The Effect of Orally Administered Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) on Obesity Parameters in Mice

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“Prolonged cannabis users show a lower prevalence of obesity and associated comorbidities. In rodent models, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) from the plant Cannabis sativa L. have shown anti-obesity properties, suggesting a link between the endocannabinoid system (ECS) and obesity. However, the oral administration route has rarely been studied in this context. The aim of this study was to investigate the effect of prolonged oral administration of pure THC and CBD on obesity-related parameters and peripheral endocannabinoids. C57BL/6 male mice were fed with either a high-fat or standard diet and then received oral treatment in ramping doses, namely 10 mg/kg of THC or CBD for 5 weeks followed by 30 mg/kg for an additional 5 weeks. Mice treated with THC had attenuated weight gain and improved glucose tolerance, followed by improvement in steatosis markers and decreased hypertrophic cells in adipose epididymal tissue. Mice treated with CBD had improved glucose tolerance and increased markers of lipid metabolism in adipose and liver tissues, but in contrast to THC, CBD had no effect on weight gain and steatosis markers. CBD exclusively decreased the level of the endocannabinoid 2-arachidonoylglycerol in the liver. These data suggest that the prolonged oral consumption of THC, but not of CBD, ameliorates diet-induced obesity and metabolic parameters, possibly through a mechanism of adipose tissue adaptation.”

“In conclusion, the present findings provide evidence for the ability of THC to improve obesity-related metabolic complications when administered orally in ramping doses. The limited effect of CBD demonstrated in our study suggests that the low prevalence of obesity and metabolic diseases seen in cannabis users is mainly attributed to the presence of THC.”

Therapeutic effect of cannabidiol on myocardial arachidonic acid content in various lipid fractions in a rat model of obesity

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“The study explored the potential protective influence of cannabidiol (CBD) on myocardial inflammation state, with a special focus on arachidonic acid (AA), and oxidative balance in lipid overload conditions.

The 7-week experiment was conducted on male Wistar rats receiving standard or high-fat diet (HFD) with intraperitoneal CBD injections for the last 14 days. The n-3 and n-6 polyunsaturated fatty acids (PUFAs) activities and AA concentration in selected fractions were evaluated by gas-liquid chromatography (GLC). The expression of proteins was determined by Western blot and the concentration of different parameters by ELISA, colorimetric, or multiplex assay kits.

Our results revealed that CBD increased n-3 PUFAs activity in phospholipid and triacylglycerol fractions, and decreased AA content in the HFD group, especially in the phospholipid pool. Simultaneously, CBD decreased the expression of nuclear factor kappa B, cyclooxygenase-1, and -2, resulting in the reduction of prostaglandin E2 and the increment of prostaglandin I2.

CBD appears to be relatively safe for the treatment of obesity-induced heart disease, as it has anti-inflammatory and partially antioxidative properties.”

Tetrahydrocannabivarin (THCV) Protects Adipose-Derived Mesenchymal Stem Cells (ASC) against Endoplasmic Reticulum Stress Development and Reduces Inflammation during Adipogenesis


“The endoplasmic reticulum (ER) fulfills essential duties in cell physiology, and impairment of this organelle’s functions is associated with a wide number of metabolic diseases. When ER stress is generated in the adipose tissue, it is observed that the metabolism and energy homeostasis of the adipocytes are altered, leading to obesity-associated metabolic disorders such as type 2 diabetes (T2D).

In the present work, we aimed to evaluate the protective effects of Δ9-tetrahydrocannabivarin (THCV, a cannabinoid compound isolated from Cannabis sativa L.) against ER stress in adipose-derived mesenchymal stem cells.

Our results show that pre-treatment with THCV prevents the subcellular alteration of cell components such as nuclei, F-actin, or mitochondria distribution, and restores cell migration, cell proliferation and colony-forming capacity upon ER stress. In addition, THCV partially reverts the effects that ER stress induces regarding the activation of apoptosis and the altered anti- and pro-inflammatory cytokine profile.

