Cardiotoxic effects of common and emerging drugs: role of cannabinoid receptors.

Drug-induced cardiotoxicity has become one of the most common and detrimental health concerns, which causes significant loss to public health and drug resources. Cannabinoid receptors (CBRs) have recently achieved great attention for their vital roles in the regulation of heart health and disease, with mounting evidence linking CBRs with the pathogenesis and progression of drug-induced cardiotoxicity. This review aims to summarize fundamental characteristics of two well-documented CBRs (CB1R and CB2R) from aspects of molecular structure, signaling and their functions in cardiovascular physiology and pathophysiology. Moreover, we describe the roles of CB1R and CB2R in the occurrence of cardiotoxicity induced by common drugs such as antipsychotics, anti-cancer drugs, marijuana, and some emerging synthetic cannabinoids. We highlight the 'yin-yang' relationship between CB1R and CB2R in drug-induced cardiotoxicity and propose future perspectives for CBR-based translational medicine toward cardiotoxicity curation and clinical monitoring.

Vaporized D-limonene selectively mitigates the acute anxiogenic effects of Δ9-tetrahydrocannabinol in healthy adults who intermittently use cannabis.

BACKGROUND: Cannabis contains hundreds of chemical constituents beyond delta-9-tetrahydrocannabinol (THC), which is believed to drive most of its acute pharmacodynamic effects. The entourage effect theory asserts that non-THC constituents can impact acute cannabis effects, but few empirical studies have systematically evaluated this theory in humans. This study assessed whether the cannabis terpenoid d-limonene mitigates the acute anxiogenic effects of THC. METHODS: Twenty healthy adults completed nine, double-blind outpatient sessions in which they inhaled vaporized THC alone (15mg or 30mg), d-limonene alone (1mg or 5mg), the same doses of THC and d-limonene together, or placebo; a subset of participants (n=12) completed a tenth session in which 30mg THC+15mg d-limonene was administered. Outcomes included subjective drug effects, cognitive/psychomotor performance, vital signs, and plasma THC and d-limonene concentrations. RESULTS: When d-limonene was administered alone, pharmacodynamic outcomes did not differ from placebo. Administration of 15mg and 30mg THC alone produced subjective, cognitive, and physiological effects typical of acute cannabis exposure. Ratings of anxiety-like subjective effects qualitatively decreased as d-limonene dose increased and concurrent administration of 30mg THC+15mg d-limonene significantly reduced ratings of "anxious/nervous" and "paranoid" compared with 30mg THC alone. Other pharmacodynamic effects were unchanged by d-limonene. D-limonene plasma concentrations were dose orderly, and concurrent administration of d-limonene did not alter THC pharmacokinetics. CONCLUSIONS: D-limonene selectively attenuated THC-induced anxiogenic effects, suggesting this terpenoid could increase the therapeutic index of THC. Future research should determine whether this effect extends to oral dose formulations and evaluate the interactions between other cannabis terpenoids or cannabinoids and THC.

Evaluating the Mechanism of Cell Death in Melanoma Induced by the Cannabis Extract PHEC-66.

Research suggests the potential of using cannabinoid-derived compounds to function as anticancer agents against melanoma cells. Our recent study highlighted the remarkable in vitro anticancer effects of PHEC-66, an extract from Cannabis sativa, on the MM418-C1, MM329, and MM96L melanoma cell lines. However, the complete molecular mechanism behind this action remains to be elucidated. This study aims to unravel how PHEC-66 brings about its antiproliferative impact on these cell lines, utilising diverse techniques such as real-time polymerase chain reaction (qPCR), assays to assess the inhibition of CB1 and CB2 receptors, measurement of reactive oxygen species (ROS), apoptosis assays, and fluorescence-activated cell sorting (FACS) for apoptosis and cell cycle analysis. The outcomes obtained from this study suggest that PHEC-66 triggers apoptosis in these melanoma cell lines by increasing the expression of pro-apoptotic markers (BAX mRNA) while concurrently reducing the expression of anti-apoptotic markers (Bcl-2 mRNA). Additionally, PHEC-66 induces DNA fragmentation, halting cell progression at the G1 cell cycle checkpoint and substantially elevating intracellular ROS levels. These findings imply that PHEC-66 might have potential as an adjuvant therapy in the treatment of malignant melanoma. However, it is essential to conduct further preclinical investigations to delve deeper into its potential and efficacy.

