Human Metabolism of Sirolimus Revisited.

Sirolimus (SRL, rapamycin) is a clinically important mTOR inhibitor used in immunosuppression, oncology, and cardiovascular drug-eluting devices. Despite its long-standing FDA approval, the human metabolic profile of SRL remains incompletely characterized. SRL is primarily metabolized by CYP3A enzymes in the liver and intestine, but the diversity, pharmacokinetics, and biological activity of its metabolites have been poorly explored due to the lack of structurally identified standards.

chronic cannabis exposure is associated with lower total brain volume in the first month of postnatal life.

I cannabis exposure is associated with deleterious offspring neural development and behaviors that emerge across the lifespan. We explored if brain morphology differed in neonates exposed and unexposed to cannabis in the first month of life. To evaluate differences in global and subcortical regional brain volume (in the amygdala and hippocampus) in neonates in the first month of life according to cannabis exposure.

Cannabinoid Profiling Across Toxicology Samples in Adolescents and Young Adults by Route of Administration and in Relation to Depression Symptoms.

Cannabis use is common, with diversity in cannabis products contributing to difficulty in accurately assessing the impact of cannabis use in vulnerable populations such as emerging adults. This study describes and assesses concurrence across toxicological matrices (oral fluid, plasma, urine, and hair) and self-reported cannabis use days. Further, it examines whether 11-nor-9-carboxy-tetrahydrocannabinol (THCCOOH, the primary metabolite of Δ9-tetrahydrocannbinol [THC]) concentration or use patterns varies by administration route (smoked flower or vaped concentrate) or predicts depression symptoms.

Endocannabinoid Tone and Oxylipins in Rheumatoid Arthritis and Osteoarthritis-A Novel Target for the Treatment of Pain and Inflammation?

Inflammation is a complicated physiological process that contributes to a variety of disorders including osteoarthritis (OA) and rheumatoid arthritis (RA). Endocannabinoids and the endocannabinoid system (ECS) play a pivotal role in the physiological response to pain and inflammation. A clinical study to investigate the role of the endocannabinoid system and related lipids in pain and inflammation in OA and RA was performed.

Effect of Cannabidiol and Δ9-tetrahydrocannabinol on Anti-Inflammatory Lipid Mediator Synthesis in Humans.

Eicosanoids-lipid mediators derived from polyunsaturated fatty acids such as arachidonic acid-have a notable role in inflammatory signaling. Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) have been shown in preclinical studies to modulate inflammatory pathways the modulating the enzymes that generate eicosanoids, namely lipoxygenase (LOX), cyclooxygenase (COX), and cytochrome P450 (CYP450). This present study aimed to investigate how CBD and THC effect plasma levels of eicosanoids generated through LOX, COX, and cytochrome P450 (CYP450) pathways.

Novel Approaches to Monitor Pharmacokinetics and Metabolism of Gemcitabine-Ibandronate Conjugate in Mice and Dogs.

Background: The use of the bone-seeking properties of bisphosphonates (BPs) to target the delivery of therapeutic drugs is a promising approach for the treatment of bone metastases. Currently, the most advanced example of this approach is a gemcitabine-ibandronate conjugate (GEM-IB), where the bone-targeting BP ibandronate (IB) is covalently linked to the antineoplastic agent gemcitabine (GEM) via a spacer phosphate group. In the present study, we describe the development of a new analytical platform to evaluate the metabolism and pharmacokinetics of GEM-IB in mice and dogs and the results of proof-of-concept studies assessing the pharmacokinetics of GEM-IB in dogs and mice.

Pharmacokinetics of Oral Cannabinoid Δ8-Tetrahydrocannabivarin and Its Main Metabolites in Healthy Participants.

Background: Tetrahydrocannabivarin (THCV) is a phytocannabinoid commonly found in cannabis with potential pharmacological properties; however, its post-acute pharmacokinetics (PK) in humans have not been studied yet. THCV has two isomers, Δ9- and Δ8-THCV, which seem to have different pharmacological properties. We investigated the PK of the Δ8-THCV isomer after oral administration as part of a two-phase, dose-ranging, placebo-controlled trial in healthy participants.

Impact of prenatal exposure to delta 9-tetrahydrocannabinol and cannabidiol on birth size and postnatal growth trajectories.

