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Cannabis effects on lipoproteins

Lazarte, Julietaa,b,c; Hegele, Robert A.a,b,c

Current Opinion in Lipidology: April 2019 - Volume 30 - Issue 2 - p 140–146
doi: 10.1097/MOL.0000000000000575

Purpose of review The endocannabinoid system affects several physiological functions. A family of endocannabinoid receptors is susceptible to cannabis constituents. Cannabis is widely used in our society and following its recent legalization in Canada, we focus on how exposure to cannabis and pharmacologic cannabinoid receptor type 1 (CB1) inhibition affect lipoprotein levels.

Recent findings Several groups have reported that exposure to cannabis does not increase weight despite the marked increase in caloric intake. In observational studies, the effect of smoked cannabis exposure on plasma lipids is variable. Some studies in specific patient populations with longer exposure to cannabis seemed to identify slightly more favorable lipoprotein profiles in the exposed group. Several larger controlled clinical trials using orally administered rimonabant, a CB1 receptor antagonist, have consistently shown relative improvements in weight and plasma levels of triglyceride and high-density lipoprotein cholesterol among patients receiving the treatment.

Summary The widely variable findings on the relationship of cannabis in various forms with plasma lipids preclude any definitive conclusions. Cannabis has complex effects on the cardiovascular system and its effects on lipid profile must be considered in this overall context. Further properly controlled research is required to better understand this topic.

aDepartment of Biochemistry, Schulich School of Medicine and Dentistry, Western University

bRobarts Research Institute, Schulich School of Medicine and Dentistry, Western University

cDepartment of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada

Correspondence to Robert A. Hegele, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 4288A-1151 Richmond Street North, London, ON N6A 5B7, Canada. Tel: +1 519 931 5271; fax: +1 519 931 5218; e-mail:

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According to a 2012 federal government survey, close to half of Canadians report some type of exposure to cannabis over their lifetime [1▪]. This may increase further now that Canada has legalized cannabis for recreational use, becoming one of the few nations including Uruguay, South Africa and several states in the United States with such a social policy. Since October 17, 2018, Canadians, 18 years or older, are allowed to possess, purchase, sell and grow cannabis for personal use, although it has been available by prescription for specific medical indications under a regulated regime since 2001 ( Given this subject's newsworthiness, we set out to review what is known about the effects, if any, of cannabis on plasma lipoproteins. Here, we use the terms ‘cannabis’ and ‘marijuana’ interchangeably. Marijuana is dried buds from the cannabis plant (Cannabis sativa or Cannabis indica or a hybrid). In contrast, hashish comes from the compressed resin of the flowers of the cannabis plant. We begin with an overview of the endocannabinoid system, its role in energy metabolism, cannabis’ constituents, the different routes of administration of cannabis, general effects of cannabis on weight, and overview of the effects of cannabis and of a cannabis derived medication on lipoproteins and metabolism. We conclude with a summary of the overall effects on lipoproteins with exposure to cannabis.

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Discovered in the early 1990s, the endocannabinoid system is a major physiological neurotransmission system. Research on Δ9-tetrahydrocannabinol (THC), which is the psychoactive component of cannabis, contributed to the discovery of the endocannabinoid system [2]. The endocannabinoid system consists primarily of two G-protein coupled receptors – namely the cannabinoid B1 (CB1) and cannabinoid B2 (CB2) receptors, together with endogenous lipid soluble endocannabinoid ligands and several enzymes. The CB1 receptor was originally found in the brain, whereas the CB2 receptor was identified in immune cells [3–5]. The CB1 receptor localizes near central and peripheral neurons, adipose tissue, myocardium and vascular endothelium [6–8]. In the brain, the CB1 receptor is found in the hippocampus, cerebral cortex, basal ganglia and cerebellum. Activation of the CB1 receptor can stimulate excitatory (glutamatergic) and inhibitory (GABAergic) neurotransmitter terminals [9,10]. Given its location, the CB1 receptor transduces effects on cognition, memory and motor function [11]. In contrast, the CB2 receptor is found in lymphoid tissue and peripheral macrophages; it modulates immune cell migration among other processes [11]. Although additional minor receptors have since been identified in this receptor family, CB1 and CB2 remain the most heavily investigated [3]. Two endogenous receptor ligands have been isolated: anandamide and 2-arachidonoyl-glycerol (2-AG) [12,13]. Anandamide has greater affinity for the CB1 receptor, whereas 2-AG has equal affinity for both receptors, similar to THC [11,14]. Minor endogenous ligands have also been recognized, but these two remain the most investigated [3].