Anti-staphylococcal activity of soilless cultivated cannabis across the whole vegetation cycle under various nutritional treatments in relation to cannabinoid content.

Antibiotic resistance in staphylococcal strains and its impact on public health and agriculture are global problems. The development of new anti-staphylococcal agents is an effective strategy for addressing the increasing incidence of bacterial resistance. In this study, ethanolic extracts of Cannabis sativa L. made from plant parts harvested during the whole vegetation cycle under various nutritional treatments were assessed for in vitro anti-staphylococcal effects. The results showed that all the cannabis extracts tested exhibited a certain degree of growth inhibition against bacterial strains of Staphylococcus aureus, including antibiotic-resistant and antibiotic-sensitive forms. The highest antibacterial activity of the extracts was observed from the 5th to the 13th week of plant growth across all the nutritional treatments tested, with minimum inhibitory concentrations ranging from 32 to 64 µg/mL. Using HPLC, Δ9-tetrahydrocannabinolic acid (THCA) was identified as the most abundant cannabinoid in the ethanolic extracts. A homolog of THCA, tetrahydrocannabivarinic acid (THCVA), reduced bacterial growth by 74%. These findings suggest that the cannabis extracts tested in this study can be used for the development of new anti-staphylococcal compounds with improved efficacy.

Contingency management is associated with positive changes in attitudes and reductions in cannabis use even after discontinuation of incentives among non-treatment seeking youth.

BACKGROUND: It is important to identify interventions that reduce harm in youth not motivated to change their cannabis use. This study evaluated how short-duration contingency management (CM) impacts cannabis use attitudes and behavior after abstinence incentives are discontinued among non-treatment seeking youth. METHODS: Participants (N=220) were randomized to 4 weeks of abstinence-based CM (CB-Abst; n=126) or monitoring (CB-Mon; n=94). Participants completed self-report and provided biochemical measures of cannabis exposure at baseline, end-of-intervention, and 4-week follow-up. Changes in self-reported cannabis use frequency (days/week; times/week) and biochemically verified creatinine-adjusted 11-nor-9-carboxy-tetrahydrocannabinol concentrations (CN-THCCOOH) were analyzed between groups from baseline to follow-up. In CB-Abst, cannabis use goals at end-of-intervention were described and changes in cannabis use at follow-up were explored by goals and cannabis use disorder (CUD) diagnosis. RESULTS: There was a group by visit interaction on cannabis use (days: beta=0.93, p=0.005; times: beta=0.71, p<0.001; CN-THCCOOH: beta=0.26, p=0.004), with reductions at follow-up detected only in CB-Abst. Following 4 weeks of abstinence, 68.4% of CB-Abst participants wanted to reduce or abstain from cannabis use following completion of CM. Those in CB-Abst who set end-of-intervention reduction goals and were without CUD had greater decreases in cannabis use frequency at follow-up (Goals*time on days/week: beta=-2.27, p<0.001; CUD*time on times/week: beta=0.48, SE=0.24, t=2.01, p=0.048). CONCLUSIONS: Findings support the utility of brief incentivized abstinence for generating motivation to reduce cannabis use and behavior change even after incentives end. This study supports CM as a potentially viable harm reduction strategy for those not yet ready to quit.

The Neurotherapeutic Arsenal in Cannabis sativa: Insights into Anti-Neuroinflammatory and Neuroprotective Activity and Potential Entourage Effects.

Cannabis, renowned for its historical medicinal use, harbours various bioactive compounds-cannabinoids, terpenes, and flavonoids. While major cannabinoids like delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have received extensive scrutiny for their pharmacological properties, emerging evidence underscores the collaborative interactions among these constituents, suggesting a collective therapeutic potential. This comprehensive review explores the intricate relationships and synergies between cannabinoids, terpenes, and flavonoids in cannabis. Cannabinoids, pivotal in cannabis's bioactivity, exhibit well-documented analgesic, anti-inflammatory, and neuroprotective effects. Terpenes, aromatic compounds imbuing distinct flavours, not only contribute to cannabis's sensory profile but also modulate cannabinoid effects through diverse molecular mechanisms. Flavonoids, another cannabis component, demonstrate anti-inflammatory, antioxidant, and neuroprotective properties, particularly relevant to neuroinflammation. The entourage hypothesis posits that combined cannabinoid, terpene, and flavonoid action yields synergistic or additive effects, surpassing individual compound efficacy. Recognizing the nuanced interactions is crucial for unravelling cannabis's complete therapeutic potential. Tailoring treatments based on the holistic composition of cannabis strains allows optimization of therapeutic outcomes while minimizing potential side effects. This review underscores the imperative to delve into the intricate roles of cannabinoids, terpenes, and flavonoids, offering promising prospects for innovative therapeutic interventions and advocating continued research to unlock cannabis's full therapeutic potential within the realm of natural plant-based medicine.

