Cannabis and Cannabinoid Research最新文献

Introduction: The 2019 outbreak of e-cigarette or vaping product use-associated lung injury (EVALI) is believed to have been caused by vitamin E acetate, an additive used in some cannabis vaporizer products. Previous studies have primarily focused on changes in sales of electronic nicotine delivery systems following the initial advisory issued by the Centers for Disease Control (CDC) on August 17, 2019. The present study is intended to examine variation by age groups in sales of regulated cannabis vape products in the state of California before, during, and after the outbreak. Methods: Weekly sales revenue of cannabis vape products (from January 1, 2018, to December 31, 2020) was obtained from a sample of recreational cannabis retailers licensed in California. An interrupted time series analysis, using AutoRegressive, Integrated, Moving Average methods, was employed to estimate changes in the sales and market share of cannabis vape products in the weeks following the CDC advisory. Results: The total volume of regulated cannabis vape product sales increased substantially over the 3-year study period (2018-2020). Sales and market share of cannabis vape products, however, declined in both young and older adults immediately following the advisory, rebounding to pre-EVALI levels only for the young adults. For sales, the potential EVALI effect following the CDC's advisory equates to an 8.0% and 2.2% decline below expected levels in the older and young adults, respectively. Conclusions: The differential age effect on sales may reflect concerns regarding health effects of cannabis vaping products and greater awareness of the outbreak among older adults. Findings highlight the importance of informing consumers about health risks associated with using cannabis vape products acquired from regulated versus illicit sources.

Background: Osteoarthritis (OA) is a progressive degenerative joint disease that presents with significant pain and functional disability. The endocannabinoid 2-arachidonoylglycerol activates cannabinoid receptors to reduce pain while its hydrolysis by the enzyme monoacylglycerol lipase (MAGL) generates arachidonic acid, the direct precursor to proalgesic eicosanoids synthesized by cyclooxygenase-2 (COX-2), highlighting the potential for crosstalk between MAGL and COX-2. While COX-2 expression in human OA cartilage has been described, the distribution of MAGL in knee osteochondral tissue has not been reported and was the goal of the current study. Methods: MAGL and COX-2 expression in International Cartilage Repair Society grade II and grade IV knee osteochondral tissue obtained from male and female subjects with OA was investigated through immunohistochemistry. Immunolocalization of both proteins was investigated within articular cartilage and subchondral bone. Results: MAGL is expressed throughout the cartilage of grade II arthritic tissue, with prominent distribution in the superficial and deep zones. Elevated expression of MAGL was evident in grade IV samples, with additional distribution observed in subchondral bone. COX-2 expression followed a similar pattern, with uniform distribution in cartilage and increased expression in grade IV tissue. Conclusions: This study establishes MAGL expression in arthritic cartilage and subchondral bone of subjects with OA. The proximity between MAGL and COX-2 suggests the potential for crosstalk between endocannabinoid hydrolysis and eicosanoid signaling in the maintenance of OA pain.

Introduction: Complex regional pain syndrome type I (CRPS-I) is a debilitating neuropathic painful condition associated with allodynia, hyperalgesia, sudomotor and/or vasomotor dysfunctions, turning investigation of its pathophysiology and new therapeutic strategies into an essential topic. We aim to investigate the impact of ischemia/reperfusion injury on the immunocontent of CB1 and CB2 cannabinoid receptor isoforms in the paws of mice submitted to a chronic postischemia pain (CPIP) model and the effects of local administration of cannabidiol (CBD) on mechanical hyperalgesia. Methods: Female Swiss mice, 30-35 g, were submitted to the CPIP model on the right hind paw. Skin and muscle samples were removed at different periods for western blot analysis. Results: No changes in the immunocontent of CB1 and CB2 receptors in paw muscle tissues after ischemia-reperfusion were observed. CBD promoted an antihyperalgesic effect in both phases. AM281 reversed the effect of CBD, whereas ruthenium red abolished the late phase. Conclusion: Our results point to the possible beneficial effects of local administration of CBD in modulating CRPS-I in humans. As possible targets for CBD antihyperalgesia in this model, the contribution of cannabinoid receptor CB1, in addition to TRPM8 is suggested.

