Epsilon Alpha
Bluelighter
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Here's a paper I wrote for a class recently, enjoy!
TL;DR: Acute use makes you resemble a prediabetic, long term use just makes you a little fatter.
Yes I am aware I accidentally a word throughout, I wrote this the night before and didn't proofread it lol.“Metabolic Effects of Chronic Cannabis Smoking (Ranganath et al., 2013).”
Introduction:
Use of Cannabis sativa and Cannabis indica, referred to as “cannabis” thus forth, for both psychoactive and medicinal purposes has been reported to occur for several thousand years [2]. Currently an estimated 17 million Americans are thought to currently use cannabis as a recreational drug, and it appears that the number of users is rapidly increasing [3]. Despite a long history of widespread human use very little is known about the metabolic effects of chronic cannabis use.
Cannabis is known to contain several naturally occurring compounds known as cannabinoids, which possess a wide range of pharmacological actions. Perhaps the most well-known cannabinoid is D9-Tetrahydrocannabinol (THC), thought to be the main psychoactive component of cannabis, which is known to activate both central and peripheral CB1R’s as well as CB2R’s of the endocannabinoid system [4]. Both cannabinoid receptors are GPCR’s and thought to be Gi/o coupled, both of which are also thought to possess generally inhibitory actions on neurotransmission [5]. However, given the varying ratios of cannabinoids in various cannabis strains and preparations there may be the possibility of other active components dominating metabolically [6].
CB1R’s are known to be widely expressed in both the central nervous system (CNS) as well as peripheral tissues, and play an important and complex role in energy homeostasis. Centrally, evidence has supported a positive role for the endocannabinoid system in both increasing the appetitive and hedonic aspects of feeding behaviour [7,8]. CB1R has been identified in every brain area thus far identified with feeding behavior and has also been identified in the parasympathetic vagus nerve, implicating many different systems with its well-known effects on promoting feeding in humans particularly increasing carbohydrate intake [9].
Peripherally, CB1R receptors are involved in energy regulation in several tissues. In adipocytes, CB1R agonism is associated with increased activity of lipoprotein lipase, which results in increased lipid accumulation [8]. Additionally, acute trials have shown that acute administration of THC to healthy volunteers is associated with glucose intolerance in humans [10]. It is believed that CB1R activation in human islets of Langerhans insulin and glucagon secretion, while CB2 agonism lowered glucose-dependent insulin secretion from β-cells [11]. Recent evidence suggests a role for an overactive endocannibinoid system in mouse and human models of obesity and hyperglycemia, potentially linking exogenous cannabinoid consumption to increased risks of obesity and type 2 diabetes mellitus [12]. It has been reported that hepatitis C positive cannabis abusers that there is a higher risk of hepatic steatosis, characterized by increased hepatic fat deposits. [13]. This agrees with Osei-Hyiaman et al. (2006) who found that hepatic CB1R activation results in increased fatty acid synthase activity [14]. In this study the authors examine if chronic cannabis use is associated with hepatic steatosis, insulin resistance, changes in β-cell function, or dyslipidemia in healthy humans.
Synopsis:
30 healthy chronic cannabis users were matched to 30 healthy controls on the basis of sex, age, ethnic background, and BMI (27±6) in this cross sectional case-control study. Chronic cannabis use was defined as smoking cannabis 4 days per week for at least 6 months with a self-reported history of cannabis use going back at least one year; additionally a drug test was performed to ensure cannabis users were not abusing other drugs. Dependence on caffeine or nicotine were not an exclusion factor, however consumption of more than 15 alcoholic beverages a week as well as use of prescribed, over the counter, or alternative medicines. Additionally, one was excluded if they were involved in greater than 60 minutes of vigorous exercise per day. All individuals in both groups were subject to a physical exam, blood and urine tests and had their histories reviewed to screen for mental and somatic health [1].
To examine the diets of both Chronic Cannabis Smokers (CCS) and the control group a 24 hour dietary recall was performed using the Healthy Eating Index 2005. This dietary recall examined both total caloric intake, dietary quality, and sources of calories. This revealed that while total caloric intake between both groups was similar the CCS had a much larger portion of their calories from carbohydrates and their diets were reported on average to be poorer than the control group. However, total caloric intake had an extremely large range for both groups to care must be taken in interpreting these [1].
