
==== Front
Pharmacol Res Perspect
Pharmacol Res Perspect
10.1002/(ISSN)2052-1707
PRP2
Pharmacology Research & Perspectives
2052-1707
John Wiley and Sons Inc. Hoboken

10.1002/prp2.70009
PRP270009
PRP2-2023-12-0465.R1
Review
REVIEW
Pharmacology and Regulation of Appetite and Food Intake
The endocannabinoid system in appetite regulation and treatment of obesity
Kurtov et al.
Kurtov Marija 1
Rubinić Igor 2 3
Likić Robert https://orcid.org/0000-0003-1413-4862
4 5 robert.likic@mef.hr

1 Department of Clinical Pharmacology and Toxicology University Hospital Sveti Duh Zagreb Croatia
2 Department of Clinical Pharmacology and Toxicology Clinical Hospital Centre Rijeka Rijeka Croatia
3 University of Rijeka, School of Medicine Rijeka Croatia
4 Department of Clinical Pharmacology and Toxicology Clinical Hospital Centre Zagreb Zagreb Croatia
5 University of Zagreb, School of Medicine Zagreb Croatia
* Correspondence
Robert Likić, Department of Clinical Pharmacology and Toxicology, Clinical Hospital Centre, Zagreb, Croatia.
Email: robert.likic@mef.hr

18 9 2024
10 2024
12 5 10.1002/prp2.v12.5 e7000923 8 2024
13 12 2023
03 9 2024
© 2024 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.
https://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Abstract

The endocannabinoid system (ECS) is a complex cell‐signaling system that is responsible for maintaining homeostasis by modulating various regulatory reactions in response to internal and environmental changes. The influence of ECS on appetite regulation has been a subject of much recent research, however, the full extent of its impact remains unknown. Current evidence links human obesity to ECS activation, increased endocannabinoid levels in both central and peripheral tissues, along with cannabinoid receptor type 1 (CBR1) up‐regulation. These findings imply the potential pharmacological use of the ECS in the treatment of obesity. Here, we present various pathophysiological processes in obesity involving the ECS, highlighting different pharmacological options for modulating endocannabinoid activity to treat obesity. However, the potential of those pharmacological possibilities remains under investigation and requires further research.

Simplified overview of ECS signaling

source-schema-version-number2.0
cover-dateOctober 2024
details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.4.8 mode:remove_FC converted:18.09.2024
Kurtov M , Rubinić I , Likić R . The endocannabinoid system in appetite regulation and treatment of obesity. Pharmacol Res Perspect. 2024;12 :e70009. doi:10.1002/prp2.70009
==== Body
pmcAbbreviations

2‐AG 2‐arachidonoylglycerol

2‐AGE 2‐arachidonyl glyceryl ether

AEA N‐arachidonoylethanolamine

AgRP Agouti‐related protein

AMPK AMP‐activated protein kinase

BMI body mass index

CBR cannabinoid receptors

CBR1 cannabinoid receptor type 1

CNS central nervous system

DAGL diacylglycerol lipase

ECS endocannabinoid system

FAAH fatty acid amide hydrolase

FDA Food and Drug Administration

MAGL monoacylglycerol lipase

MAPK mitogen‐activated protein kinase

mTOR mammalian target of rapamycin

NADA N‐arachidonoyl dopamine

NAGLy N‐arachidonylglycine

NAMA negative allosteric modulating antibody

NAMs negative allosteric modulators

NAPE‐PLD N‐acyl phosphatidylethanolamine‐specific phospholipase D

NASH non‐alcoholic steatohepatitis

NPY neuropeptide Y

ODA cis‐9,10‐octadecanoamide

OEA oleoylethanolamide

PEA palmitoylethanolamide

POMC pro‐opiomelanocortin

PPARs peroxisome proliferator‐activated receptors

SEA stearoylethanolamide

STAT3 signal transducer and activator of transcription 3

THC delta 9‐tetrahydrocannabinol

TRP transient receptor potential

UCP2 mitochondrial uncoupling protein 2

USA United States of America

WHO World Health Organization

α‐MSH α‐melanocyte‐stimulating hormone

1 INTRODUCTION

The endocannabinoid system (ECS) is a complex biological network responsible for maintaining homeostasis by modulating various regulatory reactions in response to internal and environmental changes. 1 , 2 , 3 This complex signaling system is present throughout the human body and includes endocannabinoids, cannabinoid receptors (G‐protein‐coupled receptors), and enzymes responsible for synthesizing and degrading endocannabinoids. 1 , 2 , 3

The ECS is important in regulating different range of functions such as nociception, appetite regulation, memory and learning, immune response, fertility and reproduction, glucose and lipid metabolism thus making it an interesting target for treating many conditions, including obesity. 1 , 2 , 4 The underlying molecular mechanisms of ECS dysregulation in obesity need clarification to better understand the relationship between ECS and obesity. With obesity reaching pandemic levels, there is an urgent need for new therapeutic options. Current evidence suggests that targeting the ECS might present a viable option.

2 THE ECS

Endocannabinoids are synthetised by postsynaptic neurons in response to excessive neurotransmitter release functioning as negative feedback regulators that inhibit further neurotransmitter release. The first endocannabinoids to be discovered, N‐arachidonoylethanolamine (AEA) and 2‐arachidonoylglycerol (2‐AG), are the most extensively studied. 5 Both are synthesized on‐demand from the lipid membrane of the postsynaptic neuron via multiple pathways, with 2‐AG synthesis being crucially dependent on the enzyme diacylglycerol lipase (DAGL), while AEA synthesis involves multiple enzymes. 1 , 2 , 6 An increase in the intracellular Ca2+ prompts their release into the synaptic cleft by passive diffusion, where they bind to cannabinoid receptors (CBR) present on the presynaptic neuron membrane. There are two types of cannabinoid receptors, CB1 and CB2, both of which are G‐protein‐coupled receptors that, upon activation, inhibit adenylyl cyclase and trigger mitogen‐activated protein kinase (MAPK) signaling. 7 CB1 receptors are primarily located on presynaptic terminals, where they inhibit voltage‐dependent Ca2+ channels and activate K+ channels. In contrast, CB2 receptors are predominantly found on postsynaptic membranes and influence the same channels. 7 , 8 AEA acts as a partial agonist of CBR1 and has a lower affinity for CBR2, whereas 2‐AG, present in much higher concentrations in the brain, is a full agonist of both CBR1 and CBR2. 3 , 9 , 10 CBR1 can be found in most human tissues, predominantly in the central nervous system (CNS), but also in the adipocytes, endocrine glands, gastrointestinal and other tissues, while CBR2 is primarily expressed in immune cells, but also present in neurons and glia within the CNS. 1 , 2 , 5 , 11 , 12 Several other receptors, such as transient receptor potential (TRP), peroxisome proliferator‐activated receptors (PPARs), nicotinic, glycine, GABA, and G‐protein coupled receptors 18 and 55, among others, can also be engaged by the endocannabinoids, yet the impact is not yet completely clear. 13

