Figure 1 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
(A) physiological processes and functions that the endocannabinoid system (ECS) takes part in. In this figure, we gathered probably the most crucial ones in terms of potential therapeutic applications, described in detail in this review; (B) components of the ECS; (C) simplified biochemical pathways of the two main endocannabinoids: 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine, also called anandamide (AEA). Blue shapes depict enzymes associated mainly with 2-AG, pink ones-with AEA. Green arrows indicate activation of specific receptors by the endocannabinoids. Abbreviations: 2-AG, 2-arachidonoylglycerol; AA, arachidonic acid; ABHD6/12, α/β hydrolase domain 6 or 12; AEA, N-arachidonoylethanolamine (anandamide); AMT, anandamide membrane transporter; CB1/2, cannabinoid receptor type 1 or 2; COX-2, cyclooxygenase 2; DAG, diacylglycerol; DAGL, diacylglycerol lipase; FAAH, fatty acid amide hydrolase; FABPs, fatty-acid-binding proteins; GPR18/55/119, G protein-coupled receptor 18 or 55 or 119; HSP70s, 70 kilodalton heat shock proteins; MAGL, monoacylglycerol lipase; NAAA, N-acylethanolamine acid amidase; NAPE, N-acylphosphatidylethanolamine; NAPE-PLD, N-acylphosphatidylethanolamine-hydrolyzing phospholipase D; OEA, oleoylethanolamine; PEA, palmitoylethanolamide; PPARγ, peroxisome proliferator-activated receptor γ; TRPV1, transient receptor potential vanilloid type 1 channel.
Source publication
The endocannabinoid system (ECS) is one of the most crucial systems in the human organism, exhibiting multi-purpose regulatory character. It is engaged in a vast array of physiological processes, including nociception, mood regulation, cognitive functions, neurogenesis and neuroprotection, appetite, lipid metabolism, as well as cell growth and prol...
Contexts in source publication
Context 1
... CB1 is present in many important peripheral organs and tissues, while CB2 is most notably in immune cells [9]. Thus, ECS takes part in a vast array of physiological processes and functions, including: mood regulation, pain management, cognitive functions, reward, appetite, fat and glucose metabolism, neurogenesis and neuroprotection, inflammation and immune functions, smooth muscle contractility, cell proliferation, and many others ( Figure 1A). Thus, ECS has been viewed as a potential therapeutic target in multiple diseases and disorders. ...
Context 2
... comprises cannabinoid receptors type 1 and 2 (CB1 and CB2), their endogenous ligands-endocannabinoids (eCBs), and enzymes responsible for eCBs' synthesis and degradation ( Figure 1B). eCBs include two main ones: 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine, better known as anandamide (AEA), but also palmitoylethanolamide (PEA), oleoylethanolamine (OEA), and others [36]. ...
Context 3
... 2-AG is synthesized by diacylglycerol lipase (DAGL) and degraded by monoacylglycerol lipase (MAGL or MGL) and α/β hydrolase domain 6 and 12 (ABHD6 and ABHD12) [37]. AEA is synthesized by N-acylphosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD) and degraded by fatty acid amide hydrolase (FAAH) [38] ( Figure 1C). Additionally, there are other proteins involved in ECS. ...
Citations
... In addition, in patients with severe disease, a tendency to reduce the level of 5-HETE was observed, which may indicate a reduced activity of 5-lipoxygenase (5-LOX) as a result of the action of prostaglandin PGE2 [54]. On the other hand, activation of CB2 receptors by inhibiting leukocyte recruitment and reducing the synthesis of pro-inflammatory cytokines, as well as lipid and ROS mediators, promotes both anti-inflammatory and antioxidant effects [55,56]. This may be an important element of the altered response of the immune system to SARS-CoV-2 infection in terminally ill patients, which is associated with an altered lipid metabolism [57]. ...
... The maximum number of patients who died within a week of admission and whose clinical parameters assessed at the time of admission were not significantly different from those of the surviving patients was 15 ( Table 1). The control group consisted of 15 healthy donors (female/male: 7/8; average age: 55 (47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)). There was no difference in the body mass index between the patients and the healthy control subjects. ...
