Stockholm Medical Cannabis Conference

Beyond the High: Unraveling Non-GPCR Targets in the eCBome

I. Introduction

The endocannabinoid system (eCBome), an intricate network with implications for human health and disease, extends beyond the traditionally studied G-protein coupled receptors (GPCRs) like CB1 and CB2 (1). This vast system also involves a variety of non-GPCR targets, including certain proteins and enzymes involved in endocannabinoid biosynthesis and degradation, ion channels, and nuclear receptors. The proteins, such as FAAH, MAGL, DAGL, NAPE-PLD, TRP channels, and Peroxisome Proliferator-Activated Receptors (PPARs), each play unique and complex roles within the eCBome and are gaining recognition for their considerable contribution to the physiological effects mediated by the eCBome (2,3)

These non-GPCR targets are now understood to significantly influence a multitude of physiological processes ranging from appetite regulation to pain perception and immune response (1). Furthermore, these targets hold promise for novel therapeutic interventions for an array of health conditions including metabolic, neuropsychiatric, and neurological disorders (4,5).

II. Fatty Acid Amide Hydrolase (FAAH) and Monoacylglycerol Lipase (MAGL)

Two crucial enzymes, FAAH and MAGL, control the levels of endocannabinoids (natural cannabis-like molecules in our body), thus influencing the eCBome’s activity and effect on physiological functions (6,7). FAAH primarily metabolizes anandamide, thereby controlling its availability in the body (8). It’s been suggested that inhibiting FAAH could have potential benefits like pain relief, reducing anxiety and inflammation (9). Meanwhile, MAGL degrades another endocannabinoid, 2-arachidonoylglycerol (2-AG), playing a crucial role in processes like pain perception and inflammation (10). Emerging studies also indicate that MAGL could be a valuable target in conditions such as neuropathic pain, neuroinflammatory diseases, and certain types of cancer (11). These enzymes, through their regulation of eCBome, offer potential for novel therapeutic strategies addressing a range of human pathologies.

III. Diacylglycerol Lipase (DAGL) and N-Acyl Phosphatidylethanolamine-Phospholipase D (NAPE-PLD)

Two other critical enzymes in the eCBome, DAGL and NAPE-PLD, play significant roles in endocannabinoid creation (12,13). DAGL aids in the production of 2-AG, influencing various physiological functions, including pain perception and inflammation. Studies suggest potential therapeutic uses for DAGL in treating neurodevelopmental disorders and neuroinflammation, though more research is needed (14,15).

NAPE-PLD, meanwhile, catalyzes the formation of anandamide, playing a crucial role in pain modulation, appetite regulation, and mood balance. Alterations in NAPE-PLD activity have been associated with neuroinflammation, obesity, and pain, suggesting its potential therapeutic value (16, 17). However, the functional roles and disease implications of these enzymes require further exploration to fully understand the eCBome network and to identify promising targets for therapeutic intervention.

IV. Role of Transient Receptor Potential Channels (TRP Channels) in Endocannabinoid System (eCBome)

Transient receptor potential (TRP) channels, belonging to a family of non-selective cation channels, function as pivotal contributors to the endocannabinoid system (eCBome). They partake in various human physiological processes and diseases (18,19). These channels engage with endocannabinoids and other bioactive lipids, making them integral to eCBome signaling and function (20).

For instance, TRPV1 (vanilloid) channels, which are activated by the endocannabinoid anandamide, participate in pain perception, body temperature regulation, and inflammation. Malfunction of these channels is linked to chronic pain and inflammatory diseases (21,22). TRPM8 (melastatin) channels, responsive to temperature variations, are proposed to influence cancer, neuropathic pain, and migraine (23,24).

TRPA1 (ankyrin) channels, modulated by specific cannabinoids and endogenous lipid metabolites, are associated with sensory perception, inflammation, and pain (25). Additionally, TRPV2 channels are thought to contribute to cardiac function and immunomodulation (26).

A deeper understanding of the role of TRP channels within the eCBome presents significant potential for therapeutic development. Future research could clarify the diverse and intricate roles these channels have in health and disease, paving the way for novel therapeutic interventions.

