“Interaction with cannabinoid receptor 1 (CB1) partially determines the bioactivity of the phytocannabinoids. Consequently, there has also been significant effort directed toward preparing synthetic cannabinoids with either enhanced agonistic or antagonistic activity against this receptor. The design process of these molecules, and the identification of off-target effects at this receptor for molecules designed to target other proteins, would be aided by a reliable computational tool that can accurately predict binding. Furthermore, although the mechanism of CB1 agonism is understood, the conformational behavior that underlies the molecular mechanism of partial agonism is unclear. In this report, we provide a correction for calculating a ligand’s affinity to the orthosteric site of CB1 to account for their partition into membranes, use this to register the predicted affinity (high and low) of cannabinoids, and discuss how a mechanism for THC partial agonism arises natively from the model consistent with experimental data.”
“We developed a model for predicting binding affinity and activity of cannabinoids which can be used for further drug design efforts in the design of new cannabinoid-based ligands.”
“Background: Whether cannabis is a risk factor for cardiovascular events is unknown. We examined the association between smoking cannabis and cardiovascular events in a cohort of older veterans (66 to 68 years of age) with coronary artery disease.
Methods: The THC Cohort (Heart and Cannabis) comprised 4285 veterans (mean [SD] age, 67.5 [1.01] years; 2% female) with coronary artery disease who were born in 1950 to 1952. Participants were recruited between April 5, 2018, and March 12, 2020, interviewed about health behaviors, and then classified according to their self-reported cannabis smoking status in the previous 30 days. In a separate analysis, we classified participants according to any form of cannabis use (smoking, vaping, or edible use) versus nonuse in the past 30 days. Data on demographic, behavioral, and clinical characteristics were collected by telephone interview and from national Department of Veterans Affairs and Medicare data sources. The primary outcome included a composite of fatal and nonfatal stroke, fatal and nonfatal acute myocardial infarction, and cardiovascular death. The follow-up period for each patient extended from the date of their initial interview until the end of study (June 14, 2022). All participants were followed until they experienced an outcome or until the end of the follow-up period. Survey nonresponse weights and propensity score-based weights were used to reduce bias and confounding. Hazard ratios were estimated using cause-specific hazard models.
Results: The cohort included 1015 veterans with coronary artery disease who reported smoking cannabis in the previous 30 days and 3122 veterans who did not smoke cannabis in the previous 30 days. Mean follow-up was 3.3 years, and 563 events occurred. Compared with veterans who did not smoke cannabis, smoking cannabis (past 30 days) was not associated with the composite outcome of acute myocardial infarction, stroke, and cardiovascular death (adjusted hazard ratio, 0.87 [95% CI, 0.61-1.24]). Similarly, use of any form of cannabis (smoking, vaping, dabbing, edibles) in the past 30 days was not associated with the composite outcome.
Conclusions: In this cohort of older veterans with coronary artery disease, self-reported cannabis use was not independently associated with increased cardiovascular events over a mean of 3.3 years of follow-up.”
“In this older cohort of veterans with coronary artery disease, both recent and lifetime smoking of cannabis were not associated with risk for having a CVD event, defined as heart attack, stroke, or cardiovascular death.”
“Beyond established CVD risk factors, we could not detect an association of cannabis use with CVD events, so it may not be an important contributor in this population.”
“Background: The efficacy of medical cannabis in alleviating pain has been demonstrated in clinical trials, yet questions remain regarding the extent to which specific chemical compounds contribute to analgesia versus expectation-based (placebo) responses. Effective blinding is notoriously difficult in cannabis trials, complicating the identification of compound-specific effects.
Methods: In a prospective study of 329 chronic pain patients (40% females; aged 48.9 ± 15.5) prescribed medical cannabis, we examined whether the chemical composition of cannabis cultivars could predict treatment outcomes. We used a Random Forest classifier with nested cross-validation to assess the predictive value of demographics, clinical features, and approximately 200 chemical compounds. Model robustness was evaluated using six additional machine learning algorithms.
