Advanced analytical approaches for endocannabinoids and en-docannabinoid-like substances: Applications in liver disease research

Jun-Yi Zhou; Yan-Qing Chen; Hai-Yu Zhao; Jian-Bo Wan

doi:10.1016/j.jpha.2026.101546

Article Contents

Article Navigation > Journal of Pharmaceutical Analysis > 2026 > Accepted Manu

Jun-Yi Zhou, Yan-Qing Chen, Hai-Yu Zhao, Jian-Bo Wan. Advanced analytical approaches for endocannabinoids and en-docannabinoid-like substances: Applications in liver disease research[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2026.101546

Citation:

Jun-Yi Zhou, Yan-Qing Chen, Hai-Yu Zhao, Jian-Bo Wan. Advanced analytical approaches for endocannabinoids and en-docannabinoid-like substances: Applications in liver disease research[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2026.101546

Citation:

Jun-Yi Zhou, Yan-Qing Chen, Hai-Yu Zhao, Jian-Bo Wan. Advanced analytical approaches for endocannabinoids and en-docannabinoid-like substances: Applications in liver disease research[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2026.101546

PDF( 26548 KB)

Advanced analytical approaches for endocannabinoids and en-docannabinoid-like substances: Applications in liver disease research

doi: 10.1016/j.jpha.2026.101546

a. The State Key Laboratory of Mechanism and Quality of Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, 999078, China;
b. Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China

Funds:

The work was financially supported by grants from the Research Committee of the University of Macau, Macao SAR, China (Grant No.: MYRG-GRG2024-00097-ICMS-UMDF) and the Science and Technology Development Fund, Macao SAR, China (File Nos. 0070/2025/AFJ and 005/2023/SKL). Fig. 3 and Graphical abstract were drawn by using BioRender.com.

Received Date: Jul. 11, 2025
Accepted Date: Jan. 03, 2026
Rev Recd Date: Jan. 03, 2026
Available Online: Jan. 06, 2026

Abstract

Abstract

Endocannabinoids (eCBs) and eCB-like substances are lipid mediators that play vital roles in regulating diverse physiological and pathological processes. These effects are predominantly mediated through interactions with cannabinoid receptors (CBRs), particularly CB1R and CB2R. Due to their typically low concentrations in biological samples, the development of precise and efficient analytical methods is essential for accurate quantification. The liver serves as a critical site of eCB activity, where dysregulation of eCB levels has been associated with various liver diseases. This review focuses on recent advancements in sample preparation and analytical techniques for eCBs and eCB-like substances from 2017 to 2024, providing a comprehensive evaluation of their strengths and limitations. Additionally, the roles of eCBs in liver lipid metabolism and their involvement in pathological processes are explored in detail. eCBs and eCB-like substances hold promise as diagnostic biomarkers, offering significant potential for applications in both basic research and clinical practice.
- Endocannabinoid-like substances,
- Endocannabinoids,
- Endocannabinoid system,
- Liver diseases,
- Mass spectrometry,
- N-acylethanolamines

FullText(HTML)

References(150)

