Cannabinoid modulations of pain and stress related circuits

In the past decade, significant advancements have been made in understanding the brain regions and neuronal circuits regulating neurological behaviors. The endocannabinoid (eCB) system, which is ubiquitously distributed in the brain and extensively involved in synaptic modulation, has been believed to play potential roles in neuronal circuit processes and related disorders. Although eCB-based pharmacological studies have made some clinical achievements, they still often encounter conflicting reports or undesired effects due to global manipulation of manifold brain regions and neuronal circuits, which impede the therapeutic application of eCB-based medications. In this review, we are devoted to discussing the versatile forms of eCB-mediated synaptic plasticity and dissecting currently well-studied specific cannabinoid circuits involved in behavioral domains which are closely linked to the organism’s survival and life quality, such as pain perception and stress-related emotion disorders. By gaining new insights into selective cannabinoid control in circuits, we can potentially mitigate the drawbacks of traditional pharmacology and facilitate the development of precision medicine with novel therapeutic strategies and drug discoveries.

Cannabis Use Frequency and Cannabis-Related Consequences in High-Risk Young Adults Across Cannabis Legalization

A key concern about recreational cannabis legalization is increases in use and adverse consequences, particularly among young adults (aged 18-29 years) who have the highest prevalence of cannabis use, and especially in higher-risk, more vulnerable young adults. However, few longitudinal studies have examined patterns of cannabis consumption in high-risk young adults over the course of legalization. To examine changes in cannabis use frequency and cannabis-related consequences over recreational cannabis legalization in Canada in a longitudinal sample of high-risk young adults.

Association between marijuana use and kidney stone: a cross-sectional study of NHANES 2009 to 2018

The purpose of this investigation is to determine whether regular marijuana use is related to history of kidney stones in the US population. Data were obtained from the National Health and Nutrition Examination Survey (NHANES) from 2009 to 2018. Kidney stone and marijuana use data were collected from self-report questionnaires. Multivariate logistic regression and multiple sensitivity analyses were applied to examine the relationship between marijuana usage and kidney stones.

Labour and premature delivery differentially affect the expression of the endocannabinoid system in the human placenta

Plasma concentrations of N-arachidonyletholamine (AEA), N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA) increase at term and can predict when a woman is likely to go into labour. We hypothesised that increased plasma AEA concentrations in women in preterm and term labour might also be increased and have a function in the placenta at the end of pregnancy. Here we examined the expression of the N-acylethanolamine-modulating enzymes fatty acid amide hydrolase (FAAH) and N-acyl-phosphatidylethanolamine-specific phospholipase-D (NAPE-PLD) and of the cannabinoid receptors (CB1 and CB2) in the placenta and their activation in an in vitro model of the third-trimester placenta to determine if those expressions change with labour and have functional significance. Expression of CB1, CB2, FAAH and NAPE-PLD was examined by immunohistochemistry (IHC) and RT-qPCR in placental samples obtained from four patient groups: preterm not in labour (PTNL), term not in labour (TNL), preterm in labour (PTL) and term in labour (TL). Additionally, the effects of AEA on a third-trimester human cell line (TCL-1) were evaluated. All ECS components were present in the third-trimester placenta, with NAPE-PLD and CB2 being the key modulated proteins in terms of expression. Functionally, AEA reduced TCL-1 cell numbers through the actions of the CB2 receptor whilst CB1 maintained placental integrity through the expression of the transcription regulators histone deacetylase 3, thyroid hormone receptor β 1 and the modulation of 5α reductase type 1. The placenta in the third trimester and at term is different from the placenta in the first trimester with respect to the expression of CB1, CB2, FAAH and NAPE-PLD, and the expression of these proteins is affected by labour. These data suggest that early perturbation of some ECS components in the placenta may cause AEA-induced PTL and thus PTB.

Cannabis constituents for chronic neuropathic pain; reconciling the clinical and animal evidence

Chronic neuropathic pain is a debilitating pain syndrome caused by damage to the nervous system that is poorly served by current medications. Given these problems, clinical studies have pursued extracts of the plant Cannabis sativa as alternative treatments for this condition. The vast majority of these studies have examined can- nabinoids which contain the psychoactive constituent delta-9-tetrahydrocannabinol (THC). While there have been some positive findings, meta-analyses of this clinical work indicates that this effectiveness is limited and hampered by side-effects. This review focuses on how recent preclinical studies have predicted the clinical limita- tions of THC-containing cannabis extracts, and importantly, point to how they might be improved. This work highlights the importance of targeting channels and recep- tors other than cannabinoid CB1 receptors which mediate many of the side-effects of cannabis.

Delta-8-Tetrahydrocannabinol: A Phytocannabinoid on the Rise

Delta-8-tetrahydrocannabinol (THC) is a minor psychoactive phytocannabinoid, similar to delta-9-tetrahydrocannabinol. Recent statements released by the FDA and CDC reported around 660 delta-8-THC exposure cases. With the rise in commercially available products, it is crucial to understand the pharmacological and toxicological properties of this compound. The objective of this review is to summarize current literature regarding the pharmacokinetic, and pharmacologic properties of delta-8- THC.