Originally, the biological role of the endocannabinoid system was regarded to be relief of the stress response at the nervous system level, leading to feelings of relaxation, hunger, sleepiness, forgetfulness and pain reduction [15]. However, since then, it is evident that the endocannabinoid system has far reaching involvement in various pathophysiological systems, including neurodegenerative and motor neuron disorders [10], inflammatory diseases [16,17], cardiovascular diseases [18], respiratory diseases [19], reproductive disorders [20] and endocrine and metabolic disorders [21,22]. A recent review summarizes how activation of CB1 receptor plays a role in cardiometabolic disorders, whereas activation of CB2 receptor may exert anti-inflammatory effects [23▪▪].

Box 1

Box 1

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A brief overview of the endocannabinoid system and its metabolic and cardiovascular effects

The endocannabinoid system's influence on energy metabolism has been studied for many years in animal models and human studies; for a review we recommend Pagotto et al.[21]. The endocannabinoid system modulates energy metabolism through its effects on target organs and tissues that are involved in appetite, food intake and energy disposition, including the hypothalamus, nucleus accumbens, muscles, gastrointestinal tract, liver and adipose tissue [21,22]. Indeed, blocking CB1 receptors by various means both centrally and peripherally produces an overall switch that includes decreased motivation to eat, anorexigenic effects, stimulation of muscle glucose uptake, stimulation of anorectic signals in the sensory terminals of gastrointestinal tract, decrease in lipogenesis and increased adiponectin production [21]. In particular, the endocannabinoid system modulates lipogenesis via CB1 receptors on adipocytes; if inhibited by a CB1 antagonist, lipogenesis in the adipocyte cells diminishes [21]. In addition, Osei-Hyiaman et al.[24] demonstrated the effect of the endocannabinoid system on liver lipogenesis, which can also be attenuated with a CB1 antagonist [21]. Moreover, a dysregulated and overactivated endocannabinoid system is thought to be among the contributors to obesity and type 2 diabetes mellitus [25–28].

The endocannabinoid system has a contributing role in various cardiovascular diseases including atherosclerosis [23▪▪,29]. Further, various pathways have been determined by which the endocannabinoid system modulates atherosclerosis [23▪▪]. Indeed, the CB1 receptor has a proatherosclerotic role, blocking it has demonstrated to decrease plaque formation in LDLR–/– mice [30]. The influence of the endocannabinoid system in the cardiovascular and metabolic system is extensive and continues to be an area of active research.

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Constituents of cannabis

Cannabidiol (CBD) was the first compound identified from the cannabis plant in the 1960s and is now recognized as a major constituent [31]. CBD is an agonist primarily for CB2 receptors [32,33]. CBD has no psychotropic effects and has been associated with purported beneficial effects including anti-inflammatory activity, anticonvulsant and antipsychotic effects [32,33]. Indeed, antiepileptic and antiseizure properties of CBD have been studied in clinical trials of patients with certain forms of epilepsy [34]. In addition, Δ9-THC is the second major constituent of cannabis [35]; its primary effect is psychotropic [11]. THC binds with equal affinity to receptors CB1 and CB2 and exerts its psychoactive and adverse cardiovascular effects through the activation of CB1 receptor in the central nervous and cardiovascular systems [23▪▪,36].