Upon the activation of CBR1, hyperpolarization of the presynaptic neuron occurs thus causing a reduction in neurotransmitter release. AEA and 2‐AG are rapidly hydrolysed by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively, into inactive compounds. 1 , 2 , 14 The process is illustrated in Figure 1.

FIGURE 1 Simplified overview of ECS signaling. A neurotransmitter is released from a vesicle in the presynaptic neuron into the synaptic cleft due to Ca2+ influx, where it binds to its specific receptor on the membrane of the postsynaptic neuron. This binding activates the enzymes NAPE‐PLD and DAGL, which synthesize AEA and 2‐AG, respectively, in the postsynaptic neuron. Both AEA and 2‐AG are hydrophobic, allowing them to diffuse from the postsynaptic membrane. AEA and 2‐AG then travel back across the synaptic cleft and bind to the CBR1 receptor on the presynaptic neuron. The CBR1 receptor is linked to the Gi protein, which inhibits the voltage‐gated Ca2+ channel, causing membrane hyperpolarization by stimulating K+ channels and reducing depolarization. This process decreases Ca2+ influx, thereby decreasing neurotransmitter exocytosis. Subsequently, 2‐AG undergoes passive diffusion into the presynaptic membrane, where it is degraded by MAGL, while AEA undergoes passive diffusion into the postsynaptic membrane, where it is degraded by FAAH. 2‐AG ‐ 2‐arachidonoylglycerol; AEA ‐ N‐arachidonoylethanolamine; CBR1 – cannabinoid receptor type 1; DAGL ‐ diacylglycerol lipase; FAAH ‐ fatty acid amide hydrolase; MAGL ‐ monoacylglycerol lipase; NAPE‐PLD – N‐acyl phosphatidylethanolamine‐specific phospholipase D.

Several other endocannabinoids, including 2‐arachidonyl glyceryl ether (2‐AGE), N‐arachidonoyl dopamine (NADA), oleamide (cis‐9,10‐octadecanoamide [ODA]), N‐arachidonylglycine (NAGLy), palmitoylethanolamide (PEA), stearoylethanolamide (SEA), and oleoylethanolamide (OEA) have been identified, although their roles remain less understood. 1 , 2 , 12

K+ channels and reducing depolarization. This process decreases Ca2+ influx, thereby decreasing neurotransmitter exocytosis. Subsequently, 2‐AG undergoes passive diffusion into the presynaptic membrane, where it is degraded by MAGL, while AEA undergoes passive diffusion into the postsynaptic membrane, where it is degraded by FAAH.

3 THE ECS AND OBESITY

Obesity is a complex, multifactorial disease influenced by genetic, metabolic, social, behavioral, and cultural factors leading to chronic positive energy balance. 15 The World Health Organization (WHO) defines obesity as abnormal or excessive fat accumulation that presents a health risk. The body mass index (BMI) is commonly used to assess obesity, with a BMI over 25 classified as overweight, and over 30 as obese. 16 Data indicates that in 2022 43% of adults worldwide were overweight, while 16% (890 million) were obese, leading to an increased risk of hypertension, dyslipidemia, type 2 diabetes, coronary artery disease, stroke, certain cancers, and higher overall mortality. 17

The ECS significantly influences appetite regulation, although its full impact remains unknown. Current evidence, based on studying the effect of introducing exogenous cannabinoids such as delta 9‐tetrahydrocannabinol (THC) or CBR1 blockers in humans and animals, suggests that the ECS plays a central role in energy balance, both centrally and peripherally. 18 , 19 Studies focusing on ECS regulation in humans have been scarce due to its complexity and ubiquitous nature, therefore more extensive research is required before its full potential is revealed.

3.1 Cannabinoid receptors 1

Endocannabinoids are crucial regulators of energy homeostasis, promoting energy storage by increasing appetite and food intake through central mechanisms, while also enhancing lipogenesis and glucose uptake in peripheral tissues, mainly via CBR1. 12 In animal models, antagonism of CBR1 has been shown to decrease food intake. 20 Furthermore, chronic CBR1 blockade not only affects food intake and body weight but also improves insulin and leptin sensitivity, enhances glucose and lipid profiles, and reduces hepatic steatosis and fibrosis in rodent models. 21 , 22 , 23 , 24 It is suggested this effects are modulated by different mediators (Figure 2).

FIGURE 2 The Role of CB1 receptor stimulation in appetite regulation and obesity. CB1 receptor stimulation promotes orexigenic pathways leading to the increase in the synthesis of molecules such as ghrelin, NPY, and β‐endorphin, which are associated with increased appetite and potential weight gain. Conversely, CB1 receptor activation decreases anorexigenic signals by reducing leptin sensitivity and adiponectin synthesis, diminishing the body's ability to suppress appetite and regulate energy balance. AMPK ‐ AMP‐activated protein kinase; mTOR ‐ mammalian target of rapamycin; NPY ‐ neuropeptide Y; STAT3 ‐ signal transducer and activator of transcription 3; UCP2 ‐ mitochondrial uncoupling protein 2.

