We also examined a form of excitatory long-term depression that is dependent on CB1 receptors (eCB-eLTD) and found that it was completely lacking in the animals that consumed EtOH during adolescence.
These findings indicate that repeated exposure to EtOH during adolescence leads to long-term deficits in CB1 receptor expression, eCB-eLTD, and reduced recognition memory, but that these functional deficits can be restored by treatments that increase endogenous 2-arachidonoylglycerol.”
“Abusive alcohol consumption is a health problem, worldwide.
There is extensive literature indicating that cannabinoid 1 receptor (CB1R) plays a crucial role in mediating alcohol’s reward effects.
Maternal care deprivation (MCD) is a reliable rodent model of early life stress that leads to high levels of anxiety and alterations in motivation, which may increase vulnerability to alcohol consumption.
The present study researched whether anxiety-like behaviors and the level of motivation for a natural reward, and CB1R expression in the prefrontal cortex (PFC) and nucleus accumbens (NAcc) can predict alcohol consumption in non-MCD and MCD male rats.
Results indicate that MCD increases anxiety-like behaviors, i.e., reduces time in open arms in the elevated plus maze and increases alcohol intake. In turn, the motivation for a palatable reward, i.e., a chocolate flavored pellet, was not affected by MCD.
MCD reduces CB1R expression in the PFC and increases it in the NAcc. Hence, both higher anxiety-like behaviors and higher CB1R expression in the NAcc and lower CB1R expression in the PFC are associated with higher alcohol intake.
These results suggest that early life adverse experiences induce a reprogramming of the brain’s endocannabinoid system that very likely contributes to making the brain vulnerable to develop alcohol abuse and dependence.”
https://www.ncbi.nlm.nih.gov/pubmed/31568767
https://www.sciencedirect.com/science/article/abs/pii/S0006899319305396?via%3Dihub
“Muscle pain affects approximately 11-24% of the global population.
Several studies have shown that exercise is a non-pharmacological therapy to pain control. It has been suggested that the endocannabinoid system is involved in this antinociceptive effect.
The present study aimed to investigate whether spinal cannabinoid CB2 receptors participate in the exercise-induced antinociception.
The present study suggests that activation of spinal cannabinoid CB2 receptors and reduction of activated microglia are involved in exercise-induced antinociception.”
https://www.ncbi.nlm.nih.gov/pubmed/31473278
https://www.sciencedirect.com/science/article/abs/pii/S0306452219306165?via%3Dihub
“Little is known about the endocannabinoid (eCB) system in squamous cell carcinoma of the oral tongue (SCCOT). Here we have investigated, at the mRNA level, expression of genes coding for the components of the eCB system in tumour and non-malignant samples from SCCOT patients. Expression of NAPEPLD and PLA2G4E, coding for eCB anabolic enzymes, was higher in the tumour tissue than in non-malignant tissue. Among genes coding for eCB catabolic enzymes, expression of MGLL was lower in tumour tissue while PTGS2 was increased. It is concluded that the eCB system may be dysfunctional in SCCOT.”
https://www.ncbi.nlm.nih.gov/pubmed/31423851
“There is good evidence that the eCB system is disrupted in cancer. The present study represents an initial investigation into the eCB system in SCCOT. In conclusion, the present study has shown that at the mRNA level, the eCB system is disturbed in SCCOT compared to non-malignant tongue tissue.”
“The endogenous lipid metabolism network is associated with the occurrence and progression of malignancies.
Endocannabinoids and ceramides have demonstrated their anti-proliferative and pro-apoptotic properties in a series of cancer studies.
The aim of the present study was to evaluate the expression patterns of endocannabinoids and endogenous ceramides in 67 pairs of human hepatocellular carcinoma (HCC) tissues and non-cancerous counterpart controls.
Anandamide (AEA), the major endocannabinoid, was reduced in tumor tissues, probably due to the high expression and activity of fatty acid amide hydrolase. Another important endocannabinoid, 2-arachidonylglycerol (2-AG), was elevated in tumor tissues compared with non-tumor controls, indicating that the biosynthesis of 2-AG is faster than the degradation of 2-AG in tumor cells.
Furthermore, western blot analysis demonstrated that cannabinoid receptor 1 was downregulated, while cannabinoid receptor 2 was elevated in HCC tissues, in accordance with the alterations in the levels of AEA and 2-AG, respectively. For HCC tissues, the expression levels of C18:0, 20:0 and 24:0-ceramides decreased significantly, whereas C12:0, 16:0, 18:1 and 24:1-ceramides were upregulated, which may be associated with cannabinoid receptor activation and stearoyl-CoA desaturase protein downregulation.
The exact role of endocannabinoids and ceramides in regulating the fate of HCC cells requires further investigation.”
https://www.ncbi.nlm.nih.gov/pubmed/31423220
https://www.spandidos-publications.com/10.3892/ol.2019.10399
“Evidence has been accumulating regarding alterations in components of the endocannabinoid system in patients with psychosis.
Of all the putative risk factors associated with psychosis, being at clinical high-risk for psychosis (CHR) has the strongest association with the onset of psychosis, and exposure to childhood trauma has been linked to an increased risk of development of psychotic disorder.
We aimed to investigate whether being at-risk for psychosis and exposure to childhood trauma were associated with altered endocannabinoid levels.
Individuals with both CHR and experience of childhood trauma had higher N-palmitoylethanolamine (p < 0.001) and anandamide (p < 0.001) levels in peripheral blood compared to healthy controls (HC) and those with no childhood trauma. There was also a significant correlation between N-palmitoylethanolamine levels and symptoms as well as childhood trauma.