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Cannabis administration routes and consumption rates

Cannabis or marijuana, like many drugs, has various modes of administration. The most common method is smoking. However, since its legalization in certain states in the United States, there has been a surge in interest and available options for oral administration, known as ‘edible cannabis[37]. These two routes of administration differ in that smoked cannabis enters via the pulmonary circulation, thus bypassing the liver. In contrast, edible cannabis is absorbed through the gastrointestinal tract and is then metabolized by the liver's first pass effect before it reaches the systemic circulation [37]. It would appear that edible cannabis becomes extensively metabolized, which leads to the production of cannabis metabolites in far greater quantities and more potent effects [37,38]. This underlies a fundamental difference in exposure levels for the same initial quantity of cannabis taken by different routes of administration. To date, the majority of the research on cannabis is based on smoked administration. However, given the recent legalization of cannabis and the increased interest in edibles, it is imperative to investigate their effect as well [37].

Cannabis consumption is highly variable: recreational vs. regular users and short vs. longer term users. The variability in rates of consumption has an influencing role in the overall effect observed from cannabis exposure, adding a level of complexity to the research in this area. The studies described next utilize different definitions of what constitutes a cannabis user, which must be taken into consideration when interpreting the results. Indeed, this is a limitation in this area.

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General cannabis effects on weight

Cannabis users are less likely to be obese than nonusers despite the well-known increase in food intake after smoking cannabis (colloquially known as ‘the munchies’) [39]. In fact, a study examining the effect of smoking four cannabis cigarettes per day in individuals who lived for a period of time in a residential laboratory clearly demonstrated that those exposed to cannabis significantly increased by 40% their total daily caloric intake mainly because of the increase amount of snacks eaten (P < 0.004) [40]. In contrast, data from two surveys of Americans – namely the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) with 41 633 participants and National Comorbidity Survey-Replication (NCS-R) with 9103 participants – found that cannabis users (defined as smoking for 3 or more days per week) were less likely to be obese compared to nonusers after adjusting for age, sex, race/ethnicity, educational level, marital status, residential region and tobacco smoking status. Specifically, in NESARC, the odds ratio (OR) for obesity among cannabis users was 0.61 [95% confidence interval (CI) 0.46–0.82], whereas in NCS-R the OR was 0.73 (95% CI 0.43–1.23) [41]. This intriguing finding was corroborated in smaller studies [42,43].

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Metabolic effects of smoking cannabis

Over the last several decades, large population studies were conducted to evaluate the effect of cannabis on metabolism. For instance, a study that used data from the Third National Health and Nutrition Examination Survey (NHANES III) examined a cohort of 10 623 Americans aged 20–59 years from the 1988 to 1994 time period. It reported that about 45% of participants had used cannabis at some point in their lives, and 8.7% had reported use in the most recent month prior to data collection [44]; these findings are remarkably similar to those from a recent Canadian government survey data [1▪]. Study of the NHANES III cohort corroborated a significant difference in total caloric intake between current cannabis users (defined as 11 or more days of smoking cannabis per month) and nonusers, namely 3196 ± 181 vs. 2271 ± 22 total calories per day, respectively (P ≤ 0.0001). The difference in intake did not translate into a significant weight difference between the groups [44]. On the contrary, mean BMI was significantly lower after adjusting for age, sex and other variables, namely 24.7 ± 0.30 vs. 26.6 ± 0.10 kg/m2 in cannabis users vs. nonusers, respectively (P < 0.0001). In terms of lipoprotein profile, total cholesterol was lower in cannabis users vs. nonusers, namely 4.90 ± 0.10 vs. 5.20 ± 0.02 mmol/l (P ≤ 0.05). Similarly, plasma triglyceride (TG) was lower in cannabis users vs. nonusers, namely 1.40 ± 0.08 vs. 1.60 ± 0.03 mmol/l (P ≤ 0.05). However, after adjusting for age, sex and education, these differences were no longer significant [44].

