Paclitaxel-Associated Mechanical Sensitivity and Neuroinflammation Are Sex-, Time-, and Site-Specific and Prevented through Cannabigerol Administration in C57Bl/6 Mice.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most prevalent and dose-limiting complications in chemotherapy patients. One identified mechanism underlying CIPN is neuroinflammation. Most of this research has been conducted in only male or female rodent models, making direct comparisons regarding the role of sex differences in the neuroimmune underpinnings of CIPN limited. Moreover, most measurements have focused on the dorsal root ganglia (DRG) and/or spinal cord, while relatively few studies have been aimed at characterizing neuroinflammation in the brain, for example the periaqueductal grey (PAG). The overall goals of the present study were to determine (1) paclitaxel-associated changes in markers of inflammation in the PAG and DRG in male and female C57Bl6 mice and (2) determine the effect of prophylactic administration of an anti-inflammatory cannabinoid, cannabigerol (CBG). In Experiment 1, male and female mice were treated with paclitaxel (8-32 mg/kg/injection, Days 1, 3, 5, and 7) and mechanical sensitivity was measured using Von Frey filaments on Day 7 (Cohort 1) and Day 14 (Cohort 2). Cohorts were euthanized on Day 8 or 15, respectively, and DRG and PAG were harvested for qPCR analysis of the gene expression of markers of pain and inflammation Aig1, Gfap, Ccl2, Cxcl9, Tlr4, Il6, and Calca. In Experiment 2, male and female mice were treated with vehicle or 10 mg/kg CBG i.p. 30 min prior to each paclitaxel injection. Mechanical sensitivity was measured on Day 14. Mice were euthanized on Day 15, and PAG were harvested for qPCR analysis of the gene expression of Aig1, Gfap, Ccl2, Cxcl9, Tlr4, Il6, and Calca. Paclitaxel produced a transient increase in potency to produce mechanical sensitivity in male versus female mice. Regarding neuroinflammation, more gene expression changes were apparent earlier in the DRG and at a later time point in the PAG. Also, more changes were observed in females in the PAG than males. Overall, sex differences were observed for most markers at both time points and regions. Importantly, in both the DRG and PAG, most increases in markers of neuroinflammation and pain occurred at paclitaxel doses higher than those associated with significant changes in the mechanical threshold. Two analytes that demonstrated the most compelling sexual dimorphism and that changed more in males were Cxcl9 and Ccl2, and Tlr4 in females. Lastly, prophylactic administration of CBG protected the male and female mice from increased mechanical sensitivity and female mice from neuroinflammation in the PAG. Future studies are warranted to explore how these sex differences may shed light on the mechanisms of CIPN and how non-psychoactive cannabinoids such as CBG may engage these targets to prevent or attenuate the effects of paclitaxel and other chemotherapeutic agents on the nervous system.

Cannabis Science and Therapeutics: An Overview for Clinicians.

Cannabis-based therapeutics have garnered increasing attention in recent years as patients seek alternative treatments for various medical conditions. This narrative review provides a comprehensive overview of the science behind the medical use of cannabis, focusing on the medical evidence for commonly treated conditions. In addition, the review addresses the practical considerations of using cannabis as a therapeutic agent, offering insights into dosing strategies, variations in cannabinoid formulation, and individual patient responses. Precautions, adverse consequences, and drug interactions are also discussed, with a focus on patient safety and the potential risks associated with cannabis use.

Examining the Systemic Bioavailability of Cannabidiol and Tetrahydrocannabinol from a Novel Transdermal Delivery System in Healthy Adults: A Single-Arm, Open-Label, Exploratory Study.

INTRODUCTION: Transdermal cannabinoids may provide better safety and bioavailability profiles compared with other routes of administration. This single-arm, open-label study investigated a novel topical transdermal delivery system on the pharmacokinetics of cannabidiol (CBD) and tetrahydrocannabinol (THC). METHODS: Participants were 39.5 ± 7.37 years old and healthy, based on a review by the Medical Director. Blood was collected pre-dose and 10, 20, 30, and 45 min, and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 h after topical application of 100 mg CBD:100 mg THC. Psychoactive effects were assessed prior to each timepoint. Area-under-the-curve (AUC0-12 h), maximum concentration (Cmax), time to maximum concentration (Tmax), area-under-the-curve to infinity (AUCI), terminal elimination rate constant (λ), terminal half-life (t½), and absorption rate constant (ka) were measured individually for CBD and THC. Safety was assessed by clinical chemistry, hematology, and adverse events. RESULTS: AUC0-12 h for CBD and THC was 3329.8 ± 3252.1 and 2093.4 ± 2090.6 pg/mL/h, with Cmax of 576.52 ± 1016.18 and 346.57 ± 776.85 pg/mL, respectively. Tmax for CBD and THC was 8 h, ranging from 2.5 h to 12 h and 10 min to 12 h, respectively. AUCI for CBD and THC was 6609.2 ± 7056.4 and 3721.0 ± 3251.7 pg/mL/h, with t1/2 of 5.68 ± 1.5 and 5.38 ± 1.25 h, respectively. CBD was absorbed at a faster rate compared with THC (123.36 ± 530.97 versus 71.5 ± 1142.19 h-1) but with similar λ (0.12 ± 0.029 versus 0.13 ± 0.03 h-1). No psychoactive effects were reported. Transdermal cannabinoid delivery was safe and well tolerated in the population studied. CONCLUSION: To our knowledge, this is the first pharmacokinetic study in humans that demonstrated CBD and THC entering systemic circulation via transdermal administration . This study represents an important contribution to understanding the pharmacokinetics of transdermal cannabinoids. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier-NCT05121506 (November 16, 2021).

