Chemotherapy-induced peripheral neuropathy (CIPN) is the main dose-limiting adverse effect of chemotherapy drugs such as paclitaxel (PTX). PTX causes marked molecular and cellular damage, mainly in the peripheral nervous system, including sensory neurons in the dorsal root ganglia (DRG). Several studies have shown the therapeutic potential of cannabinoids, including cannabidiol (CBD), the major non-psychotomimetic compound found in the Cannabis plant, to treat peripheral neuropathies. Here, we investigated the efficacy of PECS-101 (former HUF-101), a CBD fluorinated analog, on PTX-induced neuropathic pain in mice. PECS-101, administered after the end of treatment with PTX, did not reverse mechanical allodynia. However, PECS-101 (1 mg/kg) administered along with PTX treatment caused a long-lasting relief of the mechanical and cold allodynia. These effects were blocked by a PPAR$\gamma$, but not CB1 and CB2 receptor antagonists. Notably, the effects of PECS-101 on the relief of PTX-induced mechanical and cold allodynia were not found in macrophage-specific PPAR$\gamma$-deficient mice. PECS-101 also decreased PTX-induced increase in Tnf, Il6, and Aif1 (Iba-1) gene expression in the DRGs and the loss of intra-epidermal nerve fibers. PECS-101 did not alter motor coordination, produce tolerance, or show abuse potential. In addition, PECS-101 did not interfere with the chemotherapeutic effects of PTX. Thus, PECS-101, a new fluorinated CBD analog, could represent a novel therapeutic alternative to prevent mechanical and cold allodynia induced by PTX potentially through the activation of PPAR$\gamma$ in macrophages.

Introduction: Cancer patients report nausea as a side effect of their chemotherapy treatment. Using the pre-clinical rodent model of acute nausea-lithium chloride (LiCl)-induced conditioned gaping-our group has demonstrated that exogenous cannabinoids may have antinausea potential. Materials and Methods: With the goal of evaluating the role of sex as a factor in pre-clinical research, we first compared the conditioned gaping reactions produced by varying doses of LiCl in male and female rats using the taste reactivity test (Experiment 1). Results: LiCl produced dose-dependent conditioned gaping similarly in male and female rats with the highest dose (127.2 mg/kg) producing robust conditioned gaping, with this dose used in subsequent experiments. Next, we examined the antinausea potential of THC (Experiment 2), CBD (Experiment 3), cannabidiolic acid (CBDA; Experiment 4) and oleoyl alanine (OlAla; Experiment 5) in both male and female rats. THC, CBD, CBDA, and OlAla dose dependently reduced conditioned gaping in both male and female rats in a similar manner. Conclusions: These results suggest that cannabinoids may be equally effective in treating nausea in both males and females.

{Importance: Owing to its anti-inflammatory properties and antiviral "in vitro" effect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), cannabidiol (CBD) has been proposed as a potential treatment for coronavirus disease 2019 (COVID-19). Objective: To investigate the safety and efficacy of CBD for treating patients with mild to moderate COVID-19. Design: Randomized, parallel-group, double-blind, placebo-controlled clinical trial conducted between July 7 and October 16, 2020, in two sites in Brazil. Setting: Patients were recruited in an emergency room. Participants: Block randomized patients (1:1 allocation ratio-by a researcher not directly involved in data collection) with mild and moderate COVID-19 living in Ribeirão Preto, Brazil, seeking medical consultation, and those who voluntarily agreed to participate in the study. Interventions: Patients received 300 mg of CBD or placebo added to standard symptomatic care during 14 days. Main Outcome and Measure: The primary outcome was reduction or prevention of the deterioration in clinical status from mild/moderate to severe/critical measured with the COVID-19 Scale or the natural course of the resolution of typical clinical symptoms. Primary study outcome was assessed on days 14, 21, and 28 after enrollment. Results: A total of 321 patients were recruited and assessed for eligibility, and 105 were randomly allocated either in CBD (n=49) or in placebo (n=42) group. Ninety-one participants were included in the analysis of efficacy. There were no baseline between-group differences regarding disease severity ($\chi$(2)=0.025

