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Interacting binding insights and conformational consequences of the differential activity of cannabidiol with two endocannabinoid-activated G-protein-coupled receptors

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“Cannabidiol (CBD), the major non-psychoactive phytocannabinoid present in the plant Cannabis sativa, has displayed beneficial pharmacological effects in the treatment of several neurological disorders including, epilepsy, Parkinson’s disease, and Alzheimer’s disease. In particular, CBD is able to modulate different receptors in the endocannabinoid system, some of which belong to the family of G-protein-coupled receptors (GPCRs). Notably, while CBD is able to antagonize some GPCRs in the endocannabinoid system, it also seems to activate others. The details of this dual contrasting functional feature of CBD, that is, displaying antagonistic and (possible) agonistic ligand properties in related receptors, remain unknown. Here, using computational methods, we investigate the interacting determinants of CBD in two closely related endocannabinoid-activated GPCRs, the G-protein-coupled receptor 55 (GPR55) and the cannabinoid type 1 receptor (CB1). While in the former, CBD has been demonstrated to function as an antagonist, the way by which CBD modulates the CB1 receptor remains unclear. Namely, CBD has been suggested to directly trigger receptor’s activation, stabilize CB1 inactive conformations or function as an allosteric modulator. From microsecond-length unbiased molecular dynamics simulations, we found that the presence of the CBD ligand in the GPR55 receptor elicit conformational changes associated with antagonist-bound GPCRs. In contrast, when the GPR55 receptor is simulated in complex with the selective agonist ML186, agonist-like conformations are sampled. These results are in agreement with the proposed modulatory function of each ligand, showing that the computational techniques utilized to characterize the GPR55 complexes correctly differentiate the agonist-bound and antagonist-bound systems. Prompted by these results, we investigated the role of the CBD compound on the CB1 receptor using similar computational approaches. The all-atom MD simulations reveal that CBD induces conformational changes linked with agonist-bound GPCRs. To contextualize the results we looked into the CB1 receptor in complex with a well-established antagonist. In contrast to the CBD/CB1 complex, when the CB1 receptor is simulated in complex with the ligand antagonist AM251, inactive conformations are explored, showing that the computational techniques utilized to characterize the CB1 complexes correctly differentiate the agonist-bound and antagonist-bound systems. In addition, our results suggest a previously unknown sodium-binding site located in the extracellular domain of the CB1 receptor. From our detailed characterization, we found particular interacting loci in the binding sites of the GPR55 and the CB1 receptors that seem to be responsible for the differential functional features of CBD. Our work will pave the way for understanding the CBD pharmacology at a molecular level and aid in harnessing its potential therapeutic use.”

https://pubmed.ncbi.nlm.nih.gov/36016551/

https://www.frontiersin.org/articles/10.3389/fphar.2022.945935/full

The effects of acute alcohol administration on circulating endocannabinoid levels in humans

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“Several lines of evidence suggest that endocannabinoid signalling may influence alcohol consumption. Preclinical studies have found that pharmacological blockade of cannabinoid receptor 1 leads to reductions in alcohol intake. Furthermore, variations in endocannabinoid metabolism between individuals may be associated with the presence and severity of alcohol use disorder. However, little is known about the acute effects of alcohol on the endocannabinoid system in humans. In this study, we evaluated the effect of acute alcohol administration on circulating endocannabinoid levels by analysing data from two highly-controlled alcohol administration experiments. In the first within-subjects experiment, 47 healthy participants were randomized to receive alcohol and placebo in a counterbalanced order. Alcohol was administered using an intravenous clamping procedure such that each participant attained a nearly identical breath alcohol concentration of 0.05%, maintained over 3 h. In the second experiment, 23 healthy participants self-administered alcohol intravenously; participants had control over their exposure throughout the paradigm. In both experiments, circulating concentrations of two endocannabinoids, N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), were measured at baseline and following alcohol exposure. During the intravenous clamping procedure, acute alcohol administration reduced circulating AEA but not 2-AG levels when compared to placebo. This finding was confirmed in the self-administration paradigm, where alcohol reduced AEA levels in an exposure-dependent manner. Future studies should seek to determine whether alcohol administration has similar effects on brain endocannabinoid signalling. An improved understanding of the bidirectional relationship between endocannabinoid signalling and alcohol intake may deepen our understanding of the aetiology and repercussions of alcohol use disorder.”