Results: Here we show that incorporating chemical composition markedly improves the prediction of pain relief (AUC = 0.63 ± 0.10) compared to models using only demographic and clinical features (AUC = 0.52 ± 0.09; p < 0.001). This result is consistent across all models tested. While well-known cannabinoids such as THC and CBD provide limited predictive value, specific terpenoids, particularly α-Bisabolol and eucalyptol, emerge as key predictors of treatment response.
Conclusions: Our findings demonstrate that pain relief can be predicted from cannabis chemical profiles that are unknown to patients, providing evidence for compound-specific therapeutic effects. These results highlight the importance of considering the full range of cannabis compounds when developing more precise and effective cannabis-based therapies for pain management.”
“Chronic pain affects millions of people, and many turn to medical cannabis for relief. However, scientists debate whether cannabis truly reduces pain or if patients feel better simply because they expect it to work (placebo effect). In this study, we looked at 329 people who used medical cannabis and analyzed the chemical makeup of their treatments. Using machine learning, we tested whether the specific chemicals in cannabis could predict who would get pain relief.
We found that patients’ pain improvement could be predicted from the chemical content of their cannabis, even though patients didn’t know what chemicals they were receiving. This suggests that cannabis provides real pain relief beyond just patient expectations.
These findings show that medical cannabis has genuine therapeutic effects for pain management.”
“In conclusion, to the best of our knowledge, our study provides compelling evidence that the efficacy of MC in pain relief is not merely a placebo response but is strongly influenced by its diverse chemical composition. Our findings challenge the traditional focus on THC and CBD as the primary therapeutic agents in cannabis and highlight the importance of considering the full spectrum of chemical compounds present in MC. By embracing a more comprehensive approach to understanding MC’s therapeutic potential, we can work towards developing safer, more effective, and more precisely targeted treatments for the millions of individuals suffering from chronic pain worldwide.”
“Purpose: Cystic echinococcosis is a parasitic zoonosis caused by the larval stage of Echinococcus granulosus sensu lato. Albendazole (ABZ) is the drug of choice, although its efficacy is variable. The present research aimed to assess the in vitro and in vivo efficacy of a full-spectrum extract of Cannabis sativa inflorescences against E. granulosus sensu stricto (s.s.).
Methods: Protoscoleces and cysts were incubated in vitro with the C. sativa extract, achieving final CBD concentrations of 1, 5, 10, and 50 µg/ml. Viability was evaluated periodically. Structural and ultrastructural alterations were also recorded. For the clinical efficacy study, female CF-1 mice were infected. Six months later, mice were divided into groups (n = 10): (a) water control; (b) ABZ; (c) C. sativa extract, and (d) ABZ + C. sativa extract. Treatments were administered every 24 h for 30 days. The efficacy of the treatments was evaluated according to the weight of the cysts collected and the ultrastructural alterations observed.
Results: The C. sativa extract caused a significant decrease in the viability of protoscoleces and cysts in vitro. The greatest effect was observed with 50 µg/ml, which generated the reduction in protoscoleces viability to 0% between 6 and 24 h post-incubation (pi) and the collapse of 92 ± 13% of the cysts after 24 h pi. All the in vivo treatments reduced the weight of the cysts and caused ultrastructural alterations, especially the combination of ABZ + C. sativa extract.
Conclusion: We demonstrated the in vitro and in vivo efficacy of a full-spectrum extract of C. sativa inflorescences against E. granulosus s.s.”
“Echinococcus granulosus sensu stricto (s.s.) refers to a specific species within the Echinococcus granulosus complex, a group of tapeworms that cause cystic echinococcosis (CE) in humans and other animals. This species, also known as the “sheep strain,” is the most prevalent cause of human CE globally.”
