A descriptive study of older medical cannabis users in medical cannabis clinics

Introduction: There is a dearth of information on older users (65+ years) of medical cannabis, who may face unique challenges due to altered metabolism with aging, concurrent medication use, and risk of adverse effects. This observational study aimed to describe a large cohort of older medical cannabis users in Canada. Method(s): From Oct 2014 to Oct 2020, a commercial medical cannabis provider based in Canada collected anonymized data for research purposes from patient volunteers. Data included demographic, social, and health details (at intake) and cannabis products, self-perceived changes in symptoms and change in medications (at follow-up, variable duration). Cannabis products were categorized as cannabidiol (CBD) only, tetrahydocannabinol (THC) only or mixed CBD/THC. Of the mixed, formulations could be in 1:1 ratios (CBD+/THC+), predominantly CBD (CBD+/THC-) or predominantly THC (CBD-/THC+). Result(s): In total, 9766 subjects in the older cohort (65+ years old) completed the entire questionnaire (mean age (SD) = 73.6 (6.8) y, 60% female). They represented 23.1% of the total dataset (N = 42,267, mean (SD) =51.5 (16.8) y). The proportion of adults in the older cohort tended to increase over time (pre-2018: 17.6%;2018: 26.7%;2019: 31.2%;2020: 22.7%, when the overall intake decreased from 8869 to 5644). Among the older cohort, 15.5% were previous cannabis users and 67.7% were referred for chronic pain (mainly arthritis, chronic pain, lower back pain). Concomitant analgesic use was common (over-the-counter analgesics: 44.5%;opioids: 28.3%;NSAIDs: 24.5%). 7.9% of the sample (compared to 19.9% in the whole sample) were referred for psychiatric disorders, though 21.4% indicated antidepressant use and 12.3% indicated benzodiazepine use. Another 7% were referred for neurological disorders. Follow-up data were captured in visits (11,992) from 4698 older patients, averaging 2.5 visits per patient. The type of medical cannabis used changed over time, with increasing use of cannabis oil compared to herbal cannabis. In 2020, of 2478 visits, 78.9% use was cannabis oil and 6.7% was herbal forms (pre-2018: 57.6% vs 36.2%). The composition of cannabis oil demonstrated a preference for cannabinoid oil (CBD+) over tetrahydrocannabinol (THC+) in 6043 visits: 45.2% were using CBD+ preparations, only 3.2% were using THC+ preparations, and for CBD/THC combinations, CBD predominated (CBD+/THC-: 30.5%;CBD+/THC+: 16.8%;CBD-/THC+: 4.3%). Adverse-effects (7062 visits) included dry mouth (15.8%), drowsiness (8.6%), dizziness (4%) and hallucinations (0.6%). Patients reported improved pain, sleep and mood over time, though 15-20% reported no improvement or worsening. Medication use was mostly unchanged, though 40% of opioid users reported requiring reduced dosages. Conclusion(s): These data were drawn from a large convenience sample. The data suggest an increasing proportion of older users of medical cannabis, though COVID-19 may have affected recent use. Female users comprised a higher proportion, and cannabis oil containing CBD was preferred. Systematic studies of effectiveness and safety in older users of cannabinoids are needed given its increasing use. Funding(s): No funding was received for this work.Copyright © 2021

Current Evidence of Cannabidiol's Potential as an Anxiolytic Agent

This article will summarize the current knowledge and scientific evidence regarding cannabidiol as a possible pharmacological tool for anxiety disorders. Although the use of this substance in medical practice is gaining momentum, gaps can still be found in the current knowledge regarding its molecular targets, drug-to-drug interactions, efficacy in different populations, adequate dosage, duration of treatment, and correct formulation. Moreover, current evidence is still preliminary, lacking robust, blinded, and placebo-controlled clinical trials in many areas of investigation. After reading this article, readers should have a thorough understanding of the current scientific evidence regarding the use of CBD as an anxiolytic drug. [Psychiatr Ann. 2023;53(6):242–246.]