After a traumatic childhood in Europe during the Second World War, I found that scientific research in Israel was a pleasure beyond my expectations. Over the last 65 year, I have worked on the chemistry and pharmacology of natural products. During the last few decades, most of my research has been on plant cannabinoids, the endogenous cannabinoids arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol, and endogenous anandamide-like compounds, all of which are involved in a wide spectrum of physiological reactions. Two plant cannabinoids, $Δ$(9)-tetrahydrocannabinol and cannabidiol, are approved drugs. However, the endogenous cannabinoids and the anandamide-like constituents have not yet been well investigated in humans. For me, intellectual freedom-the ability to do research based on my own scientific interests-has been the most satisfying part of my working life. Looking back over the 91 years of my long life, I conclude that I have been lucky, very lucky, both personally and scientifically. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 63 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Introduction: The endocannabinoid system (ECS) plays a key modulatory role during synaptic plasticity and homeostatic processes in the brain and plays an important role in the neurobiological processes underlying drug addiction. Impaired endocannabinoid (eCB) signaling contributes to dysregulated synaptic plasticity, increased stress responsivity, and craving that propel addiction. Therefore, we hypothesized that boosting the ECS by exogenous administration of selective eCBs will attenuate cocaine-induced behaviors. Materials and Methods: The behavioral paradigms included psychomotor sensitization (PS) and conditioned place preference (CPP). Liquid chromatography-mass spectrometry analysis was used for quantitative profiling of eCBs in mouse brain. Results: We first measured the levels of eCBs in different brain areas of the reward system following chronic cocaine treatment. We found that following daily administration of cocaine, the levels of N-oleoyl glycine (OlGly) were significantly elevated in the nucleus accumbens (NAc) in a region-specific manner. We next tested whether administration of OlGly will attenuate cocaine-induced behaviors. We found that administration of OlGly during withdrawal, but not during acquisition of PS, attenuated the expression of cocaine sensitization. In addition, the administration of OlGly during the acquisition of cocaine CPP, but not during withdrawal, attenuated the expression of cocaine-conditioned reward. To enhance the stability of OlGly and its duration of action, two methylated derivatives of OlGly were synthesized, the monomethylated OlGly (HU-595) and dimethylated OlGly (HU-596). We found that the effect of administration of HU-595 or HU-596 during cocaine conditioning did not differ from the OlGly-induced decrease in the expression of CPP. Conclusion: Our findings suggest that the ECS is involved in the common neurobiological mechanisms underlying the development and expression of cocaine reward and drug-seeking. Boosting the ECS exogenously has beneficial effects against cocaine-induced behaviors.

BACKGROUND: Despite the absence of rigorous prospective studies, there has been an increase in the use of cannabis-based medicinal products. During the study period, the use of medical cannabis in Israel was tightly regulated by national policy. Through a prospective study of approximately 10,000 patients, we aimed to characterize the medical cannabis patient population as well as to identify treatment adherence, safety, and effectiveness. METHODS AND FINDINGS: In this study of prescribed medical cannabis patients, adherence, safety, and effectiveness were assessed at 6 months. Treatment adherence was assessed by the proportion of patients purchasing the medication out of the total number of patients (excluding deceased cases and patients transferred to another cannabis clinic). Safety was assessed by the frequency of the side-effects, while effectiveness was defined as at least moderate improvement in the patient condition without treatment cessation or serious side-effects. The most frequent primary indications requiring therapy were cancer (49.1%), followed by non-specific pain (29.3%). The average age was 54.6 ± 20.9 years, 51.1% males; 30.2% of the patients reported prior experience with cannabis. During the study follow-up, 1,938 patients died (19.4%) and 1,735 stopped treatment (17.3%). Common side-effects, reported by 1,675 patients (34.2%), were: dizziness (8.2%), dry mouth (6.7%), increased appetite (4.7%), sleepiness (4.4%), and psychoactive effect (4.3%). Overall, 70.6% patients had treatment success at 6 months. Multivariable logistic regression analysis revealed that the following factors were associated with treatment success: cigarette smoking, prior experience with cannabis, active driving, working, and a young age. The main limitation of this study was the lack of data on safety and effectiveness of the treatment for patients who refused to undergo medical assessment even at baseline or died within the first 6 months. CONCLUSIONS: We observed that supervised medical-cannabis treatment is associated with high adherence, improvement in quality of life, and a decrease in pain level with a low incidence of serious adverse events.