“Cystic echinococcosis in cattle and sheep caused by Echinococcus granulosus sensu stricto genotypes G1 and G3 in the USA”
“Background: Non-alcoholic fatty liver disease (NAFLD) is a common liver disorder caused by oxidative stress and dysregulation of lipid metabolism. The endocannabinoid system (ECS), particularly the type 1 cannabinoid (CB1) receptor, plays a crucial role in NAFLD progression. Cannabinoids, such as cannabidiol (CBD) and tetrahydrocannabinol (THC), along with terpenes, such as beta-myrcene and d-limonene, have shown potential therapeutic effects on liver health, particularly in reducing oxidative stress and modulating lipid metabolism.
This study aimed to analyse the effects of five cannabis oils (COs), each with different CBD:THC ratios and terpenes content, on hypertension, dyslipidemia, hepatic steatosis, oxidative stress, and CB1 receptor expression in an experimental model of NAFLD induced by a sucrose-rich diet (SRD) in Wistar rats for 3 weeks.
Methods: Male Wistar rats were fed either a: (1) reference diet (RD; standard commercial laboratory diet) or a: (2) sucrose-rich diet (SRD) for 3 weeks. 3 to 7 SRD + CO as following: (3) SRD + THC; (4) SRD + CBD; (5) SRD + CBD:THC 1:1; (6) SRD + CBD:THC 2:1; and (7) SRD + CBD:THC 3:1. The COs were administered orally at a dose of 1.5 mg total cannabinoids/kg body weight daily. The cannabinoid and terpenes content of all COs used in the study was determined. The terpenes found in COs were beta-myrcene, d-limonene, terpinolene, linalool, beta-caryophyllene, alpha-humulene, (-)-guaiol, (-)-alpha-bisabolol. During the experimental period, body weight, food intake and blood pressure were measured. Serum glucose, triglyceride, total cholesterol, uric acid, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (AP) levels were evaluated. Liver tissue histology, NAFLD activity score (NAS), triglyceride and cholesterol content, lipogenic enzyme activities, enzyme related to mitochondrial fatty acid oxidation, reactive oxygen species (ROS), thiobarbituric acid reactive substance (TBARS), and antioxidant enzyme activities were also evaluated. The CB1 receptor expression was also determined.
Results: The results showed that SRD-fed rats developed hypertension, dyslipidemia, liver damage, hepatic steatosis, lipid peroxidation, and oxidative stress. This was accompanied by upregulation of liver CB1 receptor expression. CBD-rich CO, CBD:THC 1:1 ratio CO; CBD:THC 2:1 ratio CO and CBD:THC 3:1 ratio CO showed antihypertensive properties. THC-rich CO, CBD:THC 1:1 ratio CO; CBD:THC 2:1 ratio CO showed the greatest beneficial effects against hepatic steatosis and liver damage. All COs exhibited antioxidant effects in liver tissue. This was associated with normal liver CB1 receptor expression.
Conclusions: This study demonstrated that COs, particularly THC-rich CO, CBD:THC ratio 1:1 CO, CBD:THC ratio 2:1 CO and terpenes, can effectively reduce dyslipidemia, liver damage and hepatic steatosis in SRD-induced NAFLD. COs with a higher proportion of CBD in their composition showed antihypertensive properties. All the COs exhibited antioxidant properties. These findings suggest that COs, especially those with CBD:THC ratios of 1:1 and 2:1 and terpenes, may represent a promising therapeutic approach for managing NAFLD and preventing its progression to more severe liver disease.”
“This study demonstrated that COs, particularly THC-rich formulations, and those with CBD:THC ratios of 1:1 and 2:1, effectively reduced dyslipidemia, hepatic steatosis, and liver damage in SRD-induced NAFLD. All COs exhibited significant antioxidant properties, which contributed to the attenuation of oxidative stress. Notably, oils containing CBD also displayed antihypertensive effects, likely due to their vasodilatory properties. The modulation of CB1 receptor is closely linked to the improvement in hepatic steatosis and oxidative stress. These results underscore the synergistic role of cannabinoids and terpenes in targeting key mechanisms involved in NAFLD pathophysiology.”
“These findings suggest that COs, especially those with balanced CBD: THC ratios (1:1 and 2:1) and with meaningful terpenes content, represent a promising therapeutic approach for managing NAFLD and preventing its progression to more severe liver diseases.”