V. Influence of Peroxisome Proliferator-Activated Receptors (PPARs) on the Endocannabinoid System (eCBome)

Peroxisome Proliferator-Activated Receptors (PPARs) function as nuclear hormone receptors and transcription factors, manipulating the expression of genes associated with cellular differentiation, metabolism, and inflammation (27). PPARs are extensively expressed in human tissues, particularly those involved in energy homeostasis, and interact with various endocannabinoid ligands (28).

PPARs exist as three main isoforms: PPARα, PPARγ, and PPARδ, each with distinct tissue distribution and functional characteristics. PPARα is primarily expressed in the liver, heart, and muscle, playing significant roles in the regulation of lipid metabolism, inflammation, and energy homeostasis (28). PPARγ is predominantly found in adipose tissues and immune cells, mediating adipocyte differentiation, glucose metabolism, and immune response modulation (29). Lastly, PPARδ, which is ubiquitously expressed, contributes to lipid metabolism, energy balance, and inflammation (30).

Several eCBome components such as certain long-chain fatty acids, eicosanoids, and their metabolites act as endogenous ligands for PPARs. Multiple cannabinoids, including CBD, bind to PPARs, modulating their activity (31). Dysregulation of PPARs is implicated in numerous pathologies, including metabolic disorders (e.g., obesity, type 2 diabetes), inflammatory conditions, and specific cancers, highlighting their potential as drug development targets  (32).

VI. How Non-GPCR eCBome Targets Influence Neuropsychiatric Disorders

Neuropsychiatric disorders represent another major area of eCBome involvement. For instance, genetic variants of the fatty acid amide hydrolase (FAAH) gene, which encodes for the primary degrading enzyme of AEA, have been associated with altered risk for mood and anxiety disorders (33, 40)

One of these targets, Fatty Acid Amide Hydrolase (FAAH), regulates the degradation of anandamide, a critical endocannabinoid involved in mood regulation and anxiety (34). Genetic variations in the FAAH gene have been linked to risk for addiction and stress-related psychiatric disorders (35). Monoacylglycerol Lipase (MAGL), another non-GPCR target, is involved in the degradation of the endocannabinoid 2-AG, which modulates synaptic transmission and neuroplasticity, processes that are altered in neuropsychiatric disorders such as schizophrenia and major depressive disorder (36).

Transient Receptor Potential (TRP) channels, which interact with numerous endocannabinoids, have been implicated in the pathogenesis of various neuropsychiatric disorders, including anxiety, depression, and neurodegenerative diseases (37). PPARs, particularly PPARα and PPARγ, have been implicated in the regulation of mood and neuroinflammation, both critical aspects of neuropsychiatric health (38). The burgeoning field of research underscores the potential of non-GPCR eCBome targets for the diagnosis, prevention, and treatment of neuropsychiatric disorders (39).

VII. Involvement of Non-GPCR eCBome Targets in Metabolic Disorders

Research in recent years has been particularly revealing of the contributions of non-GPCR eCBome targets to metabolic disorders, broadening our understanding of disease etiology and opening up possibilities for targeted therapeutic interventions. PPARs, for instance, have emerged as central players in lipid metabolism, insulin sensitivity, and adipogenesis, with dysregulation implicated in metabolic syndromes such as diabetes and obesity (40,41).

Moreover, the role of FAAH in regulating levels of anandamide, a lipid signaling molecule, has been shown to have direct implications for metabolic health. Elevated FAAH activity and consequent lower anandamide levels have been linked to obesity and insulin resistance, suggesting that FAAH inhibition could present a therapeutic opportunity (42). In a similar vein, DAGL, which synthesizes the endocannabinoid 2-AG, has been implicated in obesity, indicating its potential as a target for weight management (43).

The activity of TRP channels, specifically TRPV1, also holds relevance to metabolic health, as activation of this ion channel has been associated with reduced obesity and improved glucose homeostasis (44).

Together, these findings underscore the breadth of roles non-GPCR eCBome targets play in metabolic health, emphasizing their potential as strategic therapeutic targets for a range of metabolic disorders (45).

VIII. Impact of Non-GPCR eCBome Targets on Neurological Disorders

Investigation into the role of non-GPCR eCBome targets in neurological disorders has been making compelling strides forward, underscoring their pivotal roles in pathogenesis and treatment. PPARs, for instance, have drawn considerable attention in this context. These nuclear receptors modulate neuroinflammation and oxidative stress, processes that are critically implicated in neurodegenerative diseases like Alzheimer’s and Parkinson’s disease (46,47).

