Cannabinoids receptors in Covid-19: Perpetrators and victims

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“COVID-19 is caused by SARS-CoV-2 and leads to acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and extrapulmonary manifestations in severely affected cases. However, most of the affected cases are mild or asymptomatic.

Cannabinoids (CBs) such as tetrahydrocannabinol (THC) and cannabidiol (CBD), which act on G-protein-coupled receptors called CB1 and CB2, have anti-inflammatory effects. Many published studies show that CBs are effective in various inflammatory disorders, viral infections, and attenuation of ALI and ARDS.

Therefore, the aim of the present narrative review was to summarize the possible immunological role of CBs in COVID-19. The effects of CBs are controversial, although they have beneficial effects via CB2 receptors and adverse effects via CB1 receptors against ALI, ARDS, and hyperinflammation, which are hallmarks of COVID-19.

The present narrative review has shown that CBs effectively manage ALI and ARDS by suppressing pro-inflammatory cytokines, which are common in COVID-19. Therefore, CBs may be used to manage COVID-19 because of their potent anti-inflammatory effects with suppression of pro-inflammatory cytokines and inhibition of inflammatory signaling pathways.”

https://pubmed.ncbi.nlm.nih.gov/36043749/

https://www.eurekaselect.com/article/125986

U.S. cannabis laws projected to cost generic and brand pharmaceutical firms billions

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Lopiccolo & Chang in PLoS ONE – BU Linguistics

“Legalization of cannabis by U.S. states is likely increasing the use of cannabis as an alternative to conventional pharmaceutical drugs. We examined how cannabis legalization between 1996 and 2019 affected stock market returns for listed generic and brand pharmaceutical companies and found that returns were 1.5-2% lower at 10 days after legalization. Returns decreased in response to both medical and recreational legalization, for both generic and brand drugmakers. Investors anticipate a single legalization event to reduce drugmaker annual sales by $3B on average.”

https://pubmed.ncbi.nlm.nih.gov/36044436/

“Using a data set and estimation approach novel to health policy, we find evidence that investors predict legal cannabis access will significantly decrease sales of conventional pharmaceutical drugs. Legal cannabis applies competitive pressure to both generic and brand drug markets, across both classes of drugmakers. This makes legal cannabis distinct from typical brand drug patent expiration and generic drug entry where typically only one drug, the drug coming off patent, and its substitutes are affected. Furthermore, cannabis can be purchased without a prescription and home cultivated, unlike any other conventional medication.”

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0272492

Cannabidiol ameliorates the anxiogenic and compulsive-like behaviors induced by chronic consumption of a high-carbohydrate diet in male mice

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SpringerLink

“The excessive consumption of ultra-processed foods and the development of obesity has been associated with several comorbidities, including psychiatric disorders. Excess fat tissue promotes a low-intensity inflammatory state, mainly in the white tissue, which is essential in developing metabolic alterations and influences brain homeostasis.

In this scenario, Cannabidiol (CBD), a compound from Cannabis sativa, has presented anxiolytic and anti-inflammatory effects in murine models.

This study verified whether CBD treatment would ameliorate the compulsive-like and anxiety-like behaviors observed after mice’s chronic consumption of a high-refined carbohydrate (HC) diet.

BALB/c male mice received a control or HC diet for 12 weeks followed by vehicle and CBD (30 mg/Kg, i.p.) administration, and their behavior was evaluated in the Marble Burying test (MB) and Novel Suppressing Feeding test (NSF).

The sub-chronic, but not acute, treatment with CBD attenuated the compulsive-like and anxiogenic-like behavior induced by the HC diet.

