Cannabis and Cannabinoid Research最新文献

Introduction: Following the spread of recreational cannabis legalization and commercialization, cannabis has become increasingly available at lower prices. As policies regulating prices are common tools to control the demand for commercialized drugs, it is crucial to understand how cannabis use responds to price changes. In this study, we assessed the association between wholesale prices for legal cannabis flower and adults' self-reported current cannabis use in ten states with recreational cannabis commercialization in the U.S. Materials and Methods: We conducted a secondary data analysis using individual-level data on cannabis use from the longitudinal Population Assessment of Tobacco and Health Study, during 2015 and 2021. Our analysis included 19,812 U.S. adults from ten states that legalized recreational cannabis sales during the study period. We first conducted logistic regressions to estimate the association between state-level cannabis prices and individual current cannabis use. To address potential endogeneity of cannabis prices, we then employed generalized method of moment (GMM) estimator, using cannabis taxes as an instrumental variable (IV). Results: IV-based GMM regressions suggested that cannabis taxes were a significant predictor of cannabis prices. However, the association between legal cannabis flower prices and adults' current cannabis use was negative but statistically insignificant (coefficient = -0.18, p = 0.086). Price elasticity estimates for current cannabis use ranged from -0.66 to -0.59 across different model specifications. Conclusion: In the initial years of recreational cannabis commercialization in the U.S., the price elasticity of cannabis use among adults was negative but statistically insignificant. Given the rapid progression of commercialization, further research utilizing longer-term data is needed.

Objective: Cannabidiol (CBD), a phytocannabinoid of increasing interest for its purported therapeutic effects, is primarily consumed via ingestion and inhalation. While the toxicology of orally administered CBD has been reported, little is known about the effects of CBD inhalation. Doses selected for the present analysis allowed for evaluation of dose-response at concentrations >100-fold higher than typical human consumption levels. Materials and Methods: CBD (98.89% pure) was formulated in propylene glycol (PG) and aerosolized by nebulization to evaluate biological response after nose-only inhalation. Sprague Dawley rats (n = 35 males, 30 females) were exposed to 1.0 and 1.3 mg/L nominal concentrations of CBD and PG, respectively, for 12-180 min. Resulting average daily presented dose ranges were 8.9-138.5 mg/kg CBD and 11.3-176.0 mg/kg PG. Aerosols of 1.4 µm median diameter were achieved. Biological response indicators included clinical signs, clinical chemistry, hematology, body/organ weights, and pulmonary/systemic histopathology. Results: Inflammatory and necrotic responses were observed in the nose at the highest doses of CBD. Limited findings in the larynx and lung were mainly observed at higher doses. There were no histological findings in extrapulmonary organs. Dosimetry modeling differentiated the no observable adverse effect level between the nasal region and lungs to be 2.8 and 10.6 mg/kg CBD, respectively. Conclusions: Dose-depending findings of histological changes in the respiratory tract are observed at high doses. At lower doses consistent with typical over-the-counter vape products there appears to be substantial safety margin in the present study (93- and 353-fold lower for nose and lung, respectively).