https://pubmed.ncbi.nlm.nih.gov/36001429/

https://onlinelibrary.wiley.com/doi/10.1111/adb.13197

Pentadecanoylcarnitine is a newly discovered endocannabinoid with pleiotropic activities relevant to supporting physical and mental health

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“As an emerging dietary essential fatty acid, pentadecanoic acid (C15:0) is expected to have bioactive metabolites with broad health benefits. Here, we evaluated pentadecanoylcarnitine, an endogenous C15:0 metabolite, for dose dependent cell-based activities, including measurement of its effects on 148 clinically relevant biomarkers across twelve primary human cell systems mimicking various disease states.

Mechanisms of action for pentadecanoylcarnitine were also assessed across 78 cell-based target assays. Pentadecanoylcarnitine had dose-dependent anti-inflammatory activities, including lower IL-1α, ITAC, MCP-1, and IP-10, across five cell systems relevant to treating cardiovascular, immune, neoplastic, pulmonary, and skin diseases.

Targeted assays showed pentadecanoylcarnitine as a full-acting cannabinoid 1 and 2 receptor agonist (EC50 3.7 and 3.2 µM, 111% and 106% maximum activity compared to the positive control, respectively). Pentadecanoylcarnitine also had 5-HT1A and 5-HT1B receptor agonist and histamine H1 and H2 receptor antagonist activities.

In summary, pentadecanoylcarnitine, a second discovered full-acting endocannabinoid, had broad pleiotropic activities relevant to regulating inflammation, pain, mood, and sleep. This study’s findings further the need to evaluate the potential health impacts of C15:0 nutritional deficiencies caused by population-wide avoidance of all dietary saturated fats, including C15:0.”

https://pubmed.ncbi.nlm.nih.gov/35999445/

“In summary, similar to other essential fatty acids, we have demonstrated that C15:0 itself, and now a C15:0 metabolite, have pleiotropic effects with expected broad health benefits. Specifically, pentadecanoylcarnitine has potent pro-endocannabinoid, serotonin-supporting, and antihistamine activities relevant to promoting both physical and mental health, including its ability to regulate inflammation, pain, mood, sleep, and stress. Due to population-wide decreases in whole fat milk intake, paired with declining circulating C15:0 concentrations4, further studies are needed to evaluate possible links between the global rise in allergies, mental health conditions, and sleep disorders and C15:0 nutritional deficiencies.”

https://www.nature.com/articles/s41598-022-18266-w


Medical Cannabis Certification Is Associated With Decreased Opiate Use in Patients With Chronic Pain: A Retrospective Cohort Study in Delaware

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Cureus Competition Winners Announced - Synaptive Medical

“Opioid medications are commonly used to treat chronic pain around the world. While these medications are quite effective at reducing pain, they can create opioid dependence and lead to further drug addiction. Long-term opioid use has significantly contributed to the “opioid epidemic” that is currently ravaging the United States, leading to opioid overdoses and unintentional deaths, particularly in Delaware.

Objective To determine if medical marijuana certification helps patients in Delaware with chronic pain reduce their opiate use.

Methods In this study, we examined individuals who were provided with legal; medical cannabis certifications in the state of Delaware between June 2018 and October 2019 and were concurrently being treated with opioid medications for chronic pain at a private pain management practice. Using a posthoc analysis, we conducted a retrospective cohort study on the individuals (n = 81) to determine if there was a decrease in their opioid use following medical cannabis certification. Opioid use was measured in morphine milligram equivalent (MME) through the Delaware prescription monitoring program (PMP) database.

Results Overall, the average change in prescribed opioid use was found to be -12.3 morphine milligram equivalent (MME) units when including all individuals (p < 0.00001). Among the included individuals with baseline opioid use, medical cannabis certification was associated with a 31.3% average decrease in opioid use (n = 63). When examining subgroups based upon pain location, individuals with neck pain displayed a 41.5% average decrease in MME (n = 27), while individuals with low back pain were observed to have a 29.4% decrease in opioid use (n = 58). Similarly, individuals with knee pain (n = 14) reduced their opioid use by 32.6%.