References

[1]	H.C. Lu, K. Mackie, Review of the endocannabinoid system, Biol. Psychiatry Cogn. Neurosci. Neuroimaging 6 (2021) 607-615.
[2]	N. Joshi, E.S. Onaivi, Endocannabinoid system components: Overview and tissue distribution, Adv. Exp. Med. Biol. 1162 (2019) 1-12.
[3]	Y. Gaoni, R. Mechoulam, Isolation, structure, and partial synthesis of an active constituent of hashish, J. Am. Chem. Soc. 86 (1964) 1646-1647.
[4]	S.S. Hu, K. Mackie, Distribution of the endocannabinoid system in the central nervous system, Handb. Exp. Pharmacol. 231 (2015) 59-93.
[5]	S. Galiegue, S. Mary, J. Marchand, et al., Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations, Eur. J. Biochem. 232 (1995) 54-61.
[6]	R. Witkamp, Fatty acids, endocannabinoids and inflammation, Eur. J. Pharmacol. 785 (2016) 96-107.
[7]	R.J. Silver, The endocannabinoid system of animals, Animals 9 (2019), 686.
[8]	W.A. Devane, L. Hanus, A. Breuer, et al., Isolation and structure of a brain constituent that binds to the cannabinoid receptor, Science 258 (1992) 1946-1949.
[9]	C. Lanz, J. Mattsson, F. Stickel, et al., Determination of the endocannabinoids anandamide and 2-arachidonoyl glycerol with gas chromatography-mass spectrometry: Analytical and preanalytical challenges and pitfalls, Med. Cannabis Cannabinoids 1 (2018) 9-18.
[10]	L. Chu, S.F. Liu, Y. Wu, et al., Hair levels of steroid, endocannabinoid, and the ratio biomarkers predict viral suppression among people living with HIV/AIDS in China, Clin. Chim. Acta 535 (2022) 143-152.
[11]	T. Restin, N. Byland, C.D. Voegel, et al., Endocannabinoid and steroid analysis in infant and adult nails by LC-MS/MS, Anal. Bioanal. Chem. 414 (2022) 6201-6211.
[12]	M. Ita, J. Kelly, Characterization of cerebral cortical endocannabinoid levels in a rat inguinal surgery model using liquid chromatography-tandem mass spectrometry (LC-MS/MS), Ir. J. Psychol. Med. 39 (2022) 54-63.
[13]	M.B. Wiley, P.A. Perez, D.A. Argueta, et al., UPLC-MS/MS method for analysis of endocannabinoid and related lipid metabolism in mouse mucosal tissue, Front. Physiol. 12 (2021), 699712.
[14]	M. Rossmeisl, J. Pavlisova, P. Janovska, et al., Differential modulation of white adipose tissue endocannabinoid levels by n-3 fatty acids in obese mice and type 2 diabetic patients, Biochim. Biophys. Acta BBA Mol. Cell Biol. Lipids 1863 (2018) 712-725.
[15]	A. Paquot, J. Bestard-Escalas, G.G. Muccioli, Set up and validation of a sensitive method to quantify prostaglandins, prostaglandin-glycerol esters and prostaglandin-ethanolamides, as well as their respective precursors, Prostaglandins Other Lipid Mediat. 168 (2023), 106763.
[16]	P. Datta, M.W. Melkus, K. Rewers-Felkins, et al., Human Milk Endocannabinoid Levels as a Function of Obesity and Diurnal Rhythm, Nutrients 13 (2021), 2297.
[17]	I.G.C. Oliveira, I.D. de Souza, J.A. de Souza de Crippa, et al., A disposable pipette extraction-UHPLC-MS/MS method based on removal of phospholipids to determine anandamide, 2-arachidonoylglycerol, cannabidiol, and Δ9-tetrahydrocannabidiol in plasma samples, J. Sep. Sci. 48 (2025), e70068.
[18]	E. Aydin, M. Cebo, J. Mielnik, et al., UHPLC-ESI-MS/MS assay for quantification of endocannabinoids in cerebrospinal fluid using surrogate calibrant and surrogate matrix approaches, J. Pharm. Biomed. Anal. 222 (2023), 115090.
[19]	L.J. Ney, K.L. Felmingham, R. Bruno, et al., Simultaneous quantification of endocannabinoids, oleoylethanolamide and steroid hormones in human plasma and saliva, J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 1152 (2020), 122252.
[20]	J. Fernandez de Luco, G. Prez, B. Hernandez Cravero, et al., Synthesis of a Deuterated Standard for the Quantification of 2-Arachidonoylglycerol in Caenorhabditis elegans, J. Vis. Exp. 151 (2019), e59882.
[21]	R. Lerner, B. Lutz, L. Bindila, Tricks and tracks in the identification and quantification of endocannabinoids, eLS. (2013) 1-10.
[22]	A.A. Zoerner, F.-M. Gutzki, S. Batkai, et al., Quantification of endocannabinoids in biological systems by chromatography and mass spectrometry: a comprehensive review from an analytical and biological perspective, Biochim. Biophys. Acta BBA Mol. Cell Biol. Lipids 1811 (2011) 706-723.
[23]	W.S. Ho, D.A. Barrett, M.D. Randall, ‘Entourage’ effects of N-palmitoylethanolamide and N-oleoylethanolamide on vasorelaxation to anandamide occur through TRPV1 receptors, Br. J. Pharmacol. 155 (2008) 837-846.