Leptin, an anorexigenic hormone produced by adipocytes, plays a crucial role in appetite regulation, partly by interacting with the ECS. It decreases endocannabinoid synthesis by reducing calcium influx and downregulates CBR1 expression in the hypothalamus, leading to a decreased appetite. 12 , 19 , 25 , 26 , 27 , 28 Additionally, a lack of CBR1 stimulation enhances leptin sensitivity, whereas CBR1 stimulation reduces leptin's effect in the hypothalamus by inhibiting STAT3, a key intracellular effector of leptin. 25 , 29 However, in the context of obesity, leptin resistance disrupts its inhibitory effect on the ECS, resulting in increased food intake. 12 In animal models, peripheral CBR1 inverse agonists have been found to reverse leptin resistance and reduce plasma leptin levels by decreasing its production in adipocytes, potentially through direct effects on CBR1 in adipose tissue or by enhancing sympathetic tone and leptin clearance. 30

Food deprivation, contrastingly, triggers the release of endocannabinoids in the hypothalamus and limbic forebrain, activating CBR1 and stimulating appetite, in part through interactions with other orexigenic and anorexigenic signals. 5 , 31 , 32 Activation of CBR1 stimulates the production of the orexigenic neuropeptide Y (NPY) in NPY/AgRP neurons within the arcuate nucleus, possibly by retrograde synaptic disinhibition. 33 , 34 , 35 Interestingly, while CBR1 activation has been shown to increase activity in anorexigenic pro‐opiomelanocortin (POMC) neurons, subsequent research revealed that it primarily enhances the production of β‐endorphin, a supposed orexigenic peptide, without an increase in the anorexigenic α‐melanocyte‐stimulating hormone (α‐MSH). 36 Additionally, the orexigenic effects of ghrelin, another appetite‐stimulating hormone, produced in the gastrointestinal system, depend on a functional ECS. 37 Ghrelin increases the production of 2‐AG by raising intracellular Ca2+ levels, while CBR1 activity modulates the production of ghrelin via mTOR pathway. 27 , 38 , 39

Peripherally, the ECS regulates food intake through the vagus nerve and modulates nutrient processing in the gastrointestinal (GI) tract. 14 , 40 , 41 , 42 , 43 It was shown that the stimulation of CBR1 in the GI tract influences gastric secretion, gastric emptying, and intestinal motility. 40 On the other hand, activation of the CBR1 receptors in fat cells promotes lipogenesis and inhibits the production of adiponectin, a cytokine secreted by adipocytes involved in regulating glucose levels, insulin sensitivity, and lipid metabolism. Low levels of adiponectin, possibly caused by a CB1‐mediated decrease in AMPK activity leading to a decrease in mRNA expression, are associated with several metabolic conditions, including obesity. 44 , 45 , 46 , 47

3.2 Cannabinoid receptors 2

CBR2 agonism in animal models has been associated with reduced food intake, although the findings are not entirely consistent. 27 A key feature of CBR2 receptors is their involvement with dopamine neurons in the ventral tegmental area, where they influence the reward pathway, particularly in response to hedonic food intake. 7 Studies in animals suggest that reduced CBR2 signaling (receptor ablation or antagonist administration) leads to increased food intake, greater adipocyte mass, and obesity, while enhanced CBR2 stimulation (overexpression or agonist administration) results in decreased food intake, reduced body weight, and improved insulin sensitivity. 7 , 48 , 49 , 50 , 51 CBR2 agonism shows potential for reducing obesity‐associated inflammation; however, some studies report conflicting results, highlighting the need for further research. 52 , 53

3.3 Peroxisome proliferator‐activated receptors

Endocannabinoids also activate peroxisome proliferator‐activated receptors (PPARs), a family of nuclear receptors crucial for regulating gene expression, particularly the α and γ isoforms, which play significant roles in lipid metabolism. 54 , 55 It is proposed that PPAR activation partly mediates the neuroprotective, analgesic, anti‐inflammatory, metabolic, anti‐tumor, and cardiovascular effects of cannabinoids. These effects are achieved through complex interactions, with some compounds already being investigated that act as dual CBR1 antagonists/PPARα agonists or CBR2/PPARγ agonists. 56 , 57

3.4 ECS dysregulation

Current evidence links human obesity to the ECS dysregulation. ECS activation, increased endocannabinoid levels (both centrally and peripherally), and CBR1 up‐regulation, may be driven by high‐fat diets that increase the availability of polyunsaturated fatty acids, precursors for endocannabinoid biosynthesis. 14 , 58 , 59 , 60 , 61 , 62 , 63 , 64 The ingestion of highly palatable food activates brain reward circuits with the release of dopamine, endocannabinoids, and opiates, which induces a persistent stimulation of hypothalamic hunger signals and inhibition of satiety mediators. Therefore, obesity may be aggravated by the effect of the endocannabinoid activation in the nucleus accumbens, hippocampus, and entopeduncular nucleus, which are suspected to be directly involved in reward pathways related to hedonic eating. 14 , 65 , 66 Genetic factors, such as the FAAH 385 A/A missense polymorphism, which reduces FAAH enzymatic activity, may also contribute to ECS dysregulation in obesity. 14 , 26 , 67

An overview of the studies on the ECS and its impact on food intake, energy metabolism, and obesity is presented in Table 1.

TABLE 1 An overview of the studies on the endocannabinoid system and its impact on food intake, energy metabolism, and obesity.