The Effect of Oil-Based Cannabis Extracts on Metabolic Parameters and Microbiota Composition of Mice Fed a Standard and a High-Fat Diet.

The prevalence of obesity and obesity-related pathologies is lower in frequent cannabis users compared to non-users. It is well established that the endocannabinoid system has an important role in the development of obesity. We recently demonstrated that prolonged oral consumption of purified Δ-9 Tetrahydrocannabinol (THC), but not of cannabidiol (CBD), ameliorates diet-induced obesity and improves obesity-related metabolic complications in a high-fat diet mouse model. However, the effect of commercially available medical cannabis oils that contain numerous additional active molecules has not been examined. We tested herein the effects of THC- and CBD-enriched medical cannabis oils on obesity parameters and the gut microbiota composition of C57BL/6 male mice fed with either a high-fat or standard diet. We also assessed the levels of prominent endocannabinoids and endocannabinoid-like lipid mediators in the liver. THC-enriched extract prevented weight gain by a high-fat diet and attenuated diet-induced liver steatosis concomitantly with reduced levels of the lipid mediators palmitoyl ethanolamide (PEA) and docosahexaenoyl ethanolamide (DHEA) in the liver. In contrast, CBD-enriched extract had no effect on weight gain, but, on the contrary, it even exacerbated liver steatosis. An analysis of the gut microbiota revealed that mainly time but not treatment exerted a strong effect on gut microbiota alterations. From our data, we conclude that THC-enriched cannabis oil where THC is the main constituent exerts the optimal anti-obesity effects.

Pharmacohistory of Cannabis Use-A New Possibility in Future Drug Development for Gastrointestinal Diseases.

Humans have employed cannabis for multiple uses including medicine, recreation, food, and fibre. The various components such as roots, flowers, seeds, and leaves have been utilized to alleviate pain, inflammation, anxiety, and gastrointestinal disorders like nausea, vomiting, diarrhoea, and inflammatory bowel diseases (IBDs). It has occupied a significant space in ethnomedicines across cultures and religions. Despite multi-dimensional uses, the global prohibition of cannabis by the USA through the introduction of the Marijuana Tax Act in 1937 led to prejudice about the perceived risks of cannabis, overshadowing its medicinal potential. Nevertheless, the discovery of tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, and the endocannabinoid system renewed scientific interest in understanding the role of cannabis in modulating different conditions, including gastrointestinal disorders. Preparations combining cannabidiol and THC have shown promise in mitigating gut symptoms through anti-inflammatory and motility-enhancing effects. This review revisits the ethnomedicinal use of cannabis in gastrointestinal diseases and emphasizes the need for further research to determine optimal dosages, formulations, and safety profiles of cannabis-based medicines. It also underscores the future potential of cannabinoid-based therapies by leveraging the role of the expanded endocannabinoid system, an endocannabinoidome, in the modulation of gastrointestinal ailments.

Marijuana and Cannabidiol Use Prevalence and Symptom Management Among Patients with Cancer.

Symptoms such as pain, nausea, and anxiety are common in individuals with cancer. Treatment of these issues is often challenging. Cannabis products may be helpful in reducing the severity of these symptoms. While some studies include data on the prevalence of cannabis use among patients with cancer, detailed data remain limited, and none have reported the prevalence of cannabidiol (CBD) use in this population. Adult patients with cancer attending eight clinics at a large, NCI-designated Comprehensive Cancer Center completed a detailed, cannabis-focused questionnaire between 2021 and 2022. Eligible participants were diagnosed with invasive cancer and treated in the past 12 months. Summary statistics were calculated to describe the sample regarding cannabis use. Approximately 15% (n = 142) of consented patients (n = 934) reported current cannabis use (defined as use within the past 12 months). Among which, 75% reported cannabis use in the past week. Among current cannabis users, 39% (n = 56; 6% overall) used CBD products. Current users reported using cannabis a median of 4.5 (interquartile range: 0.6­7.0) days/week, 2.0 (1.0­3.0) times per use/day, and for 3 years (0.8­30.0). Use patterns varied by route of administration. Patients reported moderate to high relief of symptoms with cannabis use. This study is the most detailed to date in terms of cannabis measurement and provides information about the current state of cannabis use in active cancer. Future studies should include complete assessments of cannabis product use, multiple recruitment sites, and diverse patient populations. SIGNIFICANCE: Clinicians should be aware that patients are using cannabis products and perceive symptom relief with its use.

