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Suggested Citation:"8 Immunity." National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
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8

Immunity

The immune system is composed of many different cells that perform a wide variety of functions in order to provide immunity against pathogens and other foreign bodies. Many assays and methods exist to evaluate specific components of the immune system and to assess changes in immune function and status. Toward this end, there is a sizable literature reporting on investigations into the effects of plant-derived, synthetic, and endogenous cannabinoids on various aspects of immune competence in experimental animals and in cell-based assays. The scientific literature is full of studies that used these animal- and cell-based immunological

Suggested Citation:"8 Immunity." National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
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approaches to show that cannabinoids modulate (either suppressing or enhancing) the functions of most of the types of immune cells that have been evaluated. By contrast, the investigations into the effects of cannabis or cannabinoid-based therapeutics on immunity in human subjects are quite limited.

The majority of studies investigating the association between cannabis or cannabinoid use and effects on human immunity have assessed one or more immunological parameters in patients infected with human immunodeficiency virus (HIV) or viral hepatitis C (HCV). For example, in the case of HIV patients, who are extensively studied within the context of cannabis exposure, these investigations have evaluated only a small number of immunological endpoints, the most common being the number of certain types of T cells (i.e., CD4+ and CD8+ T cells) in circulation and also the viral load. The limited measurements provide little information about the effect of cannabis use on overall immune status among individuals with HIV. Other studies have evaluated the effects of cannabis on immune endpoints in healthy individuals or on their susceptibility to infectious agents. In healthy individuals, these evaluations have focused primarily on the effects of cannabis use on circulating cytokines concentrations, principally inflammatory cytokines. Again, these examples emphasize the very limited and extremely narrow scope of assessments that have been conducted to examine the effects of cannabis on immune competence in humans to date.

This chapter reviews the current evidence on the association between cannabis use and immune competence in healthy populations and in individuals with infectious disease. Because the immune system plays a primary role in fighting and protecting against disease, the chapter will review evidence on the potential association between cannabis use and indicators of immune functioning as well as the potential association between cannabis use and susceptibility to, and progression of, infectious disease and cancer. Due to the paucity of human studies evaluating the effects of cannabis on the immune system, the committee identified no good- or fair-quality systematic reviews reporting on the health endpoints addressed in this chapter. Consequently, this chapter’s conclusions are based on a review of 14 primary literature articles that best address the committee’s research questions of interest. Study limitations and research gaps are noted, and the strength of the available evidence is weighed in five formal conclusions.

IMMUNE COMPETENCE

In several of the studies reviewed below, the effects of cannabis use on immune competence were assessed via direct measurement of specific

Suggested Citation:"8 Immunity." National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
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immune effect or functions in healthy individuals. The primary advantage of evaluating specific immune responses is that the immune system is composed of many different cell types, each of which performs several distinct functions. Assessing specific immune responses provides more information on whether, how, and to what extent an agent such as cannabis affects particular cells in the immune system. Although the perturbations in immune competence discussed in this section are not health effects in the sense used throughout this report, they may alter a person’s susceptibility to infection or have broad effects on immune competence, and they are reviewed for that reason.

The challenge with this type of information is that it is difficult to ascertain whether a deficit in a specific immune function, unless extreme, necessarily results in greater susceptibility to infection by a pathogen. Conversely, it is difficult to extrapolate results showing enhanced immune responsiveness due to exposure to an agent and to determine whether that exposure may lead to an increased incidence of hypersensitivity or autoimmune disease. Therefore, the evaluation of immune competence requires a comprehensive assessment of a broad range of different cell types and their functions, which to date has not been conducted in cannabis users.

Is There an Association Between Cannabis Use and Immune Competence in Individuals Without an Infectious Disease?

Systematic Reviews

The committee did not identify a good- or fair-quality systematic review that reported on the association between cannabis use and immune competence in individuals without an infectious disease.

