Cannabinoids are receiving great attention as a novel approach in the treatment of cognitive and motor disabilities, which characterize neurological disorders. To date, over 100 phytocannabinoids have been extracted from Cannabis sativa, and some of them have shown neuroprotective properties and the capacity to influence synaptic transmission. In this study, we investigated the effects of a less-known phytocannabinoid, cannabinerol (CBNR), on neuronal physiology. Using the NSC-34 motor-neuron-like cell line and next-generation sequencing analysis, we discovered that CBNR influences synaptic genes associated with synapse organization and specialization, including genes related to the cytoskeleton and ion channels. Specifically, the calcium, sodium, and potassium channel subunits (Cacna1b, Cacna1c, Cacnb1, Grin1, Scn8a, Kcnc1, Kcnj9) were upregulated, along with genes related to NMDAR (Agap3, Syngap1) and calcium (Cabp1, Camkv) signaling. Moreover, cytoskeletal and cytoskeleton-associated genes (Actn2, Ina, Trio, Marcks, Bsn, Rtn4, Dgkz, Htt) were also regulated by CBNR. These findings highlight the important role played by CBNR in the regulation of synaptogenesis and synaptic transmission, suggesting the need for further studies to evaluate the neuroprotective role of CBNR in the treatment of synaptic dysfunctions that characterize motor disabilities in many neurological disorders.

Intestinal inflammation is mediated by a subset of cells populating the intestine, such as enteric glial cells (EGC) and macrophages. Different studies indicate that phytocannabinoids could play a possible role in the treatment of inflammatory bowel disease (IBD) by relieving the symptoms involved in the disease. Phytocannabinoids act through the endocannabinoid system, which is distributed throughout the mammalian body in the cells of the immune system and in the intestinal cells. Our in vitro study analyzed the putative anti-inflammatory effect of nine selected pure cannabinoids in J774A1 macrophage cells and EGCs triggered to undergo inflammation with lipopolysaccharide (LPS). The anti-inflammatory effect of several phytocannabinoids was measured by their ability to reduce TNFα transcription and translation in J774A1 macrophages and to diminish S100B and GFAP secretion and transcription in EGCs. Our results demonstrate that THC at the lower concentrations tested exerted the most effective anti-inflammatory effect in both J774A1 macrophages and EGCs compared to the other phytocannabinoids tested herein. We then performed RNA-seq analysis of EGCs exposed to LPS in the presence or absence of THC or THC-COOH. Transcriptomic analysis of these EGCs revealed 23 differentially expressed genes (DEG) compared to the treatment with only LPS. Pretreatment with THC resulted in 26 DEG, and pretreatment with THC-COOH resulted in 25 DEG. To evaluate which biological pathways were affected by the different phytocannabinoid treatments, we used the Ingenuity platform. We show that THC treatment affects the mTOR and RAR signaling pathway, while THC-COOH mainly affects the IL6 signaling pathway.

BACKGROUND: Although the worldwide use of medical cannabis (MC) is on the rise, there is insufficient data regarding the long-term stability of phytocannabinoids in the plant material under different storage conditions. Specifically, there is insufficient data on the effect of storage conditions on the availability of (-)-∆9-trans-tetrahydrocannabinol (THC) in vaporized cannabis. The Syqe inhaler delivers metered doses of phytocannabinoids by inhalation and utilizes accurate quantities of ground cannabis inflorescence packaged in tamper-proof cartridges. We aimed to assess the stability of phytocannabinoids in ground cannabis before and after packaging in Syqe cartridges as well as the reproducibility of THC delivery in the aerosolized dose.
METHODS: Ground MC inflorescence was stored under different temperature and humidity conditions, before or after being packaged in Syqe cartridges. Concentrations of the major phytocannabinoids therein were analyzed at different time points using ultra-high performance liquid chromatography (U-HPLC). THC doses aerosolized via the Syqe inhaler were evaluated using cartridges stored for up to 2 years at 25°C. Every vapor chip contains 13.5±0.9 mg of ground MC powder.
RESULTS: No significant changes were observed in phytocannabinoid concentrations in ground cannabis inflorescence after 3 months of bulk storage in a polypropylene container and sealed in an aluminum foil pouch at 5°C. In contrast, significant changes in phytocannabinoid concentrations were found when ground inflorescence was stored in the cartridges at 25°C for 2 years. Specifically, CBGA, THCA, and total THC concentrations decreased from 0.097±0.023, 2.7±0.3, and 2.80±0.16 mg/chip at baseline to 0.044±0.007 (55% decrease), 1.50±0.27 (44% decrease), and 2.20±0.083 (21% decrease) mg/chip following 2 years, respectively, while CBN and THC concentrations increased from 0.005±0.005 and 0.44±0.11 mg/chip at baseline to 0.14±0.006 (2700% increase) and 0.88±0.22 (100% increase) mg/chip following 2 years, respectively. Storage at 30°C revealed a steeper change in phytocannabinoid concentrations within an even shorter period. Despite the significant change of relative cannabinoid composition within the cartridge, the actual THC dose present in the aerosol remained relatively stable throughout this period and within the dosage range of 500mcg±25% required for pharmaceutical-grade inhalers.
CONCLUSIONS: MC powder in Syqe cartridges may be stored at room temperature for at least 2 years after production without affecting the aerosolized THC dose delivered to patients by more than ±25%. Future studies should analyze additional phytocannabinoids and terpenes in the cannabis inflorescence and assess the stability of different cannabis cultivars following storage in Syqe cartridges.

