Using Pre-clinical Biomarkers and Epidemiological Methods to Assess the Effects of Cannabinoids on Disease

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1 Using Pre-clinical Biomarkers and Epidemiological Methods to Assess the Effects of Cannabinoids on Disease Omayma Alshaarawy, MBBS, PhD Research Associate Department of Epidemiology and Biostatistics Michigan State University

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3 Adjusted Mean/Percent Differences in Measures of Carbohydrate Metabolism and Body Mass Index According to Marijuana Use Among Participants From the National Health and Nutrition Examination Survey, 2005 to 2010 Frequency of Marijuana Use Age, sex adjusted Insulin HOMA-IR Glucose Hemoglobin A1c Never Past use 14.0% ( 19.0%, 8.7%) 16.3% ( 21.8%, 10.3%) 3.69 ( 5.85, 1.53) 0.13 ( 0.20, 0.06) Current use 27.6% ( 33.7%, 21.0%) 28.8% ( 35.0%, 22.0%) 2.34 ( 4.64, 0.03) 0.08 ( 0.18, 0.01) Multivariable adjusted Never Past use 5.5% ( 11.5%, 1.0%) 7.0% ( 13.5%, 0.1%) 2.10 ( 4.24, 0.03) 0.07 ( 0.16, 0.03) Current use 14.9% ( 23.1%, 5.7%) 15.4% ( 23.9%, 5.9%) 0.94 ( 3.10, 1.21) 0.01 ( 0.14, 0.12) Multivariable adjusted, with BMI Never Past use 5.3% ( 11.2%, 0.9%) 6.9% ( 13.1%, 0.2%) 2.16 ( 4.22, 0.11) 0.07 ( 0.17, 0.02) Current use 11.8% ( 19.0%, 3.9%) 12.0% ( 19.4%, 4.0%) 0.47 ( 2.51, 1.57) 0.02 ( 0.11, 0.15) Multivariable adjusted, excluding diabetic persons Never Past use 7.1% ( 13.1%, 0.6%) 7.7% ( 14.1%, 0.8%) 0.62 ( 1.42, 0.19) 0.01 ( 0.05, 0.02) Current use 17.6% ( 27.4%, 6.6%) 18.2% ( 27.9%, 7.0%) 0.64 ( 1.74, 0.47) 0.04 ( 0.09, 0.02) Penner et al. The Impact of Marijuana Use on Glucose, Insulin, and Insulin Resistance among US Adults, The American Journal of Medicine

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5 Smit & Crespo. Dietary intake and nutritional status of US adult marijuana users: results from the Third National Health and Nutrition Examination Survey. Public Health Nutrition

6 Adjusted mean values of dietary factors according to average marijuana use from 1985 to 2000 in the CARDIA study Characteristics Marijuana Use Over 15-Year Study Period p Value 180 1, Never User <180 Days Days Days (n = 2,252) (n = 610) (n = 601) (n = 154) Dietary factors Daily caloric intake (kcal/d) 2,746 2,884 3,428 3,365 <0.001 Saturated fat (% daily calories) Unsaturated fat (% daily calories) Carbohydrates (% daily calories) <0.001 Protein (% daily calories) Rodondi et al. Marijuana Use, Diet, Body Mass Index, and Cardiovascular Risk Factors (from the CARDIA Study), The American Journal of Cardiology

7 Cannabis and Body Weight Hayatbakhsh et al. Cannabis use and obesity and young adults. American Journal of Drug and Alcohol Abuse Le Strat & Le Foll. Obesity and Cannabis Use: Results From 2 Representative National Surveys. American Journal of Epidemiology Beulaygue et al. Got Munchies? Estimating the Relationship between Marijuana Use and Body Mass Index. The Journal of Mental Health Policy and Economics Li et al. Associations Between Body Weight Status and Substance Use Among African American Women in Baltimore, Maryland: The CHAT Study. Substance Use Misuse Sabia et al. The Effect of Medical Marijuana Laws on Body Weight. Health Economics

Cannabis and Diabetes Mellitus The National Health and Nutrition Examination Survey (NHANES) The National Surveys on Drug Use and Health (NSDUH) Years 2005-2012 = Target population Nationally

8 Cannabis and Diabetes Mellitus The National Health and Nutrition Examination Survey (NHANES) The National Surveys on Drug Use and Health (NSDUH) Years = Target population Nationally representative of the noninstitutionalized US civilian population. = Sampling The sample employs an independent, multistage area probability sample for each State and the District of Columbia. 8