Background: The concept of an "entourage" effect in the cannabis and cannabinoids' field was first introduced in the late 1990s, during a period when most research on medical cannabinoids focused on the effects of isolated cannabinoids, such as cannabidiol and Δ9-tetrahydrocannabinol. Over the past decade, however, with the increased understanding of the endocannabinoid system, the discovery of other phytocannabinoids and their potential therapeutic uses, the term has gained widespread use in scientific reviews and marketing campaigns. Objective: Critically review the application of the term "entourage effect (EE)" in the literature and its endorsement by certain sectors of the cannabis market. Also, explore the perspectives for further interpretation and elaboration of the term based on current evidence, aiming to contribute to a more nuanced understanding of the concept and its implications for cannabinoid-based medicine. Methods: A comprehensive review of the literature was conducted to evaluate the current state of knowledge regarding the entourage effect. Relevant studies and scientific reviews were analyzed to assess the evidence of clinical efficacy and safety, as well as the regulation of cannabinoid-containing product production. Results: The EE is now recognized as a synergistic phenomenon in which multiple components of cannabis interact to modulate the therapeutic actions of the plant. However, the literature provides limited evidence to support it as a stable and predictable phenomenon. Hence, there is also limited evidence to support clinical efficacy, safety, and appropriate regulation for cannabinoid-containing products based on a "entourage" hypothesis. Conclusion: The EE has significant implications for the medical use of cannabinoid-containing products and their prescription. Nevertheless, a critical evaluation of the term's application is necessary. Further research and evidence are needed to establish the clinical efficacy, safety, and regulatory framework for these products. It's crucial that regulators, the pharmaceutical industry, the media, and health care providers exercise caution and avoid prematurely promoting the entourage effect hypothesis as a scientific proven phenomenon for cannabinoids and other cannabis-derived compound combinations.

Introduction: Across the cannabis market, multiple cannabinoids have seen rapid growth. Considering the differing effects between specific cannabinoids, it is critical to assess effects on an individual level. Hexahydrocannabinol (HHC) is one intoxicating cannabinoid that became more accessible due to regulatory shifts. The purpose of the current study was to provide descriptive data regarding HHC use patterns and perceived effects within a sample of participants who endorsed recent HHC use. Methods: One hundred nine individuals self-reported use of an HHC-cannabis product at least once within 6 months and completed an HHC use questionnaire via Prolific, an online crowdsourcing platform. Results: Findings suggest recent HHC users are using HHC relatively frequently (∼10 days during the past month) for various indications, including anxiety and pain. HHC was perceived to yield more good than bad effects, including relaxation and euphoria. Approximately 17% of the sample reported adverse effects, and ∼20% of those who stopped using HHC experienced some withdrawal symptoms. Few meaningful sex differences in subjective effect ratings were observed. Discussion: The current study provides critical preliminary data about consumer use patterns and perceived effects related to HHC. Such data are needed to further research on the potential therapeutic as well as detrimental effects of HHC and to better inform the consumers, health professionals, and regulators about a cannabinoid that is widely available the market.

Introduction: Basic pharmacokinetic (PK) and pharmacodynamic models of the phytocannabinoids Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are critical for developing translational models of exposure and toxicity. The neonatal period is a particularly important time to study the effects of cannabinoids, yet there are few studies of cannabinoid PKs by different routes such as direct injection or breast milk ingestion. To study this question, we have developed a translationally relevant rodent model of perinatal cannabinoid administration by measuring plasma levels of THC and CBD after different routes and preparations of these drugs. Materials and Methods: Adult animals and pups were injected with THC or CBD either intraperitoneally or subcutaneously, and plasma was analyzed by liquid chromatography-tandem mass spectrometry to measure cannabinoid levels collected at specified intervals. We also tested the effect of preparation of the drug using an oil-based vehicle (sesame oil) and an aqueous vehicle (Tween). Finally, we measured the plasma levels of cannabinoids in neonatal pups that were transmitted through breast milk after intraperitoneal injection to nursing dams. Results: We observed differences in the PK profiles of cannabinoids in adults and neonatal pups that were dependent on the route of administration and type of vehicle. Cannabinoids prepared in aqueous vehicle, injected intraperitoneally, resulted in a high peak in plasma concentration, which rapidly decreased. In contrast, subcutaneous injections using sesame oil as a vehicle resulted in a slow rise and low plateau in plasma concentration. Intraperitoneal injections with sesame oil as a vehicle resulted in a slower rise compared with aqueous vehicle, but an earlier and higher peak compared with subcutaneous injection. Finally, the levels of THC and CBD that were similar to direct subcutaneous injections were measured in the plasma of pups nursing from intraperitoneally injected dams. Conclusions: The route of administration and the preparation of the drug have important and significant effects on the PK profiles of THC and CBD in rats. These results can be used to create different clinically relevant exposure paradigms in pups and adults, such as short high-dose exposure or a low-chronic exposure, each of which might have significant and varying effects on development.

