The impact of marijuana use on glucose, insulin, and insulin resistance among us adults

The Impact of Marijuana Use on Glucose, Insulin, andInsulin Resistance among US AdultsElizabeth A. Penner, BS,,Hannah Buettner, Murray A. Mittleman, MD, ,aUniversity of Nebraska College of Medicine, Omaha; bDepartment of Epidemiology, Harvard School of Public Health, Boston, Mass;cCardiovascular Epidemiology Research Unit, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Mass.
BACKGROUND: There are limited data regarding the relationship between cannabinoids and metabolicprocesses. Epidemiologic studies have found lower prevalence rates of obesity and diabetes mellitus inmarijuana users compared with people who have never used marijuana, suggesting a relationship betweencannabinoids and peripheral metabolic processes. To date, no study has investigated the relationshipbetween marijuana use and fasting insulin, glucose, and insulin resistance.
METHODS: We included 4657 adult men and women from the National Health and Nutrition ExaminationSurvey from 2005 to 2010. Marijuana use was assessed by self-report in a private room. Fasting insulin andglucose were measured via blood samples after a 9-hour fast, and homeostasis model assessment of insulinresistance (HOMA-IR) was calculated to evaluate insulin resistance. Associations were estimated usingmultiple linear regression, accounting for survey design and adjusting for potential confounders.
RESULTS: Of the participants in our study sample, 579 were current marijuana users and 1975 were pastusers. In multivariable adjusted models, current marijuana use was associated with 16% lower fastinginsulin levels (95% confidence interval [CI], À26, À6) and 17% lower HOMA-IR (95% CI, À27, À6). Wefound significant associations between marijuana use and smaller waist circumferences. Among currentusers, we found no significant dose-response.
CONCLUSIONS: We found that marijuana use was associated with lower levels of fasting insulin andHOMA-IR, and smaller waist circumference.
Ó 2013 Elsevier Inc. All rights reserved.  The American Journal of Medicine (2013) -, --- KEYWORDS: Glucose; Insulin; Insulin resistance; Marijuana use Marijuana is the most commonly used illicit drug in the marijuana in 19 states and the District of Columbia, physicians United States, and use is increasing. The 2010 National will increasingly encounter marijuana use among their patient Survey on Drug Use and Health reported that between 2007 populations.Marijuana use is associated with an acute and 2010, the prevalence of marijuana use among persons aged increase in caloric intake,and people who smoke marijuana 12 years and older increased from 5.8% to 6.9%, meaning there have higher average caloric intake levels than nonuser are an estimated 17.4 million current users of marijuana.
Despite these associations with increased caloric intake, Approximately 4.6 million of these users smoked marijuana marijuana use has been associated with lower body mass daily or almost dailyWith the recent legalization of recrea- index (Band a lower prevalence of and dia- tional marijuana in 2 states and the legalization of medical betes mellitus.The mechanisms underlying this paradoxhave not been determined, and the impact of regular mari-juana use on insulin resistance and cardiometabolic risk Funding: None.
Conflict of Interest: None.
factors remains unknown. In this study of 4657 participants Authorship: All authors had access to the data and played a role in in the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2010, we examined the associa- EAP and HB are joint first authors.
tions between habitual marijuana use and measures of Requests for reprints should be addressed to Murray A. Mittleman, MD, fasting glucose and insulin levels, insulin resistance, and DrPH, 375 Longwood Ave, Boston, MA 02215.
components of the metabolic syndrome.
0002-9343/$ -see front matter Ó 2013 Elsevier Inc. All rights reserved.
The American Journal of Medicine, Vol -, No -, - 2013 corrected because of bias from quality controls (SolomonPark Research Laboratories, Kirkland, Wash), using the following formula: corrected HDL-C ¼ [(Solomon Park The NHANES is a cross-sectional, continuous survey assigned HDL-C value) Â (participant HDL-C)]/(quality administered annually by the National Center for Health control HDL-C value associated with participant sample)].
Statistidata are released in 2-year increments. The From 2007 to 2010, HDL-C testing was performed at the ics, Inc, South San Francisco, Calif).
 Despite its associations with increased mass index and prevalence of diabetes.
Blood Pressure, Body Mass Index, and Waist Circum- ference. All measurements were collected during the Have you ever, even once, smoked marijuana or physical examination in mobile examination centers, hashish?” (yes, no, refused, don’t know); according to standard NHANES protocol.Blood pressure How long has it been since you last used marijuana or estimates were calculated by averaging 3 blood pressure hashish?” (answers were given as number of days, weeks, readings. BMI was calculated as weight in kilograms divided by the square of height in meters.