Study	Main results	Study model	
Kirkham TC (2005)	Reviewed the role of endocannabinoids in regulating appetite and body weight, highlighting the behavioral pharmacology aspects and how endocannabinoids influence feeding behavior and energy homeostasis.	Review (Animal and Human Studies)	
Di Marzo V, Matias I (2005)	Discussed the endocannabinoid control of food intake and energy balance, emphasizing the complex interactions within the endocannabinoid system that regulate metabolism and appetite.	Review (Animal and Human Studies)	
Viveros M, De Fonseca F, Bermudez‐Silva F, McPartland J (2008)	Discusses the crucial role of the ECS in regulating food intake and energy metabolism, highlighting its evolutionary, developmental, and pathological aspects. It connects to obesity by explaining how the ECS, particularly through the activation of CB1 receptors, influences hunger and metabolism, contributing to weight gain and metabolic disorders, thereby presenting a target for obesity treatment interventions.	Review (Animal and Human Studies)	
Harrold JA, Williams G (2003)	Discussed the role of the cannabinoid system in both homeostatic and hedonic control of eating, indicating its influence on feeding behavior through central mechanisms.	Review (Animal and Human Studies)	
Di Marzo V (2008)	Examined the involvement of the endocannabinoid system in obesity and type 2 diabetes, suggesting that dysregulation of this system contributes to these metabolic disorders.	Review (Animal and Human Studies)	
Cota D, Marsicano G, Tschöp M, et al. (2003)	Found that the endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis, highlighting its dual role in energy homeostasis.	Animal Studies	
Szanda G, Jourdan T, Wisniewski É, et al. (2023)	Demonstrated that CB1R inhibits hypothalamic leptin signaling via β‐arrestin1 in complex with TC‐PTP and STAT3, indicating a mechanism by which cannabinoids influence appetite regulation.	Cell and Animal Studies	
Sipe JC, Waalen J, Gerber A, Beutler E (2005)	Identified an association between overweight and obesity with a missense polymorphism in FAAH 385 A/A, implicating genetic factors in the endocannabinoid system's influence on body weight which may provide indirect evidence to support cannabinoid antagonist treatment strategies in overweight disorders.	Human Studies	
Miralpeix C, Reguera AC, Fosch A, et al. (2021)	Discussed the role of hypothalamic endocannabinoids in obesity and the challenges in understanding their precise mechanisms in the context of energy balance and metabolic regulation.	Review (Animal and Human Studies)	
Watkins BA, Kim J (2015)	Reviewed the endocannabinoid system's role in directing eating behavior and macronutrient metabolism, emphasizing its influence on dietary habits and nutrient processing. The main finding is that PUFAs can modulate the ECS, which in turn affects energy balance, appetite, and overall metabolic health. This modulation by PUFAs has implications for managing obesity and metabolic disorders, particularly as individuals age, due to the ECS's role in regulating energy homeostasis and nutrient processing.	Review (Animal and Human Studies)	
Owyang C, Heldsinger A (2011)	Examines the mechanisms through which the vagus nerve regulates feeding behavior. It highlights the roles of cholecystokinin (CCK) and leptin in signaling satiety. CCK primarily controls short‐term food intake, while leptin influences long‐term eating behavior and body weight. The study found that the endocannabinoid system interacts with these mechanisms, particularly involving the vagus nerve, to modulate appetite and energy balance.	Review (Animal and Human Studies)	
Kowalski CW, Ragozzino FJ, Lindberg JEM, et al. (2020)	Found that cannabidiol activation of vagal afferent neurons requires TRPA1, suggesting a novel pathway for the endocannabinoid system in modulating satiety. The study suggests that CBD's activation of vagal afferent neurons could influence appetite regulation and energy balance through its effects on the endocannabinoid system. By modulating these pathways, CBD may play a role in managing obesity and related metabolic disorders.	Animal Studies	
DiPatrizio NV, Astarita G, Schwartz G, et al. (2011)	The study found that the endocannabinoid system in the gut regulates dietary fat intake by mobilizing endocannabinoids (2‐AG and AEA) in response to fat exposure. This process involves the vagus nerve and CBR1 receptors in the gut. Targeting the gut endocannabinoid system could help reduce overeating of fatty foods and address obesity.	Animal Studies	
Jean‐Pierre D, Alain G, Lars S (2005)	Investigated the effects of Rimonabant on metabolic risk factors in overweight patients with dyslipidemia, showing significant impacts on weight and lipid profiles.	Human Studies	
Di Marzo V, Goparaju SK, Wang L, et al. (2001)	Demonstrated that leptin‐regulated endocannabinoids are involved in maintaining food intake, revealing an interaction between leptin signaling and endocannabinoid activity.	Animal Studies	
Sipe JC, Scott TM, Murray S, et al. (2010)	The study found that carriers of the FAAH 385 A mutant alleles have significantly elevated plasma levels of AEA and related N‐acylethanolamines (NAEs) compared to wild‐type carriers, indicating endocannabinoid system activation. This elevation was particularly notable in severely obese individuals, suggesting a link between the FAAH 385 A allele and severe obesity. These findings highlight the potential of targeting the endocannabinoid system for novel obesity treatments.	Human Studies	
Richey JM, Woolcott O (2017)	Reviewed the therapeutic potential of targeting the endocannabinoid system in obesity and associated diseases, highlighting its regulatory role in energy balance.	Review (Animal and Human Studies)	
Matias I, Gatta‐Cherifi B, Tabarin A, et al. (2012)	Measured endocannabinoids in human saliva as potential biomarkers of obesity, proposing a non‐invasive method for assessing endocannabinoid activity.	Human Studies	
Blüher M, Engeli S, Klöting N, et al. (2006)	The study found that in individuals with abdominal obesity, the endocannabinoid system is dysregulated in peripheral and adipose tissues. This dysregulation is characterized by altered levels of endocannabinoids, which are implicated in the development and maintenance of obesity.	Human Studies	
Osei‐Hyiaman D, DePetrillo M, Pacher P, et al. (2005)	Found that endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet‐induced obesity, highlighting a liver‐specific pathway.	Animal Studies	
Kim J, Li Y, Watkins BA (2013)	Reviewed the relationship between dietary PUFA, endocannabinoids, and obesity, suggesting dietary interventions targeting the endocannabinoid system. Specifically, PUFAs can modulate endocannabinoid levels, potentially offering a dietary approach to manage obesity.	Review (Animal and Human Studies)	
Hansen HS, Artmann A (2008)	Explored the interplay between endocannabinoids and nutrition, emphasizing their role in metabolic regulation and dietary effects. The study highlights that certain dietary fats can modulate the levels of endocannabinoids, which play a crucial role in energy balance and metabolism, suggesting that dietary interventions targeting the ECS could be a potential strategy for managing obesity.	Review (Animal and Human Studies)	
Monteleone P, Piscitelli F, Scognamiglio P, et al. (2012)	Found that hedonic eating is associated with increased peripheral levels of ghrelin and 2‐AG, linking pleasure‐driven eating to endocannabinoid activity, which could have implications for understanding obesity.	Human Studies	
Aguilera Vasquez N, Nielsen DE (2022)	Suggests that the ECS plays a significant role in regulating eating behaviors, particularly in the context of obesity. The study reviews current evidence indicating that dysregulation of the ECS can influence appetite, food intake, and energy balance, thereby contributing to the development and maintenance of obesity.	Review (Animal and Human Studies)	
Engeli S, Böhnke J, Feldpausch M, et al. (2005)	Discussed that peripheral ECS is significantly activated in individuals with obesity. This activation is characterized by elevated levels of endocannabinoids in the peripheral tissues, which are associated with various metabolic alterations contributing to obesity.	Human Studies	