Our results suggest an association between CHR and/or childhood maltreatment and elevated endocannabinoid levels in peripheral blood, with a greater alteration in those with both CHR status and history of childhood maltreatment compared to those with either of those risks alone. Furthermore, endocannabinoid levels increased linearly with the number of risk factors and elevated endocannabinoid levels correlated with the severity of CHR symptoms and extent of childhood maltreatment. Further studies in larger cohorts, employing longitudinal designs are needed to confirm these findings and delineate the precise role of endocannabinoid alterations in the pathophysiology of psychosis.”
“A large body of evidence suggests that dietary n-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), contribute to a reduced inflammatory tone thereby lowering the risk for several chronic and degenerative diseases. Different mechanisms have been proposed to explain these anti-inflammatory effects, including those involving endocannabinoids and endocannabinoid-like molecules.
In this context, fatty acid amides (FAAs), conjugates of fatty acids with amines or amino acids, are an emerging class of compounds. Dopamine conjugates of DHA (N-docosahexaenoyl dopamine, DHDA) and EPA (N-eicosapentaenoyl dopamine, EPDA) have previously been shown to induce autophagy, apoptosis, and cell death in different tumor lines. Additionally, DHDA has displayed anti-inflammatory properties in vitro.
Here, we tested the immune-modulatory properties of EPDA in mouse RAW 264.7 and human THP-1 macrophages stimulated with lipopolysaccharide (LPS). EPDA suppressed the production of monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6) in both cell lines, and nitric oxide (NO), and macrophage-inflammatory protein-3α (MIP3A) in RAW 264.7 macrophages. At a transcriptional level, EPDA attenuated cyclooxygenase-2 (COX-2) expression in both cell lines and that of MCP-1, IL-6, and interleukin-1β (IL-1β) in THP-1 macrophages.
Although further research is needed to reveal whether EPDA is an endogenous metabolite, our data suggest that this EPA-derived conjugate possesses interesting immune-modulating properties.”
“In modern lifestyle, stress and Western diets are two major environmental risk factors involved in the etiology of neuropsychiatric disorders. Lifelong interactions between stress, Western diets, and how they can affect brain physiology, remain unknown.
A possible relation between dietary long chain polyunsaturated fatty acids (PUFA), endocannabinoids, and stress is proposed.
This review suggests that both Western diets and negative stress or distress increase n-6/n-3 PUFA ratio in the phospholipids of the plasma membrane in neurons, allowing an over-activation of the endocannabinoid system in the limbic areas that control emotions. As a consequence, an excitatory/inhibitory imbalance is induced, which may affect the ability to synchronize brain areas involved in the control of stress responses. These alterations increase vulnerability to neuropsychiatric disorders.
Accordingly, dietary intake of n-3 PUFA would counter the effects of stress on the brain of stressed subjects. In conclusion, this article proposes that PUFA, endocannabinoids, and stress form a unique system which is self-regulated in limbic areas which in turn controls the effects of stress on the brain throughout a lifetime.”
“Cannabinoid receptors have been detected in human gliomas and cannabinoids have been proposed as novel drug candidates in the treatment of brain tumors.
Aim of this study was to test the in vitro antitumor activity of COR167, a novel cannabinoid CB2-selective agonist displaying high binding affinity for human CB2 receptors, on tumor cells isolated from human glioblastoma multiforme and anaplastic astrocytoma.
COR167 was found to significantly reduce the proliferation of both glioblastoma and anaplastic astrocytoma in a dose-dependent manner at lower doses than other known, less specific CB2 agonists. This activity is independent of apoptosis and is associated with significant reduction of TGF-beta 1 and 2 levels in supernatants of glioma cell cultures.
These findings add to the role of cannabinoid CB2 receptor as a possible pharmacological target to counteract glial tumor growth and encourage further work to explore any other pharmacological effect of this novel CB2 agonist useful in the treatment of human gliomas.”
“Substance use disorder (SUD) is a major public health crisis worldwide, and effective treatment options are limited.
During the past 2 decades, researchers have investigated the impact of a variety of pharmacological approaches to treat SUD, one of which is the use of medical cannabis or cannabinoids.
Significant progress was made with the discovery of rimonabant, a selective CB1 receptor (CB1R) antagonist (also an inverse agonist), as a promising therapeutic for SUDs and obesity. However, serious adverse effects such as depression and suicidality led to the withdrawal of rimonabant (and almost all other CB1R antagonists/inverse agonists) from clinical trials worldwide in 2008.
Since then, much research interest has shifted to other cannabinoid-based strategies, such as peripheral CB1R antagonists/inverse agonists, neutral CB1R antagonists, allosteric CB1R modulators, CB2R agonists, fatty acid amide hydrolase (FAAH) inhibitors, monoacylglycerol lipase (MAGL) inhibitors, fatty acid binding protein (FABP) inhibitors, or nonaddictive phytocannabinoids with CB1R or CB2R-binding profiles, as new therapeutics for SUDs.
In this article, we first review recent progress in research regarding the endocannabinoid systems, cannabis reward versus aversion, and the underlying receptor mechanisms. We then review recent progress in cannabinoid-based medication development for the treatment of SUDs.
As evidence continues to accumulate, neutral CB1R antagonists (such as AM4113), CB2R agonists (JWH133, Xie2-64), and nonselective phytocannabinoids (cannabidiol, β-caryophyllene, ∆9-tetrahydrocannabivarin) have shown great therapeutic potential for SUDs, as shown in experimental animals.
Several cannabinoid-based medications (e.g., dronabinol, nabilone, PF-04457845) that entered clinical trials have shown promising results in reducing withdrawal symptoms in cannabis and opioid users.”
https://www.ncbi.nlm.nih.gov/pubmed/31549358
https://link.springer.com/article/10.1007%2Fs40263-019-00664-w