The endocannabinoid system as a putative target for the development of novel drugs for the treatment of psychiatric illnesses.

Cannabis is well established to impact affective states, emotion and perceptual processing, primarily through its interactions with the endocannabinoid system. While cannabis use is quite prevalent in many individuals afflicted with psychiatric illnesses, there is considerable controversy as to whether cannabis may worsen these conditions or provide some form of therapeutic benefit. The development of pharmacological agents which interact with components of the endocannabinoid system in more localized and discrete ways then via phytocannabinoids found in cannabis, has allowed the investigation if direct targeting of the endocannabinoid system itself may represent a novel approach to treat psychiatric illness without the potential untoward side effects associated with cannabis. Herein we review the current body of literature regarding the various pharmacological tools that have been developed to target the endocannabinoid system, their impact in preclinical models of psychiatric illness and the recent data emerging of their utilization in clinical trials for psychiatric illnesses, with a specific focus on substance use disorders, trauma-related disorders, and autism. We highlight several candidate drugs which target endocannabinoid function, particularly inhibitors of endocannabinoid metabolism or modulators of cannabinoid receptor signaling, which have emerged as potential candidates for the treatment of psychiatric conditions, particularly substance use disorder, anxiety and trauma-related disorders and autism spectrum disorders. Although there needs to be ongoing clinical work to establish the potential utility of endocannabinoid-based drugs for the treatment of psychiatric illnesses, the current data available is quite promising and shows indications of several potential candidate diseases which may benefit from this approach.

Causal relationship between addictive behaviors and epilepsy risk: A mendelian randomization study.

BACKGROUND: Previous studies have reported inconsistent results regarding the potential relationships between addictive behaviors and the risk of epilepsy. OBJECTIVE: To assess whether genetically predicted addictive behaviors are causally associated with the risk of epilepsy outcomes. METHODS: The causation between five addictive behaviors (including cigarettes per day, alcoholic drinks per week, tea intake, coffee intake, and lifetime cannabis use) and epilepsy was evaluated by using a two-sample Mendelian Randomization (MR) analysis. The inverse-variance weighted (IVW) method was used as the primary outcome. The other MR analysis methods (MR Egger, weighted median, simulation extrapolation corrected MR-Egger, and Mendelian Randomization Pleiotropy Residual Sum and Outlier (MR-PRESSO)) were performed to complement IVW. In addition, the robustness of the MR analysis results was assessed by leave-one-out analysis. RESULTS: The IVW analysis method indicated an approximately 20% increased risk of epilepsy per standard deviation increase in lifetime cannabis use (odds ratio [OR], 1.20; 95% confidence interval [CI]), 1.02-1.42, P = 0.028). However, there is no causal association between the other four addictive behaviors and the risk of epilepsy (cigarettes per day: OR, 1.04; 95% CI, 0.92-1.18, P = 0.53; alcoholic drinks per week: OR, 1.31; 95% CI, 0.93-1.84, P = 0.13; tea intake: OR, 1.15; 95% CI, 0.84-1.56, P = 0.39; coffee intake: OR, 0.86; 95% CI, 0.59-1.23, P = 0.41). The other MR analysis methods and further leave-one-out sensitivity analysis suggested the results were robust. CONCLUSION: This MR study indicated a potential genetically predicted causal association between lifetime cannabis use and higher risk of epilepsy. As for the other four addictive behaviors, no evidence of a causal relationship with the risk of epilepsy was found in this study.

Cannabis and cannabinoids in dermatology: protocol for a systematic review and meta-analysis of quantitative outcomes.