Primary Literature

Keen and Turner (2015) evaluated the serum levels of two inflammatory cytokines, interleukin-1 alpha (IL-1a) and tumor necrosis factor (TNF), in a total of 168 African American study participants of whom 46 were lifetime cannabis users and 77 did not use any illicit drugs. After adjusting for demographic and physiological variables, study participants who did not use illicit drugs were not significantly more likely to have higher background serum IL-1a levels than lifetime cannabis users (odds ratio [OR], 0.77, 95% confidence interval [CI] = 0.34–1.74). By contrast, study participants who did not use illicit drugs were significantly more likely to have higher serum TNF levels than lifetime cannabis users (OR, 2.73, 95% CI = 1.18–6.31).

Suggested Citation:"8 Immunity." National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
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In another study, several immune parameters were evaluated in adult Egyptians (Abo-Elnazar et al., 2014). The study included 20 cannabis users and 10 controls with no history of drug abuse. CD4+ peripheral blood T cells from cannabis users showed a statistically significant decrease in proliferative response to mitogenic stimulation (phytohemagglutinin [PHA]) in culture as measured by the methyl thiazolyl tetrazolium (MTT) stimulation index when compared to CD4+ T cells from controls (mean = 1.14 ± 0.28 versus mean = 1.47 ± 0.35, p = 0.001). Supernatants from these cultures were quantified for T cell cytokines; interleukin-10 (IL-10), which is an anti-inflammatory cytokine; and interleukin-17 (IL-17), which is a proinflammatory cytokine. When compared to CD4+ T cells from non-drug-using controls, CD4+ T cells from cannabis users showed an approximately 50 percent decrease in proinflammatory IL-17 (129.05 pg/ml ± 44.24 pg/ml versus 206.30 pg/ml ± 51.05 pg/ml, p <0.001) and a two-fold increase in anti-inflammatory IL-10 (mean = 258.10 pg/ml ± 79.91 pg/ml versus mean = 138.70 pg/ml ± 38.11 pg/ml, p = 0.002). A major limitation of Abo-Elnazar et al. (2014) is the very small number of study participants.

Pacifici et al. (2007) conducted a longitudinal study which included an evaluation of total leukocytes as well as the number of CD4+ T cells, CD8+ T cells, B cells, and natural killer (NK) cells at the beginning of the study and 12 months later in 34 healthy controls who had not used illicit drugs in the previous 12 months and in 23 study participants who were occasional or regular users of cannabis. There was a statistically significant difference between controls and cannabis-using study participants with respect to the number of NK cells at the initiation of the study (mean = 205.1 cells/µl ± 83.4 cells/µl versus 126.1 cells/µl ± 80.0 cells/µl) or when evaluated at 12 months (mean = 196.8 cells/µl ± 79.3 cells/µl versus mean = 101.7 cells/µl ± 48.5 cells/µl). By contrast, differences between controls and cannabis-using study participants in the number of CD4+ T cells, CD8+ T cells, and CD19 B cells were not statistically significant at the initiation of the study or 12 months later. In addition, PHA-induced proliferation, supernatant interleukin-2 (IL-2) (a measure of T cell function), and transforming growth factor beta 1 (TGF-β1) (a proinflammatory cytokine) were assessed at the initiation of the study. Statistically significant differences were observed between controls and cannabis users in terms of PHA-induced proliferation (mean = 96.9% ± 15.6% versus mean = 72.3% ± 32.1%) and the activity units per ml of IL-2 (mean = 10.7 U/ml ± 3.8 U/ml versus mean = 6.3 U/ml ± 4.4 U/ml), whereas the difference between controls and cannabis users in the activity units per ml of TGF-β1was not statistically significant.