Cannabis-Induced Catatonia in a 15-Year-Old Male: A Case Report

Introduction: Catatonia is a syndrome of primarily psychomotor disturbances most common in psychiatric mood disorders but that also rarely has been described in association with cannabis use. Case Presentation: A 15-year-old White male presented with left leg weakness, altered mental status, and chest pain, which then progressed to global weakness, minimal speech, and a fixed gaze. After ruling out organic causes of his symptoms, cannabis-induced catatonia was suspected, and the patient responded immediately and completely to lorazepam administration. Discussion(s): Cannabis-induced catatonia has been described in several case reports worldwide, with a wide range and duration of symptoms reported. There is little known about the risk factors, treatment, and prognosis of cannabis-induced catatonia. Conclusion(s): This report emphasizes the importance of clinicians maintaining a high index of suspicion to accurately diagnose and treat cannabis-induced neuropsychiatric conditions, which is especially important as the use of high-potency cannabis products in young people increases.Copyright © 2023, State Medical Society of Wisconsin. All rights reserved.

22nd International Congress of Iranian Society for Reproductive Medicine

The proceedings contain 158 papers. The topics discussed include: the success of various endometrioma treatments in infertility: a systematic review and meta-analysis;cell therapy accompanied by natural biomaterials, a novel therapeutic strategy for primary ovarian insufficiency treatment;ovarian hyperstimulation syndrome: a new look at an old problem;role of doppler ultrasonography and 3D ultrasound in female infertility;clinical outcome of artificial oocyte activation following intracytoplasmic sperm injection;the research priorities in infertility;how old is too old for infertility treatment?;the role of sexual dysfunction in men's health;recombinant follicle-stimulating hormone in treatment of sperm DNA fragmentation;the effect of zinc on tetrahydrocannabinol-induced Sertoli cells apoptosis;and detection of SARS-CoV-2 in follicular and endocervical fluid of in vitro fertilization candidates with positive polymerase chain reaction tests.

Medicinal Marijuana, Stress, Anxiety, and Depression: Primum non nocere

Higher levels of stress are associated with an increased risk of substance use disorders (SUDs) and other mental health conditions like depression. Short and long term changes in mood, depression, and suicidality can begin during adolescence and exacerbate by teen marijuana use according to a recent study.4 This longitudinal cohort study of over 30 years found that cannabis use during adolescence is not a medicine, but is associated with both depression and suicidality in adult life. [...]they are vulnerable to adverse cannabis outcomes, including continued opioid use and the development of additional substance use disorders.5 Public "medicinal" opinions on hydroxychloroquine and actual FDA- quality studies of safety and efficacy in SARS COVID 196 or voting marijuana a medicine is quite different than proving in a prospective, random assignment, placebo-controlled double-blind studies. Learning to inhale drug vapors may be the gateway event worth additional study.13 Most of the public health attention has been focused on vaping THC and death or severe toxic effects on lung and pulmonary function.

Cannabidiol as a personalized treatment for anxiety: clinical cases in Mexico.

Anxiety-related disorders are one of the most common mental health issues worldwide. Mexico has reported an increase in the prevalence of these ailments secondary to the confinement derived from the COVID-19 pandemic. Given the limitations of commonly used treatments for these disorders, a need arises to develop new pharmacological treatments for these patients. This paper has the primary objective of evaluating the efficacy and safety of cannabidiol isolate in drug compounding used as a personalized treatment in patients with anxiety disorders through the presentation of four clinical cases.

E-CIGARETTE OR VAPING USE-ASSOCIATED LUNG INJURY (EVALI): EFFECTS OF VAPING OR COVID-19?

