Tag Archives: endocannabinoid system

Palmitoylethanolamide as adjunctive therapy for autism: Efficacy and safety results from a randomized controlled trial.

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 Journal of Psychiatric Research Home

“Inflammation as well as glutamate excitotoxicity have been proposed to participate in the propagation of autism. Palmitoylethanolamide (PEA) is an endocannabinoid proven to prevent glutamatergic toxicity and inhibit inflammatory responses simultaneously.

The present randomized, parallel group, double-blind placebo-controlled trial is the first study depicted to probe the efficacy of co-treatment with risperidone and PEA over 10 weeks in children with autism.

Seventy children (aged 4-12 years) with autism and moderate to severe symptoms of irritability were randomly assigned to two treatment regimens. The study outcomes were measured using the Aberrant Behavior Checklist-Community Edition (ABC-C). At trial endpoint (week 10), combination of PEA and risperidone had superior efficacy in ameliorating the ABC-irritability and hyperactivity/noncompliance symptoms (Cohen’s d, 95% confidence interval (CI) = 0.94, 0.41 to 1.46, p = 0.001) compared with a risperidone plus placebo regimen. Interestingly, effect of combination treatment on hyperactivity symptoms was also observed at trial midpoint (week 5) but with a smaller effect size (d = 0.53, p = 0.04) than that at the endpoint (d = 0.94, p = 0.001). Meanwhile, there was a trend toward significance for superior effect of risperidone plus PEA over risperidone plus placebo on inappropriate speech at trial endpoint (d = 0.51, p = 0.051). No significant differences existed between the two treatment groups for the other two ABC-C subscales (lethargy/social withdrawal and stereotypic behavior).

The findings suggest that PEA may augment therapeutic effects of risperidone on autism-related irritability and hyperactivity. Future studies are warranted to investigate whether PEA can serve as a stand-alone treatment for autism.”

https://www.ncbi.nlm.nih.gov/pubmed/29807317

https://www.journalofpsychiatricresearch.com/article/S0022-3956(17)31405-X/fulltext

EFFECT OF ENDOCANNABINOID SIGNALLING ON CELL FATE: LIFE, DEATH, DIFFERENTIATION AND PROLIFERATION OF BRAIN CELLS.

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“Cell fate events are regulated by different endogenous developmental factors such as cell microenvironment, external or remote signals and epigenetic regulation. Among the many regulatory factors, endocannabinoid associated signalling pathways are known to lead several of these events in the developing nervous system and in the adult brain. Interestingly, endocannabinoids exert its modulatory actions in health and pathological conditions. Endocannabinoid signalling can promote cell survival acting on non-transformed brain cells (neurons, astrocytes or oligodendrocytes) while can either have a protumoural or antitumoural effect on transformed cells. Moreover, endocannabinoids are able to attenuate detrimental effects on neurogenesis and neuroinflammation associated with ageing. Thus, the endocannabinoid system emerges as an important regulator of cell fate to control cell survival/cell death decisions depending on the cell type and its environment.”

https://www.ncbi.nlm.nih.gov/pubmed/29797438

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14369

The Pharmacological Inhibition of Fatty Acid Amide Hydrolase Prevents Excitotoxic Damage in the Rat Striatum: Possible Involvement of CB1 Receptors Regulation.

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Molecular Neurobiology

“The endocannabinoid system (ECS) actively participates in several physiological processes within the central nervous system.

Among such, its involvement in the downregulation of the N-methyl-D-aspartate receptor (NMDAr) through a modulatory input at the cannabinoid receptors (CBr) has been established. After its production via the kynurenine pathway (KP), quinolinic acid (QUIN) can act as an excitotoxin through the selective overactivation of NMDAr, thus participating in the onset and development of neurological disorders.

In this work, we evaluated whether the pharmacological inhibition of fatty acid amide hydrolase (FAAH) by URB597, and the consequent increase in the endogenous levels of anandamide, can prevent the excitotoxic damage induced by QUIN. URB597 (0.3 mg/kg/day × 7 days, administered before, during and after the striatal lesion) exerted protective effects on the QUIN-induced motor (asymmetric behavior) and biochemical (lipid peroxidation and protein carbonylation) alterations in rats.

URB597 also preserved the structural integrity of the striatum and prevented the neuronal loss (assessed as microtubule-associated protein-2 and glutamate decarboxylase localization) induced by QUIN (1 μL intrastriatal, 240 nmol/μL), while modified the early localization patterns of CBr1 (CB1) and NMDAr subunit 1 (NR1).

Altogether, these findings support the concept that the pharmacological manipulation of the endocannabinoid system plays a neuroprotective role against excitotoxic insults in the central nervous system.”

 https://www.ncbi.nlm.nih.gov/pubmed/29802570
https://link.springer.com/article/10.1007%2Fs12035-018-1129-2

Endocannabinoid CB1 receptors are involved in antiepileptogenic effect of low frequency electrical stimulation during perforant path kindling in rats.