4 THERAPEUTIC APPROACHES AND CHALLENGES

The widespread distribution of the ECS throughout the human body, its on‐demand synthesis, and specific activation during pathological states, make selective pharmacological intervention within the ECS highly challenging. The success of CBR1 blocker, rimonabant, in treating obesity was demonstrated in clinical trials. 44 , 68 , 69 However, the systemic use of cannabinoid receptor modulators, which indiscriminately affect the function of all cannabinoid receptors across different tissues can disrupt the normal function of the ECS in non‐target cells. This disruption poses a significant risk of developing adverse effects, such as the intoxication associated with CBR1 agonists and the psychological side effects caused by CBR1 antagonists or inverse agonists. 62 , 70 Selective pharmacological targeting that ensures the anti‐obesity effect while minimizing the risk of adverse effects is therefore essential in developing anti‐obesity drugs aimed at the ECS.

4.1 Rimonabant

The discovery of the cannabinoid receptors opened the door to pharmacological intervention within the ECS. Rimonabant, an inverse agonist of the CBR1, was shown to suppress the endogenous activation of the ECS both centrally and peripherally. 44 , 68 , 71 , 72 In clinical trials, rimonabant has shown promise as an anti‐obesity agent achieving weight reduction and improvements in lipid and HbA1C levels. 44 , 68 , 71 It is estimated that half of the effect of rimonabant on HDL‐cholesterol and triglycerides levels was independent of weight loss, possibly due to stimulation of adiponectin production through CBR1 inhibition. 44 , 68 , 69 , 71 After approval as a weight‐loss drug in Europe in 2006, in 2008, before receiving FDA approval in the USA, it was withdrawn from the European market due to severe psychiatric adverse effects, including depression, anxiety, and even suicidal ideation. 62 , 70 , 72 , 73 Consequently, other clinical trials of drugs with a similiar mechanism of action were terminated. 62 , 70

4.2 Drugs in development

After rimonabant was pulled from the market due to psychological adverse effects, the search for a more selective agent began. One approach is to develop peripherally restricted CB1 antagonists, which minimize CNS side effects, 67 , 70 , 74 and CB1 negative allosteric modulators (NAMs), 75 which produce more specific receptor modulation with a better safety profile. Additionally, the potential role of CB2 receptors in energy homeostasis and inflammation is being investigated since CBR2 are expressed in the brain regions involved in appetite regulation, but are not involved in mood regulation. 49 CBR2 also influence fat tissue cells, mediating the adipocyte‐induced inflammatory response, 76 as well as browning of white adipose tissue, a process typically inhibited in obesity. 77 Besides modulating ECS activity by targeting CBR, another approach is via the enzymes responsible for the synthesis or degradation of the endocannabinoids, namely FAAH, MAGL, and DAGL. However, due to complex and tissue‐specific activity of ECS enzymes, predicting the outcomes of such interventions is challenging. 4 , 6 , 27 , 78

New therapeutic strategies are currently being explored with several drugs currently in the pipeline. The first biologic drug targeting the ECS, namacizumab, a negative allosteric modulating antibody (NAMA) that stabilizes CBR1 in an inactive conformation, was approved to initiate a phase 1 of the clinical trial in the treatment of non‐alcoholic steatohepatitis (NASH) and diabetic nephropathy. 74 Moreover, INV‐101, a peripheral CBR1 inverse agonist, has been approved to start phase 1 of the clinical trial for the treatment of Prader‐Willi syndrome characterized by overactivated ECS, which leads to excessive weight gain, hyperphagia, and neurodevelopmental symptoms. 79 A Phase 2 trial is currently evaluating the efficacy of once‐daily oral cannabis for weight loss in obese patients, with results expected in 2026. 80 There are some data suggesting that cannabis may influence weight loss, potentially through its effects on the CBR2, 81 although the evidence is not yet conclusive. 82 , 83

4.3 Advantages of targeting ECS in obesity

Taking into account all of the above, targeting the ECS for anti‐obesity treatments offers a unique therapeutic approach that differs from existing drugs, potentially addressing obesity through multiple mechanisms while minimizing some limitations of current therapies. As described, the ECS is deeply involved in the regulation of food intake, energy storage, and glucose and lipid metabolism. Drugs targeting the ECS could modulate these pathways more effectively than current anti‐obesity drugs, which often focus on singular aspects such as appetite suppression or fat absorption. In addition, targeting the ECS might help restore leptin sensitivity, thereby improving the body's natural ability to regulate weight. Moreover, CBR2 activation shows promise in reducing obesity related inflammation potentially providing metabolic benefits beyond weight loss.

5 CONCLUSION

Despite these promising observations, the main fault of any attempted endocannabinoid manipulation lies in the ubiquitous nature of the ECS across the human body, and its involvement in various physiological processes, which in turn carries a high risk of unwanted adverse effects. Future research endeavors may warrant selective ECS manipulation in specific tissues, in an attempt to circumnavigate this issue.

6 NOMENCLATURE STATEMENT

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Harding et al., 2018), and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20 (Alexander et al., 2019). 84 , 85

AUTHOR CONTRIBUTIONS

All authors contributed substantially to the conception of the work. MK and IR wrote the first draft of the work. RL performed critical revision. All authors gave final approval of the version to be published.

CONFLICT OF INTEREST STATEMENT

None to declare.

7 ETHICS STATEMENT

None.

ACKNOWLEDGMENTS

This research has received no external funding.