“The endocannabinoid system (eCBS) plays a crucial role in pain modulation through its components, including endocannabinoids, cannabinoid receptors (CB1 and CB2), and metabolic enzymes.
Recent research highlights the interaction between the eCBS and non-opioid analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and pyrazolones. These agents may enhance endogenous endocannabinoid levels or influence eCBS signaling pathways, providing a multifaceted approach to pain relief.
This review examines the pharmacological mechanisms underlying these interactions, focusing on the potential of non-opioid eCBS interactions, detailing synergistic effects that could improve analgesic efficacy while minimizing side effects. Additionally, we explore the therapeutic implications of co-administering non-opioid analgesics with eCBS modulators to create more effective pain management strategies.
The combined modulation of non-opioid pathways and the eCBS represents a promising treatment for acute and chronic pain, warranting further clinical investigation and translational research in this evolving field.”
“Emerging Therapeutic Strategies: The integration of non-opioid medications with eCBS modulators represents a novel approach in pain management strategies, aiming to minimize opioid use while maximizing therapeutic efficacy and safety profiles during chronic pain management.”
“Background: Medical cannabis consumption is rising, but limited evidence informs the safety and efficacy of cannabis use in cancer patients. A national survey of oncology trainees found that most fellows felt insufficiently informed to make clinical recommendations about cannabis.
Aim: In this secondary analysis, we aimed to measure how frequently trainees recommend in favor of cannabis and determine factors influencing this clinical practice.
Methods: In this cross-sectional survey study for fellows enrolled in oncology training programs across the United States, an online survey assessing trainee practices regarding medical cannabis was sent to 155 oncology fellowship program directors from January – March 2021; who were asked to distribute it to their fellows. The primary outcome was the frequency with which oncology fellows recommended cannabis in the prior year.
Results: Nationally, 40 programs from 25 states participated, with 189 of 462 trainees across these programs responding (40.9% response rate). 22% (95% CI: 16.3-29.0%) of participants reported recommending medical cannabis to > 5 patients in the past year. 24% (95% CI: 18.4-30.5%) of participants had prior training in medical cannabis. Regarding participant characteristics, only prior training in medical cannabis was significantly associated with recommending cannabis to > 5 patients (RR: 2.4; 95% CI: 1.4-4.2).
Conclusions: With increasing cannabis use among patients with cancer and given that a substantial number of oncology fellows recommend its use, it is crucial that fellowship training incorporate evidence-based curricula regarding medical cannabis use to guide informed decision-making between patients and their fellow providers.”
“1 in 5 oncology fellows participating in our study recommended it to > 5 patients in the past year. Prior training in medical cannabis was the sole factor associated with higher rates of discussing and recommending its use to patients. Personalized, patient-centered care for cancer patients—and all patients—is mandatorily founded on understanding and articulating the best available evidence regarding treatment options.
Accordingly, as medical cannabis gains more widespread legal status and is increasingly considered and used by our patients, it will be of critical importance that contemporary fellowship training programs incorporate rigorous, up-to-date curricula on this subject so as to prepare their trainees to engage in well-informed discussions and shared decision-making with those for whom they care.”
“Wound healing in old mice is characterized by disturbed tissue homeostasis, manifested by delayed immune cell infiltration and reduced growth factor secretion, leading to a delayed onset and prolonged duration of the inflammatory phase.
The endocannabinoid system (ECS) is an important regulator of tissue homeostasis and cell migration and is also considered to be subject to aging processes, which may contribute to observable aging phenomena. Therefore, stimulating the aged ECS could represent a therapeutic option to support tissue regeneration in aging.
Female old mice received a low-dose of medical THC daily for 3 weeks, before four excisional full skin wounds were created. At day 1, 3 and 7 post-surgery, the wound closure rate was analyzed and wound samples were examined immunohistochemically for the numbers of granulocytes, M1-macrophages and mesenchymal stem cells (MSCs). The concentrations of inflammatory cytokines and regenerative growth factors were determined by ELISA.