Background: Prenatal exposure to cannabis (or more specifically, delta 9-tetrahydrocannabinol [Δ9-THC]) has been consistently linked to low birthweight. Animal models further show that Δ9-THC is associated with rapid postnatal growth. Whether this association is modified by breastfeeding is unknown.

Quantification of 11 kratom alkaloids including mitragynine and its main metabolites in human plasma using LC-MS/MS.

Recently in the USA, kratom consumers increasingly report use of the plant for self-treatment of mood ailments, the lack of energy, chronic pain, and opioid withdrawal and dependence. Several alkaloids are present in kratom leaves, but limited data are available on their pharmacokinetics/pharmacodynamics, except for mitragynine. To support clinical studies, a high-performance liquid chromatography-tandem mass spectrometry assay for the simultaneous quantification of 11 kratom alkaloids in human plasma was developed and validated.

The Interplay of Exogenous Cannabinoid Use on Anandamide and 2-Arachidonoylglycerol in Anxiety: Results from a Quasi-Experimental Ad Libitum Study.

The public is increasingly reporting using cannabis for anxiety relief. Both cannabis use and the endocannabinoid system have been connected with anxiety relief/anxiolytic properties, but these relationships are complex, and the underlying mechanisms for them are unclear. : Work is needed to understand how the endocannabinoid system, including the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), may be impacted by the main constituents of cannabis, Δ9-tetrahydrocannabinol (THC), and cannabidiol (CBD).

Priming lymphocyte responsiveness and differential T cell signaling in pediatric IBD patients with use.

The prevalence of inflammatory bowel disease (IBD) has increased dramatically in recent years, particularly in pediatric populations. Successful remission with current therapies is limited and often transient, leading patients to seek alternative therapies for symptom relief, including the use of medical marijuana (). However, chronic cannabis use among IBD patients is associated with increased risk for surgical interventions.

Identification and Characterization of Cannabichromene's Major Metabolite Following Incubation with Human Liver Microsomes.

Cannabichromene (CBC) is a minor cannabinoid within the array of over 120 cannabinoids identified in the plant. While CBC does not comprise a significant portion of whole plant material, it is available to the public in a purified and highly concentrated form. As minor cannabinoids become more popular due to their potential therapeutic properties, it becomes crucial to elucidate their metabolism in humans.

LC-MS-MS quantification of Δ8-THC, Δ9-THC, THCV isomers and their main metabolites in human plasma.

In recent years, potential therapeutic applications of several different cannabinoids, such as Δ9-tetrahydrocannabinol (Δ9-THC), its isomer Δ8-THC and Δ9-tetrahydrocannabivarin (Δ9-THCV), have been investigated. Nevertheless, to establish dose-effect relationship and to gain knowledge of their pharmacokinetics and metabolism, sensitive and specific analytical assays are needed to measure these compounds in patients. For this reason, we developed and validated an online extraction high-performance liquid/liquid chromatography-tandem mass spectrometry (LC/LC-MS-MS) method for the simultaneous quantification of 13 cannabinoids and metabolites including the Δ8 and Δ9 isomers of THC, THCV and those of their major metabolites in human plasma.

The impact of cannabis use proximal to sleep and cannabinoid metabolites on sleep architecture.

Study Objectives: Cannabis is a common sleep aid; however, the effects of its use prior to sleep are poorly understood. This study aims to determine the impact of nonmedical whole plant cannabis use 3 hours prior to sleep and measured cannabis metabolites on polysomnogram measures.

Methods: This is a cross-sectional study of 177 healthy adults who provided detailed cannabis use history, underwent a 1-night home sleep test and had measurement of 11 plasma and urinary cannabinoids, quantified using mass spectroscopy, the morning after the home sleep test.

Vaporized D-limonene selectively mitigates the acute anxiogenic effects of Δ9-tetrahydrocannabinol in healthy adults who intermittently use cannabis.

Background: Cannabis contains hundreds of chemical constituents beyond delta-9-tetrahydrocannabinol (THC), which is believed to drive most of its acute pharmacodynamic effects. The entourage effect theory asserts that non-THC constituents can impact acute cannabis effects, but few empirical studies have systematically evaluated this theory in humans. This study assessed whether the cannabis terpenoid d-limonene mitigates the acute anxiogenic effects of THC.