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Epilepsy Research

“Administration of low-frequency electrical stimulation (LFS) at the kindling site has an antiepileptogenic effect. In the present study, we investigated the role of cannabinoid receptors type 1 (CB1) in mediating the inhibitory effects of LFS on the development of perforant path kindled seizures.

RESULTS:

Application of LFS had inhibitory effect on development of kindled seizures (kindling rate). Microinjection of AM281 (0.5 μg/μl) immediately after the last kindling stimulation (before LFS application) reduced the inhibitory effect of LFS on the kindling rate and suppressed the effects of LFS on potentiation (increasing the magnitude) of both population spike amplitude and population excitatory postsynaptic potential slope during kindling acquisition. AM281 pretreatment also prevented the effects of LFS on kindling-induced increase in early and late paired pulse depression. The higher dose of AM281 (2 μg/μl) failed to exert the effects observed with its lower dose (0.5 μg/μl). In addition, there was a decreased CB1 receptors immunostaining in kindled animals compared to control. However, application of LFS following kindling stimulations led to overexpression of CB1 receptors in the dentate gyrus.

CONCLUSION:

Obtained results showed that activation of overexpressed cannabinoid CB1 receptors by endogenous cannabinoids may have a role in mediating the inhibitory effect of LFS on perforant path kindled seizures.”

https://www.ncbi.nlm.nih.gov/pubmed/29800824

https://www.sciencedirect.com/science/article/pii/S0920121117304291?via%3Dihub

An overview of the cannabinoid type 2 receptor system and its therapeutic potential.

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“This narrative review summarizes recent insights into the role of the cannabinoid type 2 (CB2) receptor as potential therapeutic target in neuropathic pain and neurodegenerative conditions.

RECENT FINDINGS:

The cannabinoid system continues to receive attention as a therapeutic target. The CB2 receptor is primarily expressed on glial cells only when there is active inflammation and appears to be devoid of undesired psychotropic effects or addiction liability. The CB2 receptor has been shown to have potential as a therapeutic target in models of diseases with limited or no currently approved therapies, such as neuropathic pain and neurodegenerative conditions such as Alzheimer’s disease.

SUMMARY:

The functional involvement of CB2 receptor in neuropathic pain and other neuroinflammatory diseases highlights the potential therapeutic role of drugs acting at the CB2 receptor.”

https://www.ncbi.nlm.nih.gov/pubmed/29794855

https://insights.ovid.com/crossref?an=00001503-900000000-98981

Effects of exercise on experimentally manipulated craving for cannabis: A preliminary study.

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“Cannabis is the most commonly used illicit drug in the United States, and craving for cannabis is related to cannabis use.

Exercise has been demonstrated to reduce craving for substances.

The findings suggest that moderate exercise may be useful for reducing craving, particularly among those who use larger quantities of cannabis.”

 https://www.ncbi.nlm.nih.gov/pubmed/29792472

http://psycnet.apa.org/doiLanding?doi=10.1037%2Fpha0000200

“Exercise activates the endocannabinoid system.”  https://www.ncbi.nlm.nih.gov/pubmed/14625449

“Aerobic exercise training reduces cannabis craving and use in non-treatment seeking cannabis-dependent adults.”  https://www.ncbi.nlm.nih.gov/pubmed/21408154

Endocannabinoid system and pathophysiology of adipogenesis: current management of obesity.

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“The endocannabinoids are now known as novel and important regulators of energy metabolism and homeostasis.

The endocrine functions of white adipose are chiefly involved in the control of whole-body metabolism, insulin sensitivity and food intake. Adipocytes produce hormones, such as leptin and adiponectin, that can improve insulin resistance or peptides, such as TNF-α, that elicit insulin resistance. Adipocytes express specific receptors, such as peroxisome proliferator-activated receptor (PPAR)-γ, which serve as adipocyte targets for insulin sensitizers such as thiazolidinediones.

Recently, endocannabinoids and related compounds were identified in human fat cells.

The endocannabinoid system consists primarily of two receptors, cannabinoid (CB)1 and CB2, their endogenous ligands termed endocannabinoids and the enzymes responsible for ligand biosynthesis and degradation.

The endocannabinoids 2-arachidonylglycerol and anandamide or N-arachidonoylethanolamine increase food intake and promote weight gain in animals. Rimonabant, a selective CB1 blocker, reduces food intake and body weight in animals and humans.”

 https://www.ncbi.nlm.nih.gov/pubmed/29788669
https://www.futuremedicine.com/doi/10.2217/17410541.4.3.307

Involvement of the CB2 cannabinoid receptor in cell growth inhibition and G0/G1 cell cycle arrest via the cannabinoid agonist WIN 55,212-2 in renal cell carcinoma.