The aim of this study was to evaluate selected parameters of redox signaling and inflammation in the granulocytes of COVID-19 patients who recovered and those who died. Upon admission, the patients did not differ in terms of any relevant clinical parameter apart from the percentage of granulocytes, which was 6% higher on average in those patients who died. Granulocytes were isolated from the blood of 15 healthy people and survivors and 15 patients who died within a week, and who were selected post hoc for analysis according to their matching gender and age. They differed only in the lethal outcome, which could not be predicted upon arrival at the hospital. The proteins level (respective ELISA), antioxidant activity (spectrophotometry), and lipid mediators (UPUPLC–MS) were measured in the peripheral blood granulocytes obtained via gradient centrifugation. The levels of Nrf2, HO-1, NFκB, and IL-6 were higher in the granulocytes of COVID-19 patients who died within a week, while the activity of cytoplasmic Cu,Zn-SOD and mitochondrial Mn-SOD and IL-2/IL-10 were lower in comparison to the levels observed in survivors. Furthermore, in the granulocytes of those patients who died, an increase in pro-inflammatory eicosanoids (PGE2 and TXB2), together with elevated cannabinoid receptors 1 and 2 (associated with a decrease in the anti-inflammatory 15d-PGJ2), were found. Hence, this study suggests that by triggering transcription factors, granulocytes activate inflammatory and redox signaling, leading to the production of pro-inflammatory eicosanoids while reducing cellular antioxidant capacity through SOD, thus expressing an altered response to COVID-19, which may result in the onset of systemic oxidative stress, ARDS, and the death of the patient.
... Depending on study parameters, the compounds show differing, sometimes biphasic, affinities and effects at different targets, thus highlighting the contradictory and equivocal evidence state. For a more extensive review on cannabinoid mechanisms of action and pharmacological effects, see these extensive reviews on the subject: Morales et al. [24], Stasiulewicz et al. [196], Almeida et al. [197], Oultram et al. [198], Vitale et al. [25], Peng et al. [199], Matheson et al. [200], Odieka et al. [71], and Castillo-Arellano et al. [26]. Abbreviations: 5-hydroxytryptamine receptor 1A (5-HT-1A); 5-hydroxytryptamine receptor 3A (5-HT-3A); adrenergic receptor alpha-1 (A1A); adrenergic receptor alpha-2 (A2A); anandamide endocannabinoid (AEA); cannabinoid receptor 1 (CB1); cannabinoid receptor 2 (CB2); delta-opioid receptor (DOR); dopamine D2 receptor (D2); fatty acid amide hydrolase enzyme (FAAH); gamma-aminobutyric acid type A receptor (GABA-A); glycine receptor (GlyR); glycine receptor type α 1 (GlyR-α1); glycine receptor type α 3 (GlyR-α3); G-protein-coupled receptor 2 (GPR2); Gprotein-coupled receptor 3 (GPR3); G-protein-coupled receptor 6 (GPR6); G-protein-coupled receptor 12 (GPR12); G-protein-coupled receptor 18 (GPR18); G-protein-coupled receptor 55 (GPR55); Mu-opioid receptor (MOR); peroxisome proliferator-activated receptor gamma (PPAR-γ); transient receptor potential cation channel type A1 (TRPA1); transient receptor potential cation channel 8 (TRPM8); transient receptor potential vanilloid type 1 (TRPV1); transient receptor potential vanilloid type 2 (TRPV2); transient receptor potential vanilloid type 3 (TRPV3); transient receptor potential vanilloid type 4 (TRPV4). ...
The ‘entourage effect’ term was originally coined in a pre-clinical study observing endogenous bio-inactive metabolites potentiating the activity of a bioactive endocannabinoid. As a hypothetical afterthought, this was proposed to hold general relevance to the usage of products based on Cannabis sativa L. The term was later juxtaposed to polypharmacy pertaining to full-spectrum medicinal Cannabis products exerting an overall higher effect than the single compounds. Since the emergence of the term, a discussion of its pharmacological foundation and relevance has been ongoing. Advocates suggest that the ‘entourage effect’ is the reason many patients experience an overall better effect from full-spectrum products. Critics state that the term is unfounded and used primarily for marketing purposes in the Cannabis industry. This scoping review aims to segregate the primary research claiming as well as disputing the existence of the ‘entourage effect’ from a pharmacological perspective. The literature on this topic is in its infancy. Existing pre-clinical and clinical studies are in general based on simplistic methodologies and show contradictory findings, with the clinical data mostly relying on anecdotal and real-world evidence. We propose that the ‘entourage effect’ is explained by traditional pharmacological terms pertaining to other plant-based medicinal products and polypharmacy in general (e.g., synergistic interactions and bioenhancement).