Further, the enzyme FAAH, whose role in anandamide degradation has implications for neuroprotection, has been associated with the progression of Alzheimer’s disease (48). On a similar note, MAGL, which governs 2-AG levels, has been linked to neuroinflammation and neurodegeneration, thereby suggesting its potential as a therapeutic target in mitigating symptoms of Parkinson’s disease (49).

This burgeoning evidence is indicative of the transformative potential that understanding non-GPCR eCBome targets holds for the management of neurological disorders, warranting comprehensive and focused research in this area (50).

IX. Conclusion

In conclusion, the breadth and depth of research on non-GPCR eCBome targets, from FAAH and MAGL to DAGL and NAPE-PLD, TRP channels, and PPARs, underscore the far-reaching implications of these targets in human physiology and disease pathology. Their crucial roles in processes ranging from pain perception to metabolism, mood regulation, and neuroprotection, place them firmly in the crosshairs for potential therapeutic intervention (51,52).

Emerging research is beginning to unravel the therapeutic potential of these targets in disorders as diverse as neuropsychiatric, neurological, and metabolic diseases (53,54). However, our understanding is still nascent, and more comprehensive studies are required to fully elucidate the underlying molecular mechanisms and the full therapeutic potential of these targets. As research progresses, it will pave the way for precision medicine, providing new opportunities for targeted interventions and patient-tailored therapies (51,52). This endeavor could provide hope for patients and clinicians alike, heralding a new era in therapeutic interventions for a variety of diseases.

Table 1. Non-GPCR Targets in the Endocannabinoid System (eCBome), their roles, disease implications, and references.