This indicates the protective characteristics of this cannabinoid compound in the adipose tissue. Most importantly, our data demonstrate that THCV decreases the expression of genes involved in the unfolded protein response (UPR) pathway, which were upregulated upon induction of ER stress.

Altogether, our study shows that the cannabinoid THCV is a promising compound that counters the harmful effects triggered by ER stress in the adipose tissue. This work paves the way for the development of new therapeutic means based on THCV and its regenerative properties to create a favorable environment for the development of healthy mature adipocyte tissue and to reduce the incidence and clinical outcome of metabolic diseases such as diabetes.”

“Considering that nowadays there is still a need for metabolic disorder (including obesity) prevention and the enhancement of regenerative outcomes of autologous stem cells, the potential use of the natural plant compound THCV, which is non-psychotropic, could be an effective and economical way to cope with those obstacles.”

Foodomics reveals anti-obesity properties of cannabinoids from hemp oil

“Scope: Molecular networking (MN) analysis intends to provide chemical insight of untargeted mass spectrometry (MS) data to the user’s underlying biological questions. Foodomics is the study of chemical compounds in food using advanced omics methods. In this study, we developed an MS-MN-based foodomics approach to investigate the composition and anti-obesity activity of cannabinoids in hemp oil.

Methods and results: A total of 16 cannabinoids were determined in optimized microwave pretreatment of hemp oil using the developed approach. Untargeted metabolomics analysis revealed that cannabinoid extract (CE) and its major constituent (cannabidiol, CBD), could alleviate high glucose-induced increases in lipids and carbohydrates, and decreases in amino acid and nucleic acid. Moreover, CE and CBD were also found to suppress the expression levels of mdt-15, sbp-1, fat-5, fat-6, fat-7, daf-2, and elevate the expression level of daf-1,daf-7, daf-16, sod-3, gst-4, lipl-4, resulting in the decrease of lipid synthesis and the enhance of kinetism. Canonical correspondence analysis (CCA) uncovered strong associations between specific metabolic alterations and gene expression levels.

Conclusion: These findings from this exploratory study offered a new insight into the roles of cannabinoids in the treatment of obesity and related complications.”

Cannabis Use Is Inversely Associated with Metabolic Disorders in Hepatitis C-Infected Patients (ANRS CO22 Hepather Cohort)


“Background and aims: Hepatitis C virus (HCV) infection is associated with the onset of metabolic disorders which constitute risk factors for liver disease progression. Their impact may persist after the HCV infection has been cured. Cannabis use is associated with a lower risk of obesity and diabetes in both general and HCV populations. The associations between cannabis use and both dyslipidemia and hypertension have not yet been studied in persons with chronic HCV infection.

Methods: Using cross-sectional data from the French ANRS CO22 Hepather cohort, we used regression models to test for an inverse relationship between cannabis use and (i) dyslipidemia, (ii) hypertension, and (iii) the total number of metabolic disorders.

Results: Among the 6364 participants in the study population, both former and current cannabis use were associated with a lower risk of hypertension and fewer metabolic disorders. These results were independent of central obesity. Cannabis use was not associated with dyslipidemia.

Conclusions: In people chronically infected with HCV, cannabis use was associated with a lower risk of hypertension and a lower number of metabolic disorders. Post-HCV cure studies are needed to confirm these findings using longitudinal data and to test whether they translate into reduced mortality in this population.”

“In a large cohort of people with chronic HCV infection living in France, current or former cannabis use was associated with a lower risk of hypertension and a lower number of metabolic disorders.”

Cloudy with a chance of munchies: Assessing the impact of recreational marijuana legalization on obesity

“Obesity in the US arguably constitutes the most significant health epidemic over the past century. Recent legislative changes allowing for recreational marijuana use further create a need to better understand the relationship between marijuana use and health choices, leading to obesity. We examine this relationship by using a synthetic control approach to examine the impact of legalized recreational marijuana access on obesity rates by comparing Washington State to a synthetically constructed counterfactual. We find that recreational marijuana’s introduction did not lead to increased obesity rates and may have led to decreases in obesity.”