... Numerous studies have shown that cannabinoids can also potentially interact with other non-CB1/non-CB2 receptors, including transient receptor potential cation channels subfamily V member 1-TRPV1, which is known as capsaicin or vanilloid receptor VR1, peroxisome proliferator-activated receptors (PPARs), and GPCRs such as GPR55 and GPR119 [29]. Due to these mechanisms, cannabinoid receptors and others are involved in many biological processes, such as the regulation of mood, cognitive function, nociception, appetite, lipid metabolism, cell growth, and proliferation [30], which is the focus of researchers' studies. ...
Cannabis-derived therapies are gaining popularity in the medical world. More and more perfect forms of cannabinoids are sought, which could be used in the treatment of many common diseases, including metabolic syndrome, whose occurrence is also increasing. The purpose of this review was to investigate the usefulness of cannabinoids, mainly cannabidiol (CBD), in individuals with obesity, impaired glucose and lipid metabolism, high blood pressure, and non-alcoholic fatty liver disease (NAFLD). We summarised the most recent research on the broad topic of cannabis-derived influence on metabolic syndrome components. Since there is a lot of work on the effects of Δ9-THC (Δ9-tetrahydrocannabinol) on metabolism and far less on cannabidiol, we felt it needed to be sorted out and summarised in this review. The research results on the use of cannabidiol in obesity are contraindicatory. When it comes to glucose homeostasis, it appears that CBD maintains it, sensitises adipose tissue to insulin, and reduces fasting glucose levels, so it seems to be a potential target in this kind of metabolic disorder, but some research results are inconclusive. CBD shows some promising results in the treatment of various lipid disorders. Some studies have proven its positive effect by decreasing LDL and increasing HDL as well. Despite their probable efficacy, CBD and its derivatives will likely remain an adjunctive treatment rather than a mainstay of therapy. Studies have also shown that CBD in patients with hypertension has positive effects, even though the hypotensive properties of cannabidiol are small. However, CBD can be used to prevent blood pressure surges, stabilise them, and have a protective effect on blood vessels. Results from preclinical studies have shown that the effect of cannabidiol on NAFLD may be potentially beneficial in the treatment of the metabolic syndrome and its components. Nevertheless, there is limited data on CBD and NAFLD in human studies. Because of the numerous confounding factors, the conclusions are unclear, and more research in this field is required.
... There are additional extensions to the canonical ECS, termed the "extended" ECS, that are comprised of receptors with primary functions in other pathways that have accessory functions that exist upon interaction with cannabinoids (7,8). Some of these receptors include peroxisome proliferator activated receptors (coded by the ppara and pparg genes, respectively), "endocannabinoid-like" G-protein coupled receptors (i.e., gpr18, gpr55, and gpr119), nociception ion channels (coded by the trpv1 and trpv2 genes, respectively), and transporters (i.e., htr1a, adora2a, and adgrf1) (9,10). Though their primary functions are best characterized in other pathways, the extended ECS receptors functionally interact with endocannabinoid ligands, the phytocannabinoids present in the Cannabis plant, and other endogenous lipid mediators, including oleoyl-ethanolamide (OEA), palmitoyl-ethanolamide (PEA), and linoleoyl-ethanolamide (LEA) (9,10). ...
... Some of these receptors include peroxisome proliferator activated receptors (coded by the ppara and pparg genes, respectively), "endocannabinoid-like" G-protein coupled receptors (i.e., gpr18, gpr55, and gpr119), nociception ion channels (coded by the trpv1 and trpv2 genes, respectively), and transporters (i.e., htr1a, adora2a, and adgrf1) (9,10). Though their primary functions are best characterized in other pathways, the extended ECS receptors functionally interact with endocannabinoid ligands, the phytocannabinoids present in the Cannabis plant, and other endogenous lipid mediators, including oleoyl-ethanolamide (OEA), palmitoyl-ethanolamide (PEA), and linoleoyl-ethanolamide (LEA) (9,10). ...