Administration of THC improved the wound healing rate of old mice between day 1 and 7, which was associated with an altered timing and quantity of infiltrating immune cells and decreased levels of inflammatory cytokines in wound tissue on days 1 and 3 post-injury.
THC treatment significantly increased MSC infiltration but had no effect on the growth factor release.
The present study confirmed the anti-inflammatory activity of THC in vivo.
The THC-treatment improved wound healing in old mice by coordinating the temporal sequence of immune cell infiltration and cytokine release. Thus, restoration of ECS signaling could be an effective strategy to support age-related skin regeneration.”
“Introduction: On May 21, 2024, the Drug Enforcement Administration (DEA) published a proposed rule to reschedule marijuana from schedule I to III under the Controlled Substance Act (CSA), followed by a 60-day open comment period. The purpose of this study was to analyze the public attitudes regarding the proposed rule and identify trends based on time of comment submission and recurring arguments throughout the comments.
Methods: This was an observational, cross-sectional, mixed-methods study. Comments from the proposal were stratified according to the submission date as early (May 21 to June 11), mid- (June 12 to July 2), and late (July 3-22) respondents. Investigators were assigned an equal number of comments to code as in favor of, against, or no clear position on rescheduling. Comments were further coded based on type of comment (form letters, personal anecdotes), rationale for comment (racism, decriminalization, safety, and economic factors), and whether descheduling was favored. Chi-square tests were used to analyze categorical data. A random sample of comments was selected to assure a 5% margin of error.
Results: More than 42,000 comments were submitted. Of these, 380 comments were selected and coded, with 42% (n = 158) in support of rescheduling, 55% (n = 211) against rescheduling, and 2.9% (n = 11) with no clear position. Of all comments coded, 71% wanted to go further and were in support of descheduling. The early responses consisted of a majority in favor of rescheduling, while the mid- and late responses consisted of more comments against rescheduling (X2 [2, N = 369] = 35.8, p < 0.00001). Of the comments against rescheduling, a large majority supported descheduling (X2 [2, N = 265] = 32.0, p < 0.0001). As for comment structure, 69% (n = 263) of all comments coded were form letters, while 8.4% (n = 32) were personal anecdotes.
Conclusion: The number of comments in support of rescheduling decreased with time, only dominating the early respondent wave. Despite a larger number of negative attitudes toward the DEA’s proposed rule of rescheduling marijuana from schedule I to III, a majority of comments supported taking a step further to deschedule marijuana all together.”
“The study’s findings suggest that future cannabis policy discussions may need to address not just rescheduling, but potentially more far-reaching reforms to align with evolving public sentiment. As the conversation around marijuana regulation continues, policymakers will need to carefully balance public health and safety concerns with growing calls for increased access and reduced criminalization.”
“The rapid emergence of multidrug-resistant (MDR) bacterial pathogens poses a critical threat to global health, creating an urgent need for novel antimicrobial agents.
In this study, we evaluated a small library of natural and semisynthetic phytocannabinoids against a broad panel of MDR Gram-positive bacterial strains, evidencing very good activity in the low µM range.
We provide evidence of the antibacterial activity of the two separated enantiomers of cannabidiol, offering novel insights into the stereochemical aspects of their bioactivity.
To investigate the possible molecular targets and clarify the mechanism of action, we employed Inverse Virtual Screening (IVS), a computational approach optimized for predicting potential protein-ligand interactions, on three selected MDR bacterial species. Interestingly, key targets belonging to important bacterial metabolic pathways and defense mechanisms were retrieved, and the results were used to rationalize the observed biological activities.
To the best of our knowledge, this study marks the first application of IVS to microorganisms, offering a novel strategy for identifying bacterial protein targets. The results pave the way for future experimental validation, structure-based drug design, and the development of novel antibacterial agents.”
“These findings suggest that these phytocannabinoids likely exert their antibacterial effects via multi-target inhibition, interfering with multiple essential bacterial pathways.”
