Cannabidiol as a potential treatment for psychosis

Image result for therapeutic advances in psychopharmacology“Accumulating evidence implicates the endocannabinoid system in the pathophysiology of psychosis.

If the endocannabinoid system plays a role in psychosis pathophysiology, it raises the interesting possibility that pharmacological compounds that modulate this system may have therapeutic value.

Cannabidiol (CBD), a phytocannabinoid constituent of Cannabis sativa, has been heralded as one such potential treatment.

Cannabidiol (CBD), a non-intoxicating constituent of the cannabis plant, has emerged as a potential novel class of antipsychotic with a unique mechanism of action.

In this review, we set out the prospects of CBD as a potential novel treatment for psychotic disorders.

In sum, CBD currently represents a promising potential novel treatment for patients with psychosis.”

https://journals.sagepub.com/doi/10.1177/2045125319881916

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Relieving tension: effects of cannabinoids on vagal afferent sensitivity.

Publication cover image“Endocannabinoids are produced within the gastrointestinal (GI) tract and modulate energy homeostasis and food intake, at least in part, via vagally-dependent actions. The recent paper by Christie et al., [Christie, et al. J Physiol, 2019] demonstrate, for the first time, that cannabinoids exert biphasic effects on the mechanosensitivity of tension-sensitive gastric vagal afferents. At higher concentrations, anandamide increased vagal afferent sensitivity in a CB1 and TRPV1 receptor dependent manner. At lower concentrations, however, anandamide decreased afferent mechanosensitivity; while this was also dependent upon CB1 and TRPV1 receptors, it also appeared dependent upon signaling via the potent orexigenic neurohormone, ghrelin. These results provide further evidence to support the remarkable degree of neuroplasticity within vagal afferent signaling, and suggest that untangling the complex interactions of cannabinoid effects on food intake and energy homeostasis will require careful physiological and pharmacological investigations.”

https://www.ncbi.nlm.nih.gov/pubmed/31707736

https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/JP279173

“A clear understanding of the mechanisms which mediate these events may provide novel therapeutic targets for the treatment of gastrointestinal disorders due to vago-vagal pathway malfunctions.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318799/

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Cannabidiol increases the nociceptive threshold in a preclinical model of Parkinson’s disease.

Neuropharmacology

“Medications that improve pain threshold can be useful in the pharmacotherapy of Parkinson’s disease (PD). Pain is a prevalent PD’s non-motor symptom with a higher prevalence of analgesic drugs prescription for patients. However, specific therapy for PD-related pain are not available.

Since the endocannabinoid system is expressed extensively in different levels of pain pathway, drugs designed to target this system have promising therapeutic potential in the modulation of pain. Thus, we examined the effects of the 6-hydroxydopamine- induced PD on nociceptive responses of mice and the influence of cannabidiol (CBD) on 6-hydroxydopamine-induced nociception.

Further, we investigated the pathway involved in the analgesic effect of the CBD through the co-administration with a fatty acid amide hydrolase (FAAH) inhibitor, increasing the endogenous anandamide levels, and possible targets from anandamide, i.e., the cannabinoid receptors subtype 1 and 2 (CB1 and CB2) and the transient receptor potential vanilloid type 1 (TRPV1).

We report that 6-hydroxydopamine- induced parkinsonism decreases the thermal and mechanical nociceptive threshold, whereas CBD (acute and chronic treatment) reduces this hyperalgesia and allodynia evoked by 6-hydroxydopamine. Moreover, ineffective doses of either FAAH inhibitor or TRPV1 receptor antagonist potentialized the CBD-evoked antinociception while an inverse agonist of the CB1 and CB2 receptor prevented the antinociceptive effect of the CBD.

Altogether, these results indicate that CBD can be a useful drug to prevent the parkinsonism-induced nociceptive threshold reduction. They also suggest that CB1 and TRPV1 receptors are important for CBD-induced analgesia and that CBD could produce these analgesic effects increasing endogenous anandamide levels.”

https://www.ncbi.nlm.nih.gov/pubmed/31706993

“The CBD treatment decreases hyperalgesia and allodynia in experimental parkinsonism.”

https://www.sciencedirect.com/science/article/pii/S0028390819303703?via%3Dihub

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Bone Anabolic Response in the Calvaria Following Mild Traumatic Brain Injury is Mediated by the Cannabinoid-1 Receptor.