The endocannabinoid system is widely expressed throughout the body and is comprised of receptors, ligands, and enzymes that maintain metabolic, immune, and reproductive homeostasis. Increasing interest in the endocannabinoid system has arisen due to these physiologic roles, policy changes leading to more widespread recreational use, and the therapeutic potential of Cannabis and phytocannabinoids. Rodents have been the primary preclinical model of focus due to their relative low cost, short gestational period, genetic manipulation strategies, and gold-standard behavioral tests. However, the potential for lack of clinical translation to non-human primates and humans is high as cross-species comparisons of the endocannabinoid system has not been evaluated. To bridge this gap in knowledge, we evaluate the relative gene expression of 14 canonical and extended endocannabinoid receptors in seven peripheral organs of C57/BL6 mice, Sprague-Dawley rats, and non-human primate rhesus macaques. Notably, we identify species- and organ-specific heterogeneity in endocannabinoid receptor distribution where there is surprisingly limited overlap among the preclinical models. Importantly, we determined there were only five receptors (CB2, GPR18, GPR55, TRPV2, and FAAH) that had identical expression patterns in mice, rats, and rhesus macaques. Our findings demonstrate a critical, yet previously unappreciated, contributor to challenges of rigor and reproducibility in the cannabinoid field, which has profound implications in hampering progress in understanding the complexity of the endocannabinoid system and development of cannabinoid-based therapies.
... Both are very promising therapeutic targets for multiple possible indications, and thus they have been the subject of a great deal of scientific interest, also regarding harnessing their potential in medicine. 3 In recent years, CB2 is becoming more eagerly explored, 4,5 in large part due to the potentially more favorable pharmacological profile of compounds modulating CB2 activity. 6 Despite multiple selective CB2 ligands having been designed, none of the drugs containing such compounds have yet reached approval. ...
... There have been numerous attempts to utilize substances acting via CBRs, especially CB1, in pharmacotherapy, including both phytocannabinoids 12 and specifically designed, synthetic compounds. 3 They proved to be effective or are studied for their potential use for multiple indications, e.g., pain, 13 nausea, 14 obesity, 15 and many others. However, as ECS is a multipurpose system, the utilization of CB1 ligands comes with a different rate or severity of adverse effects. ...
... Several drugs containing active ingredients nonselectively targeting CB1 and CB2 have already been approved. 3 CBRs' ligands present in those drugs include cannabinoids such as dronabinol (present in Marinol) 39 or nabilone (Cesamet). 40 Moreover, nabiximols, the Cannabis-based extract containing tetrahydrocannabinol and cannabidiol, is approved as Sativex. ...
Cannabinoid receptor type 2 (CB2) is a very promising therapeutic target for a variety of potential indications. However, despite the existence of multiple high affinity CB2 ligands, none have yet been approved as a drug. Therefore, it would be beneficial to explore new chemotypes of CB2 ligands. The recent elucidation of CB2 tertiary structure allows for rational hit identification with structure-based (SB) methods. In this study, we established a virtual screening workflow based on SB techniques augmented with ligand-based ones, including molecular docking, MM-GBSA binding energy calculations, pharmacophore screening, and QSAR. We screened nearly 7 million drug-like, commercially available compounds. We selected 16 molecules for in vitro evaluation and identified two novel, selective CB2 antagonists with Ki values of 65 and 210 nM. Both compounds are structurally diverse from CB2 ligands known to date. The established virtual screening protocol may prove useful for hit identification for CB2 and similar molecular targets. The two novel CB2 ligands provide a desired starting point for future optimization and development of potential drugs.
... Several reports have highlighted the ability of eCB-like molecules to bind PPARα, whose activation controls the transcription of enzymes involved in FA metabolism, e.g., elongase and SCD1, and in the metabolism of eCB-like molecules [39,40]; moreover, FBR has been identified as a cannabinoid receptor ligand (CB2) and negative allosteric modulator (CB1) [41]. This led us to investigate whether changes in FA metabolism induced by the PPARα agonist FBR were able to influence the biosynthesis of eCB-like lipid mediators [42]. In addition, we previously showed that in rodent brain slices containing the midbrain, incubated for 1 h either with the synthetic PPARα agonist WY14643 (3 μM) [40] or CLA (100 μM) [43], there was an increase of PEA and OEA levels, which we speculated may further sustain PPARα activity. ...