Introduction: Although cannabinoid type 2 (CB2) receptor activity is known to promote diverse biological functions in the kidney, published data regarding CB2 receptor protein levels and cellular distribution within the kidney is inconsistent. The goal of the present study was to investigate the changes of CB2 in the kidney obtained from mice exposed to various forms of kidney injury using a genetic mouse model expressing green fluorescent protein (GFP) driven by the endogenous cannabinoid receptor 2 (Cnr2) promoter. Materials and Methods: Kidney injury was established in a genetic mouse model expressing green fluorescent protein (GFP) driven by the endogenous Cnr2 promoter. Kidney injury was initiated by either treatment with different chemicals [cisplatin or lipopolysaccharide (LPS)] or by unilateral ureteral obstruction (UUO). Changes in the detection of GFP were used as a proxy for CB2 levels and localization. Histological changes due to the injury stimuli were observed by time-related, morphological changes in kidney cytoarchitecture and blood parameters, such as serum creatinine levels. Cnr2 mRNA levels were detected by reverse transcription coupled to polymerase chain reaction (RT-PCR) while protein changes in the tissue lysates were measured by Western blot analysis. Cellular localization of GFP was detected by fluorescent microscopy. Results: Our data demonstrated that there was no band or a minimally detectable band for GFP using kidney lysates from vehicle- or cisplatin-treated mice. A similar lack of GFP was detected in the UUO kidney versus the contralateral control kidney. This is consistent with the low, albeit detectable levels of Cnr2 mRNA in the kidney samples from control or cisplatin treatment. In frozen kidney sections from vehicle and cisplatin-treated mice, GFP fluorescence was not detectable in tubular epithelia, glomeruli or blood vessels in the cortex. Instead, GFP was detected in rare cells within the interstitial space. A second chemical injury model using LPS found a similar lack of GFP protein levels and an absence of legitimate GFP fluorescence in the main cell types within the kidney. Conclusion: These findings suggest that Cnr2 promoter activity is minimally active in normal or injured kidneys, and that pharmacological manipulation of CB2 receptors may be associated with receptors being expressed in cells recruited to the kidney.

Purpose: The purpose of this pilot study was to investigate cannabidiol (CBD) cream's effects on muscle soreness and performance after exercise. Materials and Methods: This double-blinded, placebo-controlled experiment included 15 men and 13 women (n = 28; mean ± standard deviation age: 23.29 ± 2.54 years) untrained in lower-body resistance training. Participants were randomized into control (NG, n = 9), CBD (CG, n = 9), or placebo (PG, n = 10) groups. Participants completed a lower-body fatigue protocol (FP) consisting of unilateral maximal concentric and eccentric isokinetic muscle actions of the quadriceps and hamstrings (5 sets, 10 repetitions, both legs). CG and PG participants applied ∼100 mg CBD or placebo cream, respectively, matched for weight and appearance to the quadriceps on three separate days. NG participants engaged in a sitting rest period matched in duration to cream application processes. Questionnaires, pressure-pain threshold (PPT), peak torque test (PTT), and countermovement jump (CMJ) were assessed. Mixed-model analysis of variance was conducted to assess main effects and interactions (group × muscle × time; group × time). Results: There were no significant interactions or main effects for group for PPT, CMJ, or PTT. There were main effects for time (p < 0.05) for all soreness questions, PPT, CMJ, and PTT. There was one significant interaction (group × time; p = 0.045) for cream/rest effect questions, in which PG participants perceived the effect of cream to be greater than the effect of rest for NG participants. There were main effects for group (p ≤ 0.031) for all soreness questions, in which PG participants perceived enhanced recovery. Conclusions: The present pilot study did not discover any significant impacts of CBD cream use for muscle recovery. For individuals seeking to attenuate muscle soreness and improve performance, the current dose of this topical CBD product may not be an effective treatment.