 Scientific Reports“Brain trauma was clinically associated with increased osteogenesis in the appendicular skeleton. We showed previously in C57BL/6J mice that mild traumatic brain injury (mTBI) transiently induced bone formation in the femur via the cannabinoid-1 (CB1) receptor. Here, we subjected ICR mice to mTBI and examined the bone response in the skull using microCT. We also measured mast cell degranulation (MCD)72 h post-injury. Finally, we measured brain and calvarial endocannabinoids levels post-mTBI. mTBI led to decreased bone porosity on the contralateral (untouched) side. This effect was apparent both in young and mature mice. Administration of rimonabant (CB1 inverse agonist) completely abrogated the effect of mTBI on calvarial porosity and significantly reduced MCD, compared with vehicle-treated controls. We also found that mTBI resulted in elevated levels of anandamide, but not 2-arachidonoylglycerol, in the contralateral calvarial bone, whereas brain levels remained unchanged. In C57BL/6J CB1 knockout mice, mTBI did not reduce porosity but in general the porosity was significantly lower than in WT controls. Our findings suggest that mTBI induces a strain-specific CB1-dependent bone anabolic response in the skull, probably mediated by anandamide, but seemingly unrelated to inflammation. The endocannabinoid system is therefore a plausible target in management of bone response following head trauma.”

https://www.ncbi.nlm.nih.gov/pubmed/31700010

https://www.nature.com/articles/s41598-019-51720-w

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The Expanded Endocannabinoid System/Endocannabinoidome as a Potential Target for Treating Diabetes Mellitus.

 “The endocannabinoid (eCB) system, i.e. the receptors that respond to the psychoactive component of cannabis, their endogenous ligands and the ligand metabolic enzymes, is part of a larger family of lipid signals termed the endocannabinoidome (eCBome). We summarize recent discoveries of the roles that the eCBome plays within peripheral tissues in diabetes, and how it is being targeted, in an effort to develop novel therapeutics for the treatment of this increasingly prevalent disease.

RECENT FINDINGS:

As with the eCB system, many eCBome members regulate several physiological processes, including energy intake and storage, glucose and lipid metabolism and pancreatic health, which contribute to the development of type 2 diabetes (T2D). Preclinical studies increasingly support the notion that targeting the eCBome may beneficially affect T2D. The eCBome is implicated in T2D at several levels and in a variety of tissues, making this complex lipid signaling system a potential source of many potential therapeutics for the treatments for T2D.”

https://www.ncbi.nlm.nih.gov/pubmed/31686231

https://link.springer.com/article/10.1007%2Fs11892-019-1248-9

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Anticancer effects of n-3 EPA and DHA and their endocannabinoid derivatives on breast cancer cell growth and invasion.

Prostaglandins, Leukotrienes and Essential Fatty Acids Home“The anticancer effects of the omega-3 long chain polyunsaturated fatty acids (LCPUFA), EPA and DHA may be due, at least in part, to conversion to their respective endocannabinoid derivatives, eicosapentaenoyl-ethanolamine (EPEA) and docosahexaenoyl-ethanolamine (DHEA).

Here, the effects of EPEA and DHEA and their parent compounds, EPA and DHA, on breast cancer (BC) cell function was examined. EPEA and DHEA exhibited greater anti-cancer effects than EPA and DHA in two BC cells (MCF-7 and MDA-MB-231) whilst displaying no effect in non-malignant breast cells (MCF-10a).

Both BC lines expressed CB1/2 receptors that were responsible, at least partly, for the observed anti-proliferative effects of the omega-3 endocannabinoids as determined by receptor antagonism studies. Additionally, major signalling mechanisms elicited by these CB ligands included altered phosphorylation of p38-MAPK, JNK, and ERK proteins.

Both LCPUFAs and their endocannabinoids attenuated the expression of signal proteins in BC cells, albeit to different extents depending on cell type and lipid effectors. These signal proteins are implicated in apoptosis and attenuation of BC cell migration and invasiveness.

Furthermore, only DHA reduced in vitro MDA-MB-231 migration whereas both LCPUFAs and their endocannabinoids significantly inhibited invasiveness. This finding was consistent with reduced integrin β3 expression observed with all treatments and reduced MMP-1 and VEGF with DHA treatment.

Attenuation of cell viability, migration and invasion of malignant cells indicates a potential adjunct nutritional therapeutic use of these LCPUFAs and/or their endocannabinoids in treatment of breast cancer.”

https://www.ncbi.nlm.nih.gov/pubmed/31679810

https://www.plefa.com/article/S0952-3278(19)30112-7/fulltext

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Endocannabinoid System Alterations in Posttraumatic Stress Disorder: A Review of Developmental and Accumulative Effects of Trauma.

 Image result for sage journals chronic stress“The role of the endocannabinoid system in stress-related psychiatric symptoms has been investigated in many animal and human studies.

Although most of these studies consistently report long-lasting effects of prolonged stress and trauma on the endocannabinoid system, the nature and direction of these changes are controversial.

We reviewed the available preclinical and clinical studies investigating the endocannabinoid system alterations long after chronic stress and trauma.

We propose that the effects of prolonged stress or trauma on the endocannabinoid system are different based on the developmental age of subjects at the time of experiencing the trauma and its repetitiveness and accumulative effects.