[24]	L. Cristino, T. Bisogno, V. Di Marzo, Cannabinoids and the expanded endocannabinoid system in neurological disorders, Nat. Rev. Neurol. 16 (2020) 9-29.
[25]	F.J. Janssen, M.P. Baggelaar, J.J.A. Hummel, et al., Comprehensive analysis of structure-activity relationships of α-ketoheterocycles as sn-1-diacylglycerol lipase α inhibitors, J. Med. Chem. 58 (2015) 9742-9753.
[26]	P. Urquhart, A. Nicolaou, D.F. Woodward, Endocannabinoids and their oxygenation by cyclo-oxygenases, lipoxygenases and other oxygenases, Biochim. Biophys. Acta BBA Mol. Cell Biol. Lipids 1851 (2015) 366-376.
[27]	L. Gabrielsson, S. Mattsson, C.J. Fowler, Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy, Br. J. Clin. Pharmacol. 82 (2016) 932-942.
[28]	H. Tutunchi, A. Ostadrahimi, M. Saghafi-Asl, et al., Oleoylethanolamide supplementation in obese patients newly diagnosed with non-alcoholic fatty liver disease: Effects on metabolic parameters, anthropometric indices, and expression of PPAR-α, UCP1, and UCP2 genes, Pharmacol. Res. 156 (2020), 104770.
[29]	R. Tovar, M. de Ceglia, M. Ubaldi, et al., Administration of linoleoylethanolamide reduced weight gain, dyslipidemia, and inflammation associated with high-fat-diet-induced obesity, Nutrients 15 (2023), 4448.
[30]	B. Yang, L. Lin, R.P. Bazinet, et al., Clinical efficacy and biological regulations of ω-3 PUFA-derived endocannabinoids in major depressive disorder, Psychother. Psychosom. 88 (2019) 215-224.
[31]	T. Park, H. Chen, H.Y. Kim, GPR110 (ADGRF1) mediates anti-inflammatory effects of N-docosahexaenoylethanolamine, J. Neuroinflammation 16 (2019), 225.
[32]	J. Sihag, V. Di Marzo, (Wh)olistic (E)ndocannabinoidome-Microbiome-Axis modulation through (N)utrition (WHEN) to curb obesity and related disorders, Lipids Health Dis 21 (2022), 9.
[33]	J.Y. Zhou, Y.Q. Chen, G. Hu, et al., An integrated strategy for in-depth profiling of N-acylethanolamines in biological samples by UHPLC-HRMS, Anal. Chim. Acta 1329 (2024), 343262.
[34]	J.Y. Huang, P. Lv, Y.Z. Lian, et al., Construction of machine learning tools to predict threatened miscarriage in the first trimester based on AEA, progesterone and β-hCG in China: a multicentre, observational, case-control study, BMC Pregnancy Childbirth 22 (2022), 697.
[35]	M.Y. Zhang, Y. Gao, J. Btesh, et al., Simultaneous determination of 2-arachidonoylglycerol, 1-arachidonoylglycerol and arachidonic acid in mouse brain tissue using liquid chromatography/tandem mass spectrometry, J. Mass Spectrom. 45 (2010) 167-177.
[36]	T.L. Pedersen, I.J. Gray, J.W. Newman, Plasma and serum oxylipin, endocannabinoid, bile acid, steroid, fatty acid and nonsteroidal anti-inflammatory drug quantification in a 96-well plate format, Anal. Chim. Acta 1143 (2021) 189-200.
[37]	M. Bobrich, R. Schwarz, R. Ramer, et al., A simple LC-MS/MS method for the simultaneous quantification of endocannabinoids in biological samples, J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 1161 (2020), 122371.
[38]	S. Casati, C. Giannasi, M. Minoli, et al., Quantitative lipidomic analysis of osteosarcoma cell-derived products by UHPLC-MS/MS, Biomolecules 10 (2020), 1302.
[39]	I.G.C. Oliveira, M.E.C. Queiroz, A micro salting-out assisted liquid-liquid extraction combined with ultra-high performance liquid chromatography tandem mass spectrometry to determine anandamide and 2-arachidonoylglycerol in rat brain samples, J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 1158 (2020), 122351.
[40]	A.R. Reuter, J.M. Bumb, J.K. Mueller, et al., Association of anandamide with altered binocular depth inversion illusion in schizophrenia, World J. Biol. Psychiatry 18 (2017) 483-488.
[41]	L. Ney, C. Stone, D. Nichols, et al., Endocannabinoid reactivity to acute stress: Investigation of the relationship between salivary and plasma levels, Biol. Psychol. 159 (2021), 108022.
[42]	G. Kra, J.R. Daddam, U. Moallem, et al., Effects of environmental heat load on endocannabinoid system components in adipose tissue of high yielding dairy cows, Animals 12 (2022), 795.
[43]	B. Ramesh, N. Manjula, S.R. Bijargi, et al., Comparison of conventional and supported liquid extraction methods for the determination of sitagliptin and simvastatin in rat plasma by LC-ESI-MS/MS, J. Pharm. Anal. 5 (2015) 161-168.
[44]	M.E.C. Queiroz, I.D. de Souza, I.G. de Oliveira, et al., In vivo solid phase microextraction for bioanalysis, Trends Analyt. Chem. 153 (2022), 116656.
