Roles of Cannabinoids in Melanoma: Evidence from In Vivo Studies

ijms-logo“Melanoma is the fourth most common type of cancer diagnosed in Australians after breast, prostate, and colorectal cancers. While there has been substantial progress in the treatment of cancer in general, malignant melanoma, in particular, is resistant to existing medical therapies requiring an urgent need to develop effective treatments with lesser side effects.

Several studies have shown that “cannabinoids”, the major compounds of the Cannabis sativaL. plant, can reduce cell proliferation and induce apoptosis in melanoma cells.

Despite prohibited use of Cannabis in most parts of the world, in recent years there have been renewed interests in exploiting the beneficial health effects of the Cannabis plant-derived compounds. Therefore, the aim of this study was in the first instance to review the evidence from in vivo studies on the effects of cannabinoids on melanoma.

The findings revealed cannabinoids, individually or combined, reduced tumor growth and promoted apoptosis and autophagy in melanoma cells.

Further preclinical and animal studies are required to determine the underlying mechanisms of cannabinoids-mediated inhibition of cancer-signaling pathways. Well-structured, randomized clinical studies on cannabinoid use in melanoma patients would also be required prior to cannabinoids becoming a viable and recognized therapeutic option for melanoma treatment in patients.”

https://pubmed.ncbi.nlm.nih.gov/32839414/

https://www.mdpi.com/1422-0067/21/17/6040

Cannabinoids for People with ASD: A Systematic Review of Published and Ongoing Studies

brainsci-logo“The etiopathogenesis of autism spectrum disorder (ASD) remains largely unclear.

Among other biological hypotheses, researchers have evidenced an imbalance in the endocannabinoid (eCB) system, which regulates some functions typically impaired in ASD, such as emotional responses and social interaction. Additionally, cannabidiol (CBD), the non-intoxicating component of Cannabis sativa, was recently approved for treatment-resistant epilepsy.

Epilepsy represents a common medical condition in people with ASD. Additionally, the two conditions share some neuropathological mechanisms, particularly GABAergic dysfunctions. Hence, it was hypothesized that cannabinoids could be useful in improving ASD symptoms.

The findings were promising, as cannabinoids appeared to improve some ASD-associated symptoms, such as problem behaviors, sleep problems, and hyperactivity, with limited cardiac and metabolic side effects. Conversely, the knowledge of their effects on ASD core symptoms is scarce.

Interestingly, cannabinoids generally allowed to reduce the number of prescribed medications and decreased the frequency of seizures in patients with comorbid epilepsy. Mechanisms of action could be linked to the excitatory/inhibitory imbalance found in people with ASD. However, further trials with better characterization and homogenization of samples, and well-defined outcomes should be implemented.”

https://pubmed.ncbi.nlm.nih.gov/32825313/

https://www.mdpi.com/2076-3425/10/9/572

Cannabis, More Than the Euphoria: Its Therapeutic Use in Drug-Resistant Epilepsy

 See the source image“A significant number of epilepsy patients are refractory to conventional antiepileptic drugs. These patients experience considerable neurocognitive impairments that impact their quality of life and ability to function independently. This need for alternative treatment has generated increased interest in cannabis use as a therapeutic option in these patients.

This review seeks to analyze data presented on the pharmacology, safety, and efficacy of cannabis use in patients with drug-resistant epilepsy (DRE) and to propose any future recommendations regarding its use.

The two foremost phytocannabinoids of cannabis showing anticonvulsant properties are tetrahydrocannabinol (THC) and cannabidiol (CBD).

Due to the psychoactive properties of THC, most studies focused on CBD use in these patients. The use of CBD as an adjunct resulted in decreased seizure frequency, and secondary benefits observed included improvement in mood, alertness and sleep. Adverse events (AEs) reported were drowsiness, diarrhea, increased transaminases and worsening of seizures.