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“The anti-tumor properties of cannabinoids have been investigated in many in vitro and in vivo studies. Many of these anti-tumor effects are mediated via cannabinoid receptor types 1 and 2 (CB1 and CB2), comprising the endocannabinoid system (ECS).

In this study, we investigated the ECS based on CB 1 and CB 2 receptor gene and protein expression in renal cell carcinoma (RCC) cell lines. In view of their further use for potential treatments, we thus investigated the roles of CB1 and CB2 receptors in the anti-proliferative action and signal transduction triggered by synthetic cannabinoid agonists [such as JWH-133 and WIN 55,212-2 (WIN-55)] in RCC cell lines.

RESULTS:

The CB1 and CB2 genes expression was shown by real-time PCR and flow cytometric and western blot analysis indicating a higher level of CB2 receptor as compared to CB1 in RCC cells. Immunocytochemical staining also confirmed the expression of the CB1 and CB2 proteins. We also found that the synthetic cannabinoid agonist WIN-55 exerted anti-proliferative and cytotoxic effects by inhibiting the growth of RCC cell lines, while the CB2 agonist JWH-133 did not. Pharmacologically blocking the CB1 and CB2 receptors with their respective antagonists SR141716A and AM-630, followed by the WIN-55 treatment of RCC cells allowed uncovering the involvement of CB2, which led to an arrest in the G0/G1 phase of the cell cycle and apoptosis.

CONCLUSIONS:

This study elucidated the involvement of CB2 in the in vitro inhibition of RCC cells, and future applications of CB2agonists in the prevention and management of RCC are discussed.

In summary, our study shows the involvement of CB2 receptor in the in vitro inhibition of RCC cells. This knowledge will be useful to unravel the future applications of CB2receptor and its agonists in the prevention and management of RCC.”

 https://www.ncbi.nlm.nih.gov/pubmed/29792186
https://bmccancer.biomedcentral.com/articles/10.1186/s12885-018-4496-1

Pharmacological properties of cannabidiol in the treatment of psychiatric disorders: a critical overview.

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“Cannabidiol (CBD) represents a new promising drug due to a wide spectrum of pharmacological actions. In order to relate CBD clinical efficacy to its pharmacological mechanisms of action, we performed a bibliographic search on PUBMED about all clinical studies investigating the use of CBD as a treatment of psychiatric symptoms.

Findings to date suggest that (a) CBD may exert antipsychotic effects in schizophrenia mainly through facilitation of endocannabinoid signalling and cannabinoid receptor type 1 antagonism; (b) CBD administration may exhibit acute anxiolytic effects in patients with generalised social anxiety disorder through modification of cerebral blood flow in specific brain sites and serotonin 1A receptor agonism; (c) CBD may reduce withdrawal symptoms and cannabis/tobacco dependence through modulation of endocannabinoid, serotoninergic and glutamatergic systems; (d) the preclinical pro-cognitive effects of CBD still lack significant results in psychiatric disorders.

In conclusion, current evidences suggest that CBD has the ability to reduce psychotic, anxiety and withdrawal symptoms by means of several hypothesised pharmacological properties. However, further studies should include larger randomised controlled samples and investigate the impact of CBD on biological measures in order to correlate CBD’s clinical effects to potential modifications of neurotransmitters signalling and structural and functional cerebral changes.”

https://www.ncbi.nlm.nih.gov/pubmed/29789034

https://www.cambridge.org/core/journals/epidemiology-and-psychiatric-sciences/article/pharmacological-properties-of-cannabidiol-in-the-treatment-of-psychiatric-disorders-a-critical-overview/D7FD68F40CF30CBB48A1025C66873F26

Novel therapeutic applications of cannabinoids in cancer disease

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oatext

“The present review shows that cannabinoids exert their anti-cancer effects in a number of ways and in a variety of tissues.

The endocannabinoid system is an almost ubiquitous signalling system involved in the control of cell fate. Recent studies have investigated the possibility that drugs targeting the endocannabinoid system might be used to retard or block cancer growth.

The endocannabinoids have been shown to inhibit the growth of tumour cells in culture and animal models by modulating key cell signalling pathways. Therefore, the present review indicated that cannabinoids exert their anti-cancer effects in a number of ways and in a variety of tissues.

  • Triggering cell death, through a mechanism called apoptosis
  • Stopping cells from dividing
  • Preventing new blood vessels from growing into tumours
  • Reducing the chances of cancer cells spreading through the body, by stopping cells from moving or invading neighbouring tissue
  • Speeding up the cell’s internal ‘waste disposal machine’ – a process known as autophagy – which can lead to cell death

Furthermore, the novel therapeutic application of cannabinoids in cancer disease, described here, strongly support the idea that cannabinoids may induce benefical effect in cancer treatment.”

http://www.oatext.com/novel-therapeutic-applications-of-cannabinoids-in-cancer-disease.php