Fenofibrate (FBR), an oral medication used to treat dyslipidemia, is a ligand of the peroxisome proliferator-activated receptor α (PPARα), a nuclear receptor that regulates the expression of metabolic genes able to control lipid metabolism and food intake. PPARα natural ligands include fatty acids (FA) and FA derivatives such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), known to have anti-inflammatory and anorexigenic activities, respectively. We investigated changes in the FA profile and FA derivatives by HPLC and LC-MS in male C57BL/6J mice fed a standard diet with or without 0.2% fenofibrate (0.2% FBR) for 21 days. Induction of PPARα by 0.2% FBR reduced weight gain, food intake, feed efficiency, and liver lipids and induced a profound change in FA metabolism mediated by parallel enhanced mitochondrial and peroxisomal β-oxidation. The former effects led to a steep reduction of essential FA, particularly 18:3n3, with a consequent decrease of the n3-highly unsaturated fatty acids (HUFA) score; the latter effect led to an increase of 16:1n7 and 18:1n9, suggesting enhanced hepatic de novo lipogenesis with increased levels of hepatic PEA and OEA, which may activate a positive feedback and further sustain reductions of body weight, hepatic lipids and feed efficiency.
... The endocannabinoid system (ECS) is a broadly distributed network that regulates a myriad of physiological processes such as appetite, body weight, energy homeostasis, mood, pain management, neuroprotection, muscle contractility, inflammation, immune and cognitive functions, just to name a few [1][2][3][4][5]. Its alteration is implicated in a growing number of human diseases [6][7][8][9][10]; thus, to better understand the underlying mechanisms, it is justified to decipher the function and dysfunction of the ECS under these conditions. Most of the aforementioned effects are mediated via G protein-coupled receptors named cannabinoid receptors (CBRs) [11][12][13] ubiquitously expressed in the nervous (CB1R) and immune system (CB2R). ...
The endocannabinoid system (ECS) refers to a widespread signaling system and its alteration is implicated in a growing number of human diseases. Cannabinoid receptors (CBRs) are highly expressed in the central nervous system and many peripheral tissues. Evidence suggests that CB1Rs are expressed in human and murine skeletal muscle mainly in the cell membrane, but a subpopulation is present also in the mitochondria. However, very little is known about the latter population. To date, the connection between the function of CB1Rs and the regulation of intracellular Ca2+ signaling has not been investigated yet. Tamoxifen-inducible skeletal muscle-specific conditional CB1 knock-down (skmCB1-KD, hereafter referred to as Cre+/−) mice were used in this study for functional and morphological analysis. After confirming CB1R down-regulation on the mRNA and protein level, we performed in vitro muscle force measurements and found that peak twitch, tetanus, and fatigue were decreased significantly in Cre+/− mice. Resting intracellular calcium concentration, voltage dependence of the calcium transients as well as the activity dependent mitochondrial calcium uptake were essentially unaltered by Cnr1 gene manipulation. Nevertheless, we found striking differences in the ultrastructural architecture of the mitochondrial network of muscle tissue from the Cre+/− mice. Our results suggest a role of CB1Rs in maintaining physiological muscle function and morphology. Targeting ECS could be a potential tool in certain diseases, including muscular dystrophies where increased endocannabinoid levels have already been described.
... From a pharmacological perspective, the isolation of the main phytocannabinoids of C. sativa, THC and CBD in the 1960 s led to the later discovery of cannabinoid receptors and the finding of their endogenous ligands [11]. In this sense, cannabinoid type-1 (CB1) and cannabinoid type-2 (CB2) receptors were discovered in 1990 and 1993, respectively [12]. ...
The discovery of the endocannabinoid system (ECS) dates back only 30 years. Although many research groups have been elucidating its components, location, functions and metabolism, the peculiarities of the compounds considered "neurotransmitters" of ECS generate questions that have not yet been answered or controversies in the literature. In this context, we studied the molecular behaviour of the main endocannabinoid compounds and the main phytocannabinoids in eukaryotic outer and inner model membranes. The high lipophilicity of these compounds gives place to the hypothesis that cannabinoids may reach the molecular targets through the lipid bilayer. This consideration is not only for the cannabinoid receptors but also for other (many) targets that these bioactive molecules modulate (Watkins, 2019; Nelson et al., 2020; Jakowiecki and Filipek, 2016).