Introduction: Endocannabinoids in COVID-19 have immunomodulatory and anti-inflammatory properties but the functional role and the regulation of endocannabinoid signaling in this pandemic disorder is controversial. To exercise their biologic function, endocannabinoids need to travel across the intercellular space and within the blood stream to reach their target cells. How the lipophilic endocannabinoids are transported in the vascular system and how these hydrophobic compounds cross cell membranes is still unclear. Extracellular vesicles (EVs) are released and incorporated by many cell types including immune cells. EVs are small lipid-membrane covered particles and contain RNA, lipids and proteins. They play an important role in intercellular communication by transporting these signaling molecules from their cells of origin to specific target cells. EVs may represent ideal transport vehicles for lipophilic signaling molecules like endocannabinoids and this effect could also be evident in COVID-19. Materials and Methods: We measured the endocannabinoids anandamide, 2-AG, SEA, PEA and OEA in patients with COVID-19 in EVs and plasma. RNA sequencing of microRNAs (miRNAs) derived from EVs (EV-miRNAs) and mRNA transcripts from blood cells was used for the construction of signaling networks reflecting endocannabinoid and miRNA communication by EVs to target immune cells. Results: With the exception of anandamide, endocannabinoid concentrations were significantly enriched in EVs in comparison to plasma and increased with disease severity. No enrichment in EVs was seen for the more hydrophilic steroid hormones cortisol and testosterone. High EV-endocannabinoid concentrations were associated with downregulation of CNR2 (CB2) by upregulated EV-miRNA miR-146a-5p and upregulation of MGLL by downregulated EV-miR-199a-5p and EV-miR-370-5p suggesting counterregulatory effects. In contrast, low EV-levels of anandamide were associated with upregulation of CNR1 by downregulation of EV-miR-30c-5p and miR-26a-5p along with inhibition of FAAH. Immunologically active molecules in immune cells regulated by endocannabinoid signaling included VEGFA, GNAI2, IGF1, BDNF, IGF1R and CREB1 and CCND1 among others. Discussion and Conclusions: EVs carry immunologically functional endocannabinoids in COVID-19 along with miRNAs which may regulate the expression of mRNA transcripts involved in the regulation of endocannabinoid signaling and metabolism. This mechanism could fine-tune and adapt endocannabinoid effects in recipient cells in relationship to the present biological context.

Background: Exploring the morphological traits of historical Cannabis populations from the Maghreb can provide invaluable information about the characteristics of the Maghreb Landrace Kif and contribute to the preservation of this vulnerable Cannabis resource. Aim: The purpose of the present study was to analyze the morphological characteristics of Cannabis specimens collected before worldwide introgressive hybridization and summarize the morphological traits of the Maghreb Landrace Kif. Discussion: Despite the limited number of specimens collected in the Maghreb, this study identified distinct types of Cannabis in the herbaria, including the Maghreb Landrace Kif, European hemp, and potentially East Asian hemp. By examining the morphological traits of kif specimens and reviewing the relevant literature, the study identifies the morphological traits that tend to characterize Maghreb Landrace Kif. Morphologically, Kif is different from drug-type Cannabis indica ("Sativa" and "Indica"). It resembles European hemp Cannabis sativa, but has female inflorescence characteristics that allow it to be distinguished from the latter, even when the growing conditions are optimal. These are the density of pistillate inflorescences (perigonal bract-to-leaf index), and the capitate stalked glandular trichomes cover density on the perigonal bracts. Conclusion: The characteristics of pistillate inflorescences identified in this study can be used to distinguish and select plants before phytochemical and genetic analysis, thus facilitating the identification of the Maghreb Landrace Kif.