During the past 30 days, on how many days did you use Responses to these questions were used to classify Characterization of Sociodemographics and participants as never users (never smoked marijuana, n ¼ 2103); past users (smoked marijuana at least once but not in Participants reported age, sex, race/ethnicity, education the past 30 days, n ¼ 1975); and current users (smoked level, income, marital status, tobacco use, physical activity marijuana at least once in the prior 30 days, n ¼ 579).
level, and alcohol use. Race/ethnicity was classified asHispanic, non-Hispanic white, non-Hispanic black, orother. We classified education level as less than high school, high school or equivalent, or some college. Income Insulin, Glucose, Homeostatic Model Assessment Insulin was categorized as less than $20,000, $20,000 to $44,999, Resistance Score, High-Density Lipoprotein Cholesterol, $45,000 to $74,999, and greater than or equal to $75,000.
Hemoglobin A1c, and Triglycerides. Participants pro- Participants were classified into 3 groups of tobacco ciga- vided blood samples in the morning after a 9-hour fast.
rette exposure: current user of tobacco cigarettes, past user The homeostasis model assessment of insulin resistance of tobacco cigarettes, and lifetime nonsmoker (defined as (HOMA-IR), a measure of insulin resistance, was calculated <100 cigarettes in lifetime). Physical activity was classified as fasting serum insulin (mU/mL) Â fasting plasma glucose as active, defined as report of any regular moderate or vigorous physical activity, or inactive, defined as report of From 2005 to 2006, high-density lipoprotein cholesterol no regular moderate or vigorous physical activity. Alcohol (HDL-C) testing was performed at Johns Hopkins Univer- use was classified as nondrinkers, less than or equal to 1 sity, using the Hitachi 717 and Hitachi 912 (Roche Diag- drink per week, 1 to 14 drinks per week, or more than 14 nostics, Indianapolis, Ind). In this cycle, values were Characteristics (%) of Participants from the National Health and Nutrition Examination Survey (n ¼ 4657), 2005 to 2010* Analyses were weighted to reflect national population estimates.
multiple linear regression models with BMI, logarithmic All analyses were weighted to adjust for the complex fasting insulin levels, fasting glucose levels, logarithmic sampling design of the NHANES. We used chi-square tests to compare baseline characteristics across never, former, and levels, HDL-C levels, systolic blood pressure, diastolic blood pressure, and waist circumference as continuous Because data on income were missing in 306 participants outcomes. We first examined models adjusted for age (7%) in the study population, we used Markov chain Monte and sex, and then performed multivariable regressions Carlo multiple imputation to simulate 5 complete datasets.
accounting for all of the following covariates, which were All statistical analyses were performed in each dataset. The specified a priori as potential confounders: age, sex, race/ results were then averaged using the mi estimate command ethnicity, education level, income, marital status, tobacco in STATA, and P values and confidence intervals (CIs) use, physical activity level, and alcohol use. Because BMI incorporating the uncertainty in the imputed estimates were may mediate the association between marijuana use and our We then compared the imputed and observed study outcomes, we examined the impact of further adjust- values to assess the reasonableness of the imputation model.
ing for BMI in multivariable models.
Insulin, HOMA-IR, and triglycerides were skewed and We examined whether there was a nonlinear association log-transformed to approximate normality. We fit separate between frequency of marijuana use and logarithmic fasting The American Journal of Medicine, Vol -, No -, - 2013 Mean Values (Standard Errors) of Fasting Insulin and Glucose According to Average Marijuana Use Among Participants from the National Health and Nutrition Examination Survey, 2005 to 2010 BMI ¼ body mass index; DBP ¼ diastolic blood pressure; HbA1c ¼ hemoglobin A1c; HDL-C ¼ high-density lipoprotein cholesterol; HOMA-IR ¼ homeostasis model assessment of insulin resistance; SBP ¼ systolic blood pressure.
*Means for insulin, HOMA-IR, and triglycerides are geometric.
insulin and HOMA-IR among current users of marijuana by relationship and no evidence for a U- or J-shaped curve. We including the difference between median intake and reported did not find any significant associations between marijuana intake and the square of this value as continuous terms in use and triglyceride levels, systolic blood pressure, or dia- our multivariable regression model. Because people with diabetes mellitus may alter their marijuana use habits, we In an analysis adjusting for BMI, a potential mediator also performed a sensitivity analysis excluding participants of the associations between marijuana use and the car- with diabetes mellitus. All analyses were conducted using diometabolic outcomes, the associations between current STATA 12 (StataCorp LP, College Station, Tex).
marijuana use and fasting levels of insulin, HOMA-IR, andwaist circumference were attenuated, but remained statisti-cally significant (). In addition, the results were not materially different in analyses that excluded participants Of the 4657 NHANES participants in our study sample, 579 (representing 12.2%) were current users of marijuana and1975 (representing 47.7%) had used marijuana at least oncein their lifetime, but not in the past 30 days. Compared with lifetime nonusers, participants who reported marijuana use In this large, cross-sectional study, we found that subjects in the past month tended to be male, younger, and current who reported using marijuana in the past month had lower levels of fasting insulin and HOMA-IR, as well as smaller In unadjusted analyses, past and current marijuana use waist circumference and higher levels of HDL-C. These were associated with lower levels of fasting insulin, glucose, associations were attenuated among those who reported HOMA-IR, BMI, and hemoglobin A1c (Current using marijuana at least once, but not in the past 30 days, marijuana use also was found to be inversely associated with suggesting that the impact of marijuana use on insulin and waist circumference. Models adjusted for age and sex insulin resistance exists during periods of recent use.