Objective: To assess whether the effects of oral administration of 300 mg of Cannabidiol (CBD) for 28 days on mental health are maintained for a period after the medication discontinuation. Methods: This is a 3-month follow-up observational and clinical trial study. The data were obtained from two studies performed simultaneously by the same team in the same period and region with Brazilian frontline healthcare workers during the COVID-19 pandemic. Scales to assess emotional symptoms were applied weekly, in the first month, and at weeks eight and 12. Results: The primary outcome was that, compared to the control group, a significant reduction in General Anxiety Disorder-7 Questionnaire (GAD-7) from baseline values was observed in the CBD group on weeks two, four, and eight (Within-Subjects Contrasts, time-group interactions: F(1-125) = 7.67; p = 0.006; $η$(p) (2) = 0.06; F(1-125) = 6.58; p = 0.01; $η$(p) (2) = 0.05; F(1-125) = 4.28; p = 0.04; $η$(p) (2) = 0.03, respectively) after the end of the treatment. Conclusions: The anxiolytic effects of CBD in frontline health care professionals during the COVID-19 pandemic were maintained up to 1 month after the treatment discontinuation, suggesting a persistent decrease in anxiety in this group in the real world. Future double-blind placebo-controlled clinical trials are needed to confirm the present findings and weigh the benefits of CBD therapy against potential undesired or adverse effects.

Phytocannabinoids possess a wide range of immune regulatory properties, mediated by the endocannabinoid system. Monocyte/macrophage innate immune cells express endocannabinoid receptors. Dysregulation of macrophage function is involved in the pathogenesis of different inflammatory diseases, including inflammatory bowel disease. In our research, we aimed to evaluate the effects of the phytocannabinoids D9 tetrahydrocannabinol (THC) and cannabidiol (CBD) on macrophage activation. Macrophages from young and aged C57BL/6 mice were activated in vitro in the presence of pure cannabinoids or cannabis extracts. The phenotype of the cells, nitric oxide (NO•) secretion, and cytokine secretion were examined. In addition, these treatments were administered to murine colitis model. The clinical statuses of mice, levels of colon infiltrating macrophages, and inflammatory cytokines in the blood, were evaluated. We demonstrated inhibition of macrophage NO• and cytokine secretion and significant effects on expression of cell surface molecules. In the murine model, clinical scores were improved and macrophage colon infiltration reduced following treatment. We identified higher activity of cannabis extracts as compared with pure cannabinoids. Each treatment had a unique effect on cytokine composition. Overall, our results establish that the effects of cannabinoid treatments differ. A better understanding of the reciprocal relationship between cannabinoids and immunity is essential to design targeted treatment strategies.

Activation of the cannabinoid-1 receptor (CB(1)R) and the mammalian target of rapamycin complex 1 (mTORC1) in the renal proximal tubular cells (RPTCs) contributes to the development of diabetic kidney disease (DKD). However, the CB(1)R/mTORC1 signaling axis in the kidney has not been described yet. We show here that hyperglycemia-induced endocannabinoid/CB(1)R stimulation increased mTORC1 activity, enhancing the transcription of the facilitative glucose transporter 2 (GLUT2) and leading to the development of DKD in mice; this effect was ameliorated by specific RPTCs ablation of GLUT2. Conversely, CB(1)R maintained the normal activity of mTORC1 by preventing the cellular excess of amino acids during normoglycemia. Our findings highlight a novel molecular mechanism by which the activation of mTORC1 in RPTCs is tightly controlled by CB(1)R, either by enhancing the reabsorption of glucose and inducing kidney dysfunction in diabetes or by preventing amino acid uptake and maintaining normal kidney function in healthy conditions.