SESSION TITLE: Critical Care in Chest Infections Case Report Posters 2 SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: EVALI is an acute lung injury that occurs due to the use of e-cigarettes or vaporizer products that usually contain THC or nicotine. There was an outbreak of EVALI in 2019. This is a diagnosis of exclusion with foamy macrophages with pneumocyte vacuolization being the best diagnostic clues. (1) Vitamin E acetate laced products seem to be the causing factor. CASE PRESENTATION: A 34-year-old female presented to the emergency department due to increasing shortness of breath, fever, pleuritic chest pain, cough, and headaches for the last 9 days. Two days prior she presented to urgent care where she was given an albuterol inhaler and azithromycin. At arrival, the patient was found to have tachycardia with a rate of 120-130, afebrile, SpO2 at 96% on room air, BP at 100/59. Her initial workup was grossly normal except for an elevated WBC and elevated D-Dimer. Chest X-ray revealed opacities in the lower lungs consistent with pneumonia. CTA of the chest revealed patchy pulmonary opacities consistent with COVID pneumonia. She took three separate SARS-CoV-2 PCR tests which all came back negative. The patient underwent a large workup which included infectious disease, pulmonology, and cardiology consults. She was treated with broad-spectrum antibiotics for the presumed diagnosis of pneumonia but her condition quickly deteriorated, eventually requiring 6L of O2 via nasal cannula. Screening for a large array of bacteria, fungus, and viruses all resulted negative. Upon further discussion with the patient, she admitted to smoking a THC vaporizer every night for the last seven months and that she had recently purchased a new fluid for her THC vaporizer through the internet. Bronchoscopy was also acquired but did not show any specific findings, including being negative for eosinophils. Discontinuation of antibiotics and initiation of IV steroids treatment provided rapid improvement of the patient's condition. Based on her history of THC vaping, the clinical presentation of fever, hypoxia, her chest x-ray, and chest CT showing extensive lung infiltrates, infections were ruled out and the most likely diagnosis of EVALI was made which responded well to steroids. DISCUSSION: COVID and EVALI initially can present similarly as respiratory problems, fever, and the need for oxygen. It is important to gather history on the patient as a vaping history is needed to suspect EVALI as imaging can show a wide range from ground-glass opacities to acute hypersensitivity pneumonitis. (2) CONCLUSIONS: There are some distinguishing features of EVALI from COVID one being in EVALI there is a large increase in the white count and lastly the response to steroids is the key (2). Steroids are the primary care for someone with EVALI with most patients recovering in 1-3 days with the use of steroids. (2) Reference #1: Bierwirth, A., Orellana, G., Milazzo, E. and Hamdan, A., 2020. TETRAHYDROCANNABINOL VAPING-ASSOCIATED LUNG INJURY (EVALI): A US EPIDEMIC?. Chestnet Journal. Reference #2: MacMurdo, M., Lin, C., Saeedan, M., Doxtader, E., Mukhopadhyay, S., Arrossi, V., Reynolds, J., Ghosh, S. and Choi, H., 2020. e-Cigarette or Vaping Product Use-Associated Lung Injury. Chestnet Journal. DISCLOSURES: No relevant relationships by Narden Gorgy No relevant relationships by Matheus Moreira Sanches Peraci No relevant relationships by George Walbridge No relevant relationships by John Zakhary

Cultural, Social and Psychological Factors of the Conservative Consumer towards Legal Cannabis Use—A Review since 2013

Cannabis consumption has become the center of much debate globally. The positive public perception of the medicinal benefits of cannabis and the rise of recreational usage of cannabis necessitate dramatic changes in cannabis reform policy. As a consequence, there is an increase in cannabis legalization around the globe, although it is still facing many rejections. It is crucial to understand the factors affecting public acceptance of cannabis use to support the contextualization and success of cannabis legalization. This review aims to address consumer cultural, social and psychological factors regarding the legal use of cannabis. Based on this review, cultures influence the endorsement or rejection of cannabis use depending on political views, religious sentiments and affiliated subcultures (adult, youth and adolescent subcultures). Regarding the social factors, socioeconomic status, measured by income, education level and occupation, is a key determinant of cannabis use. The beliefs opposing cannabis legalization are due to the negative stigma surrounding cannabis use. Nevertheless, growing awareness about the pharmaceutical and therapeutic effects of cannabis has led to an increase in positive attitudes towards cannabis legalization. Thus, dissemination of cannabis use benefits reaffirmed by scientific evidence could be a strategic way to alleviate the public’s negative feedback on cannabis legalization.

In the Swim of Cannabis: Developmental Toxicity and Metabolomic Pathway Alterations of Zebrafish Larvae Exposed to THC for the Assessment of Its Potential Environmental and Human Health Impact.