[45]	X. Kou, G. Chen, S. Huang, et al., In vivo sampling: A promising technique for detecting and profiling endogenous substances in living systems, J. Agric. Food Chem. 67 (2019) 2120-2126.
[46]	I.D. Souza, L.W. Hantao, M.E.C. Queiroz, Polymeric ionic liquid open tubular capillary column for on-line in-tube SPME coupled with UHPLC-MS/MS to determine endocannabinoids in plasma samples, Anal. Chim. Acta 1045 (2019) 108-116.
[47]	L.F.C. Miranda, R.R. Goncalves, M.E.C. Queiroz, A dual ligand sol-gel organic-silica hybrid monolithic capillary for in-tube sPME-MS/MS to determine amino acids in plasma samples, Molecules 24 (2019), 1658.
[48]	V.R. Acquaro Junior, G.A. Gomez-Rios, M. Tascon, et al., Analysis of endocannabinoids in plasma samples by biocompatible solid-phase microextraction devices coupled to mass spectrometry, Anal. Chim. Acta 1091 (2019) 135-145.
[49]	C. Montesano, G. Vannutelli, V. Piccirilli, et al., Application of a rapid μ-SPE clean-up for multiclass quantitative analysis of sixteen new psychoactive substances in whole blood by LC-MS/MS, Talanta 167 (2017) 260-267.
[50]	F. Fanti, F. Vincenti, G. Imparato, et al., Determination of endocannabinoids and their conjugated congeners in the brain by means of μSPE combined with UHPLC-MS/MS, Talanta 257 (2023), 124392.
[51]	C. Di Meo, D. Tortolani, S. Standoli, et al., Effects of rare phytocannabinoids on the endocannabinoid system of human keratinocytes, Int. J. Mol. Sci. 23 (2022), 5430.
[52]	W. Gao, A. Walther, M. Wekenborg, et al., Determination of endocannabinoids and N-acylethanolamines in human hair with LC-MS/MS and their relation to symptoms of depression, burnout, and anxiety, Talanta 217 (2020), 121006.
[53]	D. Luque-Cordoba, M. Calderon-Santiago, M.D. Luque de Castro, et al., Study of sample preparation for determination of endocannabinoids and analogous compounds in human serum by LC-MS/MS in MRM mode, Talanta 185 (2018) 602-610.
[54]	C. Marchioni, I.D. de Souza, C.F. Grecco, et al., A column switching ultrahigh-performance liquid chromatography-tandem mass spectrometry method to determine anandamide and 2-arachidonoylglycerol in plasma samples, Anal. Bioanal. Chem. 409 (2017) 3587-3596.
[55]	C. Sempio, J. Klawitter, M. Jackson, et al., Analysis of 14 endocannabinoids and endocannabinoid congeners in human plasma using column switching high-performance atmospheric pressure chemical ionization liquid chromatography-mass spectrometry, Anal. Bioanal. Chem. 413 (2021) 3381-3392.
[56]	M. Hammarlund-Udenaes, Microdialysis as an important technique in systems pharmacology: A historical and methodological review, AAPS J. 19 (2017) 1294-1303.
[57]	V.I. Chefer, A.C. Thompson, A. Zapata, et al., Overview of brain microdialysis, Curr. Protoc. Neurosci. 47 (2009) 7.1. 1-7.1. 28.
[58]	A. Serrano, F.J. Pavon, M.W. Buczynski, et al., Deficient endocannabinoid signaling in the central amygdala contributes to alcohol dependence-related anxiety-like behavior and excessive alcohol intake, Neuropsychopharmacology 43 (2018) 1840-1850.
[59]	F. Xia, J.B. Wan, Chemical derivatization strategy for mass spectrometry-based lipidomics, Mass Spectrom. Rev. 42 (2023) 432-452.
[60]	Y.Q. Chen, H. Shen, R.J. Yang, et al., Accurate quantification of endogenous N-acylethanolamides by chemical isotope labeling coupled with liquid chromatography-tandem mass spectrometry, Anal. Chim. Acta 1179 (2021), 338839.
[61]	W.B. Liu, W.-D. Zhang, T.Z. Li, et al., Four-dimensional untargeted profiling of N-acylethanolamine lipids in the mouse brain using ion mobility-mass spectrometry, Anal. Chem. 94 (2022) 12472-12480.
[62]	J. Ding, X.T. Luo, Y.R. Yao, et al., Investigation of changes in endocannabinoids and N-acylethanolamides in biofluids, and their correlations with female infertility, J. Chromatogr. A 1509 (2017) 16-25.
[63]	M.L. Zhu, X.W. Xu, Y.L. Hou, et al., Boronic derivatization of monoacylglycerol and monitoring in biofluids, Anal. Chem. 91 (2019) 6724-6729.
[64]	M.L. Zhu, K.G. Lu, Y.T. Jin, et al., Boronic derivatization-based strategy for monoacylglycerol identification, isomer annotation and quantification, Anal. Chim. Acta 1190 (2022), 339233.
[65]	D. Kratz, D. Thomas, R. Gurke, Endocannabinoids as potential biomarkers: It’s all about pre-analytics, J. Mass Spectrom. Adv. Clin. Lab 22 (2021) 56-63.