7.1 DATA AVAILABILITY STATEMENT

Data are available upon reasonable request from the authors.
==== Refs
REFERENCES

1 Farrimond JA , Mercier MS , Whalley BJ , Williams CM . Cannabis sativa and the endogenous cannabinoid system: therapeutic potential for appetite regulation. Phytother Res. 2011;25 (2 ):170‐188.21213357
2 Lu HC , Mackie K . An introduction to the endogenous cannabinoid system. Biol Psychiatry. 2016;79 (7 ):516‐525.26698193
3 Felder CC , Glass M . Cannabinoid receptors and their endogenous agonists. Annu Rev Pharmacol Toxicol. 1998;38 (1 ):179‐200.9597153
4 Toczek M , Malinowska B . Enhanced endocannabinoid tone as a potential target of pharmacotherapy. Life Sci. 2018;204 :20‐45.29729263
5 Kirkham TC . Endocannabinoids in the regulation of appetite and body weight. Behav Pharmacol. 2005:16 (5‐6 ):297‐313.16148436
6 Matheson J , Zhou XMM , Bourgault Z , Le Foll B . Potential of fatty acid amide hydrolase (FAAH), Monoacylglycerol lipase (MAGL), and Diacylglycerol lipase (DAGL) enzymes as targets for obesity treatment: a narrative review. Pharmaceuticals. 2021;14 (12 ):1316.34959715
7 Rodríguez‐Serrano LM , Chávez‐Hernández ME . Role of the CB2 cannabinoid receptor in the regulation of food intake: a systematic review. Int J Mol Sci 2023 Dec;24 (24 ):17516.38139344
8 Jordan CJ , Xi ZX . Progress in brain cannabinoid CB2 receptor research: from genes to behavior. Neurosci Biobehav Rev. 2019;98 :208‐220.30611802
9 Gonsiorek W , Lunn C , Fan X , Narula S , Lundell D , Hipkin RW . Endocannabinoid 2‐Arachidonyl Glycerol Is a Full Agonist through Human Type 2 Cannabinoid Receptor: Antagonism by Anandamide. Mol Pharmacol. 2000;57 (5 ):1045‐1050.10779390
10 Zou S , Kumar U . Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system. Int J Mol Sci. 2018;19 (3 ):833.29533978
11 Howlett A , Blume L , Dalton G . CB1 cannabinoid receptors and their associated proteins. CMC. 2010;17 (14 ):1382‐1393.
12 Schulz P , Hryhorowicz S , Rychter AM , et al. What role does the endocannabinoid system play in the pathogenesis of obesity? Nutrients. 2021;13 (2 ):373.33530406
13 Wright NJD . A review of the direct targets of the cannabinoids cannabidiol, Δ9‐tetrahydrocannabinol, N‐arachidonoylethanolamine and 2‐arachidonoylglycerol. AIMS Neuroscience. 2024;11 (2 ):144‐165.38988890
14 Di Marzo V , Matias I . Endocannabinoid control of food intake and energy balance. Nat Neurosci. 2005;8 (5 ):585‐589.15856067
15 Kolotkin RL , Meter K , Williams GR . Quality of life and obesity. Obes Rev. 2001;2 (4 ):219‐229.12119993
16 Piché ME , Tchernof A , Després JP . Obesity phenotypes, diabetes, and cardiovascular diseases. Circ Res. 2020;126 (11 ):1477‐1500.32437302
17 Obesity and overweight [Internet] . 2024 [cited 2024 Aug 19]. https://www.who.int/news‐room/fact‐sheets/detail/obesity‐and‐overweight
18 Viveros M , De Fonseca F , Bermudez‐Silva F , McPartland J . Critical role of the endocannabinoid system in the regulation of food intake and energy metabolism, with phylogenetic, developmental, and pathophysiological implications. EMIDDT. 2008;8 (3 ):220‐230.
19 Harrold JA , Williams G . The cannabinoid system: a role in both the homeostatic and hedonic control of eating? Br J Nutr. 2003;90 (4 ):729‐734.13129440
20 Colombo G , Agabio R , Diaz G , Lobina C , Reali R , Gessa GL . Appetite suppression and weight loss after the cannabinoid antagonist SR 141716. Life Sci. 1998;63(8):PL113–7 :PL113‐PL117.9718088
21 Bell‐Anderson KS , Aouad L , Williams H , et al. Coordinated improvement in glucose tolerance, liver steatosis and obesity‐associated inflammation by cannabinoid 1 receptor antagonism in fat Aussie mice. Int J Obes. 2011;35 (12 ):1539‐1548.
22 Fong TM , Guan XM , Marsh DJ , et al. Antiobesity efficacy of a novel Cannabinoid‐1 receptor inverse Agonist,N‐[(1S,2S)‐3‐(4‐Chlorophenyl)‐2‐(3‐cyanophenyl)‐1‐methylpropyl]‐2‐methyl‐2‐{[5‐(trifluoromethyl)pyridin‐2‐yl]oxy}propanamide (MK‐0364), in rodents. J Pharmacol Exp Ther. 2007;321 (3 ):1013‐1022.17327489
23 Gary‐Bobo M , Elachouri G , Gallas JF , et al. Rimonabant reduces obesity‐associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats. Hepatology. 2007;46 (1 ):122‐129.17526015
24 Tam J , Godlewski G , Earley BJ , et al. Role of adiponectin in the metabolic effects of cannabinoid type 1 receptor blockade in mice with diet‐induced obesity. American Journal of Physiology‐Endocrinology and Metabolism. 2014;306 (4 ):E457‐E468.24381003
25 Szanda G , Jourdan T , Wisniewski É , et al. Cannabinoid receptor type 1 (CB(1)R) inhibits hypothalamic leptin signaling via β‐arrestin1 in complex with TC‐PTP and STAT3. iScience. 2023;26 (7 ):107207.37534180
26 Sipe JC , Waalen J , Gerber A , Beutler E . Overweight and obesity associated with a missense polymorphism in fatty acid amide hydrolase (FAAH). Int J Obes. 2005;29 (7 ):755‐759.
27 Miralpeix C , Reguera AC , Fosch A , et al. Hypothalamic endocannabinoids in obesity: an old story with new challenges. Cell Mol Life Sci. 2021;78 (23 ):7469‐7490.34718828
28 Rossi F , Punzo F , Umano GR , Argenziano M , Giudice EMD . Role of cannabinoids in obesity. Int J Mol Sci. 2018;19 (9 ):2690.30201891
29 Cardinal P , André C , Quarta C , et al. CB1 cannabinoid receptor in SF1‐expressing neurons of the ventromedial hypothalamus determines metabolic responses to diet and leptin. Molecular Metabolism. 2014;3 (7 ):705‐716.25352999