As the pharmacological properties and therapeutic applications of Cannabis sativa L. pace with the upsurge of interest of the scientific community in harnessing its constituent phytocannabinoids, illicit use may raise serious health issues. Tetrahydrocannabinol (THC) is one of the most well-known phytoactive constituents of cannabis and continues to garner scientific and public attention not only because of its pharmacological value but also because over-the-counter products of THC and prescription medications are becoming increasingly available from pharmacies, dispensaries, Internet, local retail stores, or by illicit means. Hence, a multidimensional approach was employed to examine the impact of THC on zebrafish larvae. The acute toxicity, expressed as LC50, was 1.54 mg/L. Adverse effects were observed on the phenotype, such as tail bending, pericardial edema, etc., even at concentrations lower than LC50, and fundamental functions of larvae (e.g., heart rate and cardiac contractility, and rhythm) were significantly affected. Behavioral changes were noticed, which were reflected in locomotor activity and sensitivity to light/dark changes. Finally, an untargeted metabolomic study was carried out to shed light on the metabolic alterations that occurred, providing substantiating evidence of the observed phenotype alterations. Overall, the potentially detrimental effects of THC on a vertebrate model are depicted.

UP IN SMOKE: PATTERNS OF THC USE AND CANNABINOID HYPEREMESIS SYNDROME AT AN ACADEMIC MEDICAL CENTER

Background/Aim The prevalence of marijuana use has increased in the United States as many states have legalized its use. Cannabinoid hyperemesis syndrome (CHS) is an adverse effect that 17-30% of chronic users of marijuana will experience. The impact of the COVID- 19 pandemic on healthcare disruptions has been well established. The effect of the pandemic on vice-associated conditions has been described with increases in alcohol and substance related hospitalizations and mortality. Few studies have evaluated the effect of the COVID- 19 pandemic on CHS with regards to prevalence, admissions, readmissions, and healthcare burden. We sought to identify the impact of the COVID-19 pandemic on CHS using admissions and readmissions as metrics to evaluate healthcare burden. Methods Using Slicer-Dicer, an electronic medical record based self-service query tool, all cases of CHS requiring hospital admissions and those resulting in readmissions were recorded at the university's 3 hospital centers and stratified by gender, age, and location. Data was separated into pre-COVID (August 5, 2018 to April 5, 2020) and post-COVID (April 6, 2020 to October 5, 2021). Additionally, all positive cases of tetrahydrocannabinol (THC) tested were recorded and stratified by postal code. The primary outcome was identification of CHS cases requiring admission from the emergency department pre-COVID and post-COVID. The secondary outcome was identifying any differences in admission and readmission rates pre- COVID and post-COVID. Results A significant increase in total THC positive cases (p = <0.001) was seen with 2485 pre-COVID and 2936 post-COVID cases. 68 patients were diagnosed with CHS pre-COVID and 75 post-COVID. Cases requiring admission were 27.9% pre-COVID CHS and 30.7% post-COVID with a significant increase in admissions from one campus from 0% to 30.4% (p = 0.025). Pre-COVID CHS cases requiring readmission after an index admission was 31.6% and post-COVID was 26.1%. No significance was seen when stratifying the cohorts by gender and age. Discussion Our study shows a significant increase in CHS diagnoses and admissions with an associated significant increase in THC-positivity when comparing the pre-COVID and post-COVID cohorts. This is consistent with prior studies describing an increase in alcohol and substance use during the pandemic. Data from the Centers for Disease Control and Prevention also reveal a 30% increase in substance related deaths in 2020 when compared to 2019. Some suggest that factors related to the pandemic including social isolation stress, substance use in isolation, and decreased access to substance use treatment or programs are contributors. This study highlights the importance to identify this association to better understand and respond to pandemic-associated risk factors for substance use disorders to help alleviate its effect on healthcare burden.

Let's Look at Cannabis from This Angle: COVID-19

Cannabis sativa (Can nabis=hemp) contains cannabinoid-derived main components. Cannabinoids exert biological effects by stimulating cannabinoid receptors distributed throughout the body. Cannabis products affect various systems in the body such as the cardiovascular, respiratory, nervous and immune systems. They show analgesic, antiemetic, anxiolytic, antidepressant, anti-inflammatory, antimicrobial, antihypertensive, antitussive and cardioprotective effects. COVID-19 affects different organ systems in the body and causes symptoms depending on the mutation, such as dry cough, shortness of breath, nausea, vomiting, loss of appetite and sense of smell. In this article, effectiveness of C. sativa and its components on COVID-19 have been evaluated, based on the fact that components or the extracts can affect the whole body due to cannabinoid receptors. Although cannabis and its components have potential beneficial effects for the entry of COVID-19 through the receptors into the body and the symptoms, further studies are needed for their safe use. Appropriate formulation and administration routes should be determined to eliminate the side effects and risk of addiction.