[66]	W. Rohrig, S. Achenbach, B. Deutsch, et al., Quantification of 24 circulating endocannabinoids, endocannabinoid-related compounds, and their phospholipid precursors in human plasma by UHPLC-MS/MS, J. Lipid Res. 60 (2019) 1475-1488.
[67]	P. Poznanski, J. Giebultowicz, J. Durdzinska, et al., Mechanisms underlining inflammatory pain sensitivity in mice selected for high and low stress-induced analgesia: The role of endocannabinoids and microglia, Int. J. Mol. Sci. 23 (2022), 11686.
[68]	B. Maria, S. Beata, Optimization and validation of online column-switching assisted HPLC-spectrometric method for quantification of dansylated endocannabinoids and neurotransmitters in animal models of brain diseases, Open J. Anal. Bioanal. Chem. 3 (2019) 83-93.
[69]	T. Lange, T. Depmeier, T. Strunker, et al., HPLC fluorescence assay for measuring the activity of NAPE-PLD and the action of inhibitors affecting this enzyme, J. Pharm. Biomed. Anal. 229 (2023), 115354.
[70]	E.M.P. Silva, A. Vitiello, A. Miro, et al., Recent HPLC-UV approaches for cannabinoid analysis: From extraction to method validation and quantification compliance, Pharmaceuticals 18 (2025), 786.
[71]	Y.S. Jung, Y.H. Kim, K. Radhakrishnan, et al., An inverse agonist of estrogen-ted receptor γ regulates 2-arachidonoylglycerol synthesis by modulating diacylglycerol lipase expression in alcohol-intoxicated mice, Arch. Toxicol. 94 (2020) 427-438.
[72]	T. Obata, Y. Sakurai, Y. Kase, et al., Simultaneous determination of endocannabinoids (arachidonylethanolamide and 2-arachidonylglycerol) and isoprostane (8-epiprostaglandin F2alpha) by gas chromatography-mass spectrometry-selected ion monitoring for medical samples, J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 792 (2003) 131-140.
[73]	A. Fontana, V. Di Marzo, H. Cadas, et al., Analysis of anandamide, an endogenous cannabinoid substance, and of other natural N-acylethanolamines, Prostaglandins Leukot. Essent. Fat. Acids 53 (1995) 301-308.
[74]	K. Kempe, F.F. Hsu, A. Bohrer, et al., Isotope dilution mass spectrometric measurements indicate that arachidonylethanolamide, the proposed endogenous ligand of the cannabinoid receptor, accumulates in rat brain tissue post mortem but is contained at low levels in or is absent from fresh tissue, J. Biol. Chem. 271 (1996) 17287-17295.
[75]	R. Abohalaka, T.E. Bozkurt, T. Recber, et al., The effects of systemic and local fatty acid amide hydrolase and monoacylglycerol lipase inhibitor treatments on the metabolomic profile of lungs, Biomed. Chromatogr. 36 (2022), e5231.
[76]	S.M. Daryanavard, H. Zolfaghari, A. Abdel-Rehim, et al., Recent applications of microextraction sample preparation techniques in biological samples analysis, Biomed. Chromatogr. 35 (2021), e5105.
[77]	A. Garcia-Ac, P.A. Segura, L. Viglino, et al., Comparison of APPI, APCI and ESI for the LC-MS/MS analysis of bezafibrate, cyclophosphamide, enalapril, methotrexate and orlistat in municipal wastewater, J. Mass Spectrom. 46 (2011) 383-390.
[78]	E. Flament, J.M. Gaulier, N. Paret, et al., Application to several suspected poisoning cases of a validated analytical method for the determination of muscarine in human biological matrices using liquid chromatography with high-resolution mass spectrometry detection, Drug Test Anal. 16 (2024) 331-338.
[79]	H. Li, Q. Qin, X.Z. Shi, et al., Modified metabolites mapping by liquid chromatography-high resolution mass spectrometry using full scan/all ion fragmentation/neutral loss acquisition, J. Chromatogr. A 1583 (2019) 80-87.
[80]	V. Kantae, S. Ogino, M. Noga, et al., Quantitative profiling of endocannabinoids and related N-acylethanolamines in human CSF using nano LC-MS/MS, J. Lipid Res. 58 (2017) 615-624.
[81]	B.S. He, X.Y. Di, F. Guled, et al., Quantification of endocannabinoids in human cerebrospinal fluid using a novel micro-flow liquid chromatography-mass spectrometry method, Anal. Chim. Acta 1210 (2022), 339888.
[82]	Y. Yu, C.L. Yao, J.Q. Zhang, et al., Profiling the chemical differences of diterpenoid alkaloids in different processed products of Aconiti Lateralis Radix Praeparata by UHPLC-LTQ-Orbitrap mass spectrometry combined with untargeted metabolomics and mass spectrometry imaging, Chin. J. Nat. Med. 23 (2025) 1009-1015.