INTRODUCTION: Following the discovery of various effects on skin function by modifying endocannabinoid systems, multiple preclinical studies have revealed the promise of cannabis and cannabinoids in the treatment of a variety of skin diseases. However, its clinical efficacy is still debated. METHODS AND ANALYSIS: The protocol has been prepared using the Preferred Items for Systematic Review and Meta-analysis Protocols guidelines. A systematic search will be conducted using PubMed, EMBASE, SCOPUS, the Cochrane Central Register of Controlled Trials and Web of Science. We will include randomised controlled trials and observational studies investigating alterations to dermatological characteristics following administration of cannabis and cannabinoids for dermatological diseases and disorders. The two reviewers will perform both the title and abstract and full-text screenings. The Cochrane Risk-of-Bias 2 and ROBINS-1 tools will be used to evaluate the risk of bias. If a group of comparable studies for each quantitative outcome can be discovered, we will conduct a random effects meta-analysis. We will investigate heterogeneity using a combination of visual inspection of the forest plot, the Cochran's Q test and Higgins' test [I2]. Sensitivity analyses will be performed to assess the statistical robustness of the primary outcome. To evaluate a publication bias, the Egger's regression asymmetry test and funnel plots will be considered. ETHICS AND DISSEMINATION: This study does not require ethical approval because no original data will be collected. The findings will be presented at conferences and published in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42023397189.

Prevalence of Cannabis Use Disorder and Reasons for Use Among Adults in a US State Where Recreational Cannabis Use Is Legal.

Importance: Medical and nonmedical cannabis use and cannabis use disorders (CUD) have increased with increasing cannabis legalization. However, the prevalence of CUD among primary care patients who use cannabis for medical or nonmedical reasons is unknown for patients in states with legal recreational use. Objective: To estimate the prevalence and severity of CUD among patients who report medical use only, nonmedical use only, and both reasons for cannabis use in a state with legal recreational use. Design, Setting, and Participants: This cross-sectional survey study took place at an integrated health system in Washington State. Among 108 950 adult patients who completed routine cannabis screening from March 2019 to September 2019, 5000 were selected for a confidential cannabis survey using stratified random sampling for frequency of past-year cannabis use and race and ethnicity. Among 1688 respondents, 1463 reporting past 30-day cannabis use were included in the study. Exposure: Patient survey-reported reason for cannabis use in the past 30 days: medical use only, nonmedical use only, and both reasons. Main Outcomes and Measures: Patient responses to the Composite International Diagnostic Interview-Substance Abuse Module for CUD, corresponding to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition CUD severity (0-11 symptoms) were categorized as any CUD (≥2 symptoms) and moderate to severe CUD (≥4 symptoms). Adjusted analyses were weighted for survey stratification and nonresponse for primary care population estimates and compared prevalence of CUD across reasons for cannabis use. Results: Of 1463 included primary care patients (weighted mean [SD] age, 47.4 [16.8] years; 748 [weighted proportion, 61.9%] female) who used cannabis, 42.4% (95% CI, 31.2%-54.3%) reported medical use only, 25.1% (95% CI, 17.8%-34.2%) nonmedical use only, and 32.5% (95% CI, 25.3%-40.8%) both reasons for use. The prevalence of CUD was 21.3% (95% CI, 15.4%-28.6%) and did not vary across groups. The prevalence of moderate to severe CUD was 6.5% (95% CI, 5.0%-8.6%) and differed across groups: 1.3% (95% CI, 0.0%-2.8%) for medical use, 7.2% (95% CI, 3.9%-10.4%) for nonmedical use, and 7.5% (95% CI, 5.7%-9.4%) for both reasons for use (P = .01). Conclusions and Relevance: In this cross-sectional study of primary care patients in a state with legal recreational cannabis use, CUD was common among patients who used cannabis. Moderate to severe CUD was more prevalent among patients who reported any nonmedical use. These results underscore the importance of assessing patient cannabis use and CUD symptoms in medical settings.

A machine learning approach for understanding the metabolomics response of children with autism spectrum disorder to medical cannabis treatment.