Penner et al.[45] subsequently examined 4657 participants from the NHANES survey from the 2005 to 2010 time period, and reported no significant differences in mean HDL-C and TG levels among groups with varying degrees of exposure to cannabis. However, when using a multiple linear regression model adjusted for age, sex, race, educational level and other factors, they reported that current cannabis users (defined as smoking at least once in the past 30 days) had higher levels of HDL-C compared to nonusers, with a mean difference of +1.63 mg/dl (95% CI = 0.23–3.04, P < 0.05) [45].

Evaluation of participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study, which consisted of a serial follow-up of 5115 young adults between 18 and 30 years, identified no differences between cannabis users vs. nonusers in either total cholesterol, that is 4.91 ± 0.08 vs. 4.77 ± 0.02 mmol/l (P = 0.07), or HDL-C, that is 1.32 ± 0.03 vs. 1.32 ± 0.01 mmol/l (P = 0.96) [39]. Cannabis users were defined as individuals who smoked more than 1800 days over a 15-year period. Interestingly, TG was noted to be higher in cannabis users vs. nonusers, namely 1.13 ± 0.01 vs. 0.95 ± 0.01 mmol/l (P < 0.001) [39].

A very small (N = 12) study found that heavy smokers of hashish when given 20 g of 3.6% of THC pure resin to smoke had a 21.0% increase in total cholesterol and a 20.2% decrease in TG, from nonsmoking baseline levels (both significant with P < 0.05) [46]. Changes in total cholesterol and TG levels were not observed in the nonsmoker group over the same period. In addition, the hashish user group had a 4.9% decrease in HDL-C (P = 0.05), whereas LDL-C levels did not change [46].

There are a few observational studies of the long-term effects of cannabis exposure. Muniyappa et al.[42] followed chronic cannabis smokers defined as individuals who smoked for at least 4 days/week for the last 6 months with a minimum history of a year of smoking. The chronic smokers were followed for 12.0 ± 9.0 years and found to have no differences in lipoprotein parameters with the control nonsmoker group. Specifically, there were no statistically significant differences in levels of total cholesterol, LDL-C or TG. However, HDL-C levels in chronic smokers vs. controls were somewhat lower in an age-matched, race-matched and BMI-matched analysis: 1.30 ± 0.40 vs. 1.40 ± 0.30 mmol/l (P = 0.02). In an investigation by Jayanthi et al.[47], chronic smokers (N = 18), defined as having had a mean smoking duration of 6 years with a range of 78–350 marijuana cigarettes per week, had significantly higher serum levels of apolipoprotein (apo) C-III vs. nonsmoking controls (P < 0.002), after controlling for sex, ethnicity, tobacco use and alcohol use. Apo C-III is a marker for hypertriglyceridemia and coronary artery disease [47–49]. In addition, mean TG levels trended nonsignificantly higher in the chronic user vs. nonuser group: 112.0 ± 14.4 vs. 91.2 ± 12.5 mg/dl (P = 0.09). Despite the nonsignificant increase in TG, the study reported a significant positive correlation between apo C-III and TG levels; however, there is no evidence in the literature of a cannabis effect on apo C-III (r = 0.51, P < 0.001) [47,50].

Some studies have focused on specific patient populations who have higher rates of exposure to cannabis compared to the general population [51,52]. For instance, a study of 109 schizophrenic patients examined lipoprotein profiles among cannabis users and nonusers (determined by laboratory tests), and found no differences in TG or HDL-C levels [52]. However, in a posthoc analysis, a trend toward higher TG and lower HDL-C was seen among nonusers: for TG, the mean change from baseline was 0.31 mmol/l (95% CI 0.13–0.48 mmol/l; P = 0.0005), whereas for HDL-C, the mean change from baseline was −0.22 mmol/l (95% CI −0.33 to −0.11 mmol/l; P = 0.0001) [52]. An investigation of 1813 patients with psychosis found that frequent smokers (defined as having smoked at least once per week in the previous 12 months) were less likely to meet the criteria for the metabolic syndrome, mainly because their TG and HDL-C did not reach diagnostic cut points. Specifically, ORs in smokers compared to nonsmokers for attaining cut points for high TG and low HDL-C were 0.61 (95% CI 0.45–0.83, P < 0.05) and 0.68 (95% CI 0.51–0.92, P < 0.05), respectively [51].