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Efficacy of inhaled cannabis for treating pain is controversial. Effective treatment for chemotherapy-induced neuropathy represents an unmet medical need. We hypothesized that cannabis reduces neuropathic pain by reducing functional coupling in the raphe nuclei.
We assessed the impact of inhalation of vaporized cannabis plant (containing 10.3% Δ9-tetrahydrocannabinol/0.05% cannabidiol) or placebo cannabis on brain resting-state blood oxygen level-dependent functional connectivity and pain behavior induced by paclitaxel in rats. Rats received paclitaxel to produce chemotherapy-induced peripheral neuropathy or its vehicle. Behavioral and imaging experiments were performed after neuropathy was established and stable. Images were registered to, and analyzed using, a 3D magnetic resonance imaging rat atlas providing site-specific data on more than 168 different brain areas.
Prior to vaporization, paclitaxel produced cold allodynia. Inhaled vaporized cannabis increased cold withdrawal latencies relative to prevaporization or placebo cannabis, consistent with Δ9-tetrahydrocannabinol-induced antinociception. In paclitaxel-treated rats, the midbrain serotonergic system, comprising the dorsal and median raphe, showed hyperconnectivity to cortical, brainstem, and hippocampal areas, consistent with nociceptive processing. Inhalation of vaporized cannabis uncoupled paclitaxel-induced hyperconnectivity patterns. No such changes in connectivity or cold responsiveness were observed following placebo cannabis vaporization.
Inhaled vaporized cannabis plant uncoupled brain resting-state connectivity in the raphe nuclei, normalizing paclitaxel-induced hyperconnectivity to levels observed in vehicle-treated rats. Inhaled vaporized cannabis produced antinociception in both paclitaxel- and vehicle-treated rats. Our study elucidates neural circuitry implicated in the therapeutic effects of Δ9-tetrahydrocannabinol and supports a role for functional imaging studies in animals in guiding indications for future clinical trials.

Introduction: The endocannabinoid system (ECS) plays an important role in food reward. For example, in humans, liking of palatable foods is assumed to be modulated by endocannabinoid activity. Studies in rodents suggest that the ECS also plays a role in sweet taste intensity perception, but it is unknown to what extent this can be extrapolated to humans. Therefore, this study aimed at elucidating whether Δ9-tetrahydrocannabinol (THC) or cannabidiol (CBD) affects sweet taste intensity perception and liking in humans, potentially resulting in alterations in food preferences. Materials and Methods: In a randomized placebo-controlled, double-blind crossover study, 10 healthy males participated in three test sessions that were 2 weeks apart. During the test sessions, participants received THC-rich, CBD-rich, or placebo Cannabis by inhalation divided over two doses (4 + 1 mg THC; 25 + 10 mg CBD). Participants tasted seven chocolate milk-like drinks that differed in sugar concentration and they rated sweet taste intensity and liking of the drinks. They were then asked to rank the seven drinks according to how much they liked the drinks and were offered ad libitum access to their favorite drink. In addition, they completed a computerized food preference task and completed an appetite questionnaire at the start, midway, and end of the test sessions. Results: Inhalation of the Cannabis preparations did not affect sweet taste intensity perception and liking, ranking order, or ad libitum consumption of the favorite drink. In addition, food preferences were not influenced by the interventions. Reported fullness was lower, whereas desire to eat was higher throughout the THC compared to the CBD condition. Conclusions: These results suggest that administration of Cannabis preparations at the low doses tested does not affect sweet taste intensity perception and liking, nor does it influence food preferences in humans.