Jatoi et al. (2002) conducted a study involving 85 study participants with advanced cancer and weight loss to compare the effect of megestrol acetate (800 mg/day) and oral dronabinol tablets (2.5 mg twice daily),

Suggested Citation:"8 Immunity." National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
×

separately and in combination, on levels of serum interleukin-6 (IL-6), a cytokine associated with anorexia and weight loss. There was no statistically significant change in serum IL-6 levels 1 month after study initiation among study participants receiving dronabinol alone (mean difference = −0.62 pg/ml ± 3.5pg/ml) or in combination with megestrol acetate (mean difference = −0.2 pg/ml ± 3.1 pg/ml).

A longitudinal study followed study participants from birth to 38 years of age in order to investigate potential associations between cannabis use occurring between 18 and 38 years of age and physical health problems at 38 years of age, including systemic inflammation as measured by C-reactive protein levels (Meier et al., 2016). Among 947 study participants, there was no statistically significant association between joint-years of cannabis use and systemic inflammation after controlling for biological sex and tobacco use (β 0.00, 95% CI = −0.07–0.08). After controlling for biological sex, systemic inflammation at 26 years of age, and tobacco use, the association between joint-years of cannabis use and changes in systemic inflammation between 26 and 38 years of age was not statistically significant (β 0.05, 95% CI = −0.03–0.13).

Discussion of Findings

One trend that appeared to be supported by several studies was the observation that regular exposure to cannabis smoke decreased several regulatory factors that are secreted by leukocytes and that are well established in mediating inflammation. Consistent with the premise that cannabinoids may possess anti-inflammatory activity, one study showed an enhanced production of an anti-inflammatory mediator, which could be indicative of a decline in immune competence (Abo-Elnazar et al., 2014). By contrast, anti-inflammatory activity of cannabis, under certain conditions, could be beneficial because inflammation is a key event in the processes of many diseases. For example, chronic inflammation is believed to be central in HIV-associated neurocognitive disorders and anti-inflammatory activity of cannabis could potentially be beneficial in decreasing the progression of neurocognitive decline (Gill and Kolson, 2014). The finding that cannabinoids may possess anti-inflammatory activity is consistent with findings in studies conducted in experimental animal and in cell culture experiments (Klein, 2005).

The limitations of the studies conducted to date are numerous, with the most significant being the absence of a comprehensive evaluation of the effects of cannabis smoke on immune competence. In addition, several of the studies used a small number of study participants with very limited information on the study participants’ level of exposure to cannabis. Based on the very limited evaluations of only a few immune parameters,

Suggested Citation:"8 Immunity." National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
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it is not possible to draw overarching conclusions concerning the effects of cannabis smoke or cannabinoids on immune competence.

CONCLUSION 8-1

8-1(a) There is limited evidence of a statistical association between cannabis smoking and a decrease in the production of several inflammatory cytokines in healthy individuals.

8-1(b) There is insufficient evidence to support or refute a statistical association between cannabis smoking and other adverse immune cell responses in healthy individuals.

SUSCEPTIBILITY TO AND PROGRESSION OF INFECTIOUS DISEASE

The primary role of the immune system is to protect against infectious agents (e.g., bacteria, viruses, parasites). The immune system confers this protection by its ability to recognize what is foreign, often termed as “non-self,” which it then seeks to destroy using a broad repertoire of different cell types and mechanisms. Significant changes in immune competence can result in serious adverse health effects. For example, inappropriate or exaggerated immune responses can result in autoimmunity or allergy. Conversely, the suppression of immune function can lead to an increased susceptibility to infectious agents, an increased duration of infection, or a reduced ability to recognize and destroy cancer cells. A large body of literature using animal models and cell cultures has described the immunosuppressive properties of cannabinoids. Reduced immune competence due to cannabis smoke or cannabinoid treatment would be especially relevant in cases when immunocompromised HIV patients used the cannabis to stimulate their appetite or cancer patients used it to relieve the nausea associated with cancer chemotherapeutic drugs. Very few studies have investigated the effects of cannabis smoke or cannabinoids on the susceptibility to, or clearance of, infectious agents or on progression of cancer in human subjects. This section discusses findings from the few studies that have evaluated the association between cannabis use and immune status in terms of an individual’s susceptibility to infection and the health status of individuals with HIV, HCV, and other infectious diseases.