Effects of Cannabidiol on Appetite and Body Weight: A Systematic Review


“Background and objective: Cannabidiol, one of the main components of the Cannabis sativa plant, is a non-psychotropic cannabinoid that has recently drawn the attention of researchers and clinicians for its potential therapeutic applications. In this systematic review, we aim to describe the possible effects of cannabidiol in appetite and body weight.

Methods: Both authors independently ran a thorough search in both PubMed and Cochrane databases up to 31 July, 2022 and included every peer-reviewed, original randomized controlled clinical trial that reported data on either of the said outcomes. Risk of assessment bias was performed with Cochrane’s risk of bias tool and results were summarized in tables.

Results: A total of 11 trials were included in this review. Of these, the majority reported on cannabidiol reducing appetite and/or body weight whilst some have found no significant changes and one trial described an increase in appetite.

Conclusions: This systematic review suggests that cannabidiol has an anorexigenic effect, correlated with a decrease in body weight. However, most of the studies included in the present review raised some concerns in terms of risk of bias. We believe further research is needed in order to clarify potential mechanisms involved in the effect of cannabidiol on feeding/appetite.”

“In light of the available evidence, CBD appears to have an anorexigenic effect that may be more substantial in individuals with a higher BMI. Cannabinoids are known to have an orexigenic effect mediated by CB1 and CB2 receptors, but distinctly from Δ9-THC, which possesses an orexigenic effect, CBD appears to decrease food intake. This observation is very interesting and clearly relevant in the context of obesity, a disease whose prevalence is increasing worldwide and which constitutes a risk factor for the development of comorbid conditions such as hyperinsulinemia, insulin resistance, type 2 diabetes, hypertension, dyslipidemia, coronary heart disease, gallbladder disease, and certain malignancies [4546]. Therefore, the evidence presented in the present work points to the need for additional primary research in order to unveil and clarify mechanisms of not only appetite modulation by CBD, but also on other metabolic effects of CBD that may contribute to changes in body weight.”

Yin and yang of cannabinoid CB1 receptor: CB1 deletion in immune cells causes exacerbation while deletion in non-immune cells attenuates obesity

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“While blockade of cannabinoid receptor 1 (CB1) has been shown to attenuate diet-induced obesity (DIO), its relative role in different cell types has not been tested. The current study investigated the role of CB1 in immune vs non-immune cells during DIO by generating radiation-induced bone marrow chimeric mice that expressed functional CB1 in all cells except the immune cells or expressed CB1 only in immune cells. CB1-/- recipient hosts were resistant to DIO, indicating that CB1 in non-immune cells is necessary for induction of DIO. Interestingly, chimeras with CB1-/- in immune cells showed exacerbation in DIO combined with infiltration of bone-marrow-derived macrophages to the brain and visceral adipose tissue, elevated food intake, and increased glucose intolerance. These results demonstrate the opposing role of CB1 in hematopoietic versus non-hematopoietic cells during DIO and suggests that targeting immune CB1 receptors provides a new pathway to ameliorate obesity and related metabolic disorders.”

Cannabidiol (CBD) Protects Adipose-Derived Mesenchymal Stem Cells (ASCs) against Endoplasmic Reticulum Stress Development and Its Complications


“Background: Recent studies suggested that individuals with metabolic disorders have altered function of adipocytes and adipose stem cell subpopulations, which impairs tissue homeostasis, promoting insulin resistance and diabetes development. The non-psychoactive phytocannabinoid CBD was found to modulate adipose tissue metabolism, however, its exact role in controlling ASCs’ fate is still poorly understood.

Objectives: This investigation aimed to elucidate whether pretreatment of ASCs with CBD can protect against ER stress development and maintain the cytophysiological properties of cells.