The current literature consistently demonstrates decreased levels of endocannabinoid ligands and receptors if the trauma occurs in childhood, whereas decreased levels of endocannabinoid ligands and increased levels of cannabinoid receptors are reported when trauma has happened in adulthood.

It is important to note that these changes are region-specific in the brain and also there are important sex differences, which are beyond the scope of this review.”

https://www.ncbi.nlm.nih.gov/pubmed/31660473

“More studies are needed to compare the effects of childhood and adulthood trauma, with or without PTSD presentations, on the eCB system. These studies would have important clinical implications, not only for individuals with trauma and PTSD who commonly have comorbid recreational cannabis use, and medical marijuana users with PTSD being one of its main indicators but also for studies investigating the potential therapeutic use of cannabinoids and eCB enhancers in PTSD treatment.”

https://journals.sagepub.com/doi/10.1177/2470547019864096

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Roles of the Hepatic Endocannabinoid and Apelin Systems in the Pathogenesis of Liver Fibrosis.

cells-logo“Hepatic fibrosis is the consequence of an unresolved wound healing process in response to chronic liver injury and involves multiple cell types and molecular mechanisms. The hepatic endocannabinoid and apelin systems are two signalling pathways with a substantial role in the liver fibrosis pathophysiology-both are upregulated in patients with advanced liver disease. Endogenous cannabinoids are lipid-signalling molecules derived from arachidonic acid involved in the pathogenesis of cardiovascular dysfunction, portal hypertension, liver fibrosis, and other processes associated with hepatic disease through their interactions with the CB1 and CB2 receptors. Apelin is a peptide that participates in cardiovascular and renal functions, inflammation, angiogenesis, and hepatic fibrosis through its interaction with the APJ receptor. The endocannabinoid and apelin systems are two of the multiple cell-signalling pathways involved in the transformation of quiescent hepatic stellate cells into myofibroblast like cells, the main matrix-producing cells in liver fibrosis. The mechanisms underlying the control of hepatic stellate cell activity are coincident despite the marked dissimilarities between the endocannabinoid and apelin signalling pathways. This review discusses the current understanding of the molecular and cellular mechanisms by which the hepatic endocannabinoid and apelin systems play a significant role in the pathophysiology of liver fibrosis.”

https://www.ncbi.nlm.nih.gov/pubmed/31653030

https://www.mdpi.com/2073-4409/8/11/1311

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Medical Marijuana Guidelines for Practice: Health Policy Implications.

Journal of Pediatric Health Care Home“Cannabis use in pediatric health care remains limited, however, there is increasing evidence on the pharmacologic benefits of medical marijuana for chronic conditions in childhood. Realizing the need for guidance in practice, the National Council of State Boards of Nursing (NCSBN) published guidelines to aid in decision making in nursing practice. While focusing primarily on adult use of cannabis, the guidelines do address special populations such as children and adolescents. This article reviews the endocannabinoid system, current state of legislation on medical marijuana, policy considerations, recent FDA approval of a cannabis product for pediatric use, NCSBN National Nursing Guidelines for Medical Marijuana, and pediatric implications for nursing practice.”

https://www.ncbi.nlm.nih.gov/pubmed/31655786

https://www.jpedhc.org/article/S0891-5245(19)30399-2/fulltext

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A time-dependent contribution of hippocampal CB1, CB2, and PPARγ receptors to cannabidiol-induced disruption of fear memory consolidation.

Publication cover image“Preclinical studies have shown that cannabidiol (CBD) mitigates fear memories by facilitating their extinction or interfering with their generalization and reconsolidation. The brain regions and mechanisms underlying these effects, and their temporal window, are still poorly understood. The present paper aimed at investigating related questions in the dorsal hippocampus (DH) during contextual fear consolidation.

KEY RESULTS:

CBD impaired memory consolidation when given immediately or 1 h after fear conditioning, but not after 3 h. The DH Arc expression was reduced by systemic CBD treatment in both cases. Immediately after fear conditioning, the CBD effect was abolished by CB1 or CB2 receptor blockade, partly reduced by 5-HT1A or A2A antagonism, and remained unchanged after antagonism of PPARγ receptors. 1 h after fear conditioning, the CBD effect was only prevented by PPARγ receptor antagonism. Besides, the FAAH inhibition impaired memory consolidation when URB597 was infused immediately, but not 1 hour after fear conditioning.

CONCLUSIONS AND IMPLICATIONS:

CBD disrupts memory consolidation up to 1 h after fear conditioning, allowing an extended window of opportunity to mitigate aversive memories after their acquisition. The results suggest time-dependent participation of DH anandamide, CB1, CB2, and PPARγ receptors in this process.”

https://www.ncbi.nlm.nih.gov/pubmed/31648363

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14895

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