It can safely be concluded that there is a significant benefit in DRE patients using CBD as adjunctive therapy. However, further controlled and adequately powered studies are needed to assess the pharmacokinetics and impact of the long-term use of cannabis.”

https://pubmed.ncbi.nlm.nih.gov/32832296/

“The anticonvulsant properties of cannabis have been reported for several years; however, its use as adjunctive therapy in DRE has increased in recent years. Cannabis mediates the ECS, which affects neuronal excitability. This makes it a superior choice for the adjunctive treatment of DRE patients.”

https://www.cureus.com/articles/36299-cannabis-more-than-the-euphoria-its-therapeutic-use-in-drug-resistant-epilepsy

Cannabinoid Effects on Experimental Colorectal Cancer Models Reduce Aberrant Crypt Foci (ACF) and Tumor Volume: A Systematic Review

See the source image “Colorectal cancer represents a heavy burden for health systems worldwide, being the third most common cancer worldwide. Despite the breakthroughs in medicine, current chemotherapeutic options continue to have important side effects and may not be effective in preventing disease progression.

Cannabinoids might be substances with possible therapeutic potential for cancer because they can attenuate the side effects of chemotherapy and have antiproliferative and antimetastatic effects.

We aim to determine, through a systematic review of experimental studies performed on animal CRC models, if cannabinoids can reduce the formation of preneoplastic lesions (aberrant crypt foci), number, and volume of neoplastic lesions.

Results: Eight in vivo experimental studies were included in the analysis after the full-text evaluation. Seven studies were azoxymethane (AOM) colorectal cancer models, and four studies were xenograft models. Cannabidiol botanical substance (CBD BS) and rimonabant achieved high aberrant crypt foci (ACF) reduction (86% and 75.4%, respectively). Cannabigerol, O-1602, and URB-602 demonstrated a high capacity for tumor volume reduction. Induction of apoptosis, interaction with cell survival, growth pathways, and angiogenesis inhibition were the mechanisms extracted from the studies that explain cannabinoids’ actions on CRC.

Conclusions: Cannabinoids have incredible potential as antineoplastic agents as experimental models demonstrate that they can reduce tumor volume and ACF formation. It is crucial to conduct more experimental studies to understand the pharmacology of cannabinoids in CRC better.”

https://pubmed.ncbi.nlm.nih.gov/32765628/

“Current literature findings demonstrate that cannabinoids might have potential as antineoplastic agents because they can reduce tumor volume and ACF formation.”

https://www.hindawi.com/journals/ecam/2020/2371527/

Role of cannabinoids in alcohol-induced neuroinflammation

 Progress in Neuro-Psychopharmacology and Biological Psychiatry“Alcohol is a psychoactive substance highly used worldwide, whose harmful use might cause a broad range of mental and behavioural disorders. Underlying brain impact, the neuroinflammatory response induced by alcohol is recognised as a key contributing factor in the progression of other neuropathological processes, such as neurodegeneration. These sequels are determined by multiple factors, including age of exposure.

Strikingly, it seems that the endocannabinoid system modulation could regulate the alcohol-induced neuroinflammation. Although direct CB1 activation can worsen alcohol consequences, targeting other components of the expanded endocannabinoid system may counterbalance the pro-inflammatory response.

Indeed, specific modulations of the expanded endocannabinoid system have been proved to exert anti-inflammatory effects, primarily through the CB2 and PPARγ signalling. Among them, some endo- and exogeneous cannabinoids can block certain pro-inflammatory mediators, such as NF-κB, thereby neutralizing the neuroinflammatory intracellular cascades.