demonstrated statistically significant associations between There have been discrepant findings on the relationship past and current use of marijuana with lower levels of between marijuana use and BMI. A study of young adults fasting insulin, glucose, HOMA-IR, and BMI. Also, current examining associations between marijuana use and cardio- use was associated with higher HDL-C levels and lower vascular risk factors reported no significant trend between waist circumference (In multivariable-adjusted marijuana use and whereas analyses of 2 large models, the associations of current marijuana use with lower nationally representative surveys found lower BMI and levels of fasting insulin and HOMA-IR, as well as with decreased prevalence of obesity.Few studies have higher HDL-C levels and lower waist circumference, explored possible underlying explanations for these associ- remained statistically significant (Compared with ations. However, a recent analysis using NHANES III data participants reporting never having used marijuana in their showed that marijuana users had a lower prevalence of lifetimes, current use was associated with 16% lower fasting diabetes mellitus compared with nonusers;similar results insulin levels (95% CI, À26 to À6), 17% lower HOMA-IR have been found with administration of cannabidiol in (95% CI, À27 to À6), and 1.63 mg/dL higher HDL-C levels a mouse model.In the present study, we demonstrate (95% CI, 0.23-3.04) in multivariable adjusted models.
a significant association between current marijuana use and Among current users, we found no significant dose-response lower levels of fasting insulin and insulin resistance in 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 1.37 (À0.01, 2.74) À0.65 (À1.13, À0.18) À0.49 (À1.68, 0.70) À1.08 (À2.39, 0.24) À0.36 (À1.28, 0.56) À1.54 (À2.24, À0.83) À3.50 (À5.31, À1.69) 0.15 (À1.19, 1.49) À0.08 (À0.63, 0.47) À1.04 (À2.55, 0.47) À0.01 (À1.06, 1.04) À2.8% (À4.6%, 10.7%) 1.22 (À0.25, 2.70) Multivariable adjusted, excludingdiabetic persons 0.49 (À0.87, 1.84) À0.15 (À0.71, 0.41) BMI ¼ body mass index; HOMA-IR ¼ homeostasis model assessment of insulin resistance.
*Insulin, HOMA-IR, and triglycerides were log-transformed.
†Adjusted for age, sex, race/ethnicity, education level, income, marital status, tobacco use, alcohol use, and physical activity.
The American Journal of Medicine, Vol -, No -, - 2013 multivariable adjusted analyses even after excluding underestimation of drug use would likely yield results participants with prevalent diabetes mellitus.
biased toward observing no association.
Particular focus has been given to the plant cannabinoid It is possible that the inverse association in fasting insulin (-)-trans-D9-tetrahydrocannabinol, which acts as a partial levels and insulin resistance seen among current marijuana agonist at both the cannabinoid type 1 and 2 receptors, and users could be in part due to changes in use patterns among cannabidiol, which has lower affinity for the cannabinoid those with a diagnosis of diabetes (ie, those with diabetes receptors but appears to antagonize both cannabinoid type 1 may have been told to cease smoking). However, in the and In addition, it has been found that repeated sensitivity analysis excluding those subjects with a diag- administration of cannabinoids reduces cannabinoid type 1 nosis of diabetes mellitus, associations between marijuana receptor density, producing a tolerance to its physiologic use and insulin levels, HOMA-IR, waist circumference, and Thus, a dose-response relationship may be ex- HDL-C were similar and remained statistically significant.
pected; however, we did not find any evidence of this in thepresent study.
Although not completely elucidated, the mechanisms by which cannabinoids affect peripheral metabolism via these With the recent trends in legalization of marijuana in the receptors have been studied extensively; the cannabinoid United States, it is likely that physicians will increasingly type 1 receptor antagonist, rimonabant, was found to encounter patients who use marijuana and should there- improve insulin sensitivity in wild-type mice, but not in fore be aware of the effects it can have on common adiponectin knockout mice, suggesting that adiponectin at disease processes, such as diabetes mellitus. We found least partially mediates the improvement in insulin sensi- that current marijuana use is associated with lower levels tivityadiponectin has been reported to improve insulin of fasting insulin, lower HOMA-IR, and smaller waist sensitivity.This rimonabant-induced improvement in insulin resistance has been confirmed in human studies.Furthermore, in a randomized clinical trial, rimonabant was significantly associated with an increase in plasma adipo- 1. Results from the 2010 National Survey on Drug Use and Health: nectin levels, as well as weight loss and a reduction in waist Volume I. Summary of National Findings. Rockville, MD: Substance circumference.Cannabis itself, when administered to Abuse and Mental Health Services Administration; 2011.
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