Cannabinoids in Spine Surgery: A Comprehensive Review

Cannabinoids have gained attention for their potential therapeutic effects in various fields, including pain control, augmenting fusion, neuroprotection, wound healing, inflammation, mental health, and clinical outcomes/complications. We explore the history and mechanism of action of cannabinoids, as well as their role in each of these areas. By examining existing research, the potential benefits and limitations of incorporating cannabinoids into spine non-operative and operative protocols are highlighted. Ultimately, this review aims to contribute to the understanding of cannabinoids as a viable option for optimizing patient outcomes in the context of spine surgery.

Cannabidiol Oil Ingested as Sublingual Drops or Within Gelatin Capsules Shows Similar Pharmacokinetic Profiles in Healthy Males

Cannabidiol (CBD) is a nonintoxicating phytocannabinoid used in clinical treatments and sold widely in consumer products. CBD products may be designed for sublingual or oral delivery, but it is unclear whether either is advantageous for CBD absorption. This study compared CBD pharmacokinetics after providing CBD oil as sublingual drops and within orally ingested gelatin capsules, at a dose relevant to consumer products.

Cannabinoids for the Treatment of Hair, Scalp, and Skin Disorders: A Systematic Review

Cannabinoid products have been studied in the treatment of various dermatologic conditions. We searched PubMed/MEDLINE for articles published before 1 February 2023 that described the use of cannabinoids in the management of hair, scalp, and skin conditions, identifying 18 original articles that encompassed 1090 patients who used various forms of cannabinoid products. Where specified, topical cannabidiol (CBD) was the most commonly utilized treatment (64.3%, 173/269), followed by oral dronabinol (14.4%, 39/269), oral lenabasum (14.1%, 38/269), and oral hempseed oil (5.9%, 16/269). Using the GRADE approach, we found moderate-quality evidence supporting the efficacy of cannabinoid products in managing atopic dermatitis, dermatomyositis, psoriasis, and systemic sclerosis and moderate-quality evidence supporting a lack of efficacy in treating trichotillomania. There was low to very low quality evidence supporting the efficacy of cannabinoid products in managing alopecia areata, epidermolysis bullosa, hyperhidrosis, seborrheic dermatitis, and pruritus. Our findings suggest that cannabinoids may have efficacy in managing symptoms of certain inflammatory dermatologic conditions. However, the evidence is still limited, and there is no standardized dosage or route of administration for these products. Large randomized controlled trials and further studies with standardized treatment regimens are necessary to better understand the safety and efficacy of cannabinoids.

Pharmacological blockade of 2-AG degradation ameliorates clinical, neuroinflammatory and synaptic alterations in experimental autoimmune encephalomyelitis

The endocannabinoid system (ECS) is critically involved in the pathophysiology of Multiple Sclerosis (MS), a neuroinflammatory and neurodegenerative disease of the central nervous system (CNS). Over the past decade, the neuroprotective and anti-inflammatory effects of the ECS have been studied, and inhibiting the degradation of the endocannabinoid 2-arachydonoylglycerol (2-AG) is emerging as a promising strategy to counteract brain damage in MS. In this study, a systemic and preventive in vivo treatment with MAGLi 432, the reversible inhibitor of monoacylglycerol lipase (MAGLi), was performed in experimental autoimmune encephalomyelitis (EAE) mice. Clinical, biochemical, electrophysiological and immunofluorescence analyses were carried out to evaluate the impact of the drug on motor disability, neuroinflammation and synaptic damage. MAGLi 432 induced a less severe EAE disease, accompanied by an increase of 2-AG and a reduction of acid arachidonic (AA) and prostaglandins (PGs) brain levels.

Toxicity of Cannabigerol: Examination of Long-Term Toxicity and Lifespan in Caenorhabditis elegans and 14-Day Study in Sprague Dawley Rats

Cannabigerol (CBG) is becoming widely available despite little being known about its potential toxicity or long-term effects. The present investigation involved two distinct studies. The first study explored acute and long-term effects of CBG on toxicity, lifespan, and aging in adult Caenorhabditis elegans (C. elegans). Animals were treated with CBG (0.075 lM–3.75 mM) to determine acute toxicity, mortality, and motility. Acute heat- induced stress survival (thermotolerance; 37°C for 4 h) following CBG administration (0.075–3.75 mM) was measured. Long-term toxicity of lifelong CBG administration (7.5, 75, or 375 lM CBG) was determined through changes in motility and lifespan duration. In the second study, healthy, adult, Sprague Dawley rats received 0, 35, 70, or 140 mg/kg-bw/day CBG (n = 5 per sex per group) daily for 14 days via oral gavage. Signs of gross toxicity and changes in behavior, body weight, food consumption, and serum chemistry were monitored. Liver, kidney, and adrenal gland weights were recorded, and histopathology of select tissues was examined.

A Two-Phase, Dose-Ranging, Placebo-Controlled Study of the Safety and Preliminary Test of Acute Effects of Oral D8-Tetrahydrocannabivarin in Healthy Participants

Tetrahydrocannabivarin (THCV) is an understudied cannabinoid that appears to have effects that vary as a function of dose. No human study has evaluated the safety and nature of effects in a wide range of THCV doses. This was a two-phase, dose-ranging, placebo-controlled trial of the D8 isomer of oral THCV in healthy adults. Phase 1 utilized an unblinded, single-ascending dose design (n = 3). Phase 2 used a double-blind, random- ized, within-participant crossover design (n = 18). Participants received single acute doses of placebo and 12.5, 25, 50, 100, and 200 mg of THCV. Safety measures and subjective and cognitive effects were assessed predose and up to 8 h postdose.