Our data reinforced the harmful effects of the HC diet’s chronic consumption on compulsive and anxious behaviors and the potential of CBD as a drug treatment for psychiatric disorders associated with obesity.”

https://pubmed.ncbi.nlm.nih.gov/36040711/

https://link.springer.com/article/10.1007/s11011-022-01071-9

Experience With Medical Marijuana for Cancer Patients in the Palliative Setting

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Cureus Competition Winners Announced - Synaptive Medical

“Objectives: Medical marijuana is a symptom treatment option for palliative cancer patients; however, its useful applications remain limited. The goals of this study were to review the characteristics of patients who received medical marijuana under our ambulatory palliative care program and to determine barriers to access and use of medical marijuana in this population.

Methods: This study was a retrospective analysis of patients who were enrolled in the medical marijuana registry through the ambulatory palliative care department at Upstate Cancer Center. Data from June 2017 to June 2020 were analyzed. Patients were included if they had a diagnosis of cancer, were certified by a qualified practitioner in the New York Medical Marijuana Program, and received care at Upstate Medical University. Patients were excluded if no marijuana certificate was found or if they transferred care.

Results: The study population was 184 patients. Ninety-three patients (51.5%) received at least one prescription from a New York licensed marijuana dispensary while 72 (39.13%) were certified but never obtained any medical marijuana. For patients who took at least one dose of medical marijuana, 48.14% experienced an improvement in pain, 44.95% used fewer opioids, and 85.11% had an improvement in at least one symptom. Adverse effects were low at 3.72%.

Conclusion: Medical marijuana has an important role in the palliation of symptoms in advanced cancers with few adverse effects. There are still many barriers to effective use. More prospective research is needed to optimize delivery and dosing.”

https://pubmed.ncbi.nlm.nih.gov/35915672/

“Medical marijuana appears to have an important role in the palliation of symptoms in advanced cancers with few adverse effects although not all patients certified for use, go on to obtain it. There are many remaining barriers to effective use including financial toxicity and end-of-life care, introducing this so late in life that the benefit is limited.”

https://www.cureus.com/articles/102316-experience-with-medical-marijuana-for-cancer-patients-in-the-palliative-setting

Long-Term Impact of Medical Marijuana Laws on the Burden of Cannabis Use Disorders in US Male and Female Adolescents and Young Adults

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SpringerLink

“Deregulation of cannabis use has raised concerns regarding its potential effects on health, particularly in adolescents and young adults.

Here, we extracted data from the Global Burden of Disease database to estimate the long-term effect (> 5 years) of medical marijuana laws (MML) on 2019 cannabis use disorders Disability Adjusted Life Years (2019 CUD DALYs) in US male and female adolescents (15-19 years old) and young adults (20-24 years old). Socio-cultural, demographic and economic characteristics were used as baseline covariates. To improve the robustness of estimation, we took advantage of machine learning techniques.

We found no significant effect of MML on 2019 CUD DALYS in each of our four age/sex groups. Estimates from a marginal structural model taking into account age and sex strata in the same model were also non-significant.

Our findings suggest that MML may have a negligible effect (if any) on cannabis use disorders in this population group.”

https://pubmed.ncbi.nlm.nih.gov/36036345/

https://link.springer.com/article/10.1007/s10597-022-01018-5

Cannabidivarin alleviates neuroinflammation by targeting TLR4 co-receptor MD2 and improves morphine-mediated analgesia

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Frontiers - Crunchbase Company Profile & Funding

“Toll-like receptor 4 (TLR4) is a pattern-recognition receptor (PRR) that regulates the activation of immune cells, which is a target for treating inflammation.

In this study, Cannabidivarin (CBDV), an active component of Cannabis, was identified as an antagonist of TLR4. In vitro, intrinsic protein fluorescence titrations revealed that CBDV directly bound to TLR4 co-receptor myeloid differentiation protein 2 (MD2). Cellular thermal shift assay (CETSA) showed that CBDV binding decreased MD2 stability, which is consistent with in silico simulations that CBDV binding increased the flexibility of the internal loop of MD2.