Suggested Citation:"8 Immunity." National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
×

Is There an Association Between Cannabis Use and Immune Status in Individuals with HIV?

Systematic Reviews

The committee did not identify a good- or fair-quality systematic review that reported on the association between cannabis use and immune status in individuals with HIV.1

Primary Literature

Several studies have been conducted with the specific objective of determining whether cannabis smoking or therapeutic dronabinol produces adverse effects on immune competence in HIV patients. In a prospective randomized controlled trial (RCT), 62 study participants ages 18 years and older who were infected with HIV were randomized to receive cannabis (up to three cigarettes daily), dronabinol (2.5 mg oral tablet three times daily), or an oral placebo over a 21-day period (Bredt et al., 2002). The change in absolute lymphocyte concentration among study participants receiving cannabis was statistically significantly greater than among study participants receiving the placebo (median change = 300 cells/µl versus 0.00 cells/µl, p = 0.1). As compared to study participants receiving the placebo, those receiving dronabinol experienced significantly greater changes in %CD8+CD38+HLA-DR+ cells (median change −3.50 versus 0.05, p = 0.001) and in %CD8+CD69+ cells (median change −0.30 versus 0.05, p = 0.04) during the study period. Bredt et al. (2002) state that these statistically significant changes “do not constitute [a] meaningful pattern of changes in immune phenotype of function” (Bredt et al., 2002, p. 87S).

By contrast, study participants in neither of the cannabinoid study arms experienced statistically significantly greater changes in lymphoproliferative responses to various mitogenic stimuli than did study participants in the placebo arm. No cannabis- or dronabinol-related changes were observed. Likewise, changes in cytokine (i.e., IFNγ, IL-2, TNFa) production among study participants in the cannabinoid study arms, and in NK activity among study participants in the dronabinol arm, were not significantly greater than among study participants receiving the placebo. No cannabis- or dronabinol-associated adverse effects were observed over the 21-day exposure period on the percentage of circulating CD4+ or CD8+ cells or on disease progression, as measured by viral load (Abrams

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1Chapter 4 discusses Lutge et al. (2013), a systematic review that investigates the medical use of cannabis by patients with HIV/AIDS but does not specifically address the association between cannabis use and immune competence in this population.

Suggested Citation:"8 Immunity." National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
×

et al., 2003). Overall, there were no “clear discernible negative changes” (p. 87S) among study participants who received dronabinol or cannabis as compared to those who received the placebo. Significant limitations of this study were the very short time period of cannabinoid exposure and the small number of study participants included in the study.

A longitudinal study evaluated the effects of recreational cannabis use on CD4+ and CD8+ T cell populations and disease progression in men infected with HIV (3,236 participants, of which 59 percent used cannabis) and men not infected with HIV (481 participants, of which 61 percent used cannabis) (Chao et al., 2008). HIV-negative and HIV-positive study participants were followed for a maximum of 18 and 11 years, respectively. After controlling for health risk behaviors and other potential confounders, any cannabis use and monthly or less frequent cannabis use were both associated with a statistically significant 1 percent decrease in CD4+ cell count among men not infected with HIV, while weekly or more frequent cannabis use was associated with a 5 percent decrease in CD8+ cell count among men infected with HIV. However, Chao et al. (2008, p. 5) state that there were no “clinically meaningful associations, adverse or otherwise, between use of marijuana . . . and T cell counts and percentages in either HIV-uninfected or HIV-infected men.” A major shortcoming of this study was the absence of information concerning the frequency and level of exposure to cannabis.