Introduction: The endocannabinoid system (ECS) is a widespread neurotransmitter system. A key characteristic of the ECS is that there are multiple endogenous ligands (endocannabinoids). Of these, the most extensively studied are arachidonoyl ethanolamide (AEA) and 2-arachidonoyl-glycerol (2-AG), both act as agonists at the cannabinoid CB₁ receptor. In humans, three CB₁ variants have been identified: hCB₁, considered the most abundant G protein-coupled receptor in the brain, alongside the less abundant and studied variants, hCB_1a and hCB_1b. CB₁ exhibits a preference for coupling with inhibitory G_i/o proteins, although its interactions with specific members of the G_i/o family remain poorly characterized. This study aimed to compare the AEA and 2-AG-induced activation of various G protein subtypes at CB₁. Furthermore, we compared the response of human CB₁ (hCB₁, hCB_1a, hCB_1b) and explored species differences by examining rodent receptors (mCB₁, rCB₁). Materials and Methods: Activation of individual G protein subtypes in HEK293 cells transiently expressing CB₁ was measured with G protein dissociation assay utilizing TRUPATH biosensors. The performance of the TRUPATH biosensors was evaluated using Z-factor analysis. Pathway potencies and efficacies were analyzed using the operational analysis of bias to determine G protein subtype selectivity for AEA and 2-AG. Results: Initial screening of TRUPATH biosensors performance revealed variable sensitivities within our system. Based on the biosensor performance, the G protein subtypes pursued for further characterization were G_i1, G_i3, G_oA, G_oB, G_Z, G₁₂, and G₁₃. Across all pathways, AEA demonstrated partial agonism, whereas 2-AG exhibited full or high-efficacy agonism. Notably, we provide direct evidence that the hCB₁ receptor couples to G₁₂ and G₁₃ proteins. Our findings do not indicate any evidence of G protein subtype selectivity. Similar observations were made across the human receptor variants (hCB₁, hCB_1a, hCB_1b), as well as at mCB₁ and rCB₁. Discussion: There was no evidence suggesting G protein subtype selectivity for AEA and 2-AG at CB₁, and this finding remained consistent across human receptor variants and different species.

Since ancient times, humanity has been exploring natural substances with the aim of increasing stress resistance, enhancing biochemical homeostasis, and treating different diseases. In this way, the objective of the present review is to compare the biological effects of cannabinoids (CNBs) with adaptogens, this exploration allows us to consider the controversy if they can be classified together considering the effects on the body. First, the work revises different features of adaptogens such as their chemical structure, ligand-receptors properties, and homeostasis-stress capabilities. Also, this review includes an overview of preclinical and clinical studies of the effect of adaptogens considering a broad spectrum of adverse biological, chemical, and physical factors. Then, the work does a review of the CNBs effects on the body including the principal uses for the treatment of several diseases as neurodegenerative disorders, arthritis, cancer, cardiovascular affections, diabetes, anxiety, chronic pain, among others. In addition, the different characteristics of the specific endocannabinoid system are described explaining the wide CNBs body effects. Finally, this review presents a comparative analysis between CNBs and adaptogens properties, expecting to contribute to understanding if CNBs can be classified as adaptogens.

Aim: Few studies have directly compared the bioavailability of different cannabinoid formulations. Our goal was to assess the pharmacokinetic parameters and relative bioavailability of two Δ9-tetrahydrocannabinol:cannabidiol (THC:CBD) formulations: orally administered THC:CBD extract and oromucosally administered nabiximols. Methods: This pilot crossover study counterbalanced (1) 1 mL of orally administered THC:CBD extract (10 mg/mL each of THC and CBD in grapeseed oil) and (2) oromucosally administered nabiximols (four sprays of 2.7 mg THC and 2.5 mg CBD per spray, for a total dose of 10.8 mg THC and 10 mg CBD). Blood samples were obtained pre-dose and at 16 post-dose timepoints over 24 h. Pharmacokinetic parameters were calculated for THC, 11-hydroxy-tetrahydrocannabinol (11-OH-THC), and CBD. Results: Twelve occasional cannabis users (6 male, 6 female) were tested under fasting conditions. C_max for THC and CBD was significantly higher with significantly shorter half-lives for THC:CBD extract versus nabiximols. C_max for nabiximols was significantly higher in males compared with females. Under both treatment conditions, THC and CBD were undetectable by 24 h post-dose, and 11-OH-THC was markedly reduced from its peak. No serious adverse events were reported. Conclusions: Little is known about the comparative pharmacokinetics of commercially available cannabis products. This pilot study shows that the extract formulation achieved higher THC and CBD concentrations within a shorter time frame than nabiximols. These findings may have implications for clinical populations using these formulations therapeutically. Future studies should examine multiple doses in the context of therapeutic outcomes to characterize the relative clinical utility of these formulations.