Moreover, CBDV was found to restrain LPS-induced activation of TLR4 signaling axes of NF-κB and MAPKs, therefore blocking LPS-induced pro-inflammatory factors NO, IL-1β, IL-6 and TNF-α. Hot plate test showed that CBDV potentiated morphine-induced antinociception. Furthermore, CBDV attenuated morphine analgesic tolerance as measured by the formalin test by specifically inhibiting chronic morphine-induced glial activation and pro-inflammatory factors expression in the nucleus accumbent.

This study confirms that MD2 is a direct binding target of CBDV for the anti-neuroinflammatory effect and implies that CBDV has great translational potential in pain management.”

https://pubmed.ncbi.nlm.nih.gov/36032146/

“The results imply that CBDV could be a potential therapeutic agent for improving morphine-mediated analgesia.”

https://www.frontiersin.org/articles/10.3389/fimmu.2022.929222/full

Cannabidiol attenuates hypersensitivity and oxidative stress after traumatic spinal cord injury in rats

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Neuroscience Letters

“Neuropathic pain (NP) arises as a direct consequence of traumatic spinal cord injury (SCI), which leads to devastating consequences for people suffering from this condition since no specific treatment has been defined. One relevant mechanism in generating painful stimuli involves the direct participation of reactive oxygen species (ROS) at the cellular and subcellular levels.

Cannabidiol (CBD) is one of the two most crucial cannabinoid components of the cannabis plant and has been proposed as a potential treatment for NP. Its antioxidant, neuroprotective and anti-inflammatory properties have been documented. However, there is insufficient evidence regarding CBD as treatment of NP induced by SCI or the mechanisms that underlie this effect.

In this study, we evaluated the antinociceptive effect of CBD as an acute treatment after the nociceptive behaviors characteristic of NP were established (hypersensitivity threshold and hypersensitivity response). Furthermore, the participation of oxidative stress was determined by lipid peroxidation (LP) and glutathione concentration (GSH) in female Wistar rats with SCI.

Acute treatment with CBD (2.5-20 mg/kg, i.p.) decreased nociceptive behaviors in a dose-dependent manner, decreased LP, and increased GSH concentration in injured tissue 15 days after injury. The findings of this study suggest that the antinociceptive effect induced by CBD is regulated by reducing oxidative stress by decreasing the LP and increasing the concentration of antioxidant (GSH) defenses.”

https://pubmed.ncbi.nlm.nih.gov/36028005/

“Cannabidiol decreases hyperalgesia in a dose–response manner after spinal cord injury.”

https://www.sciencedirect.com/science/article/abs/pii/S0304394022004165?via%3Dihub

Cannabidiol enhances the antinociceptive effects of morphine and attenuates opioid-induced tolerance in the chronic constriction injury model

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Behavioural Brain Research

“Neuropathic pain (NP) is a complex health problem that includes sensorial manifestations such as evoked and ongoing pain. Cannabidiol (CBD) has shown potential in the treatment of NP and the combination between opioids and cannabinoids has provided promising results on pain relief. Thus, our study aimed to investigate the effect of treatment combination between CBD and morphine on evoked and ongoing pain, and the effect of CBD on morphine-induced tolerance in the model of chronic constriction injury (CCI) of the sciatic nerve in rats.

Mechanical thresholds (i.e., evoked pain) were evaluated before and 7 days after surgery. We also employed a 4-day conditioned place preference (CPP) protocol, to evaluate relief of ongoing pain (6 to 9 days after surgery). Treatment with morphine (2 and 4mg/kg) or CBD (30mg/kg) induced a significant antinociceptive effect on evoked pain.

The combination of CBD (30mg/kg) and morphine (1mg/kg) produced an enhanced antinociceptive effect, when compared to morphine alone (1mg/Kg). Treatment with morphine (1 and 2mg/kg) or CBD (30mg/kg) alone failed to induce significant scores in the CPP test. However, combined treatment of CBD (30mg/kg) and morphine (1mg/kg) provided significant positive scores, increased the number of entrances in the drug-paired chamber in the CPP test and did not alter locomotor activity in rats. Lastly, treatment with CBD partially attenuated morphine-induced tolerance.