In summary, high-quality evidence regarding the effect of cannabis on lipoproteins remains sparse and inconsistent. In aggregate, smoking cannabis appears to have marginal effects in a favorable direction with respect to TG and HDL-C, but this is certainly not definitive. Further rigorous, controlled prospective studies are required in which rates of cannabis administration can be controlled and standardized. In addition, it would be informative to focus on specific patient populations, such as those with psychiatric conditions or cancer, in whom exposure to cannabis may be even greater than in the general public.

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Metabolic effects of cannabis-based pharmaceuticals

Some pharmaceutical agents have been designed to operate through the endocannabinoid system with the expectation of beneficial effects on the metabolic system. One such compound that attained fairly advanced development was rimonabant (SR141716, Servier), an antagonist selective to the CB1 receptor. Obese mice treated with rimonabant showed decreases in food intake, weight, in plasma levels of leptin, insulin and free fatty acids [53]. Another preclinical investigation demonstrated that obese mice on rimonabant had increased expression of adiponectin, substantial weight loss and an improved serum lipid profile, particularly a significant improvement in LDL-C and TG levels, with no change in HDL-C [54]. These results, coupled with observations that the endocannabinoid system was overactivated in obese individuals, stimulated the development of CB1 receptor antagonist for weight loss and improved metabolic readouts, including lipoproteins [26,27,53].

The RIO-Europe study evaluated rimonabant's efficacy and safety in reducing body weight and improving cardiovascular risk factors in 1507 overweight or obese patients [55] (selected results from some clinical trials of rimonabant are shown in Table 1). Individuals in the 5 and 20 mg dose arms had significant weight loss: mean change from baseline, respectively, was −3.40 ± 5.70 kg (P = 0.002) and −6.60 ± 7.20 kg (P < 0.001) [55]. With respect to lipoproteins, the 20 mg dose arm had an additional decrease in TG levels (mean change from baseline −0.20 ± 0.64 mmol/l, P < 0.001) and increase in HDL-C levels (mean change from baseline 0.26 ± 0.26 mmol/l, P < 0.001) [55].

Table 1

Table 1

The RIO-North America study was next undertaken in 3045 obese patients [56]. Significant beneficial changes in TG and HDL-C were observed in both treatment arms, with the greatest change in the 20 mg dose arm: least-squares mean difference percentage change in TG was −8.60 ± 1.00, P < 0.001 and −16.10 ± 2.70, P < 0.001 [56]. In addition, it was reported that fewer patients met the metabolic syndrome criteria post-treatment vs. pre-treatment in the rimonabant 20 mg group, that is 21.2 vs. 34.8% as against 29.2 vs. 31.7% in the placebo group (P for treatment effect was < 0.001). However, in line with previous studies of rimonabant, total cholesterol and LDL-C levels did not change [56].

The RIO-Lipid trial studied 1306 obese individuals with untreated hyperlipidemia. The study emphasized once again the effects of rimonabant on significantly attenuating hunger, caloric intake and body weight. The mean placebo corrected change in body weight from baseline was −6.7 ± 0.5 kg (P < 0.001). In the rimonabant 20 mg arm, TG levels decreased from baseline (−15.8 ± 38.0, P < 0.001), whereas HDL-C increased from baseline (+23.4 ± 21.8 mmol/l, P < 0.001) [57]. In addition, the 20 mg arm had a significant increase in plasma adiponectin from baseline (+2.70 ± 2.50 μg/ml, P < 0.001) and a significant decrease in C-reactive protein from baseline (−0.90 mg/l, P = 0.02) [57].