[83]	A. Islam, E. Takeyama, M.M. Nabi, et al., Stress upregulates 2-arachidonoylglycerol levels in the hypothalamus, midbrain, and hindbrain, and it is sustained by green nut oil supplementation in SAMP8 mice revealed by DESI-MSI, Biochem. Biophys. Res. Commun. 609 (2022) 9-14.
[84]	Q. Zhai, A. Islam, B. Chen, et al., Endocannabinoid 2-arachidonoylglycerol levels in the anterior cingulate cortex, caudate putamen, nucleus accumbens, and piriform cortex were upregulated by chronic restraint stress, Cells 12 (2023), 393.
[85]	E. Gonzalez de San Roman, A. Llorente-Ovejero, J. Martinez-Gardeazabal, et al., Modulation of neurolipid signaling and specific lipid species in the triple transgenic mouse model of Alzheimer’s disease, Int. J. Mol. Sci. 22 (2021), 12256.
[86]	E. Salviati, F. Guida, D. La Gioia, et al., Enhanced visualization of endocannabinoids spatial distribution in mouse brain via MALDI-2 mass spectrometry imaging, Talanta 290 (2025), 127811.
[87]	A. Mobed, F. Kohansal, A. Ahmadalipour, et al., Bioconjugation of 2-arachidonoyl glycerol (2-AG) biotinylated antibody with gold nano-flowers toward immunosensing of 2-AG in human plasma samples: A novel immuno-platform for the screening of immunomodulation and neuroprotection using biosensing, Anal. Methods 13 (2021) 311-321.
[88]	F. Kohansal, A. Mobed, R. Ansari, et al., An innovative electrochemical immuno-platform towards ultra-sensitive monitoring of 2-arachidonoyl glycerol in samples from rats with sleep deprivation: Bioanalysis of endogenous cannabinoids using biosensor technology, RSC Adv. 12 (2022) 14154-14166.
[89]	N. Aletaha, K. Ghaseminasab, M. Hasanzadeh, et al., An innovative sandwich type biosensor towards sensitive and selective monitoring of 2-arachidonoylglycerol in human plasma samples using P(β-CD)-AuNPs-DDT as amplificant agent: A new immuno-platform for the recognition of endocannabinoids in real samples, Biosensors 12 (2022), 791.
[90]	S. Grasso, M. Santonico, G. Pennazza, et al., BIONOTE as an innovative biosensor for measuring endocannabinoid levels, Sensors 21 (2021), 489.
[91]	H. Bazyar, K. Nasiri, P. Ghanbari, et al., Circulating endocannabinoid levels in pregnant women with gestational diabetes mellitus: A case-control study, BMC Endocr. Disord. 22 (2022), 268.
[92]	I. Forner-Piquer, C. Giommi, F. Sella, et al., Endocannabinoid system and metabolism: The influences of sex, Int. J. Mol. Sci. 25 (2024), 11909.
[93]	T. Karasu, T.H. Marczylo, M. Maccarrone, et al., The role of sex steroid hormones, cytokines and the endocannabinoid system in female fertility, Hum. Reprod. Update 17 (2011) 347-361.
[94]	P. Nidadavolu, A. Bilkei-Gorzo, F. Effah, et al., Dynamic changes in the endocannabinoid system during the aging process: Focus on the middle-age crisis, Int. J. Mol. Sci. 23 (2022), 10254.
[95]	J. Fernández-Ruiz, O. Sagredo, M. Gómez-Ruiz, et al., Ageing, neurodegeneration and the endocannabinoid system, Current Topics in Behavioral Neurosciences, Springer, Berlin, 2025, pp. 1–40.
[96]	E.C. Hanlon, E. Tasali, R. Leproult, et al., Circadian rhythm of circulating levels of the endocannabinoid 2-arachidonoylglycerol, J. Clin. Endocrinol. Metab. 100 (2015) 220-226.
[97]	L.K. Vaughn, G. Denning, K.L. Stuhr, et al., Endocannabinoid signalling: Has it got rhythm, Br. J. Pharmacol. 160 (2010) 530-543.
[98]	W. Mazier, N. Saucisse, B. Gatta-Cherifi, et al., The endocannabinoid system: Pivotal orchestrator of obesity and metabolic disease, Trends Endocrinol. Metab. 26 (2015) 524-537.
[99]	A. Mallat, S. Lotersztajn, Endocannabinoids and liver disease. I. Endocannabinoids and their receptors in the liver, Am. J. Physiol. Gastrointest. Liver Physiol. 294 (2008) G9-G12.
[100]	T. Auguet, A. Berlanga, E. Guiu-Jurado, et al., Endocannabinoid receptors gene expression in morbidly obese women with nonalcoholic fatty liver disease, BioMed. Res. Int. 2014 (2014), 502542.
[101]	F. Teixeira-Clerc, M.P. Belot, S. Manin, et al., Beneficial paracrine effects of cannabinoid receptor 2 on liver injury and regeneration, Hepatology 52 (2010) 1046-1059.
[102]	A. Guillot, N. Hamdaoui, A. Bizy, et al., Cannabinoid receptor 2 counteracts interleukin-17-induced immune and fibrogenic responses in mouse liver, Hepatology 59 (2014) 296-306.
[103]	Y. Ishii, T. Sakamoto, R. Ito, et al., F2-isoprostanes and 2-arachidonylglycerol as biomarkers of lipid peroxidation in pigs with hepatic ischemia/reperfusion injury, J. Surg. Res. 161 (2010) 139-145.