Furthermore, a number of cannabinoids are able to activate complementary anti-inflammatory pathways, which are necessary for the transition from chronically overactivated microglia to a regenerative microglial phenotype. Thus, cannabinoid modulation provides cooperative anti-inflammatory mechanisms that may be advantageous to resolve a pathological neuroinflammation in an alcohol-dependent context.”

https://pubmed.ncbi.nlm.nih.gov/32758518/

“Cannabinoid modulation represents an extremely interesting therapeutic target in alcohol-induced chronic neuroinflammation.”

https://www.sciencedirect.com/science/article/pii/S0278584620303705?via%3Dihub

Fig. 1

Cytotoxic Effects of Cannabinoids on Human HT-29 Colorectal Adenocarcinoma Cells: Different Mechanisms of THC, CBD, and CB83

ijms-logo “In this study, we investigated the effects of exposition to IC50 dose for 24 h of a new synthetic cannabinoid (CB83) and of phytocannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on HT-29 colorectal carcinoma cells. Cell viability and proliferative activity evaluated using the MTT, lactate dehydrogenase (LDH), and CyQUANT assays showed that cell viability was significantly affected when CB83, THC, and CBD were administered to cells.

The results obtained showed that the reduced glutathione/oxidized glutathione ratio was significantly reduced in the cells exposed to CBD and significantly increased in the cells treated with the CB83 when compared to the controls. CBD treatment causes a significant increase in malondialdehyde content. The catalase activity was significantly reduced in HT-29 cells after incubation with CB83, THC, and CBD. The activities of glutathione reductase and glutathione peroxidase were significantly increased in cells exposed to THC and significantly decreased in those treated with CBD. The ascorbic acid content was significantly reduced in cells exposed to CB83, THC, and CBD. The ultrastructural investigation by TEM highlighted a significantly increased percentage of cells apoptotic and necrotic after CB83 exposition. The Annexin V-Propidium Iodide assay showed a significantly increased percentage of cells apoptotic after CB83 exposition and necrotic cells after CBD and THC exposition.

Our results proved that only CBD induced oxidative stress in HT-29 colorectal carcinoma cells via CB receptor-independent mechanisms and that CB83 caused a mainly CB2 receptor-mediated antiproliferative effect comparable to 5-Fuorouracil, which is still the mainstay drug in protocols for colorectal cancer.”

https://pubmed.ncbi.nlm.nih.gov/32752303/

https://www.mdpi.com/1422-0067/21/15/5533

Cannabidiol normalizes resting-state functional connectivity in treatment-resistant epilepsy

See the source image“Resting-state (rs) network dysfunction is a contributing factor to treatment resistance in epilepsy. In treatment-resistant epilepsy (TRE), pharmacological and nonpharmacological therapies have been shown to improve such dysfunction.

In this study, our goal was to prospectively evaluate the effect of highly purified plant-derived cannabidiol (CBD; Epidiolex®) on rs functional magnetic resonance imaging (fMRI) functional connectivity (rs-FC).

We hypothesized that CBD would change and potentially normalize the rs-FC in TRE.

Results: Participants with TRE showed average decrease of 71.7% in SF (p < 0.0001) and improved CSSS, AEP, and POMS confusion, depression, and fatigue subscores (all p < 0.05) on-CBD with POMS scores becoming similar to those of HCs. Paired t-tests showed significant pre-/on-CBD changes in rs-FC in cerebellum, frontal areas, temporal areas, hippocampus, and amygdala with some of them correlating with improvement in behavioral measures. Significant differences in rs-FC between pre-CBD and HCs were found in cerebellum, frontal, and occipital regions. After controlling for changes in SF with CBD, these differences were no longer present when comparing on-CBD to HCs.

Significance: This study indicates that highly purified CBD modulates and potentially normalizes rs-FC in the epileptic brain. This effect may underlie its efficacy. This study provides Class III evidence for CBD’s normalizing effect on rs-FC in TRE.”

https://pubmed.ncbi.nlm.nih.gov/32745959/

https://www.epilepsybehavior.com/article/S1525-5050(20)30476-5/fulltext

The Treatment of Cognitive, Behavioural and Motor Impairments from Brain Injury and Neurodegenerative Diseases through Cannabinoid System Modulation-Evidence from In Vivo Studies

jcm-logo“Neurological disorders such as neurodegenerative diseases or traumatic brain injury are associated with cognitive, motor and behavioural changes that influence the quality of life of the patients. Although different therapeutic strategies have been developed and tried until now to decrease the neurological decline, no treatment has been found to cure these pathologies.