30 Tam J , Cinar R , Liu J , et al. Peripheral Cannabinoid‐1 receptor inverse Agonism reduces obesity by reversing leptin resistance. Cell Metab. 2012;16 (2 ):167‐179.22841573
31 Di Marzo V . The endocannabinoid system in obesity and type 2 diabetes. Diabetologia. 2008;51 (8 ):1356‐1367.18563385
32 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 ):423‐431.12897210
33 Morozov YM , Koch M , Rakic P , Horvath TL . Cannabinoid type 1 receptor‐containing axons innervate NPY/AgRP neurons in the mouse arcuate nucleus. Molecular Metabolism. 2017;6 (4 ):374‐381.28377876
34 Tarragon E , Moreno JJ . Cannabinoids, chemical senses, and regulation of feeding behavior. Chem Senses. 2019;44 (2 ):73‐89.30481264
35 Cota D . Role of the endocannabinoid system in energy balance regulation and obesity. In: Korbonits M , ed. Frontiers of Hormone Research. KARGER; 2008 [cited 2024 Aug 19]:135‐145.
36 Koch M , Varela L , Kim JG , et al. Hypothalamic POMC neurons promote cannabinoid‐induced feeding. Nature. 2015;519 (7541 ):45‐50.25707796
37 Thompson NM , Gill DAS , Davies R , et al. Ghrelin and des‐Octanoyl ghrelin promote Adipogenesis directly in vivo by a mechanism independent of the type 1a growth hormone Secretagogue receptor. Endocrinology. 2004;145 (1 ):234‐242.14551228
38 Mani BK , Castorena CM , Vianna CR , et al. Combined loss of ghrelin receptor and cannabinoid CB1 receptor in mice decreases survival but does not additively reduce body weight or eating. Neuroscience. 2020;447 :53‐62.31520709
39 Senin LL , Al‐Massadi O , Folgueira C , et al. The gastric CB1 receptor modulates ghrelin production through the mTOR pathway to regulate food intake. PLoS One. 2013;8 (11 ):e80339.24303008
40 Watkins BA , Kim J . The endocannabinoid system: directing eating behavior and macronutrient metabolism. Front Psychol 2015 Jan 6;5:1506. doi:10.3389/fpsyg.2014.01506
41 Owyang C , Heldsinger A . Vagal control of satiety and hormonal regulation of appetite. J Neurogastroenterol Motil. 2011;17 (4 ):338‐348.22148102
42 Kowalski CW , Ragozzino FJ , Lindberg JEM , et al. Cannabidiol activation of vagal afferent neurons requires TRPA1. J Neurophysiol. 2020;124 (5 ):1388‐1398.32965166
43 DiPatrizio NV , Astarita G , Schwartz G , Li X , Piomelli D . Endocannabinoid signal in the gut controls dietary fat intake. Proc Natl Acad Sci USA. 2011;108 (31 ):12904‐12908.21730161
44 Després JP , Golay A , Sjöström L . Rimonabant in Obesity‐Lipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005 Nov 17;353 (20 ):2121‐2134. doi: 10.1056/NEJMoa044537.16291982
45 Di Marzo V , Goparaju SK , Wang L , et al. Leptin‐regulated endocannabinoids are involved in maintaining food intake. Nature. 2001;410 (6830 ):822‐825.11298451
46 Wei Q , Lee JH , Wu CS , et al. Metabolic and inflammatory functions of cannabinoid receptor type 1 are differentially modulated by adiponectin. World J Diabetes. 2021;12 (10 ):1750‐1764.34754376
47 Engeli S . Peripheral metabolic effects of endocannabinoids and cannabinoid receptor blockade. Obes Facts. 2008;1 (1 ):8‐15.20054157
48 Bermudez‐Silva FJ , Sanchez‐Vera I , Suárez J , et al. Role of cannabinoid CB2 receptors in glucose homeostasis in rats. Eur J Pharmacol. 2007;565 (1–3 ):207‐211.17499236
49 Verty ANA , Stefanidis A , McAinch AJ , Hryciw DH , Oldfield B . Anti‐obesity effect of the CB2 receptor agonist JWH‐015 in diet‐induced obese mice. Nadal A , PLoS One. 2015;10 (11 ):e0140592.26588700
50 Romero‐Zerbo SY , Garcia‐Gutierrez MS , Suárez J , et al. Overexpression of cannabinoid CB2 receptor in the brain induces Hyperglycaemia and a lean phenotype in adult mice. J Neuroendocrinol. 2012;24 (8 ):1106‐1119.22487302
51 Agudo J , Martin M , Roca C , et al. Deficiency of CB2 cannabinoid receptor in mice improves insulin sensitivity but increases food intake and obesity with age. Diabetologia. 2010;53 (12 ):2629‐2640.20835701
52 O'Keefe L , Vu T , Simcocks AC , et al. Treatment of diet‐induced obese rats with CB2 agonist AM1241 or CB2 antagonist AM630 reduces leptin and alters Thermogenic mRNA in adipose tissue. Int J Mol Sci. 2023;24 (8 ):7601.37108770
53 Schmitz K , Mangels N , Häussler A , Ferreirós N , Fleming I , Tegeder I . Pro‐inflammatory obesity in aged cannabinoid‐2 receptor‐deficient mice. Int J Obes. 2016;40 (2 ):366‐379.
54 Iannotti FA , Vitale RM . The endocannabinoid system and PPARs: focus on their Signalling crosstalk, action and transcriptional regulation. Cells. 2021;10 (3 ):586.33799988
55 Hempel B , Crissman M , Pari S , et al. PPARα and PPARγ are expressed in midbrain dopamine neurons and modulate dopamine‐ and cannabinoid‐mediated behavior in mice. Mol Psychiatry. 2023;28 (10 ):4203‐4214.37479780
56 Lago‐Fernandez A , Zarzo‐Arias S , Jagerovic N , Morales P . Relevance of peroxisome proliferator activated receptors in multitarget paradigm associated with the endocannabinoid system. Int J Mol Sci. 2021;22 (3 ):1001.33498245
57 O'Sullivan SE . An update on PPAR activation by cannabinoids. Br J Pharmacol. 2016;173 (12 ):1899‐1910.27077495
58 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 ):1298‐1305.15864349
59 Kim J , Li Y , Watkins BA . Fat to treat fat: emerging relationship between dietary PUFA, endocannabinoids, and obesity. Prostaglandins Other Lipid Mediat. 2013;104–105 :32‐41.