[104]	X.J. Qian, W.Z. Liu, Y. Chen, et al., A UPLC-MS/MS method for simultaneous determination of arachidonic acid, stearic acid, and related endocannabinoids in human plasma, Heliyon 10 (2024), e28467.
[105]	S. Zelber-Sagi, S. Azar, A. Nemirovski, et al., Serum levels of endocannabinoids are independently associated with nonalcoholic fatty liver disease, Obesity 25 (2017) 94-101.
[106]	Y.F. Chen, Z.K. Fan, X. Gao, et al., n-3 polyunsaturated fatty acids in phospholipid or triacylglycerol form attenuate nonalcoholic fatty liver disease via mediating cannabinoid receptor 1/adiponectin/ceramide pathway, J. Nutr. Biochem. 123 (2024), 109484.
[107]	J. Westerbacka, A. Kotronen, B.A. Fielding, et al., Splanchnic balance of free fatty acids, endocannabinoids, and lipids in subjects with nonalcoholic fatty liver disease, Gastroenterology 139 (2010) 1961-1971.
[108]	W.T. Kimberly, J.F. O’Sullivan, A.K. Nath, et al., Metabolite profiling identifies anandamide as a biomarker of nonalcoholic steatohepatitis, JCI Insight 2 (2017), e92989.
[109]	Z. Zajkowska, A. Borsini, N. Nikkheslat, et al., Differential effect of interferon-alpha treatment on AEA and 2-AG levels, Brain Behav. Immun. 90 (2020) 248-258.
[110]	E. Patsenker, P. Sachse, A. Chicca, et al., Elevated levels of endocannabinoids in chronic hepatitis C may modulate cellular immune response and hepatic stellate cell activation, Int. J. Mol. Sci. 16 (2015) 7057-7076.
[111]	E. Patsenker, A. Chicca, V. Petrucci, et al., 4-O’-methylhonokiol protects from alcohol/carbon tetrachloride-induced liver injury in mice, J. Mol. Med. 95 (2017) 1077-1089.
[112]	P. Caraceni, A. Viola, F. Piscitelli, et al., Circulating and hepatic endocannabinoids and endocannabinoid-related molecules in patients with cirrhosis, Liver Int. 30 (2010) 816-825.
[113]	S.V. Siegmund, T. Qian, S. de Minicis, et al., The endocannabinoid 2-arachidonoyl glycerol induces death of hepatic stellate cells via mitochondrial reactive oxygen species, FASEB J. 21 (2007) 2798-2806.
[114]	A. Floreani, D. Pizzuti, N.V. Bergasa, et al., The endocannabinoid system in cholestasis, Dig. Liver Dis. 43 (2011) 1026-1027.
[115]	K.T. Suk, I. Mederacke, G.Y. Gwak, et al., Opposite roles of cannabinoid receptors 1 and 2 in hepatocarcinogenesis, Gut 65 (2016) 1721-1732.
[116]	J.Y. Yang, Y.F. Tian, R.H. Zheng, et al., Endocannabinoid system and the expression of endogenous ceramides in human hepatocellular carcinoma, Oncol. Lett. 18 (2019) 1530-1538.
[117]	L.N. Zhou, L.L. Ding, P.Y. Yin, et al., Serum metabolic profiling study of hepatocellular carcinoma infected with hepatitis B or hepatitis C virus by using liquid chromatography-mass spectrometry, J. Proteome Res. 11 (2012) 5433-5442.
[118]	Y. Avraham, E. Israeli, E. Gabbay, et al., Endocannabinoids affect neurological and cognitive function in thioacetamide-induced hepatic encephalopathy in mice, Neurobiol. Dis. 21 (2006) 237-245.
[119]	M. Rajesh, H. Pan, P. Mukhopadhyay, et al., Cannabinoid-2 receptor agonist HU-308 protects against hepatic ischemia/reperfusion injury by attenuating oxidative stress, inflammatory response, and apoptosis, J. Leukoc. Biol. 82 (2007) 1382-1389.
[120]	S. Batkai, D. Osei-Hyiaman, H. Pan, et al., Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury, FASEB J. 21 (2007) 1788-1800.
[121]	K. Yang, S.E. Choi, W.I. Jeong, Hepatic cannabinoid signaling in the regulation of alcohol-associated liver disease, Alcohol Res. Curr. Rev. 41 (2021), 12.
[122]	G. Lavanco, V. Castelli, A. Brancato, et al., The endocannabinoid-alcohol crosstalk: Recent advances on a bi-faceted target, Clin. Exp. Pharmacol. Physiol. 45 (2018) 889-896.
[123]	A.P. Levene, R.D. Goldin, The epidemiology, pathogenesis and histopathology of fatty liver disease, Histopathology 61 (2012) 141-152.
[124]	R. Tian, J. Yang, X. Wang, et al., Honokiol acts as an AMPK complex agonist therapeutic in non-alcoholic fatty liver disease and metabolic syndrome, Chin. Med. 18 (2023), 30.
[125]	M.J. Watt, P.M. Miotto, W. De Nardo, et al., The liver as an endocrine organ: Linking NAFLD and insulin resistance, Endocr. Rev. 40 (2019) 1367-1393.
[126]	G.G. Martin, D. Landrock, L.J. Dangott, et al., Human liver fatty acid binding protein-1 T94A variant, nonalcohol fatty liver disease, and hepatic endocannabinoid system, Lipids 53 (2018) 27-40.
[127]	W.T. Cheng, S.Y. Pei, J. Wu, et al., Cannabinoid-2 receptor depletion promotes non-alcoholic fatty liver disease in mice via disturbing gut microbiota and tryptophan metabolism, Acta Pharmacol. Sin. 46 (2025) 1676-1691.