In the last decades, the implication of the endocannabinoid system in the neurological function has been extensively studied, and the cannabinoids have been tried as a new promising potential treatment. In this study, we aimed to overview the recent available literature regarding in vivo potential of natural and synthetic cannabinoids with underlying mechanisms of action for protecting against cognitive decline and motor impairments.

The results of studies on animal models showed that cannabinoids in traumatic brain injury increase neurobehavioral function, working memory performance, and decrease the neurological deficit and ameliorate motor deficit through down-regulation of pro-inflammatory markers, oedema formation and blood-brain barrier permeability, preventing neuronal cell loss and up-regulating the levels of adherence junction proteins.

In neurodegenerative diseases, the cannabinoids showed beneficial effects in decreasing the motor disability and disease progression by a complex mechanism targeting more signalling pathways further than classical receptors of the endocannabinoid system. In light of these results, the use of cannabinoids could be beneficial in traumatic brain injuries and multiple sclerosis treatment, especially in those patients who display resistance to conventional treatment.”

https://pubmed.ncbi.nlm.nih.gov/32726998/

https://www.mdpi.com/2077-0383/9/8/2395

Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis

cancers-logo“In recent years, and even more since its legalization in several jurisdictions, cannabis and the endocannabinoid system have received an increasing amount of interest related to their potential exploitation in clinical settings. Cannabinoids have been suggested and shown to be effective in the treatment of various conditions. In cancer, the endocannabinoid system is altered in numerous types of tumours and can relate to cancer prognosis and disease outcome. Additionally, cannabinoids display anticancer effects in several models by suppressing the proliferation, migration and/or invasion of cancer cells, as well as tumour angiogenesis. However, the therapeutic use of cannabinoids is currently limited to the treatment of symptoms and pain associated with chemotherapy, while their potential use as cytotoxic drugs in chemotherapy still requires validation in patients. Along with cannabinoids, cannabis contains several other compounds that have also been shown to exert anti-tumorigenic actions. The potential anti-cancer effects of cannabinoids, terpenes and flavonoids, present in cannabis, are explored in this literature review.”

https://pubmed.ncbi.nlm.nih.gov/32708138/

https://www.mdpi.com/2072-6694/12/7/1985

Protective role of neuronal and lymphoid cannabinoid CB 2 receptors in neuropathic pain

 eLife logo“Cannabinoid CB2 receptor (CB2) agonists are potential analgesics void of psychotropic effects.

Peripheral immune cells, neurons and glia express CB2, however the involvement of CB2 from these cells in neuropathic pain remains unresolved. We explored spontaneous neuropathic pain through on-demand self-administration of the selective CB2 agonist JWH133 in wild-type and knockout mice lacking CB2 in neurons, monocytes or constitutively. Operant self-administration reflected drug-taking to alleviate spontaneous pain, nociceptive and affective manifestations. While constitutive deletion of CB2 disrupted JWH133-taking behavior, this behavior was not modified in monocyte-specific CB2 knockouts and was increased in mice defective in neuronal CB2 knockouts suggestive of increased spontaneous pain. Interestingly, CB2-positive lymphocytes infiltrated the injured nerve and possible CB2transfer from immune cells to neurons was found. Lymphocyte CB2depletion also exacerbated JWH133 self-administration and inhibited antinociception.

This work identifies a simultaneous activity of neuronal and lymphoid CB2that protects against spontaneous and evoked neuropathic pain.”

https://pubmed.ncbi.nlm.nih.gov/32687056/

https://elifesciences.org/articles/55582