Methods: Human ASCs were cultured under control and adipogenic conditions. Prior to the experiments, cells in the experimental group were pretreated with CBD following the addition of an ER stress inducer-tunicamycin. After the experiments, the cells were subsequently tested for expression of the apoptotic, ER stress, and anti-inflammatory-related genes using RT-qPCR. Oxidative stress was analysed with flow cytometric assays.

Results: Cells pretreated with CBD displayed decreased apoptosis and enhanced proliferation rate. Additionally, the expression of pro-inflammatory cytokines and miRNAs was significantly reduced. The obtained results also demonstrated an obvious reduction in intracellular accumulated ROS and NO, as well as mitigated ER stress through the down-regulation of IRE-1PERKCHOP, and ATF6 transcripts upon CBD treatment.

Conclusion: The presented data provide the evidence that CBD protects ASCs against ER stress development and its complications and, thus, offers new insights for the management of obesity through the regulation of adipose tissue dynamics.”

“The regenerative potential of ASCs in the treatment of multiple disorders lies in their differentiation, migration, and secretory activity. However, these conditions impair the cytophysiological properties of ASCs, limiting their application in autologous therapies. What is more, impaired ASCs in vivo suffer from reduced multipotency and produce a vast number of inflammatory cytokines and oxidative stress factors, which in turn contributes to disease progression. Hence, development of strategies that reverse their senescence and ageing, and, as a consequence, restore regenerative properties are strongly desirable.

To our knowledge, this is the first report on the impact of CBD pretreatment on metabolically impaired ASCs suffering from ER stress. Our current study revealed that CBD modulates ASCs metabolism by promoting their growth kinetics, multipotency, and viability, which due to enhanced ER stress were strongly limited. Taking into account that CBD lacks psychopharmacological activity, further studies aiming at unravelling its influence on different stem cells populations are recommended and justified. Further studies on the effects of CBD on ASCs could explore other measures of its regenerative capacity than studied in the presented research. Furthermore, unravelling the precise molecular mechanisms of action via CBD that protect ASCs against cytophysiological impairment would be valuable. While our findings are supported by the existing literature, our research was not free of limitations. An important drawback is that we did not explore which cannabinoid receptors are responsible for the observed effects of CBD. Thus, further experiments utilizing agonists and antagonists of cannabinoid receptors are necessary to elucidate which of them are involved in CBD’s way of action.

Taking into consideration that ASCs are nowadays a commonly applied tool in regenerative medicine, the ability to enhance their stemness and regenerative potential may contribute not only to more effective therapies but also to significantly reducing the costs associated with their isolation and expansion.”

Cannabidiol ameliorates the anxiogenic and compulsive-like behaviors induced by chronic consumption of a high-carbohydrate diet in male mice


“The excessive consumption of ultra-processed foods and the development of obesity has been associated with several comorbidities, including psychiatric disorders. Excess fat tissue promotes a low-intensity inflammatory state, mainly in the white tissue, which is essential in developing metabolic alterations and influences brain homeostasis.

In this scenario, Cannabidiol (CBD), a compound from Cannabis sativa, has presented anxiolytic and anti-inflammatory effects in murine models.

This study verified whether CBD treatment would ameliorate the compulsive-like and anxiety-like behaviors observed after mice’s chronic consumption of a high-refined carbohydrate (HC) diet.

BALB/c male mice received a control or HC diet for 12 weeks followed by vehicle and CBD (30 mg/Kg, i.p.) administration, and their behavior was evaluated in the Marble Burying test (MB) and Novel Suppressing Feeding test (NSF).

The sub-chronic, but not acute, treatment with CBD attenuated the compulsive-like and anxiogenic-like behavior induced by the HC diet.

Our data reinforced the harmful effects of the HC diet’s chronic consumption on compulsive and anxious behaviors and the potential of CBD as a drug treatment for psychiatric disorders associated with obesity.”