Background: Over the last decade, there has been a significant increase in the production of multiple tetrahydrocannabidiol (THC) related products via the acid catalysis of cannabidiol (CBD). The widespread availability of CBD and the unregulated or poorly regulated nature of its use have flooded the market with THC-containing products of unverifiable provenance and frequently contaminated by trace metals and residual solvents. Under non-optimized, poorly controlled, or harsh reaction conditions, these acid-catalyzed transformations yield multiple cannabinoids including Δ⁹-THC and Δ⁸-THC, along with numerous side products. These side products are rarely identified or quantified accurately, and their safety and pharmacology remain largely unknown. Aims: This review aims to present an up-to-date understanding of one of the fundamental transformations in cannabinoid chemistry: the cyclization of CBD to THC. This knowledge will facilitate the development of safer, cleaner, more affordable, and accessible cannabinoid products while guiding medical practitioners and regulators. Materials and Methods: We conducted a literature review of studies published over the last 5-6 years on the interconversion of CBD to THC. Our review focused on the following key aspects: (1) advances in understanding reaction mechanisms and optimizing desirable reaction outcomes; (2) development of new catalysts, including "green chemistry" approaches such as solid-supported acids; and (3) implementation of fit-for-purpose analytical methods to better characterize reaction outcomes and reassess the accuracy of cannabis and hemp product labeling. Results: Provided strict quality controls of materials, reaction conditions, and related isolation techniques, the latest research of the acid-catalyzed CBD cyclization shows that it is feasible to access products with elevated and consistently high quality, enriched with either CBD or THC fractions, in a cost-effective manner. Among a spectrum of possible products, easy access to low-potency THC compositions may be particularly relevant for serving the needs of medical patients consuming cannabis and hemp-derived cannabinoids including dose titration as well as to supporting safe and responsible use in recreational markets now saturated with overly potent products.

Background: Activation of cannabinoid receptor 1 (CB1R) in the nervous system modulates the processing of acute and chronic pain. CB1R activity is regulated by desensitization and internalization. SH3-containing GRB2-like protein 3-interacting protein 1 (SGIP1) inhibits the internalization of CB1R. This causes increased and prolonged association of the desensitized receptor with G protein-coupled receptor kinase 3 (GRK3) and beta-arrestin on the cell membrane and results in decreased activation of extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Genetic deletion of SGIP1 in mice leads to altered CB1R-related functions, such as decreased anxiety-like behaviors, modified cannabinoid tetrad behaviors, reduced acute nociception, and increased sensitivity to analgesics. In this work, we asked if deletion of SGIP1 affects chronic nociception and analgesic effect of Δ⁹-tetrahydrocannabinol (THC) and WIN 55,212-2 (WIN) in mice. Methods: We measured tactile responses of hind paws to increasing pressure in wild-type and SGIP1 knock-out mice. Inflammation in the paw was induced by local injection of carrageenan. To determine the mechanical sensitivity, the paw withdrawal threshold (PWT) was measured using an electronic von Frey instrument with the progression of the applied force. Results: The responses to mechanical stimuli varied depending on the sex, genotype, and treatment. SGIP1 knock-out male mice exhibited lower PWT than wild-type males. On the contrary, the female mice exhibited comparable PWT. Following THC or WIN treatment in male mice, SGIP1 knock-out males exhibited PWT lower than wild-type males. THC treatment in SGIP1 knock-out females resulted in PWT higher than after THC treatment of wild-type females. However, SGIP1 knock-out and wild-type female mice exhibited similar PWT after WIN treatment. Conclusions: We provide evidence that SGIP1, possibly by interacting with CB1R, is involved in processing the responses to chronic pain. The absence of SGIP1 results in enhanced sensitivity to mechanical stimuli in males, but not females. The antinociceptive effect of THC is superior to that of WIN in SGIP1 knock-out mice in the carrageenan-induced model of chronic pain.