Finally, the SERENADE trial (Study Evaluating Rimonabant Efficacy in Drug-Naïve Diabetic Patients) investigated the effect of rimonabant monotherapy in 281 patients with type 2 diabetes [58]. Again, patients randomized to the 20 mg arm had a significant improvement in levels of TG (mean percentage change vs. placebo −17.28 ± 5.78%, P = 0.0031) and HDL-C (mean percentage change vs. placebo 7.30 ± 1.75%, P < 0.0001). In addition, a decrease in non-HDL-C level was observed in patients on treatment (mean percentage change vs. placebo −5.53 ± 2.76%, P = 0.046), while once again, total cholesterol and LDL-C did not change [58].

Thus, multiple studies showed rimonabant had a beneficial effect on weight loss and on both TG and HDL-C. In particular, HDL-C levels increased to a greater degree than with the average increase seen with fibrate monotherapy [22]. However, total cholesterol and LDL-C did not change significantly across all trials. Interestingly, the RIO-Lipids trial reported a shift in the size distribution of LDL toward larger size particles in the rimonabant 20 mg treatment group compared to placebo, which might lower the atherogenicity of the LDL pool [22,59].

Effects on lipids across all trials were reported to be independent of weight loss [22,55,60]. Indeed, when adjusting the observed HDL-C levels (from the RIO-Lipid study) by the effect produced by weight loss alone, it was determined that 40% of the change could be attributed to rimonabant alone [22]. Similarly, in terms of TG levels, 55% of the observed change could be attributed to rimonabant independent of the weight loss effect [22]. The investigators further suggested that the effects on TG and HDL-C were related mechanistically to enhanced expression of adiponectin [54,55,60]. This is relevant as adiponectin has a role in the control of glucose, insulin, fatty acids and is considered an antiobesity molecule [54]. In line with this, a systematic review of the effects of blocking the CB1 receptor reported decreased lipogenesis and increased adiponectin levels [21].

Despite the consistent benefits of rimonabant on obesity and lipoprotein fractions, its adverse effects, particularly psychotropic effects, were substantial, and ultimately ended further development of the medication [61]. Common adverse effects included dizziness, nausea, anxiety and depression; these all occurred at significantly higher frequencies with rimonabant in a dose-dependent manner [61,62]. Indeed, rimonabant-treated patients were more likely to discontinue treatment because of depression or anxiety despite the fact that the trials excluded patients with a history of serious mental illness [61]. Although rimonabant's development was terminated, these clinical trial findings remain pertinent as researchers look to elucidate future therapeutics for obesity and related metabolic disorders, including dyslipidemias.

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Understanding the pathophysiological effects of cannabis is paramount for a proactive healthcare system. The effects in humans of cannabis and the biology of the endocannabinoid system are growing research areas. However, high-quality scientific studies are still scarce. We note some tenuous concordance of lipid effects between smoked cannabis and pharmacologic CB1 receptor antagonism. However, most studies on smoked cannabis were small, poorly controlled and observational in nature, with a range of various effects. Further studies evaluating long-term exposure are needed to clearly implicate both potential deleterious and beneficial effects. In addition, there is a need for investigations in specific patient populations who are characterized by higher exposure to cannabis.

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Financial support and sponsorship

R.A.H. is supported by the Jacob J. Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Research Chair in Human Genetics and the Martha G. Blackburn Chair in Cardiovascular Research. R.A.H. has also received operating grants from the Canadian Institutes of Health Research (Foundation award) and the Heart and Stroke Foundation of Ontario (G-18–0022147).

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Conflicts of interest

J.L. has no conflicts of interest to declare. R.A.H. is a consultant and speakers’ bureau member for Aegerion, Akcea/Ionis, Amgen, Gemphire, Sanofi and Regeneron. All unrelated to the topic of this article.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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cannabis; endocannabinoid system; lipoproteins; obesity; rimonabant

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