Cannabis and Diabetes Mellitus Exposure of interest (cannabis use) The National Health and Nutrition Examination Survey (NHANES) The drug use questionnaire was administered using the Audio Computer

9 Cannabis and Diabetes Mellitus Exposure of interest (cannabis use) The National Health and Nutrition Examination Survey (NHANES) The drug use questionnaire was administered using the Audio Computer Assisted Self Interview system (ACASI). The National Surveys on Drug Use and Health (NSDUH) = Participants were asked if they ever used cannabis, age of first use, and if they used cannabis in the past 30 days. 9

10 Cannabis and Diabetes Mellitus Outcome of interest (diabetes mellitus) The National Health and Nutrition Examination Survey (NHANES) Self-reported physiciandiagnosis Current use of oral hypoglycemic medication or insulin Glycosylated hemoglobin level (HbA1c) 6.5% The National Surveys on Drug Use and Health (NSDUH) Self-reported physiciandiagnosis. Statistical analysis Multivariable-adjusted logistic regression Weighting and variance estimation appropriate for complex survey data STATA, version 13 = 10

11 Cannabis and Diabetes Mellitus Study-specific estimates that quantify the association linking diabetes mellitus and recently active cannabis use Survey NHANES NSDUH NHANES NSDUH NHANES NSDUH NHANES NSDUH Meta-analysis summary OR Covariate adjusted OR (95% CI) 0.6 (0.3, 1.2) 0.7 (0.5, 0.9) 0.4 (0.2, 0.7) 0.5 (0.4, 0.7) 0.9 (0.4, 2.1) 0.8 (0.5, 1.1) 0.7 (0.4, 1.2) 0.9 (0.6, 1.2) 0.7 (0.6, 0.8) 1 Alshaarawy O and Anthony JC. Cannabis Smoking and Diabetes Mellitus: Results from Meta-analysis with Eight Independent Replication Samples. Epidemiology

12 Cannabis use and Diabetes Mellitus Survey Additionally adjusted for BMI OR (95% CI) NHANES NHANES NHANES NHANES Meta-analysis summary OR 0.8 (0.4, 1.5) 0.4 (0.2, 0.8) 1.0 (0.4, 2.1) 0.8 (0.4, 1.4) 0.7 (0.5, 0.97) 1 Alshaarawy O, Anthony JC. Cannabis Smoking and Diabetes Mellitus: Results from Meta-analysis with Eight Independent Replication Samples. Epidemiology

13 The Cannabinoid System Receptors (GPCR) CB1 CB2 Endocannabinoids Anandamide (AEA) 2-arachidonoylglycerol (2-AG) Enzymes Fatty acid amide hydrolase (FAAH) Monoacylglycerol lipase (MAGL) 13

14 CB1 receptors Activation of CB1 receptors is responsible for the well-known appetiteinducing actions of cannabinoids (Kirkham et al. British Journal of Pharmacology 2002). Activation of CB1 receptor promotes weight gain (Di Marzo. Diabetologia 2008). Rimonabant, a selective CB1 receptor inverse agonist has been shown to reduce body weight alongside improvements in other elements of the metabolic syndrome (Sam et al. Journal of Obesity 2011). 14

15 CB1 receptors Marijuana CB1 Food intake Weight Insulin resistance Marijuana Food intake Weight Insulin resistance 15

16 CB2 receptors CB2 receptors participate in the regulation of cytokine release and function CB2 activation is found to reduce TNFα, IL-2, IL-6, and IL-11; all elevated in diabetes and correlated to insulin resistance (Cabral & Griffin- Thomas. Expert Reviews in Molecular Medicine 2009, Calle & Fernandez. Diabetes Metabolism 2012). The anti-inflammatory potential of CB2 activation was demonstrated in many inflammatory diseases in animal models (Croxford & Yamamura. Neuroimmunology 2005). 16

17 Is the inverse association between cannabis use and diabetes mellitus due to the activation of CB2 receptors expressed predominantly in the immune system? 17

18 Cannabis and C- reactive protein An acute phase reactant synthesized primarily by the liver, with levels increasing in response to injury, infection, or inflammation. Circulating levels of CRP can be clinically useful in the prognosis/diagnosis of cardiovascular events and diabetes mellitus (Sattar & Hingorani. Diabetes 2009). In NHANES, serum CRP has been quantified by latex-enhanced nephelometry. 18

