Abstract 

Background

There are limited data regarding the relationship between cannabinoids and metabolic processes. Epidemiologic studies have found lower prevalence rates of obesity and diabetes mellitus in marijuana users compared with people who have never used marijuana, suggesting a relationship between cannabinoids and peripheral metabolic processes. To date, no study has investigated the relationship between marijuana use and fasting insulin, glucose, and insulin resistance.

Methods

We included 4657 adult men and women from the National Health and Nutrition Examination Survey from 2005 to 2010. Marijuana use was assessed by self-report in a private room. Fasting insulin and glucose were measured via blood samples after a 9-hour fast, and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated to evaluate insulin resistance. Associations were estimated using multiple 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 past users. In multivariable adjusted models, current marijuana use was associated with 16% lower fasting insulin levels (95% confidence interval [CI], −26, −6) and 17% lower HOMA-IR (95% CI, −27, −6). We found significant associations between marijuana use and smaller waist circumferences. Among current users, we found no significant dose-response.

Conclusions

We found that marijuana use was associated with lower levels of fasting insulin and HOMA-IR, and smaller waist circumference.

Discussion

In this large, cross-sectional study, we found that subjects who reported using marijuana in the past month had lower levels of fasting insulin and HOMA-IR, as well as smaller waist circumference and higher levels of HDL-C. These associations were attenuated among those who reported using marijuana at least once, but not in the past 30 days, suggesting that the impact of marijuana use on insulin and insulin resistance exists during periods of recent use.

There have been discrepant findings on the relationship between marijuana use and BMI. A study of young adults examining associations between marijuana use and cardiovascular risk factors reported no significant trend between marijuana use and BMI,⁵ whereas analyses of 2 large nationally representative surveys found lower BMI and decreased prevalence of obesity.⁴, ⁶ Few studies have explored possible underlying explanations for these associations. However, a recent analysis using NHANES III data showed that marijuana users had a lower prevalence of diabetes mellitus compared with nonusers;⁷similar results have been found with administration of cannabidiol in a mouse model.¹¹ In the present study, we demonstrate a significant association between current marijuana use and lower levels of fasting insulin and insulin resistance in multivariable adjusted analyses even after excluding participants with prevalent diabetes mellitus.

Particular focus has been given to the plant cannabinoid (-)-trans-Δ⁹-tetrahydrocannabinol, which acts as a partial agonist at both the cannabinoid type 1 and 2 receptors, and cannabidiol, which has lower affinity for the cannabinoid receptors but appears to antagonize both cannabinoid type 1 and 2.¹², ¹³ In addition, it has been found that repeated administration of cannabinoids reduces cannabinoid type 1 receptor density, producing a tolerance to its physiologic effects.¹², ¹⁴ Thus, a dose-response relationship may be expected; however, we did not find any evidence of this in the present study.

Although not completely elucidated, the mechanisms by which cannabinoids affect peripheral metabolism via these receptors have been studied extensively; the cannabinoid type 1 receptor antagonist, rimonabant, was found to improve insulin sensitivity in wild-type mice, but not in adiponectin knockout mice, suggesting that adiponectin at least partially mediates the improvement in insulin sensitivity;¹⁵ adiponectin has been reported to improve insulin sensitivity.¹⁶ This rimonabant-induced improvement in insulin resistance has been confirmed in human studies.¹⁷ Furthermore, in a randomized clinical trial, rimonabant was significantly associated with an increase in plasma adiponectin levels, as well as weight loss and a reduction in waist circumference.¹⁸ Cannabis itself, when administered to obese rats, was associated with weight reduction and an increase in the weight of pancreata, implying beta-cell protection.¹⁹ In addition, cannabinoid type 1 knockout mice are resistant to diet-induced obesity, suggesting that the role of this receptor is central in the metabolic processes leading to obesity.²⁰ Given that 2 of the main active phytocannabinoids in marijuana, (-)-trans-Δ⁹-tetrahydrocannabinol and cannabidiol, are classified as partial agonists and antagonists, respectively, and are thus capable of producing antagonistic effects at the cannabinoid receptors, it is possible that the associations observed in the aforementioned studies, as well as in the present study, are due at least in part to this adiponectin-mediated mechanism.

In our analyses, we presented alternative models, controlling for BMI as a potential confounder of the relationship between marijuana use and the remainder of the cardiometabolic parameters. We generated this model because of the potential for BMI to affect marijuana use and independently affect the cardiometabolic parameters. On the other hand, BMI may be a mediator of the association between marijuana use and the cardiometabolic outcomes, and thus was excluded from our primary multivariable model.

Conclusions

With the recent trends in legalization of marijuana in the United States, it is likely that physicians will increasingly encounter patients who use marijuana and should therefore be aware of the effects it can have on common disease processes, such as diabetes mellitus. We found that current marijuana use is associated with lower levels of fasting insulin, lower HOMA-IR, and smaller waist circumference.

Source: http://www.amjmed.com