An Elusive Case of E-Cigarette, or Vaping, Product Use Associated Lung Injury (EVALI) Lacking Respiratory Symptoms

Introduction: Electronic vaping-associated lung injury (EVALI), attributed to inhalation through E-cigarettes and other devices was first characterized in the US in July 2019. By February 2020, 2807 cases were reported. Patients often present with respiratory, gastrointestinal, and constitutional symptoms. The presence of EVALI without respiratory complaints is under-recognized, only reported three times in the literature thus far. Case: A 22-year-old female student presented with five days of fever, watery, nonmucoid, non-bloody diarrhea, nausea, 3-4 episodes of vomiting, and generalized weakness, without cough, dyspnea, chest or abdominal pain. Social history revealed vaping e-cigarettes containing nicotine and tetrahydrocannabinol for the past 3-4 years with increased use recently due to upcoming exams. She denied smoking traditional cigarettes, marijuana, or illicit drugs. A temperature of 101oF and 98% SaO2 were recorded. Physical examination was notable for bilateral diffuse crackles with a normal abdominal examination. Initial labs demonstrated a WBC of 14,600 without a shift and the remaining labs were within normal limits. Despite the absence of respiratory symptoms, her chest radiograph revealed bilateral multifocal airspace disease. Further investigation with Chest CT showed extensive multifocal bilateral infiltrates and predominantly peripheral ground-glass opacities. COVID-19 PCR was negative three times. Influenza A and B, RSV, mycoplasma, and legionella testing were negative. She was unable to provide sputum for culture. Stool cultures were negative and an abdominal and pelvic CT was normal. She denied any history of dietary intolerances, prior diarrhea, or chronic colitis. Empiric treatment for atypical community-acquired pneumonia with intravenous ceftriaxone and azithromycin was initiated, with little improvement over the subsequent 4 days. Lack of clinical effect with antibiotics prompted a suspicion for EVALI and intravenous methylprednisolone 1mg/kg every 8 hours was initiated. There was a significant improvement of her gastrointestinal and constitutional symptoms within 24 hours. After three days of IV steroids, she was discharged on an enteral taper. A repeat Chest CT scan 2 weeks later demonstrated complete resolution of the previously identified ground-glass opacities. Discussion: The use of E-cigarettes has grown by 900% between 2011 and 2019 among young adults but used by older individuals as well. This has contributed to the burgeoning EVALI epidemic. Although COVID has taken the centre stage while identifying diffuse interstitial lung abnormalities, there must be a high index of suspicion regarding the incidence of EVALI, especially in young patients, considering the varied presentations and the potential absence of respiratory symptoms.

Health effects and known pathology associated with the use of E-cigarettes.

In recent years, new nicotine delivery methods have emerged, and many users are choosing electronic cigarettes (e-cigarettes) over traditional tobacco cigarettes. E-cigarette use is very popular among adolescents, with more than 3.5 million currently using these products in the US. Despite the increased prevalence of e-cigarette use, there is limited knowledge regarding the health impact of e-cigarettes on the general population. Based on published findings by others, E-cigarette is associated with lung injury outbreak, which increased health and safety concerns related to consuming this product. Different components of e-cigarettes, including food-safe liquid solvents and flavorings, can cause health issues related to pneumonia, pulmonary injury, and bronchiolitis. In addition, e-cigarettes contain alarmingly high levels of carcinogens and toxicants that may have long-lasting effects on other organ systems, including the development of neurological manifestations, lung cancer, cardiovascular disorders, and tooth decay. Despite the well- documented potential for harm, e-cigarettes do not appear to increase susceptibility to SARS-CoV- 2 infection. Furthermore, some studies have found that e-cigarette users experience improvements in lung health and minimal adverse effects. Therefore, more studies are needed to provide a definitive conclusion on the long-term safety of e-cigarettes. The purpose of this review is to inform the readers about the possible health-risks associated with the use of e-cigarettes, especially among the group of young and young-adults, from a molecular biology point of view.