Conclusion The results display an association between medical cannabis certification and a decrease in opiate use among the study group individuals. This study suggests that medical cannabis use may help individuals to reduce their opiate requirements along with physician intervention. More research is needed to validate these findings with appropriate controls and verification of cannabis use.”

https://pubmed.ncbi.nlm.nih.gov/35004055/

“The results of this study indicate that medical marijuana certification is associated with a decrease in prescription opiate use for chronic pain treatment and supports greater use of this adjunct treatment modality. Given the significance of opioid addiction in American society, any treatment or additional resource to reduce opioid overuse can aid in the multifactorial management of chronic pain. Although marijuana use causes a variety of side effects, the findings here suggest that the use of medical cannabis as an adjunct treatment for chronic pain may be beneficial to public health.”

https://www.cureus.com/articles/77114-medical-cannabis-certification-is-associated-with-decreased-opiate-use-in-patients-with-chronic-pain-a-retrospective-cohort-study-in-delaware

Association between county level cannabis dispensary counts and opioid related mortality rates in the United States: panel data study

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The BMJ (@bmj_latest) / Twitter

“Objective: To examine county level associations between the prevalence of medical and recreational cannabis stores (referred to as dispensaries) and opioid related mortality rates.

Participants: The study used US mortality data from the Centers for Disease Control and Prevention combined with US census data and data from Weedmaps.com on storefront dispensary operations. Data were analyzed at the county level by using panel regression methods.

Main outcome measure: The main outcome measures were the log transformed, age adjusted mortality rates associated with all opioid types combined, and with subcategories of prescription opioids, heroin, and synthetic opioids other than methadone. The associations of medical dispensary and recreational dispensary counts with age adjusted mortality rates were also analyzed.

Results: County level dispensary count (natural logarithm) is negatively related to the log transformed, age adjusted mortality rate associated with all opioid types (β=-0.17, 95% confidence interval -0.23 to -0.11). According to this estimate, an increase from one to two storefront dispensaries in a county is associated with an estimated 17% reduction in all opioid related mortality rates. Dispensary count has a particularly strong negative association with deaths caused by synthetic opioids other than methadone (β=-0.21, 95% confidence interval -0.27 to -0.14), with an estimated 21% reduction in mortality rates associated with an increase from one to two dispensaries. Similar associations were found for medical versus recreational storefront dispensary counts on synthetic (non-methadone) opioid related mortality rates.

Conclusions: Higher medical and recreational storefront dispensary counts are associated with reduced opioid related death rates, particularly deaths associated with synthetic opioids such as fentanyl. While the associations documented cannot be assumed to be causal, they suggest a potential association between increased prevalence of medical and recreational cannabis dispensaries and reduced opioid related mortality rates. This study highlights the importance of considering the complex supply side of related drug markets and how this shapes opioid use and misuse.”

https://pubmed.ncbi.nlm.nih.gov/33504472/

“We studied county level associations between cannabis storefront dispensaries and opioid related mortality rates in the US between 2014 and 2018. Our study found that increased medical and recreational storefront dispensary counts are associated with reduced opioid related mortality rates during the study period. These associations appear particularly strong for deaths related to synthetic opioids such as fentanyl.”

https://www.bmj.com/content/372/bmj.m4957

Medical cannabinoids: a pharmacology-based systematic review and meta-analysis for all relevant medical indications

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“Background: Medical cannabinoids differ in their pharmacology and may have different treatment effects. We aimed to conduct a pharmacology-based systematic review (SR) and meta-analyses of medical cannabinoids for efficacy, retention and adverse events.

Results: In total, 152 RCTs (12,123 participants) were analysed according to the type of the cannabinoid, outcome and comparator used, resulting in 84 comparisons. Significant therapeutic effects of medical cannabinoids show a large variability in the grade of evidence that depends on the type of cannabinoid. CBD has a significant therapeutic effect for epilepsy (SMD – 0.5[CI – 0.62, – 0.38] high grade) and Parkinsonism (- 0.41[CI – 0.75, – 0.08] moderate grade). There is moderate evidence for dronabinol for chronic pain (- 0.31[CI – 0.46, – 0.15]), appetite (- 0.51[CI – 0.87, – 0.15]) and Tourette (- 1.01[CI – 1.58, – 0.44]) and moderate evidence for nabiximols on chronic pain (- 0.25[- 0.37, – 0.14]), spasticity (- 0.36[CI – 0.54, – 0.19]), sleep (- 0.24[CI – 0.35, – 0.14]) and SUDs (- 0.48[CI – 0.92, – 0.04]). All other significant therapeutic effects have either low, very low, or even no grade of evidence. Cannabinoids produce different adverse events, and there is low to moderate grade of evidence for this conclusion depending on the type of cannabinoid.