Thames et al. (2016) examined the independent and combined effects of HIV and cannabis smoking on neurocognitive function in 55 HIV positive and 34 HIV negative study participants who reported previously using cannabis for 12 months or more. As part of this study, the percentage of CD4+ T cells was monitored. Differences in the frequency of cannabis use were not associated with statistically significant differences in the nadir count of CD4+ T cells. A modest but statistically significant increase in the percentage of circulating CD4+ T cells (p = 0.04) and a statistically significant decrease in viral load (p = 0.03) were associated with light (i.e., 2–14 times per week) and moderate to heavy (i.e., 18–90 times per week) cannabis use as compared to nonusers. A shortcoming of this study was the small number of study participants.

Discussion of Findings

Collectively, the studies suggest that cannabis smoke and/or cannabinoids do not adversely affect the immune status of HIV patients. However, each of the four studies possessed major shortcomings in experimental design which could have contributed to the absence of adverse effects being observed in HIV patients who used cannabis or cannabinoids; these shortcomings include study durations that where insufficient to

Suggested Citation:"8 Immunity." National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
×

observe adverse effects in the endpoints being measured, small numbers of study participants, and poorly defined and variable levels of cannabinoid exposure.

CONCLUSION 8-2 There is insufficient evidence to support or refute a statistical association between cannabis or dronabinol use and adverse effects on immune status in individuals with HIV.

Is There an Association Between Cannabis Use and the Immune Status of Individuals Infected with Viral Hepatitis C?

Systematic Reviews

The committee did not identify a good- or fair-quality systematic review that reported on the association between cannabis use and the immune status of individuals infected with HCV.

Primary Literature

HCV is a chronic disorder of the liver which can lead to fibrosis and progress to cirrhosis and ultimately to end-stage liver disease or hepatocellular carcinoma. Liver fibrosis is mediated, in part, through a chronic immune-mediated inflammatory response. A study of liver biopsies from 270 untreated patients with chronic hepatitis C was conducted in which patients were categorized as either nonusers, occasional cannabis users, or daily cannabis users (Hezode et al., 2005). A significantly higher proportion of daily cannabis users (68.5 percent)—as compared to occasional cannabis users (42.5 percent) or nonusers (39.7 percent)—had a fibrosis progression rate faster than the median fibrosis progression rate for the cohort as a whole. There was a statistically significant association between daily cannabis use and faster than median fibrosis progression rate when no cannabis use was the referent (OR, 3.4, 95% CI = 1.5–7.4). After controlling for potential confounders, including alcohol and tobacco use, daily cannabis use was also determined to be an independent predictor of severe fibrosis (OR, 2.3, 95% CI = 1.1–4.8). A subsequent prospective study investigated 690 patients infected with both HIV and HCV and who had no significant liver fibrosis or end-stage liver disease at baseline, of whom 40 percent smoked cannabis daily at study baseline (Brunet et al., 2013). This study found no statistically significant association between daily cannabis use and progression to significant liver fibrosis (hazard ratio, 1.02, 95% CI = 0.93–1.12). Finally, Liu et al. (2014) conducted a study to evaluate potential associations between cannabis use and liver disease progression

Suggested Citation:"8 Immunity." National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
×

and outcomes from treatment for HCV. Among 376 participants for whom liver biopsies and cannabis use information was available, cannabis use as compared to nonuse was not significantly associated with fibrosis stage (p = 0.66) or with hepatic inflammation grade (p = 0.75). Among 348 participants, cannabis use as compared to nonuse was not significantly associated with steatosis as assessed by biopsies (p = 0.32). Compared to nonuse of cannabis, there was no statistically significant association between cannabis use and treatment outcomes as measured by rates of sustained viral response among 359 participants receiving interferon-based HCV antiviral treatment (p = 0.13).

Discussion of Findings

Although all three studies were of good quality, their results were mixed. Two studies suggested that cannabis use was not significantly associated with progression of liver disease or with fibrosis stage in HCV patients. Since chronic inflammation is a significant contributing factor to the progression of liver fibrosis, these findings appear to be consistent with the anti-inflammatory activity of cannabinoids observed in the immune competence literature reviewed above. However, a third study found that daily cannabis use was significantly associated with the severe fibrosis and faster progression of fibrosis, thereby complicating any conclusions about the association between liver disease progression and cannabis use. Overall, the available evidence that cannabis use is not associated with the progression of liver fibrosis and hepatic disease in individuals with HCV is stronger than the available evidence that cannabis use is associated with the progression of liver fibrosis and hepatic disease in individuals with HCV.