Stefan Broselid, Ph.D.
Editor-In-Chief, Aurea Care Medical Science Journal


  1. Mechoulam R, Parker LA. The endocannabinoid system and the brain. Annu Rev Psychol. 2013;64:21-47. doi:10.1146/annurev-psych-113011-143739
  2. Kano M. Control of synaptic function by endocannabinoid-mediated retrograde signaling. Proc Jpn Acad Ser B Phys Biol Sci. 2014;90(7):235-250. doi:10.2183/pjab.90.235
  3. Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci. 2003;4(11):873-884. doi:10.1038/nrn1247
  4. Lu HC, Mackie K. An Introduction to the Endogenous Cannabinoid System. Biol Psychiatry. 2016;79(7):516-525. doi:10.1016/j.biopsych.2015.07.028
  5. 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. doi:10.3390/ijms19030833
  6. Ahn K, McKinney MK, Cravatt BF. Enzymatic pathways that regulate endocannabinoid signaling in the nervous system. Chem Rev. 2008;108(5):1687-1707. doi:10.1021/cr0782067
  7. Di Marzo V. New approaches and challenges to targeting the endocannabinoid system. Nat Rev Drug Discov. 2018;17(9):623-639. doi:10.1038/nrd.2018.115
  8. Kathuria S, Gaetani S, Fegley D, et al. Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med. 2003;9(1):76-81. doi:10.1038/nm803
  9. Huggins JP, Smart TS, Langman S, Taylor L, Young T. An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee. Pain. 2012;153(9):1837-1846. doi:10.1016/j.pain.2012.04.014
  10. Dinh TP, Carpenter D, Leslie FM, et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci U S A. 2002;99(16):10819-10824. doi:10.1073/pnas.152334899
  11. Nomura DK, Morrison BE, Blankman JL, et al. Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science. 2011;334(6057):809-813. doi:10.1126/science.1209200
  12. Bisogno T, Howell F, Williams G, et al. Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol. 2003;163(3):463-468. doi:10.1083/jcb.200305129
  13. Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N. Molecular characterization of a phospholipase D generating anandamide and its congeners. J Biol Chem. 2004;279(7):5298-5305. doi:10.1074/jbc.M306642200
  14. Janssen FJ, van der Stelt M. Inhibitors of diacylglycerol lipases in neurodegenerative and metabolic disorders. Bioorg Med Chem Lett. 2016;26(16):3831-3837. doi:10.1016/j.bmcl.2016.06.076 about? 
  15. Gao Y, Vasilyev DV, Goncalves MB, et al. Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice. J Neurosci. 2010;30(6):2017-2024. doi:10.1523/JNEUROSCI.5693-09.2010
  16. Fu J, Bottegoni G, Sasso O, et al. A catalytically silent FAAH-1 variant drives anandamide transport in neurons. Nat Neurosci. 2012;15(1):64-69. doi:10.1038/nn.2986
  17. Iannotti FA, Di Marzo V, Petrosino S. Endocannabinoids and endocannabinoid-related mediators: Targets, metabolism and role in neurological disorders. Prog Lipid Res. 2016;62:107-128. doi:10.1016/j.plipres.2016.02.002 
  18. Bishnoi M, Bosgraaf CA, Abooj M, Zhong L, Premkumar LS. Streptozotocin-induced early thermal hyperalgesia is independent of glycemic state of rats: role of transient receptor potential vanilloid 1(TRPV1) and inflammatory mediators. Mol Pain. 2011;7:52. doi:10.1186/1744-8069-7-52
  19. Zygmunt PM, Petersson J, Andersson DA, et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature. 1999;400(6743):452-457. doi:10.1038/22761
  20. Starowicz K, Nigam S, Di Marzo V. Biochemistry and pharmacology of endovanilloids. Pharmacol Ther. 2007;114(1):13-33. doi:10.1016/j.pharmthera.2007.01.005
  21. Agarwal N, Pacher P, Tegeder I, et al. Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. Nat Neurosci. 2007;10(7):870-879. doi:10.1038/nn1916
  22. Smart D, Gunthorpe MJ, Jerman JC, et al. The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1). Br J Pharmacol. 2000;129(2):227-230. doi:10.1038/sj.bjp.0703050
  23. Liu Y, Mikrani R, He Y, et al. TRPM8 channels: A review of distribution and clinical role. Eur J Pharmacol. 2020;882:173312. doi:10.1016/j.ejphar.2020.173312 
  24. Bautista DM, Siemens J, Glazer JM, et al. The menthol receptor TRPM8 is the principal detector of environmental cold. Nature. 2007;448(7150):204-208. doi:10.1038/nature05910
  25. Bautista DM, Jordt SE, Nikai T, et al. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell. 2006;124(6):1269-1282. doi:10.1016/j.cell.2006.02.023
  26. Matsumura T, Hashimoto H, Sekimizu M, et al. Tranilast for advanced heart failure in patients with muscular dystrophy: a single-arm, open-label, multicenter study. Orphanet J Rare Dis. 2022;17(1):201. Published 2022 May 16. doi:10.1186/s13023-022-02352-3 
  27. Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med. 2002;53:409-35. doi: 10.1146/
  28. O’Sullivan SE. An update on PPAR activation by cannabinoids. Br J Pharmacol. 2016;173(12):1899-910. doi: 10.1111/bph.13497.