Conclusions: Cannabinoids are effective therapeutics for several medical indications if their specific pharmacological properties are considered. We suggest that future systematic studies in the cannabinoid field should be based upon their specific pharmacology.”

https://pubmed.ncbi.nlm.nih.gov/35982439/

“Cannabinoids are effective therapeutics for several medical indications if their specific pharmacological properties are considered. We suggest that future systematic studies in the cannabinoid field should be based upon their specific pharmacology.”

https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-022-02459-1

Incidence and Predictors of Cannabis-Related Poisoning and Mental and Behavioral Disorders among Patients with Medical Cannabis Authorization: A Cohort Study

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“Objective: As medical cannabis use increases in North America, establishing its safety profile is a priority. The objective of this study was to assess rates of emergency department (ED) visits and hospitalizations due to poisoning by cannabis, and cannabis-related mental health disorders among medically authorized cannabis patients in Ontario, Canada, between 2014 and 2017.

Methods: This is a retrospective cohort study of patients who received medical cannabis authorization in Ontario, Canada, using data collected in participating cannabis clinics. Outcomes included ED visit/hospitalization with a main diagnosis code for: cannabis/cannabinoid poisoning; and mental/behavioral disorders due to cannabis use. Cox proportional hazard regressions were utilized to analyze the data.

Results: From 29,153 patients who received medical authorization, 23,091 satisfied the inclusion criteria. During a median follow-up of 240 days, 14 patients visited the ED or were hospitalized for cannabis poisoning-with an incidence rate of 8.06 per 10,000 person-years (95% CI: 4.8-13.6). A total of 26 patients visited the ED or were hospitalized for mental and behavioral disorders due to cannabis use-with an incidence rate of 15.0 per 10,000 person-years (95% CI: 10.2-22.0). Predictors of cannabis-related mental and behavioral disorders include prior substance use disorders, other mental disorders, age, diabetes, and chronic obstructive pulmonary disease.

Conclusions: The results suggest that the incidence of cannabis poisoning or cannabis-related mental and behavioral disorders was low among patients who were authorized to use cannabis for medical care. Identified predictors can help to target patients with potential risk of the studied outcomes.”

https://pubmed.ncbi.nlm.nih.gov/35866679/

https://www.tandfonline.com/doi/abs/10.1080/10826084.2022.2102193?journalCode=isum20

Antifungal and anti-aflatoxigenic properties of organs of Cannabis sativa L.: relation to phenolic content and antioxidant capacities

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SpringerLink

“Aflatoxin B1 is a carcinogenic mycotoxin that frequently contaminates crops worldwide.

Current research indicates that the use of natural extracts to combat mycotoxin contamination may represent an eco-friendly, sustainable strategy to ensure food safety. Although Cannabis sativa L. has long been known for its psychoactive cannabinoids, it is also rich in many other bioactive molecules.

This study examines extracts from various organs of Cannabis sativa L. to determine their ability to limit aflatoxin production and growth of Aspergillus flavus.

The results indicate that flower extract is most effective for limiting the synthesis of aflatoxin B1, leading to an almost-complete inhibition of toxin production at a concentration of 0.225 mg dry matter per gram of culture medium. Since flower extract is rich in phenolic compounds, its total antioxidant ability and radical-scavenging capacity are determined.

Compared with other anti-aflatoxigenic extracts, the anti-oxidative potential of Cannabis sativa L. flower extract appears moderate, suggesting that its anti-mycotoxin effect may be related to other bioactive compounds.”

https://pubmed.ncbi.nlm.nih.gov/34143269/

https://link.springer.com/article/10.1007/s00203-021-02444-x

The Effects of Nutrient Signaling Regulators in Combination with Phytocannabinoids on the Senescence-Associated Phenotype in Human Dermal Fibroblasts

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“Identifying effective anti-aging compounds is a cornerstone of modern longevity, aging, and skin-health research. There is considerable evidence of the effectiveness of nutrient signaling regulators such as metformin, resveratrol, and rapamycin in longevity and anti-aging studies; however, their potential protective role in skin aging is controversial.