CONCLUSION 8-3 There is limited evidence of no statistical association between daily cannabis use and the progression of liver fibrosis or hepatic disease in individuals with viral hepatitis C (HCV).

Is There an Association Between Cannabis Use and Susceptibility to Oral Human Papilloma Virus (HPV)?

Systematic Reviews

The committee did not identify a good- or fair-quality systematic review that reported on the association between cannabis use and susceptibility to oral HPV.

Suggested Citation:"8 Immunity." National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
×

Primary Literature

Risk factors associated with oral HPV infection were investigated in a cross-sectional study involving 128 HIV-negative and 161 HIV-positive study participants (Muller et al., 2015). Cannabis use was identified as a statistically significant risk factor for detection of oral HPV in HIV-negative study participants (OR, 4.0, 95% CI = 1.3–12.4), although this risk was statistically nonsignificant after adjusting for other variables, including tobacco, alcohol, and other drug use (OR, 2.1, 95% CI = 0.6–7.5). By comparison, cannabis use was not a statistically significant risk factor for detection of oral HPV in HIV-positive individuals, whether before (OR, 1.6, 95% CI = 0.7–3.4) or after (OR, 1.3, 95% CI = 0.4–3.9) adjusting for potential confounders. The factors responsible for the differential effects between HIV-negative and HIV-positive individuals are unclear. Likewise, Kahn et al. (2015) conducted a cross-sectional study to evaluate the prevalence of oral HPV infection and to investigate associations between vaccination and oral infection in HIV-infected youth. The study included 272 HIV-infected study participants between the ages of 12 and 24 years, with a mean age of 21.5 years. In univariable analyses, no statistically significant association between lifetime cannabis use, as compared to nonuse, and oral HPV infection was identified (OR, 0.68, 95% CI = 0.36–1.30). A significant limitation of both studies was the inability to determine whether regular cannabis use increased risky behavior that would predispose study participants to oral HPV infection. Likewise, there was no follow-up on whether cannabis altered the course of HPV infection or its downstream consequences.

Discussion of Findings

Kahn et al. (2015) reported no statistically significant association between cannabis use and oral HPV. Muller et al. (2015) reported that, prior to adjusting for potential confounders, cannabis use was significantly associated with oral HPV in HIV-negative individuals, but not in HIV-positive individuals. The plausibility of this finding is questionable in light of the fact that HIV-infected patients have decreased T cell–mediated immunity, which is critical in anti-viral immune responses, including against HPV. Therefore, it would be expected that HIV-infected patients would be at least as, if not significantly more, susceptible to HPV infection as would HIV-negative patients. A major limitation of Kahn et al. (2015) is that it is not possible to determine, based on the study design, whether the reported association between regular cannabis use and increased incidence of oral HPV in HIV-negative individuals is attributable to cannabis-mediated immune suppression or to other causes, such as increased high-risk behavior.

Suggested Citation:"8 Immunity." National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
×

CONCLUSION 8-4 There is insufficient evidence to support or refute a statistical association between regular cannabis use and increased incidence of oral human papilloma virus (HPV).

Is There an Association Between Cannabis Use and Aspergillus Infection?

Systematic Reviews

The committee did not identify a good- or fair-quality systematic review that reported on the association between cannabis use and infection with Aspergillus.