To determine body fat content GE Healthcare iDXA scanner (MRI) was used to examine body composition between the L4-L5 vertebras. Hepatic fat was measured using the same scanner by single volume resonance spectroscopy, in an 8mL volume on the posterior right lobe of the liver [1]. Visceral adipose tissue was found to be higher in CCS than control however did not follow a clear dose-response relationship this is partly in agreement with the authors’ hypothesis. Additionally, contrary to the authors’ hypothesis there was no significant association between hepatic fat content and cannabis use [1].
To test β-cell function and insulin resistance 75g oral glucose tolerance test was conducted following a 10 hour overnight fast and blood was drawn at -10, 0, 15, 30, 45, 60, 90, 120, and 180 minutes relative to the time of the glucose load. Plasma was then immediately frozen at -80 centigrade and later was analyzed for several parameters to determine if chronic cannabis use effects macronutrient or endocrine hormone levels. The assays for serum lipids, glucose, insulin, C-peptide, and hemoglobin A1c were not given; however were said to be routine. Plasma free fatty acids were examined with a NEFA-HR kit and run on a COBAS FARA-II analyzer. ELISA was used to quantify plasma levels of: adiponectin, glucagon-like peptide-1, total peptide YY, and both acyl and desaceyl ghrelin [1].
Fasting plasma glucose, insulin, and hemoglobin HA1c were used to characterize glycemic control and did not differ between the CCS and control groups. Additionally, though HDL was lower in the CCS LDL cholesterol, triglycerides, and FFA levels were not significantly different. The indexes QUICKI and HIRI were used to characterize hepatic insulin resistance; OGIS a measure of peripheral glucose disposal were not found to differ between groups. However, adipose tissue insulin resistance (AIRI) and the free fatty acid suppression index were found to be significantly higher in cannabis smokers. Interestingly fasting levels of: insulin, C-peptide, peptide YY, ghrelin, and fasting GLP-1 did not vary between CCS and control [1].
Interestingly, measures of plasma levels of the liver enzyme alkaline phosphatase were significantly higher in CCS while liver transaminases, alanine aminotransferase, and, aspartate aminotransferase characterized from the blood taken at the time of the physical exam did not differ between groups [1].
Critique:
As cannabis is the most widely used illicit drug in America and its use appears to be increasing it is important to understand its metabolic effects in healthy individuals [1]. In this study the authors found that chronic cannabis use was associated with increased visceral adipose tissue in the abdomen, and increased adipose insulin resistance. However, this study is the first to report that chronic cannabis use in healthy individuals is not associated with reduced insulin sensitivity in non-adipose tissue, hepatic steatosis, glucose intolerance, impaired β-cell function, or changes in several incretins [1].These findings are contrary to the acute effects documented for cannabis exposure, so perhaps given that CB1R expression is altered with chronic or use during adolescence as CCS had an average age of first use of 15±3 years. As it has been documented that brain CB1R expression is downregulated with chronic use this would be an interesting scenario to test [15]. Additionally, as an increased risk for hepatic steatosis was reported in hepatitis C positive individuals but not healthy individuals additional research should be done to explore the cellular mechanisms responsible for the increased risk phytocannabinoids pose to individuals with hepatitis C or other liver disorders. To test this hypothesis, selective radiolabeled CB1R and CB2R ligands could be used to screen for differential whole body expression between CCS and non-users. Additionally, as only 30 individuals were used in both groups and tobacco use was much higher in CCS perhaps replicating the study with a larger population and better controlling for tobacco use would be appropriate.
By testing for a wide range of incretins over a 170 minute time surrounding an oral glucose tolerance test the authors tested for many potential causes of metabolic issues expected to be caused by cannabis. Measurement of both insulin and C-peptide allowed for indirect assessment of β-cell function to be made. Though no differences were found in chronic cannabis smokers relative to control in terms of incretins, glucose tolerance, and insulin secretion, the tests were done in situations that would not have allowed same day consumption of cannabis. This results in effects of acute consumption being unrecorded, which may have significance, as acute use has been shown to affect several appetite related incretins in HIV positive men [16]. A potential avenue for future research would be to address acute cannabis consumption in conjunction with an oral glucose tolerance test. Additionally, to address the potential issues presented by the high variability of natural cannabis future studies could provide a standardized ratio of cannabinoids for consumption or test the cannabis consumed by the CCS group [6].