Autism spectrum disorder (ASD) is a neurodevelopmental condition impacting behavior, communication, social interaction and learning abilities. Medical cannabis (MC) treatment can reduce clinical symptoms in individuals with ASD. Cannabis-responsive biomarkers are metabolites found in saliva that change in response to MC treatment. Previously we showed levels of these biomarkers in children with ASD successfully treated with MC shift towards the physiological levels detected in typically developing (TD) children, and potentially can quantify the impact. Here, we tested for the first time the capabilities of machine learning techniques applied to our dynamic, high-resolution and rich feature dataset of cannabis-responsive biomarkers from a limited number of children with ASD before and after MC treatment and a TD group to identify: (1) biomarkers distinguishing ASD and TD groups; (2) non-cannabinoid plant molecules with synergistic effects; and (3) biomarkers associated with specific cannabinoids. We found: (1) lysophosphatidylethanolamine can distinguish between ASD and TD groups; (2) novel phytochemicals contribute to the therapeutic effects of MC treatment by inhibition of acetylcholinesterase; and (3) THC- and CBD-associated cannabis-responsive biomarkers are two distinct groups, while CBG is associated with some biomarkers from both groups.

The Anti-Inflammatory Effects of Cannabis sativa Extracts on LPS-Induced Cytokines Release in Human Macrophages.

Inflammation is the response of the innate immune system to any type of injury. Although acute inflammation is critical for survival, dysregulation of the innate immune response leads to chronic inflammation. Many synthetic anti-inflammatory drugs have side effects, and thus, natural anti-inflammatory compounds are still needed. Cannabis sativa L. may provide a good source of anti-inflammatory molecules. Here, we tested the anti-inflammatory properties of cannabis extracts and pure cannabinoids in lipopolysaccharide (LPS)-induced inflammation in human THP-1 macrophages. We found that pre-treatment with cannabidiol (CBD), delta-9-tetrahydrocannabinol (THC), or extracts containing high levels of CBD or THC reduced the level of induction of various cytokines. The CBD was more efficient than THC, and the extracts were more efficient than pure cannabinoids. Finally, IL-6, IL-10, and MCP-1 cytokines were most sensitive to pre-treatments with CBD and THC, while IL-1ß, IL-8, and TNF-α were less responsive. Thus, our work demonstrates the potential of the use of cannabinoids or/and cannabis extracts for the reduction of inflammation and establishes IL-6 and MCP-1 as the sensitive markers for the analysis of the effect of cannabinoids on inflammation in macrophages.

The Exploration of Cannabis and Cannabinoid Therapies for Migraine.

PURPOSE OF REVIEW: There is increasing interest in the use of cannabis and cannabinoid therapies (CCT) by the general population and among people with headache disorders, which results in a need for healthcare professionals to be well versed with the efficacy and safety data. In this manuscript, we review cannabis and cannabinoid terminology, the endocannabinoid system and its role in the central nervous system (CNS), the data on efficacy, safety, tolerability, and potential pitfalls associated with use in people with migraine and headache disorders. We also propose possible mechanisms of action in headache disorders and debunk commonly held myths about its use. RECENT FINDINGS: Preliminary studies show that CCT have evidence for the management of migraine. While this evidence exists, further randomized, controlled studies are needed to better support its clinical use. CCT can be considered an integrative treatment added to mainstream medicine for people with migraine who are refractory to treatment and/or exhibit disability and/or interest in trying these therapies. Further studies are warranted to specify appropriate formulation, dosage, and indication(s). Although not included in guidelines or the AHS 2021 Consensus Statement on migraine therapies, with the legalization of CCT for medical or unrestricted use across the USA, recent systematic reviews highlighting the preliminary evidence for its use in migraine, it is vital for clinicians to be well versed in the efficacy, safety, and clinical considerations for their use. This review provides information which can help people with migraine and clinicians who care for them make mutual, well-informed decisions on the use of cannabis and cannabinoid therapies for migraine based on the existing data.

Long-Term Treatment with Cannabidiol-Enriched Cannabis Extract Induces Synaptic Changes in the Adolescent Rat Hippocampus.