Hydroxychloroquine (HCQ) Exhibits Better Binding to the Main Protease (Mpro) Compared to Spike Protein (S protein) of SARS-CoV-2: An In-silico Analysis

Background: Despite various efforts in preventing and treating SARS-CoV-2 infec-tions;transmission and mortality have been increasing at alarming rates globally. Since its first oc-currence in Wuhan, China, in December 2019, the number of cases and deaths due to SARS-CoV--2 infection continues to increase across 220 countries. Currently, there are about 228 million cases and 4.6 million deaths recorded globally. Although several vaccines/drugs have been reported to prevent or treat SARS-CoV-2, their efficacy to protect against emerging variants and duration of protection are not fully known. Hence, more emphasis is given to repurpose the existing pharmacological agents to manage the infected individuals. One such agent is hydroxychloroquine (HCQ), which is a more soluble derivative of antimalarial drug chloroquine. HCQ has been tested in clinical trials to mitigate SARS-CoV-2 infection-induced complications while reducing the time to clinical recovery (TTCR). However, several concerns and questions about the utility and efficacy of HCQ for treating SARS-CoV-2 infected individuals still persist. Identifying key proteins regulated by HCQ is likely to provide vital clues required to address these concerns. Objective: The objective of this study is to identify the ability of HCQ for binding to the most wide-ly studied molecular targets of SARS-CoV-2 viz., spike glycoprotein (S protein), and main pro-tease (Mpro, also referred as chymotrypsin like protease) using molecular docking approaches and correlate the results with reported mechanisms of actions of HCQ. Methods: X-ray crystallographic structures of spike glycoprotein and main protease of SARS-CoV-2 were retrieved from Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB). The structure of Hydroxychloroquine was retrieved from the PubChem compound database. The binding interactions of the HCQ with target proteins were predicted using C-Docker algorithm, and visualized using Discovery studio visualizer. Results: Data from molecular docking studies showed very strong binding of HCQ to the main pro-tease compared to spike glycoprotein. Conclusion: The antiviral activity of HCQ is attributed to its ability to bind to the main protease compared to surface glycoprotein. Therefore, future studies should focus more on developing a combination agent/strategy for targeting surface glycoprotein and main protease together.

Simultaneous Quantification of 17 Cannabinoids in Cannabis Inflorescence by Liquid Chromatography-Mass Spectrometry

With an increasing appreciation for the unique pharmacological properties associated with distinct, individual cannabinoids of Cannabis sativa, there is demand for accurate and reliable quantification for a growing number of them. Although recent methods are based on highly selective chromatography-mass spectrometry technology, most are limited to a few cannabinoids, while relying on unnecessarily sophisticated and expensive ultra-high performance liquid chromatography and tandem mass spectrometry. Here we report an optimised, simple extraction method followed by a reliable and simple high performance liquid chromatography method for separation. The detection is performed using a time-of-flight mass spectrometer that is available in most natural products research laboratories. Due to the simplicity of instrumentation, and the robustness resulting from a high resolution in the chromatography of isobaric cannabinoids, the method is well suited for routine phytocannabinoid analysis for a range of applications. The method was validated in terms of detection and quantification limits, repeatability, and recoveries for a total of 17 cannabinoids: detection limits were in the range 11–520 pg when using a 1 µL sample injection volume, and the recovery percentages ranged from 85% to 108%. The validated method was subsequently applied to determine cannabinoid composition in the inflorescences of several medicinal Cannabis sativa varieties.

Cannabinoids Alleviate the LPS-Induced Cytokine Storm via Attenuating NLRP3 Inflammasome Signaling and TYK2-Mediated STAT3 Signaling Pathways In Vitro.