Primary Literature

Infection with Aspergillus species can be life-threatening in immunocompromised patients, including those with prolonged neutropenia, hematopoietic stem cell transplant, solid organ transplant, inherited or acquired immunodeficiencies, diabetes, corticosteroid use, or diabetes (Cescon et al., 2008; Denning et al., 1991). Cannabis has been demonstrated to harbor Aspergillus spores, and case reports suggest that cannabis use may be associated with aspergillosis in immunocompromised patients. For example, a letter published in the Annals of Internal Medicine in 1975 described a case of Aspergillus fumigatus pneumonitis in a 17-year-old male with chronic granulomatous disease. Heavy growth of Aspergillus fumigatus was observed in a culture taken from the patient’s cannabis and pipe, and the author states that the “infection may have been acquired through inhalation of smoke from marijuana contaminated with fungi” (Chusid et al., 1975, p. 682). More recent case reports and case series have described aspergillosis in current or former cannabis users with acute myelogenous leukemia (Szyper-Kravitz et al., 2001), chronic myelogenous leukemia post bone marrow transplant (Hamadeh et al., 1988), small-cell lung cancer (Sutton et al., 1986), colorectal cancer (Cescon et al., 2008), renal transplant (Marks et al., 1996; Vethanayagam et al., 2000), chronic obstructive pulmonary disease (Sakkour et al., 2008), diabetes (Remington et al., 2015), and HIV/AIDS (Denning et al., 1991; Johnson et al., 1999). Aspergillosis has also been observed in current or former cannabis users with structural lung damage but who were not immunocompromised (Gargani et al., 2011) Many of the case reports involved smoking cannabis, although one involved a diabetic patient who inhaled vaporized cannabis for treatment of neuropathic pain (Remington et al., 2015). Box 8-1 describes a case series and a case-control study on the association between cannabis use and aspergillosis.

Suggested Citation:"8 Immunity." National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
×

Discussion of Findings

Sporadic case reports published over the last 40 years suggest that Aspergillus infection may be associated with cannabis use. The case-control study of Aspergillus infection in HIV positive patients did not find cannabis use to be significantly associated with the presence of the fungus in induced sputum or bronchoalveolar lavage specimens, although the number of study participants was small (Wallace et al., 1998). Despite the limited nature of the literature on aspergillosis and cannabis use, consensus guidelines and scientists suggest that immunocompromised patients avoid cannabis use due to its potential for increasing the risk of Aspergillus infection (Remington et al., 2015; Sullivan et al., 2001).

RESEARCH GAP

Research is needed to determine whether chronic cannabis smoke or cannabinoid treatment alters immune competence in healthy or immunocompromised individuals as evidenced by an increased incidence of infectious diseases; an extended duration of time to resolution of infectious diseases; and altered progression of cancer through the modulation of immune competence.

Suggested Citation:"8 Immunity." National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
×

SUMMARY

One challenge associated with determining whether an agent alters immune competence is the diversity of the cellular elements that constitute the immune system and the many functions that these different cell types perform. The committee found a very limited number of studies in which the effects of cannabis use on the human immune system were assessed. Almost without exception, these evaluations were very narrow in scope, assessing only one or a few immunological endpoints and thus providing little information concerning the effects of cannabis use on immune status. Some studies were limited to determining the number of circulating leukocyte populations, such as T cells, with no assessments of cell function.

Although based on limited evidence, an interesting finding was the association between cannabis use in healthy individuals and a decrease in

Suggested Citation:"8 Immunity." National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
×

the production of certain inflammatory cytokines. Similar findings have been reported in animal- and cell-based experiments. More studies will need to be conducted to verify the anti-inflammatory activity of cannabis in humans. Presently, there is either insufficient or no data to ascertain whether cannabis use alters other immune responses in healthy individuals. In addition, several studies have evaluated the effects of cannabis on either susceptibility to, or progression of, infectious diseases—namely, HIV, HCV, or the papilloma virus. There is insufficient evidence to determine whether there is an association between regular use of cannabis and increased incidence of papilloma virus or between cannabis or cannabinoid (e.g., dronabinol) use and adverse effects on immune status among individuals with HIV. In addition, there is limited evidence to support the conclusion that cannabis use does not enhance the progression of liver disease in HCV patients. Box 8-2 provides a summary of the findings from this chapter.