The endocannabinoid system (eCS) is widely distributed in mammalian tissues and it is classically formed by cannabinoid receptors, endogenous bioactive lipids and its synthesis and degradation enzymes. Due to the modulatory role of eCS in synaptic activity in the Central Nervous System (CNS), phytocannabinoids have been increasingly used for the treatment of neurological disorders, even though little is known in terms of the long-term effect of these treatments on CNS development, mainly in the timeframe that comprises childhood and adolescence. Furthermore, an increased number of clinical trials using full-spectrum Cannabis extracts has been seen, rather than the isolated form of phytocannabinoids, when exploring the therapeutical benefits of the Cannabis plant. Thus, this study aims to evaluate the effect of cannabidiol (CBD)-enriched Cannabis extract on synaptic components in the hippocampus of rats from adolescence to early adulthood (postnatal day 45 to 60). Oral treatment of healthy male Wistar rats with a CBD-enriched Cannabis extract (3 mg/kg/day CBD) during 15 days did not affect food intake and water balance. There was also no negative impact on locomotor behaviour and cognitive performance. However, the hippocampal protein levels of GluA1 and GFAP were reduced in animals treated with the extract, whilst PSD95 levels were increased, which suggests rearrangement of glutamatergic synapses and modulation of astrocytic features. Microglial complexity was reduced in CA1 and CA3 regions, but no alterations in their phagocytic activity have been identified by Iba-1 and LAMP2 co-localization. Collectively, our data suggest that CBD-enriched Cannabis treatment may be safe and well-tolerated in healthy subjects, besides acting as a neuroprotective agent against hippocampal alterations related to the pathogenesis of excitatory and astrogliosis-mediated disorders in CNS.

History of Cannabis Regulation and Medicinal Therapeutics: It's Complicated.

The genus Cannabis has a complex history, with great variations in the genus itself, as well as in its current uses worldwide. Today, it is the most commonly used psychoactive substance, with 209 million users in 2020. The legalization of cannabis for medicinal or adult use is complex. From its origins as a therapeutic agent in 2800 bc China, to the current knowledge on cannabinoids and the cannabinoid system, to the complex status of cannabis regulation across continents-knowledge gained from the history of cannabis use can inform research on cannabis-based treatments for patients with medical conditions that remain challenging in 21st century medicine, warranting research and evidence-based policy options. Changes in cannabis-related policymaking, scientific advances, and perceptions may result in increasing patient inquiries about its medicinal usage, regardless of personal opinions, thus meriting education and training of clinicians. This commentary outlines the long history of cannabis use, its current therapeutic potential from a regulatory research perspective, and the continued challenges in research and regulation in the ever-changing era of modern cannabis use. It is crucial to understand the history and complexity of cannabis use as medicine to better understand its potential for clinical therapeutics and the effects of modern-day legalization on other health- and society-related issues.

Evaluation of the Analgesic Effect of High-Cannabidiol-Content Cannabis Extracts in Different Pain Models by Using Polymeric Micelles as Vehicles.

Currently, cannabis is considered an attractive option for the treatment of various diseases, including pain management. Thus, developing new analgesics is paramount for improving the health of people suffering from chronic pain. Safer natural derivatives such as cannabidiol (CBD) have shown excellent potential for the treatment of these diseases. This study aimed to evaluate the analgesic effect of a CBD-rich cannabis extract (CE) encapsulated in polymeric micelles (CBD/PMs) using different pain models. The PEG-PCL polymers were characterized by gel permeation chromatography and 1H-NMR spectroscopy. PMs were prepared by solvent evaporation and characterized by dynamic light scattering (DLS) and transmission electron microscopy. The analgesic activity of CBD/PMs and nonencapsulated CE rich in CBD (CE/CBD) was evaluated using mouse thermal, chemical, and mechanical pain models. The acute toxicity of the encapsulated CE was determined by oral administration in mice at a dose of 20 mg/kg for 14 days. The release of CBD from the nanoparticles was assessed in vitro using a dialysis experiment. CBD/PMs with an average hydrodynamic diameter of 63.8 nm obtained from a biocompatible polyethylene glycol-block-polycaprolactone copolymer were used as nanocarriers for the extract formulations with 9.2% CBD content, which corresponded with a high encapsulation efficiency of 99.9%. The results of the pharmacological assays indicated that orally administered CBD/PMs were safe and exerted a better analgesic effect than CE/CBD. The micelle formulation had a significant analgesic effect in a chemical pain model, reaching a percentage of analgesia of 42%. CE was successfully encapsulated in a nanocarrier, providing better stability. Moreover, it proved to be more efficient as a carrier for CBD release. The analgesic activity of CBD/PMs was higher than that of free CE, implying that encapsulation is an efficient strategy for improving stability and functionality. In conclusion, CBD/PMs could be promising therapeutics for pain management in the future.