Recently Active Cannabis use and Serum CRP (mg/l) Levels Data for the US Based on the National Health and Nutrition Examination 2005-2010 Alshaarawy O and

19 Recently Active Cannabis use and Serum CRP (mg/l) Levels Data for the US Based on the National Health and Nutrition Examination Alshaarawy O and Anthony JC. Cannabis smoking and serum C-reactive protein: A quantile regressions approach based on NHANES Drug and Alcohol Dependence

20 Limitations NHANES and the NSDUH have an observational cross-sectional study design. Cannabis use was self-reported. There were no data on the route of administration, frequency of cannabis use beyond the 30 days prior to the interview, or potency of cannabis. 20

21 Cannabis and Markers of Inflammation We aim to add new epidemiological estimates to the cannabis-immunomodulatory body of research using the Coronary Artery Risk Development in Young Adults (CARDIA) study with 25 years of repeated measurements of cannabis use (Friedman et al. Journal of Clinical Epidemiology 1988). The CARDIA study additionally provides measurement on: Fibrinogen, an important component of the coagulation cascade, that has been associated with inflammation (Davalos and Akassoglou. Seminars in Immunopathology 2012). Interleukin-6 (IL-6) a key cytokine produced by leukocytes as well as a variety of other cells, promoting B cells differentiation, expansion and activation of T cells, and the regulation of acute-phase responses (Schaper and Rose-John. Cytokine & Growth Factor Reviews 2015). Alshaarawy O et al. Cannabis Use and Markers of Systemic Inflammation. The CARDIA Study. Under preparation 21

22 Cannabis and Markers of Inflammation The CARDIA study was designed to measure risk factors for cardiovascular disease in a biracial (Black and White) cohort of 5115 women and men who underwent their initial exam in The study was designed to provide approximately equal representation across groups of age, sex, race, and education. Community-based random sampling was performed in Birmingham, Chicago, and Minneapolis. In Oakland, respondents living in Oakland and Berkeley were randomly recruited from the Kaiser Permanente health plan membership. Follow-up examinations occurred during (Year 2), (Year 5), (Year 7), (Year 10), (Year 15), (Year 20), and (Year 25). 22

23 Cannabis and Markers of Inflammation The majority of participants have been examined at each follow-up (91%, 86%, 81%, 79%, 74%, 72% and 72% respectively). Participants were asked to attend a morning examination after fasting for 12 hours and to avoid smoking and heavy physical activity for 30 minutes before the exam. Outcomes: Fibrinogen was measured at 3 exams (Y5, Y7 and Y20). C-reactive protein was measured at 4 exams (Y7, Y15, Y20 and Y25). IL-6 was measured in Y20. 23

24 Cannabis and Markers of Inflammation Cannabis use: A detailed, self-administered questionnaire based on items from the National Household Survey on Drug Abuse was administered at each exam. Ever users of cannabis were asked about the frequency of lifetime use (1-2 times, 3-9 times, times and 100+ times). Recently active use was defined as cannabis use at least 1 day in the 30 days prior to the interview. 24

25 Cannabis and Markers of Inflammation The Generalized Estimating Equations modelling (GEE) developed by Liang and Zeger was then used to evaluate whether cannabis use might be associated with inflammatory biomarkers (Liang and Zeger. Biometrika 1986). To investigate the impact of bias introduced by these losses to follow-up, we used inverse probability weighting (IPW). Using data from all 8 exams, we then used multiple imputations to generate 10 complete datasets by replacing missing values of cannabis use and other covariates using sequential regression multivariate imputations (Azur et al. International journal of methods in psychiatric research 2011). 25

26 Cannabis and Markers of Inflammation M ean plasm a fibrinogen (m g/dl) Never use Past use R ecently active use Y5 Y7 Y20 Exam year 26

27 Cannabis and Markers of Inflammation M ean ln(crp; m g/dl) Never use Past use R ecently active use 0.0 Y7 Y15 Y20 Y25 Exam year 27