60 Hansen HS , Artmann A . Endocannabinoids and nutrition. J Neuroendocrinol 2008 May;20 (s1 ):94–9.18426507
61 Sipe JC , Scott TM , Murray S , Harismendy O , Simon GM , Cravatt BF . Biomarkers of endocannabinoid system activation in severe obesity. Biomarkers of Endocannabinoid System Activation in Severe Obesity. Vol 5 . In; 2010:e8792.
62 Richey JM , Woolcott O . Re‐visiting the endocannabinoid system and its therapeutic potential in obesity and associated diseases. Curr Diab Rep. 2017;17 (10 ):99.28913816
63 Matias I , Gatta‐Cherifi B , Tabarin A , Clark S , Leste‐Lasserre T , Marsicano G . Endocannabinoids measurement in human saliva as potential biomarker of obesity. Endocannabinoids Measurement in Human Saliva as Potential Biomarker of Obesity. Vol 7 . In; 2012.
64 Blüher M , Engeli S , Klöting N , Berndt J , Fasshauer M , Bátkai S . Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. Diabetes. 2006;55 :3053‐3060.17065342
65 Monteleone P , Piscitelli F , Scognamiglio P , et al. Hedonic eating is associated with increased peripheral levels of ghrelin and the endocannabinoid 2‐Arachidonoyl‐glycerol in healthy humans: a pilot study. J Clin Endocrinol Metab. 2012;97 (6 ):E917‐E924.22442280
66 Aguilera Vasquez N , Nielsen DE . The endocannabinoid system and eating Behaviours: a review of the current state of the evidence. Curr Nutr Rep. 2022;11 (4 ):665‐674.35980538
67 Engeli S , Böhnke J , Feldpausch M , et al. Activation of the peripheral endocannabinoid system in human obesity. Diabetes. 2005;54 (10 ):2838‐2843.16186383
68 Scheen AJ , Finer N , Hollander P , Jensen MD , Van Gaal LF . Efficacy and Tolerability of Rimonabant in Overweight or Obese Patients with Type 2 Diabetes: a Randomised Controlled Study. Lancet. 2006;368 (9548 ):1660‐1672.17098084
69 Van Gaal LF , Rissanen AM , Scheen AJ , Ziegler O , Rössner S . Effects of the Cannabinoid‐1 Receptor Blocker Rimonabant on Weight Reduction and Cardiovascular Risk Factors in Overweight Patients: 1‐Year Experience from the RIO‐Europe Study. 2005;365 (9468 ):1389‐1397.
70 Nguyen T , Thomas BF , Zhang Y . Overcoming the psychiatric side effects of the cannabinoid CB1 receptor antagonists: current approaches for therapeutics development. CTMC. 2019;19 (16 ):1418‐1435.
71 Pi‐Sunyer FX , Aronne LJ , Heshmati HM , Devin J , Rosenstock J . RIO‐North America study group FT. effect of Rimonabant, a Cannabinoid‐1 receptor blocker, on weight and Cardiometabolic risk factors in overweight or obese patients: RIO‐North America: a randomized controlled trial. JAMA. 2006;295 (7 ):761‐775.16478899
72 Bosquez‐Berger T , Szanda G , Straiker A . Requiem for Rimonabant: therapeutic potential for cannabinoid CB1 receptor antagonists after the fall. DDC. 2023;2 (3 ):689‐707.
73 Christensen R , Kristensen PK , Bartels EM , Bliddal H , Astrup A . Efficacy and safety of the weight‐loss drug rimonabant: a meta‐analysis of randomised trials. Lancet. 2007;370 (9600 ):1706‐1713.18022033
74 Di Marzo V . New approaches and challenges to targeting the endocannabinoid system. Nat Rev Drug Discov. 2018;17 (9 ):623‐639.30116049
75 Dasram MH , Walker RB , Khamanga SM . Recent advances in endocannabinoid system targeting for improved specificity: strategic approaches to targeted drug delivery. IJMS. 2022;23 (21 ):13223.36362014
76 Deveaux V , Cadoudal T , Ichigotani Y , Teixeira‐Clerc F , Louvet A , Manin S , et al. Cannabinoid CB2 receptor potentiates obesity‐associated inflammation, insulin resistance and hepatic steatosis. PLoS One. 2009;4 (6 ):e5844 19513120
77 Rossi F , Bellini G , Luongo L , et al. Cannabinoid receptor 2 as Antiobesity target: inflammation, fat storage, and Browning modulation. J Clin Endocrinol Metab. 2016;101 (9 ):3469‐3478.27294325
78 Gregus AM , Buczynski MW . Druggable Targets in Endocannabinoid Signaling. In: Kihara Y, Editor. Druggable Lipid Signaling Pathways [Internet]. Cham: Springer International Publishing; 2020:177‐201.
79 Knani I , Earley BJ , Udi S , et al. Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader–Willi syndrome. Molecular Metabolism. 2016;5 (12 ):1187‐1199.27900261
80 Cannabis for Obesity Trial [Internet] . ClinicalTrials.gov. National Library of Medicine. 2024. Accessed September 12, 2024. https://clinicaltrials.gov/study/NCT06137365
81 Reis MG , Ferreira AJF , Sohouli MH , Taimeirão DR , Vieira RAL , Guimarães NS . Effect of cannabis and subproducts on anthropometric measures: a systematic review and meta‐analysis. Int J Obes. 2024;48 (1 ):44‐54.
82 Muniyappa R , Sable S , Ouwerkerk R , et al. Metabolic effects of chronic cannabis smoking. Diabetes Care. 2013;36 (8 ):2415‐2422.23530011
83 Fearby N , Penman S , Thanos P . Effects of Δ9‐Tetrahydrocannibinol (THC) on obesity at different stages of life: a literature review. IJERPH. 2022;19 (6 ):3174.35328862
84 Harding SD , Sharman JL , Faccenda E , et al. The IUPHAR/BPS guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY. Nucleic Acids Res. 2018;46 (D1 ):D1091‐D1106.29149325
85 Alexander SPH , Christopoulos A , Davenport AP , et al. The concise guide to PHARMACOLOGY 2023/24: G protein‐coupled receptors. British J Pharmacology [Internet]. 2023;180 (S2 ):S23‐S144. doi:10.1111/bph.16177