It is important to emphasize that many of the studies in which the effects of cannabis on the immune system were evaluated possess significant shortcomings in experimental design, such as small numbers of study participants, a study that was insufficient to determine adverse effects, a narrow scope of immunological assessments, and limited information concerning the levels of cannabis exposure. Each of these limitations precludes drawing conclusions concerning the effects of cannabis on immune competence in humans with any reasonable level of certainty.

REFERENCES

Abo-Elnazar, S., M. Moaaz, H. Ghoneim, T. Molokhia, and W. El-Korany. 2014. Th17/Treg imbalance in opioids and cannabinoids addiction: Relationship to NF-kB activation in CD4+ T cells. Egyptian Journal of Immunology 21(2):33–47.

Abrams, D. I., J. F. Hilton, R. J. Leiser, S. B. Shade, T. A. Elbeik, F. T. Aweeka, N. L. Benowitz, B. M. Bredt, B. Kosel, J. A. Aberg, S. G. Deeks, T. F. Mitchell, K. Mulligan, P. Bacchetti, J. M. McCune, and M. Schambelan. 2003. Short-term effects of cannabinoids in patients with HIV-1 infection: A randomized, placebo-controlled clinical trial. Annals of Internal Medicine 139(4):258–266.

Bredt, B. M., D. Higuera-Alhino, S. B. Shade, S. J. Hebert, J. M. McCune, and D. I. Abrams. 2002. Short-term effects of cannabinoids on immune phenotype and function in HIV-1-infected patients. Journal of Clinical Pharmacology 42(11 Suppl):82S–89S.

Brunet, L., E. E. M. Moodie, K. Rollet, C. Cooper, S. Walmsley, M. Potter, and M. B. Klein. 2013. Marijuana smoking does not accelerate progression of liver disease in HIV-hepatitis C coinfection: A longitudinal cohort analysis. Clinical Infectious Diseases 57(5):663–670.

Cescon, D. W., A. V. Page, S. Richardson, M. J. Moore, S. Boerner, and W. L. Gold. 2008. Invasive pulmonary aspergillosis associated with marijuana use in a man with colorectal cancer. Journal of Clinical Oncology 26(13):2214–2215.

Suggested Citation:"8 Immunity." National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
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Suggested Citation:"8 Immunity." National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
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Suggested Citation:"8 Immunity." National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
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Suggested Citation:"8 Immunity." National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. doi: 10.17226/24625.
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Significant changes have taken place in the policy landscape surrounding cannabis legalization, production, and use. During the past 20 years, 25 states and the District of Columbia have legalized cannabis and/or cannabidiol (a component of cannabis) for medical conditions or retail sales at the state level and 4 states have legalized both the medical and recreational use of cannabis. These landmark changes in policy have impacted cannabis use patterns and perceived levels of risk.

However, despite this changing landscape, evidence regarding the short- and long-term health effects of cannabis use remains elusive. While a myriad of studies have examined cannabis use in all its various forms, often these research conclusions are not appropriately synthesized, translated for, or communicated to policy makers, health care providers, state health officials, or other stakeholders who have been charged with influencing and enacting policies, procedures, and laws related to cannabis use. Unlike other controlled substances such as alcohol or tobacco, no accepted standards for safe use or appropriate dose are available to help guide individuals as they make choices regarding the issues of if, when, where, and how to use cannabis safely and, in regard to therapeutic uses, effectively.

Shifting public sentiment, conflicting and impeded scientific research, and legislative battles have fueled the debate about what, if any, harms or benefits can be attributed to the use of cannabis or its derivatives, and this lack of aggregated knowledge has broad public health implications. The Health Effects of Cannabis and Cannabinoids provides a comprehensive review of scientific evidence related to the health effects and potential therapeutic benefits of cannabis. This report provides a research agenda—outlining gaps in current knowledge and opportunities for providing additional insight into these issues—that summarizes and prioritizes pressing research needs.

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