In summary, our results support the indication of CBD as an adjuvant to opioid therapy for the attenuation of NP and opioid-induced analgesic tolerance.”

https://pubmed.ncbi.nlm.nih.gov/36028000/

“Taken together, the present results demonstrate that CBD or morphine exert antinociceptive effects in both mechanically evoked pain and ongoing pain after CCI in rats. The treatment combination of CBD and a sub-therapeutic dose of morphine, provided marked antinociceptive effects in both evoked and ongoing pain.”

https://www.sciencedirect.com/science/article/abs/pii/S0166432822003448?via%3Dihub

Cannabinoid Cancer Biology and Prevention

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“Plant-based, synthetic, and endogenous cannabinoids have been shown to control a diverse array of biological processes, including regulation of cell fate across cancers. Their promise as broad-based antitumor agents in preclinical models has led to the initiation of pilot clinical trials. Session 5 of the National Cancer Institute’s Cannabis, Cannabinoids and Cancer Research Symposium provides an overview of this research topic.

Overall, the presentations highlight cannabinoid signal transduction and specific molecular mechanisms underlying cannabinoid antitumor activity. They also demonstrate the broad-based antitumor activity of the plant-based, synthetic, and endogenous cannabinoid compounds. Importantly, evidence is presented demonstrating when cannabinoids may be contraindicated as a treatment for cancer, as in the case of human papilloma virus-meditated oropharynx cancer or potentially other p38 MAPK pathway-driven cancers.

Finally, it is discussed that a key to advancing cannabinoids into the clinic is to conduct well-designed, large-scale clinical trials to determine whether cannabinoids are effective antitumor agents in cancer patients.”

https://pubmed.ncbi.nlm.nih.gov/34850900/

“These sessions present multiple lines of preclinical evidence supporting that the cannabinoids THC and CBD act as broad-based antitumor agents controlling many aspects of cancer progression, including cell proliferation, apoptosis, invasion, metastasis, and immune surveillance. “

https://academic.oup.com/jncimono/article/2021/58/99/6446216?login=false


Analysis of Potential Anti-Cancer Effects of Cannabinol and Cannabidiol using HCC1806 and HEK293 Cell Lines

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URSCA 2018

“Humans produce endocannabinoids that act as neuromodulators in the endocannabinoid system. They bind to Gαi protein-coupled cannabinoid receptors to control the release of many neurotransmitters. Cannabinoids receptor 1 (CB1) mediates psychoactive effects through its location mostly in the central nervous system while Cannabinoid receptor 2 (CB2) regulates various immune responses through its location in peripheral tissues.

The endocannabinoid system has been used as a molecular target by research to treat diseases such as multiple sclerosis, cardiovascular disorders, obesity and inflammatory pain. Thus, the endocannabinoid system is a potential molecular target to treat cancer. With the proposed legalization of recreational marijuana and with growing number of patients using cannabis for medicinal purpose, there is an urgent need to provide data on potential medicinal value of cannabis and cannabinoids.

The Cannabis Sativa plant naturally synthesizes numerous different cannabinoids of which (CBN) and cannabidiol (CBD) have promising properties in cancer treatment. CBD is a phytocannabinoid known for its anticonvulsant and anti-nausea properties. Previous research suggests that CBD can target breast cancer cells while preserving normal cells. CBN is another phyotocannabinoid with anti-inflammatory properties that can potentially aid to reduce inflammation resulting from cancer.

This study aims to determine if CBN and CBD have an effect on cancer cells and normal cells. We hypothesize that we may observe an increase in apoptosis of cancer cells treated with the two compounds but no effect or perhaps even a slight increase in normal cell growth. Preliminary data in lab suggests that these compounds have anti-cancer properties and we want to solidify this evidence through repetition of the experiment.”

https://journals.macewan.ca/ursca/article/view/1582