{Environmental heat load (HL) adversely affects the performance of dairy cows. The endocannabinoid system (ECS) regulates metabolism and the stress response, thus we hypothesized that HL may affect the ECS of dairy cows. Our objective was to determine the levels of endocannabinoids (eCBs) and gene and protein expressions of the ECS components in adipose tissue (AT) and plasma of early postpartum (PP) and late-lactation cows. In addition, we examined eCBs in milk, and studied the interaction of eCBs with bovine cannabinoids receptors CB1 and CB2. In the first experiment, plasma and AT were sampled from cows calving during summer (S

The endocannabinoid system consists mainly of 2-arachidonoylglycerol and anandamide, as well as cannabinoid receptor type 1 and type 2 (CB2). Based on previous studies, we hypothesized that a circulating peptide previously identified as osteogenic growth peptide (OGP) maintains a bone-protective CB2 tone. We tested OGP activity in mouse models and cells, and in human osteoblasts. We show that the OGP effects on osteoblast proliferation, osteoclastogenesis, and macrophage inflammation in vitro, as well as rescue of ovariectomy-induced bone loss and prevention of ear edema in vivo are all abrogated by genetic or pharmacological ablation of CB2. We also demonstrate that OGP binds at CB2 and may act as both an agonist and positive allosteric modulator in the presence of other lipophilic agonists. In premenopausal women, OGP circulating levels significantly decline with age. In adult mice, exogenous administration of OGP completely prevented age-related bone loss. Our findings suggest that OGP attenuates age-related bone loss by maintaining a skeletal CB2 tone. Importantly, they also indicate the occurrence of an endogenous peptide that signals via CB2 receptor in health and disease.

A series of novel cannabinoid-type derivatives were synthesized by the coupling of (1S,4R)-(+) and (1R,4S)-(-)-fenchones with various resorcinols/phenols. The fenchone-resorcinol derivatives were fluorinated using Selectfluor and demethylated using sodium ethanethiolate in dimethylformamide (DMF). The absolute configurations of four compounds were determined by X-ray single crystal diffraction. The fenchone-resorcinol analogs possessed high affinity and selectivity for the CB2 cannabinoid receptor. One of the analogues synthesized, 2-(2',6'-dimethoxy-4'-(2″-methyloctan-2″-yl)phenyl)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-ol (1d), had a high affinity (K(i) = 3.51 nM) and selectivity for the human CB2 receptor (hCB2). In the [(35)S]GTP$\gamma$S binding assay, our lead compound was found to be a highly potent and efficacious hCB2 receptor agonist (EC(50) = 2.59 nM, E((max)) = 89.6%). Two of the fenchone derivatives were found to possess anti-inflammatory and analgesic properties. Molecular-modeling studies elucidated the binding interactions of 1d within the CB2 binding site.

BACKGROUND: the endocannabinoid system (ECS) participates in many physiological and pathological processes including pain generation, modulation, and sensation. Its involvement in chronic orofacial pain (OFP) in general, and the reflection of its involvement in OFP in salivary endocannabinoid (eCBs) levels in particular, has not been examined. OBJECTIVES: to evaluate the association between salivary (eCBs) levels and chronic OFP. METHODS: salivary levels of 2 eCBs, anandamide (AEA), 2-arachidonoylglycerol (2-AG), 2 endocannabinoid-like compoundsN-palmitoylethanolamine (PEA), N-oleoylethanolamine (OEA), and their endogenous precursor and breakdown product, arachidonic acid (AA), were analyzed using liquid chromatography/tandem mass spectrometry in 83 chronic OFP patients and 43 pain-free controls. The chronic OFP patients were divided according to diagnosis into musculoskeletal, neurovascular/migraine, and neuropathic pain types. RESULTS: chronic OFP patients had lower levels of OEA (p = 0.02) and 2-AG (p = 0.01). Analyzing specific pain types revealed lower levels of AEA and OEA in the neurovascular group (p = 0.04, 0.02, respectively), and 2-AG in the neuropathic group compared to controls (p = 0.05). No significant differences were found between the musculoskeletal pain group and controls. Higher pain intensity was accompanied by lower levels of AA (p = 0.028), in neuropathic group. CONCLUSIONS: lower levels of eCBs were found in the saliva of chronic OFP patients compared to controls, specifically those with neurovascular/migraine, and neuropathic pain. The detection of changes in salivary endocannabinoids levels related to OFP adds a new dimension to our understanding of OFP mechanisms, and may have diagnostic as well as therapeutic implications for pain.