Background: This article highlights the formulation of a solid Δ⁹-tetrahydrocannabinol (THC)-loaded ingestible prepared from pure THC distillate. Methods: A THC-containing ethanol-assisted cannabinoid nanoemulsion (EACNE) was created using a solvent displacement technique. Subsequently, the EACNE was converted to a solid powdery material while still retaining its THC potency, a format uniquely suited for "microdosing" applications. Results: EACNE had an average lipid droplet size of ∼190 nm, with a polydispersity index of 0.15, and an average droplet ζ potential of -49±10 mV. The nanoemulsion (NE) was colloidally stable for at least 6 weeks, with no meaningful change in cannabinoid potency over the experimental period, as determined by high-performance liquid chromatography analysis. The EACNE remained stable when subjected to physical stresses such as heat, freeze/thaw cycles, carbonation, dilution to beverage concentrations, high sucrose concentrations, and a pH range between 5 and 8. The microencapsulated EACNE demonstrated limited free-flowing behavior but was freely redispersible in water without any visible phase separation. Conclusions: We report the design, creation, and characterization of a THC NE generated without the use of specialized equipment, such as a microfluidizer or a high-pressure homogenizer. This emulsion could readily be converted to a water-redispersible powder. This embodiment is particularly suited for THC "microdosing," a practice that might decouple the health benefits of THC from its psychotropic effects.

Introduction: The endocannabinoids (eCBs), 2-arachidonoylglycerol (2-AG) and arachidonoyl ethanolamine (AEA), are produced by separate enzymatic pathways, activate cannabinoid (CB) receptors with distinct pharmacological profiles, and differentially regulate pathophysiological processes. The genetically encoded sensor, GRAB_eCB2.0, detects real-time changes in eCB levels in cells in culture and preclinical model systems; however, its activation by eCB analogues produced by cells and by phyto-CBs remains uncharacterized, a current limitation when interpreting changes in its response. This information could provide additional utility for the tool in in vivo pharmacology studies of phyto-CB action. Materials and Methods: GRAB_eCB2.0 was expressed in cultured HEK293 cells. Live cell confocal microscopy and high-throughput fluorescent signal measurements. Results: 2-AG increased GRAB_eCB2.0 fluorescent signal (EC₅₀=85 nM), and the cannabinoid 1 receptor (CB₁R) antagonist, SR141716 (SR1), decreased GRAB_eCB2.0 signal (IC₅₀=3.3 nM), responses that mirror their known potencies at the CB₁R. GRAB_eCB2.0 fluorescent signal also increased in response to AEA (EC₅₀=815 nM), the eCB analogues 2-linoleoylglycerol and 2-oleoylglycerol (EC₅₀=632 and 868 nM, respectively), Δ⁹-tetrahydrocannabinol (Δ⁹-THC), and Δ⁸-THC (EC₅₀=1.6 and 2.0 μM, respectively), and the artificial CB₁R agonist, CP55,940 (CP; EC₅₀=82 nM); however their potencies were less than what has been described at CB₁R. Cannabidiol (CBD) did not affect basal GRAB_eCB2.0 fluorescent signal and yet reduced the 2-AG stimulated GRAB_eCB2.0 responses (IC₅₀=9.7 nM). Conclusions: 2-AG and SR1 modulate the GRAB_eCB2.0 fluorescent signal with EC₅₀ values that mirror their potencies at CB₁R, whereas AEA, eCB analogues, THC, and CP increase GRAB_eCB2.0 fluorescent signal with EC₅₀ values significantly lower than their potencies at CB₁R. CBD reduces the 2-AG response without affecting basal signal, suggesting that GRAB_eCB2.0 retains the negative allosteric modulator (NAM) property of CBD at CB₁R. This study describes the pharmacological profile of GRAB_eCB2.0 to improve interpretation of changes in fluorescent signal in response to a series of known eCBs and CB₁R ligands.