Short-Term Cannabidiol with Δ-9-Tetrahydrocannabinol in Parkinson's Disease: A Randomized Trial.

Background: Cannabis use is frequent in Parkinson's disease (PD), despite inadequate evidence of benefits and risks.

Objective: The aim is to study short-term efficacy and tolerability of relatively high cannabidiol (CBD)/low Δ-9-tetrahydrocannabinol (THC) to provide preliminary data for a longer trial.

Methods: Persons with PD with ≥20 on motor Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) who had negative cannabis testing took cannabis extract (National Institute of Drug Abuse) oral sesame oil solution for 2 weeks, increasing to final dose of 2.

-Caryophyllene Inhibits Monoacylglycerol Lipase Activity and Increases 2-Arachidonoyl Glycerol Levels In Vivo: A New Mechanism of Endocannabinoid-Mediated Analgesia?

The mechanisms of -caryophyllene (BCP)-induced analgesia are not well studied. Here, we tested the efficacy of BCP in an acute postsurgical pain model and evaluated its effect on the endocannabinoid system. Rats were treated with vehicle and 10, 25, 50, and 75 mg/kg BCP.

Structural Identification of Zotarolimus (ABT-578) Metabolites Generated by Human Liver Microsomes Using Ion-Trap and High-Resolution Time-of-Flight Mass Spectrometry in Combination with the Analysis of Fragmentation Patterns.

Zotarolimus (ABT-578) is a sirolimus derivative that, like sirolimus and everolimus, is an inhibitor of cell growth via inhibition of the mechanistic target of rapamycin (mTOR). Zotarolimus was developed for coating coronary stents to prevent smooth muscle cell proliferation and restenosis. Albeit zotarolimus-eluting cardiovascular devices have been on the market for years, details of zotarolimus drug metabolism in humans are still unknown.

Sex differences in endocannabinoid tone in a pilot study of cannabis use disorder and acute cannabis abstinence.

Cannabis use disorder (CUD) presents differently in men and women, particularly in symptoms of cannabis withdrawal. Novel pharmacotherapeutic interventions for CUD, such as those that target the endocannabinoid (eCB) system, must be developed in a manner consistent with these sex differences. The present pilot study sought to prospectively assess sex differences in cannabis withdrawal in a small sample of adults with moderate-to-severe CUD and to determine if withdrawal was associated with peripheral eCB and eCB congener tone.

Cognitive Safety Data from a Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Phase IIb Study of the Effects of a Cannabidiol and Δ9-Tetrahydrocannabinol Drug on Parkinson's Disease-Related Motor Symptoms.

Background: Cannabis is increasingly available worldwide but its impact on cognition in Parkinson's disease (PD) is unknown.

Objective: Present cognitive safety data from study of an oral high-dose cannabidiol (CBD; 100 mg) and low-dose Δ9-tetrahydocannabinol (THC; 3.3 mg) drug in PD.

Associations between Prenatal and Postnatal Exposure to Cannabis with Cognition and Behavior at Age 5 Years: The Healthy Start Study.

Background: Prenatal exposure to cannabis may influence childhood cognition and behavior, but the epidemiologic evidence is mixed. Even less is known about the potential impact of secondhand exposure to cannabis during early childhood.

Objective: This study sought to assess whether prenatal and/or postnatal exposure to cannabis was associated with childhood cognition and behavior.

Effects of oral Δ9-tetrahydrocannabinol and cannabidiol combinations on a sustained attention task in rats.

A well-documented side effect of cannabis and Δ9-tetrahydrocannabinol (THC) acute administration is deficits in cognition and attention. Cannabidiol (CBD), a nonintoxicating constituent of cannabis, may modulate THC's impairing effects. A goal of this study was to determine the effects of THC and CBD, alone and in combination, on performance in the rodent Psychomotor Vigilance Test (rPVT), a translational paradigm used to quantify sustained attention.

Cannabinoid Exposure and Subjective Effects of THC and CBD in Edible Cannabis Products.

The popularity of edible cannabis products continues to grow in states with legal cannabis access, but few studies have investigated the acute effects of these commercially available products. The present study sought to explore the effects of three commercially available edible products with different levels of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). A sample of regular cannabis users (=99) were evaluated.