[128]	W.Y. Deng, F. Chen, Y. Zhao, et al., Anti-hepatitis B virus activities of natural products and their antiviral mechanisms, Chin. J. Nat. Med. 21 (2023) 803-811.
[129]	Y.A. Lee, M.C. Wallace, S.L. Friedman, Pathobiology of liver fibrosis: A translational success story, Gut 64 (2015) 830-841.
[130]	J.J. Heidelbaugh, M. Bruderly, Cirrhosis and chronic liver failure: Part I. Diagnosis and evaluation, Am. Fam. Physician 74 (2006) 756-762.
[131]	E. Patsenker, M. Stoll, G. Millonig, et al., Cannabinoid receptor type I modulates alcohol-induced liver fibrosis, Mol. Med. 17 (2011) 1285-1294.
[132]	J.G. Chen, S.W. Zhang, Liver cancer epidemic in China: Past, present and future, Semin. Cancer Biol. 21 (2011) 59-69.
[133]	N. Ebrahimi, N.P. Far, S.S. Fakhr, et al., The endocannabinoid system, a new gatekeeper in the pharmacology of human hepatocellular carcinoma, Environ. Res. 228 (2023), 115914.
[134]	W.M. Choi, H.H. Kim, M.H. Kim, et al., Glutamate signaling in hepatic stellate cells drives alcoholic steatosis, Cell Metab. 30 (2019) 877-889.
[135]	L. Huang, M.A. Quinn, G.A. Frampton, et al., Recent advances in the understanding of the role of the endocannabinoid system in liver diseases, Dig. Liver Dis. 43 (2011) 188-193.
[136]	Y. Dagon, Y. Avraham, Y. Ilan, et al., Cannabinoids ameliorate cerebral dysfunction following liver failure via AMP-activated protein kinase, FASEB J 21 (2007) 2431-2441.
[137]	S.W. Nam, H. Liu, J.Z. Wong, et al., Cardiomyocyte apoptosis contributes to pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated mice, Clin. Sci. 127 (2014) 519-526.
[138]	F.J. Pavon, A. Serrano, M. Romero-Cuevas, et al., Oleoylethanolamide: A new player in peripheral control of energy metabolism. Therapeutic implications, Drug Discov. Today Dis. Mech. 7 (2010) e175-e183.
[139]	M. Baldassarre, F.A. Giannone, L. Napoli, et al., The endocannabinoid system in advanced liver cirrhosis: Pathophysiological implication and future perspectives, Liver Int. 33 (2013) 1298-1308.
[140]	J. Ros, J. Claria, J. To-Figueras, et al., Endogenous cannabinoids: A new system involved in the homeostasis of arterial pressure in experimental cirrhosis in the rat, Gastroenterology 122 (2002) 85-93.
[141]	M.M. Aranha, H. Cortez-Pinto, A. Costa, et al., Bile acid levels are increased in the liver of patients with steatohepatitis, Eur. J. Gastroenterol. Hepatol. 20 (2008) 519-525.
[142]	L. Moezi, M. Rezayat, M. Samini, et al., Potentiation of anandamide effects in mesenteric beds isolated from bile duct-ligated rats: Role of nitric oxide, Eur. J. Pharmacol. 486 (2004) 53-59.
[143]	Y. Avraham, I. Magen, O. Zolotarev, et al., 2-Arachidonoylglycerol, an endogenous cannabinoid receptor agonist, in various rat tissues during the evolution of experimental cholestatic liver disease, Prostaglandins Leukot. Essent. Fat. Acids 79 (2008) 35-40.
[144]	A. Makol, K.D. Watt, V.R. Chowdhary, Autoimmune hepatitis: A review of current diagnosis and treatment, Hepat. Res. Treat 2011 (2011), 390916.
[145]	V.L. Hegde, S. Hegde, B.F. Cravatt, et al., Attenuation of experimental autoimmune hepatitis by exogenous and endogenous cannabinoids: Involvement of regulatory T cells, Mol. Pharmacol. 74 (2008) 20-33.
[146]	M. Sabahi, S.A. Ahmadi, A. Kazemi, et al., The effect of oleoylethanolamide (OEA) add-on treatment on inflammatory, oxidative stress, lipid, and biochemical parameters in the acute ischemic stroke patients: Randomized double-blind placebo-controlled study, Oxid. Med. Cell Longev. 2022 (2022), 5721167.
[147]	L. Li, L. Li, L. Chen, et al., Effect of oleoylethanolamide on diet-induced nonalcoholic fatty liver in rats, J. Pharmacol. Sci. 127 (2015) 244-250.
[148]	L. Chen, L. Li, J.D. Chen, et al., Oleoylethanolamide, an endogenous PPAR-α ligand, attenuates liver fibrosis targeting hepatic stellate cells, Oncotarget 6 (2015) 42530-42540.
[149]	A. Romano, M. Friuli, L. Del Coco, et al., Chronic oleoylethanolamide treatment decreases hepatic triacylglycerol level in rat liver by a PPARγ/SREBP-mediated suppression of fatty acid and triacylglycerol synthesis, Nutrients 13 (2021), 394.
[150]	Q. Yang, H.Y. Liu, Y.W. Zhang, et al., Anandamide induces cell death through lipid rafts in hepatic stellate cells, J. Gastroenterol. Hepatol. 25 (2010) 991-1001.