28 Estimated relationship of baseline cannabis use (Y5) and plasma fibrinogen (mg/dl at Y5, Y7, Y20) levels, and baseline cannabis use (Y7) and CRP (mg/l at Y7, Y15, Y20, Y25) levels. CARDIA Study; Birmingham, AL; Chicago, IL; Minneapolis, MN; and Oakland, CA Recency of use Lifetime frequency of past use Cannabis use Any past use Recent use 1-2 times 3-10 times times 100+times Panel A: Fibrinogen β (95%CI) Crude -13 (-18, -8) -17 (-23, -11) 2 ( -6, 10) -13 (-19, -6) -13 (-19, -8) -20 (-25, -14) Age-sex adjusted -12 (-17, -7) -10 (-15, -4) -1 (-8, 7) -13 (-19, -7) -14 (-20, -9) -13 (-18, -7) Multivariable adjusted Additionally adjusted for BMI -8 (-13, -3) -6 (-12, 0) 1 (-7, 8) -8 (-15, -2) -9 (-14, -4) -10 (-15, -4) -6 (-10, -2) -4 (-10, 2) -1 (-8, 5) -5 (-10, 1) -6 (-11, -1) -8 (-13, -3) Panel B: ln (CRP) β (95%CI) Crude (-0.27, -0.10) (-0.23, -0.01) (-0.15, 0.12) (-0.29, -0.06) (-0.31, -0.11) (-0.29, -0.11) Age-sex adjusted (-0.25, -0.08) (-0.15, 0.07) (-0.17, 0.10) (-0.29, -0.06) (-0.31, -0.11) (-0.19, -0.01) Multivariable adjusted Additionally adjusted for BMI (-0.20, -0.03) (-0.13, 0.10) (-0.15, 0.11) (-0.22, 0.00) (-0.24, -0.04) (-0.19, 0.00) (-0.15, <0.00) (-0.11, 0.10) (-0.15, 0.07) (-0.16, 0.04) (-0.18, <0.00) (-0.14, 0.03) 28

29 Estimated relationship of cannabis use (Y5, Y7, Y20) and fibrinogen levels (mg/dl at Y5, Y7, Y20), and cannabis use (Y7, Y15, Y20, Y25) and CRP levels (mg/l at Y7, Y15, Y20, Y25). CARDIA Study; Birmingham, AL; Chicago, IL; Minneapolis, MN; and Oakland, CA Recency of use Lifetime frequency of past use Cannabis use Any past use Recent use 1-2 times 3-10 times times 100+times Panel A: Fibrinogen β (95%CI) Crude -11 (-16, -6) -15 (-20, -9) 0 (-8, 8) -9 (-16, -2) -12 (-18, -6) -18 (-23, -12) Age-sex adjusted -9 (-14, -4) -10 (-16, -4) -1 (-9, 6) -10 (-16, -3) -12 (-18, -7) -11 (-17, -6) Multivariable -5 (-10, <0) -4 (-10, 2) 0 (-7, 8) -5 (-11, 2) -7 (-12, -1) -8 (-13, -2) adjusted Additionally adjusted for BMI -4 (-8, <0) -3 (-8, 2) -2 (-8, 5) -3 (-9, 2) -4 (-9, 0) -6 (-11, -1) Panel B: ln (CRP) β (95%CI) Crude (-0.21, -0.04) (-0.25, -0.06) (-0.10, 0.01) (-0.26, -0.03) (-0.27, -0.07) (-0.26, -0.08) Age-sex adjusted (-0.18, -0.02) (-0.20, -0.01) 0.05 (-0.11, 0.13) (-0.26, -0.04) (-0.26, -0.07) (-0.17, 0.01) Multivariable adjusted Additionally adjusted for BMI (-0.14, 0.03) (-0.16, 0.04) 0.02 (-0.10, 0.01) (-0.20, 0.02) (-0.20, 0.00) (-0.15, 0.04) (-0.09, 0.05) 0.00 (-0.09, 0.08) (-0.11, 0.09) (-0.13, 0.05) (-0.10, 0.06) (-0.08, 0.07) 29

30 Future directions Recruitment for Greater Lansing area Community Health Survey The aim of the survey is to prospectively assess the health status of the Lansing community with research questions such as The immunomodulatory effects of cannabis The effect of the route of administration Collecting biological samples to measure different biomarkers 30

31 Thank you Funding sources: NCCIH K99-AT009156, NIDA T32DA Acknowledgments : Prof. James Anthony, Prof Karl Olson (Olson lab), and Prof Norbert Kaminski (Kaminski lab) The views expressed are those of the speaker and do not necessarily represent the views of the National Center for Complementary and Integrative Health, the National Institute of Drug Abuse, the National Institutes of Health; or Michigan State University. 31

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