  29. Tontonoz P, Spiegelman BM. Fat and beyond: the diverse biology of PPARγ. Annu Rev Biochem. 2008;77:289-312. doi:10.1146/annurev.biochem.77.061307.091829
  30. Evans RM, Barish GD, Wang YX. PPARs and the complex journey to obesity. Nat Med. 2004;10(4):355-61. doi: 10.1038/nm1025.
  31. Wang YX. PPARs: diverse regulators in energy metabolism and metabolic diseases. Cell Res. 2010;20(2):124-37. doi: 10.1038/cr.2010.13.
  32. O’Sullivan SE, Kendall DA. Cannabinoid activation of peroxisome proliferator-activated receptors: potential for modulation of inflammatory disease. Immunobiology. 2010;215(8):611-6. doi: 10.1016/j.imbio.2009.09.007.
  33. Mayo LM, Asratian A, Linde J, Holm L, N√§tt D, Augier G, et al. Protective effects of elevated anandamide on stress and fear-related behaviors: translational evidence from humans and mice. Mol Psychiatry. 2020;25(4):993-1005. doi:10.1038/s41380-019-0448-z.
  34. Dincheva I, Drysdale AT, Hartley CA, et al. FAAH genetic variation enhances fronto-amygdala function in mouse and human. Nature. 2015;518(7540): 77-83. doi:10.1038/nature14107.
  35. Zhong P, Wang W, Pan B, et al. Monoacylglycerol lipase inhibition blocks chronic stress-induced depressive-like behaviors via activation of mTOR signaling. Neuropsychopharmacology. 2014;39(7):1763-76. doi:10.1038/npp.2014.23.
  36. Nomura DK, Morrison BE, Blankman JL, et al. Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science. 2011;334(6057):809-813. doi:10.1126/science.1209200.
  37. Zoppi S, P√©rez Nievas BG, Madrigal JL, et al. Regulatory role of the cannabinoid CB2 receptor in stress-induced neuroinflammation in mice. British Journal of Pharmacology. 2014;171(11):2814-26. doi:10.1111/bph.12642.
  38. Sartorius T, Dull RO, Rosenbaum D, et al. Peroxisome proliferator-activated receptor γ controls the outcome of chronic viral myocarditis. Circulation. 2006;114(15):1581-1589. doi:10.1161/CIRCULATIONAHA.106.621224.
  39. Di Marzo V. Targeting the endocannabinoid system: to enhance or reduce? Nat Rev Drug Discov. 2008;7(5):438-455. doi:10.1038/nrd2553.
  40. Kersten S, Desvergne B, Wahli W. Roles of PPARs in health and disease. Nature. 2000;405(6785):421-424. doi:10.1038/35013000.
  41. Wei BQ, Mikkelsen TS, McKinney MK, Lander ES, Cravatt BF. A second fatty acid amide hydrolase with variable distribution among placental mammals. J Biol Chem. 2006;281(48):36569-36578. doi:10.1074/jbc.M606646200.
  42. Bluher M. The distinction of metabolically ‘healthy’ from ‘unhealthy’ obese individuals. Curr Opin Lipidol. 2010;21(1):38-43. doi:10.1097/MOL.0b013e3283346ccc.
  43. 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 (Basel). 2021;14(12):1316. Published 2021 Dec 17. doi:10.3390/ph14121316
  44. Di Marzo V. New approaches and challenges to targeting the endocannabinoid system. Nat Rev Drug Discov. 2018;17(9):623-639. doi:10.1038/nrd.2018.115.
  45. O’Sullivan SE. Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br J Pharmacol. 2007;152(5):576-582. doi:10.1038/sj.bjp.0707412.
  46. Domi E, Uhrig S, Soverchia L, et al. Genetic Deletion of Neuronal PPARγ Enhances the Emotional Response to Acute Stress and Exacerbates Anxiety: An Effect Reversed by Rescue of Amygdala PPARγ Function. J Neurosci. 2016;36(50):12611-12623. doi:10.1523/JNEUROSCI.4127-15.2016 
  47. Piro JR, Benjamin DI, Duerr JM, et al. A Dysregulated Endocannabinoid-Eicosanoid Network Supports Pathogenesis in a Mouse Model of Alzheimer’s Disease. Cell Rep. 2012;1(6):617-623. doi:10.1016/j.celrep.2012.05.001.
  48. Nomura DK, Morrison BE, Blankman JL, et al. Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science. 2011;334(6057):809-813. doi:10.1126/science.1209200.
  49. Cristino L, Bisogno T, Di Marzo V. Cannabinoids and the expanded endocannabinoid system in neurological disorders. Nat Rev Neurol. 2020;16(1):9-29. doi:10.1038/s41582-019-0284-z.
  50. Katona I, Freund TF. Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat Med. 2008;14(9):923-930. doi:10.1038/nm.f.1869.
  51. Di Marzo V, Silvestri C. Lifestyle and metabolic syndrome: contribution of the endocannabinoidome. Nutrients. 2019;11(8):1956. doi:10.3390/nu11081956.
  52. Pertwee RG. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philos Trans R Soc Lond B Biol Sci. 2012;367(1607):3353-3363. doi:10.1098/rstb.2011.0381.
  53. Marsicano G, Lutz B. Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. Eur J Neurosci. 1999;11(12):4213-4225. doi:10.1046/j.1460-9568.1999.00847.x.
  54. Lu HC, Mackie K. An introduction to the endogenous cannabinoid system. Biol Psychiatry. 2016;79(7):516-525. doi:10.1016/j.biopsych.2015.07.028.