In light of the increasing appearance of phytocannabinoids in beauty products without rigorous research on their rejuvenation efficacy, we decided to investigate the potential role of phytocannabinoids in combination with nutrient signaling regulators in skin rejuvenation. Utilizing CCD-1064Sk skin fibroblasts, the effect of metformin, triacetylresveratrol, and rapamycin combined with phytocannabinoids on cellular viability, functional activity, metabolic function, and nuclear architecture was tested.

We found triacetylresveratrol combined with cannabidiol increased the viability of skin fibroblasts (p < 0.0001), restored wound-healing functional activity (p < 0.001), reduced metabolic dysfunction, and ameliorated nuclear eccentricity and circularity in senescent fibroblasts (p < 0.01). Conversely, metformin with or without phytocannabinoids did not show any beneficial effects on functional activity, while rapamycin inhibited cell viability (p < 0.01) and the speed of wound healing (p < 0.001).

Therefore, triacetylresveratrol and cannabidiol can be a valuable source of biologically active substances used in aging and more studies using animals to confirm the efficacy of cannabidiol combined with triacetylresveratrol should be performed.”

https://pubmed.ncbi.nlm.nih.gov/35955938/

“We, for the first time, show that application of TRSV in combination with CBD constitutes a very promising anti-aging and regenerative regimen that can potentially be used for treatment or/and prevention of appearance of aging spots and treating cutaneous wounds. Moreover, we found pCBs alone appeared to be highly efficacious as an anti-aging treatment. Further work should study and test pCBs alone, as well as TRSV in combination with CBD as anti-aging remedies.”

https://www.mdpi.com/1422-0067/23/15/8804/htm

Acyclic Diterpene Phytol from Hemp Seed Oil ( Cannabis sativa L.) Exerts Anti-Inflammatory Activity on Primary Human Monocytes-Macrophages

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“Seeds from non-drug varieties of hemp (Cannabis sativa L.) have been used for traditional medicine, food, and fiber production. Our study shows that phytol obtained from hemp seed oil (HSO) exerts anti-inflammatory activity in human monocyte-macrophages.

Fresh human monocytes and human macrophages derived from circulating monocytes were used to evaluate both plasticity and anti-inflammatory effects of phytol from HSO at 10-100 mM using FACS analysis, ELISA, and RT-qPCR methods. The quantitative study of the acyclic alcohol fraction isolated from HSO shows that phytol is the most abundant component (167.59 ± 1.81 mg/Kg of HSO).

Phytol was able to skew monocyte-macrophage plasticity toward the anti-inflammatory non-classical CD14+CD16++ monocyte phenotype and toward macrophage M2 (CD200Rhigh and MRC-1high), as well as to reduce the production of IL-1β, IL-6, and TNF-α, diminishing the inflammatory competence of mature human macrophages after lipopolysaccharide (LPS) treatment.

These findings point out for the first time the reprogramming and anti-inflammatory activity of phytol in human monocyte-macrophages. In addition, our study may help to understand the mechanisms by which phytol from HSO contributes to the constant and progressive plasticity of the human monocyte-macrophage linage.”

https://pubmed.ncbi.nlm.nih.gov/35954130/

“These results showed that phytol, which was isolated and identified for the first time in HSO, can help to better understand the specific mechanism by which this acyclic diterpene exerts beneficial effects on monocyte-macrophage plasticity. So far, HSO has already been demonstrated to include healthy polyunsaturated fatty acids, as well as antioxidant tocopherols and anti-inflammatory phytosterols in its unsaponifiable fraction. In recent years, inflammation has emerged as a leading pathophysiologic mechanism in atherosclerosis and other diseases, so the effects of phytol on different hallmarks of the inflammatory response contribute to the recommendation of HSO as an interesting source of functional compounds.”

https://www.mdpi.com/2304-8158/11/15/2366/htm