Another potential area for research is determining if the effects of cannabis on adipose tissue but not hepatic fat content is due to accumulation of lipid soluble cannabinoids which further results in lipid accumulation in the visceral fat depot. Additionally, it has been demonstrated that AMPK inactivation by THC is greater in adipocytes suggesting possible depot specific effects [17].
In conclusion, this study was well conducted despite potential issues with over representation of tobacco use in the CSS group, and small sample sizes. Given the fact that the results obtained for chronic use do not agree with the existing literature for acute use, a larger and better controlled follow up study should be conducted to further verify results. Acute cannabis consumption in CCS should be considered for follow up studies as well as examining potential changes in whole body CB1R and if possible CB2R expression.
References:
1) Muniyappa R, Sable S, Ouwerkerk R et-al. Metabolic Effects of Chronic Cannabis Smoking. Diabetes Care. 2013
2) Jiang HE, Li X, Zhao YX et-al. A new insight into Cannabis sativa (Cannabaceae) utilization from 2500-year-old Yanghai Tombs, Xinjiang, China. J Ethnopharmacol. 2006;108 (3): 414-22.
3) Results from the 2010 National Survey on Drug Use and Health: Summary of National Findings [Internet]. Rockville, MD, Substance Abuse and Mental Health Services Administration. Available from http://www.samhsa.gov/data/nsduh/2k10nsduh/2k10results.htm. Accessed 12 February, 2013.
4) Fisar Z. Phytocannabinoids and endocannabinoids. Curr Drug Abuse Rev. 2009;2 (1): 51-75.
5) Pertwee RG. The pharmacology of cannabinoid receptors and their ligands: an overview. Int J Obes (Lond). 2006;30 Suppl 1 : S13-8.
6) Potter DJ, Clark P, Brown MB. Potency of delta 9-THC and other cannabinoids in cannabis in England in 2005: implications for psychoactivity and pharmacology. J. Forensic Sci. 2008;53 (1): 90-4.
7) Cota D, Tschöp MH, Horvath TL et-al. Cannabinoids, opioids and eating behavior: the molecular face of hedonism? Brain Res Rev. 2006;51 (1): 85-107.
8) Cota D, Marsicano G, Tschöp M et-al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J. Clin. Invest. 2003;112 (3): 423-31.
9) Di marzo V, Piscitelli F, Mechoulam R. Cannabinoids and endocannabinoids in metabolic disorders with focus on diabetes. Handb Exp Pharmacol. 2011;(203): 75-104.
10) Hollister LE, Reaven GM. Delta-9-tetrahydrocannabinol and glucose tolerance. Clin. Pharmacol. Ther. 1974;16 (2): 297-302.
11) Bermúdez-silva FJ, Suárez J, Baixeras E et-al. Presence of functional cannabinoid receptors in human endocrine pancreas. Diabetologia. 2008;51 (3): 476-87.
12) Matias I, Gonthier MP, Orlando P et-al. Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. J. Clin. Endocrinol. Metab. 2006;91 (8): 3171-80.
13) Hézode C, Zafrani ES, Roudot-thoraval F et-al. Daily cannabis use: a novel risk factor of steatosis severity in patients with chronic hepatitis C. Gastroenterology. 2008;134 (2): 432-9.
14) Osei-hyiaman D, Depetrillo M, Pacher P et-al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J. Clin. Invest. 2005;115 (5): 1298-305.
15) Hirvonen J, Goodwin RS, Li CT et-al. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Mol. Psychiatry. 2012;17 (6): 642-9.
16) Riggs PK, Vaida F, Rossi SS et-al. A pilot study of the effects of cannabis on appetite hormones in HIV-infected adult men. Brain Res. 2012;1431 : 46-52.
17) Kola B, Hubina E, Tucci SA et-al. Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J. Biol. Chem. 2005;280 (26): 25196-201.
TL;DR: Acute use makes you resemble a prediabetic, long term use just makes you a little fatter.
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