the endocannabinoid system (ECS), consist of the endogenous lipid ligands N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonylglycerol (2-AG), their biosynthetic and degradative enzymes, and the CB1 and CB2 receptors that they activate. Endocannabinoids are present on immune cells such as monocytes, macrophages, basophils, lymphocytes, and dendritic cells and are enzymatically produced and released “on demand” in a similar fashion as the eicosanoids. Cannabidiol (CBD) and cannabinol (CBN) can alter the functional activities of the immune system [14]. Cannabis and its active cannabinoids act as immune-modulating agents, affecting T-cells, B-cells, mono- cytes, and microglia, causing an overall reduction in proinflammatory cytokine expression and an increase in anti-inflammatory cytokines. The role of ECS, CB1, CB2 and cannabi- noids in various physiological systems, including immunity and different pathologies, has been well discussed by Olah et al. [15], and Almogi-Hazan and Or [16]. More recently, De Silva et al.[17] suggested the role of neuroimmune activation and the subsequent in- crease in 18-kDa translocator protein (TSPO) levels in cannabis users. In a cross-sectional study of 24 long-term cannabis users and 27 non-cannabis using controls, by using PET scans, they measured the total distribution volume across regions of interest, stress and anxiety, peripheral measures of inflammatory cytokines and C-reactive protein levels, and found that cannabis users had higher total distribution volume, thus implicating it in the development of cannabis use disorder. Greater TSPO levels in the brain were found to be associated with stress and anxiety and with higher circulating C-reactive protein levels in cannabis users. Cannabidiol may serve as an immune suppressor via the suppression of activation of various immune cell types, the induction of apoptosis, and the promotion of regulatory cells, which, in turn, control other immune cell targets [18]. Although cannabis impairs cell-mediated and humoral immunity in animal models and decreases resistance to bac- terial and viral infections [19], there is no conclusive evidence to suggest that cannabis use impairs immune function, as measured by the number of T cell lymphocytes, B cell lymphocytes, macrophages, or levels of immunoglobulin in humans [20–22]. On the other hand, and more importantly, the chronic heavy smoking of cannabis weakens the immune system, leading to increased symptoms of chronic bronchitis, coughing, production of sputum, and wheezing [23–25], and impairs the pulmonary function, pulmonary respon- siveness, and bronchial cell characteristics in cannabis-only smokers. Tashkin et al. [26] further show that chronic cannabis smoking is associated with poorer lung function and greater abnormalities in the large airways of marijuana smokers than in nonsmokers, and a greater rate of decline in respiratory function among marijuana-only smokers than in tobacco-only smokers [27]. Both studies showed that long-term smoking of marijuana Viruses 2021, 13, 1099 3 of 13 increased bronchitis symptoms. Cannabis smokers also show significantly higher levels of cytologic components in their sputum when compared with sputum from tobacco smok- ers [28]. Thus, marijuana smoking may predispose individuals to pulmonary infection, especially among patients whose immune defenses are already compromised by HIV infection and/or cancer-related chemotherapy [26]. They reported that THC produced a concentration-dependent reduction in T cell proliferation and IFN-γ production via a CB2 receptor-dependent pathway, and at the level of gene expression, THC increased the expres- sion of Th1 cytokines (IFN-γ/IL-2) and reduced the expression of Th2 cytokines (IL-4/IL-5). However, they caution that the suppression of cell-mediated immunity by D9-THC may place marijuana smokers at risk for infection or cancer. Caiaffa and colleagues [29] reported almost four times higher incidence of bacterial pneumonia in HIV-seropositive subjects than among HIV-negative subjects, and smoking illicit drugs (marijuana, cocaine, or crack) had the strongest effect on the risk of bacterial pneumonia among HIV-seropositive