Given the reported multitarget action of these compounds and the differential behaviour towards the different receptors, studying the properties and dynamics of these cannabinoids in POPC and POPE model membranes become relevant.
In this regard, we have studied the differential modulation of the endocannabinoids anandamide and 2-arachidonoyl-glycerol and the phytocannabinoids cannabidiol and trans-Δ⁹-tetrahydrocannabinol to eukaryotic outer and inner model membranes. Results show that behaviours favour the mobility of the bioactive molecules studied by the external eukaryotic model membrane. As well as, the internal eukaryotic model membrane is less fluid, favouring the stabilisation of folded conformations or the positioning of the molecules in the centre of the bilayer. These results provide relevant evidence that contributes to a deep inside understanding of the behaviour of the primary endogenous ligands of ECS, together with the principal phytocannabinoids of C. sativa.
... The most promising receptors and molecular targets in the endocannabinoid system have been identified which suggests strategic targeting approaches may improve drug delivery [23]. The literature is replete with target sites in the body and activate or inhibit signal transduction pathways with endocannabinoid (EC) degrading enzyme inhibitors, EC uptake inhibitors, upregulated cannabinoid receptors (CB-R) in pathophysiological states, cannabimimetic compounds and other drugs which when taken concurrently with cannabinoids, enhance the therapeutic properties of cannabinoids [24,25]. ...
Opportunities for developing innovative and intelligent drug delivery technologies by targeting the endocannabinoid system are becoming more apparent. This review provides an overview of strategies to develop targeted drug delivery using the endocannabinoid system (ECS). Recent advances in endocannabinoid system targeting showcase enhanced pharmaceutical therapy specificity while minimizing undesirable side effects and overcoming formulation challenges associated with cannabinoids. This review identifies advances in targeted drug delivery technologies that may permit access to the full pharmacotherapeutic potential of the ECS. The design of optimized nanocarriers that target specific tissues can be improved by understanding the nature of the signaling pathways, distribution in the mammalian body, receptor structure, and enzymatic degradation of the ECS. A closer look at ligand-receptor complexes, endocannabinoid tone, tissue distribution, and G-protein activity leads to a better understanding of the potential of the ECS toolkit for therapeutics. The signal transduction pathways examine the modulation of downstream effector proteins, desensitization, signaling cascades, and biased signaling. An in-depth and overall view of the targeted system is achieved through homology modeling where mutagenesis and ligand binding examine the binding site and allow sequence analysis and the formation of libraries for molecular docking and molecular dynamic simulations. Internalization routes exploring receptor-mediated endocytosis and lipid rafts are also considered for explicit signaling. Furthermore, the review highlights nanotechnology and surface modification aspects as a possible future approach for specific targeting.
... According to the National Report on Drug Situation in 2020 -New evolution and trends (1) the recreational cannabis consumption, although having the lowest rates in Europe, preserves its ever-growing trend, thus continuing to be the most consumed drug in Romania. The most frequent consumption rate is observed in the young population, of fertile age (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34) years old), with the same sex ratio male/female 2/1, like in any other age groups. In Romania, one in 10 young adults (18-34 years old) has tried to smoke cannabis (10%), one in 20 smoked in the last year (5.8%) and 1 in 40 declared cannabis consumption when questioned (2.5%) (2). ...
... ECS is involved in multiple physiological processes, like nociception, cognitive function, mood regulation, appetite regulation, lipid metabolism, neurogenesis, neuroprotection, cell growth and proliferation etc. The receptor localization and the ligand type explain the effects of cannabinoids (26). For example, the CB 1 receptors in the hypothalamus are involved in appetite regulation, those in the amygdale cause memory effects and emotional reactions, those in the peripheral nerves act upon pain sensation. ...
... In the literature, AEA is already proposed as a potential biomarker for pregnancy progression, while the FAAH concentration in peripheral blood is considered a biomarker for infertility (69). Most recent studies focus on the treatment of reproductive dysfunctions, through the manipulation of the endocannabinoid system; nevertheless, there are numerous challenges to overcome in this direction (26), just like it is still difficult to talk about elements of the ECS as biomarkers for various physiological and pathological processes, due to their lack of specificity, with small exceptions, like the heterogeneity and complexity of the ECS. ...