Cannabinoids, mainly cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), are the most studied group of compounds obtained from Cannabis sativa because of their several pharmaceutical properties. Current evidence suggests a crucial role of cannabinoids as potent anti-inflammatory agents for the treatment of chronic inflammatory diseases; however, the mechanisms remain largely unclear. Cytokine storm, a dysregulated severe inflammatory response by our immune system, is involved in the pathogenesis of numerous chronic inflammatory disorders, including coronavirus disease 2019 (COVID-19), which results in the accumulation of pro-inflammatory cytokines. Therefore, we hypothesized that CBD and THC reduce the levels of pro-inflammatory cytokines by inhibiting key inflammatory signaling pathways. The nucleotide-binding and oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome signaling has been implicated in a variety of chronic inflammatory diseases, which results in the release of pyroptotic cytokines, interleukin-1ß (IL-1ß) and IL-18. Likewise, the activation of the signal transducer and activator of transcription-3 (STAT3) causes increased expression of pro-inflammatory cytokines. We studied the effects of CBD and THC on lipopolysaccharide (LPS)-induced inflammatory response in human THP-1 macrophages and primary human bronchial epithelial cells (HBECs). Our results revealed that CBD and, for the first time, THC significantly inhibited NLRP3 inflammasome activation following LPS + ATP stimulation, leading to a reduction in the levels of IL-1ß in THP-1 macrophages and HBECs. CBD attenuated the phosphorylation of nuclear factor-κB (NF-κB), and both cannabinoids inhibited the generation of oxidative stress post-LPS. Our multiplex ELISA data revealed that CBD and THC significantly diminished the levels of IL-6, IL-8, and tumor necrosis factor-α (TNF-α) after LPS treatment in THP-1 macrophages and HBECs. In addition, the phosphorylation of STAT3 was significantly downregulated by CBD and THC in THP-1 macrophages and HBECs, which was in turn attributed to the reduced phosphorylation of tyrosine kinase-2 (TYK2) by CBD and THC after LPS stimulation in these cells. Overall, CBD and THC were found to be effective in alleviating the LPS-induced cytokine storm in human macrophages and primary HBECs, at least via modulation of NLRP3 inflammasome and STAT3 signaling pathways. The encouraging results from this study warrant further investigation of these cannabinoids in vivo.

A phase i does-escalation and expansion study of epidiolex (cannabidiol) in patients with biochemically recurrent prostate cancer

Background: There is a need for a low toxicity option for men with prostate cancer with biochemical recurrence (BCR) following primary curative therapy. Cannabinoids (CBD) have antitumor activity in preclinical studies, but products may vary in activity without clear standardization. As epidiolex is a standardized FDA approved oral CBD solution for treatment of certain types of seizures, we studied epidiolex in patients with BCR of prostate cancer to determine safety and dosing of this therapy to support future studies. Methods: We present an open-label, single center, phase I dose escalation study followed by a dose expansion. Patients with BCR prostate cancer after primary definitive local therapy (prostatectomy +/- salvage radiotherapy or primary definitive radiotherapy) were eligible. Majority of our patients' prostate-specific antigen (PSA) doubling time was ≤ 12 months. All patients were screened for urine tetrahydrocannabinol (THC) prior to enrollment. With use of a Bayesian optimal interval design, patients received escalating doses of epidiolex starting at 600mg daily and up to 800mg daily. All patients were treated for 90 days followed by a 10 day taper. The Primary endpoints were safety and tolerability. Patients were monitored for both acute (30 days) and chronic (90 days) treatment-related toxicities. Secondary endpoints included change in PSA levels and testosterone levels from baseline throughout the treatment period. Results: A total of 21 patients were enrolled but four withdrew from the study (one patient was hospitalized with COVID-19 and three patients requested to stop due to grade 2 adverse events (AEs). There were seven patients included in the dose escalation phase. Four patients received 600mg daily;two of the four in this phase did not finish the first 30 days (one with COVID-19 and one withdrew). The other three patients received 800 mg daily. No dose-limiting toxicities were observed at any dose level so an additional 14 patients were enrolled at the 800mg dose. Treatment-related chronic AEs occurring in >10% of patients were grade 1 or 2 diarrhea (47.6%), grade 1 or 2 nausea (23.8%) and grade 1 or 2 fatigue (19%). The mean PSA at baseline was 2.9 ng/ml. One patient developed oligo-metastasis disease, two patients progressed after the study period, and one patient died from a non-treatment or disease-related cause. Conclusions: Epidiolex at a dose of 800mg daily appears to be safe and tolerable in patients with BCR of prostate cancer, supporting a safe dose for future studies to determine if there is clinical activity to delay development of hormone refractory metastatic disease.