Short communication: Tissue distribution of major cannabinoids following intraperitoneal injection in male rats.

Currently, peripheral tissue distribution of cannabinoids after treatment is poorly understood. This pilot study sought to examine the early tissue distribution of major cannabinoids 30 minutes following an intraperitoneal injection of vehicle (1:9 Tween 80/SAL), and doses of THC (1 mg/kg) and CBD (5 mg/kg) that are feasible for human consumption in serum, adipose, brain, lung, liver, jejunum, and muscle of male Sprague-Dawley rats. The jejunum and adipose were most enriched in THC. Similarly, CBD was enriched in the jejunum and adipose but also the liver. In contrast, the brain had the lowest concentration of cannabinoids relative to other tissues. The liver had the greatest concentration of the THC metabolites, 11-OH-THC and COOH-THC, compared to all other tissues. Overall, these findings highlight broad tissue distribution and marked differences in tissue concentration not previously appreciated. Thus, as cannabinoid research continues to rapidly grow, consideration of the potential bioactive effects of these molecules in peripheral tissues is warranted in future studies.

A comprehensive breath test that confirms recent use of inhaled cannabis within the impairment window.

Legalization of cannabis for medicinal and/or recreational use is expanding globally. Although cannabis is being regulated country by country, an accurate recent use test with indisputable results correlated with impairment has yet to be discovered. In the present study, a new approach for determining recent cannabis use within the impairment window after smoking was developed by studying 74 subjects with a mean age of 25 years and average use history of 9 years. Horizontal gaze nystagmus was evaluated along with subject self-assessments of impairment, and blood and breath samples were collected before and after smoking cannabis. Breath and blood pharmacokinetic parameters and cannabinoid profiles determined recent use within the impairment window. No subjects were positive for recent use pre-smoking, although all subjects had detectable cannabinoids in breath samples. We describe an inhaled cannabis recent use test that correlates with impairment and helps protect against wrongful prosecution and workplace discrimination.

The potential of cannabinoids and inhibitors of endocannabinoid degradation in respiratory diseases.

The global incidence of respiratory diseases and complications is increasing. Therefore, new methods of treatment, as well as prevention, need to be investigated. A group of compounds that should be considered for use in respiratory diseases is cannabinoids. There are three groups of cannabinoids - plant-derived phytocannabinoids, synthetic cannabinoids, and endogenous endocannabinoids including the enzymes responsible for their synthesis and degradation. All cannabinoids exert their biological effects through either type 1 cannabinoid receptors (CB1) and/or type 2 cannabinoid receptors (CB2). In numerous studies (in vitro and in vivo), cannabinoids and inhibitors of endocannabinoid degradation have shown beneficial anti-inflammatory, antioxidant, anti-cancer, and anti-fibrotic properties. Although in the respiratory system, most of the studies have focused on the positive properties of cannabinoids and inhibitors of endocannabinoid degradation. There are few research reports discussing the negative impact of these compounds. This review summarizes the properties and mechanisms of action of cannabinoids and inhibitors of endocannabinoid degradation in various models of respiratory diseases. A short description of the effects selected cannabinoids have on the human respiratory system and their possible use in the fight against COVID-19 is also presented. Additionally, a brief summary is provided of cannabinoid receptors properties and their expression in the respiratory system and cells of the immune system.

Medical cannabis or cannabinoids for chronic non-cancer and cancer related pain: a systematic review and meta-analysis of randomised clinical trials.

OBJECTIVE: To determine the benefits and harms of medical cannabis and cannabinoids for chronic pain. DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, EMBASE, AMED, PsycInfo, CENTRAL, CINAHL, PubMed, Web of Science, Cannabis-Med, Epistemonikos, and trial registries up to January 2021. STUDY SELECTION: Randomised clinical trials of medical cannabis or cannabinoids versus any non-cannabis control for chronic pain at ≥1 month follow-up. DATA EXTRACTION AND SYNTHESIS: Paired reviewers independently assessed risk of bias and extracted data. We performed random-effects models meta-analyses and used GRADE to assess the certainty of evidence. RESULTS: A total of 32 trials with 5174 adult patients were included, 29 of which compared medical cannabis or cannabinoids with placebo. Medical cannabis was administered orally (n=30) or topically (n=2). Clinical populations included chronic non-cancer pain (n=28) and cancer related pain (n=4). Length of follow-up ranged from 1 to 5.5 months. Compared with placebo, non-inhaled medical cannabis probably results in a small increase in the proportion of patients experiencing at least the minimally important difference (MID) of 1 cm (on a 10 cm visual analogue scale (VAS)) in pain relief (modelled risk difference (RD) of 10% (95% confidence interval 5% to 15%), based on a weighted mean difference (WMD) of -0.50 cm (95% CI -0.75 to -0.25 cm, moderate certainty)). Medical cannabis taken orally results in a very small improvement in physical functioning (4% modelled RD (0.1% to 8%) for achieving at least the MID of 10 points on the 100-point SF-36 physical functioning scale, WMD of 1.67 points (0.03 to 3.31, high certainty)), and a small improvement in sleep quality (6% modelled RD (2% to 9%) for achieving at least the MID of 1 cm on a 10 cm VAS, WMD of -0.35 cm (-0.55 to -0.14 cm, high certainty)). Medical cannabis taken orally does not improve emotional, role, or social functioning (high certainty). Moderate certainty evidence shows that medical cannabis taken orally probably results in a small increased risk of transient cognitive impairment (RD 2% (0.1% to 6%)), vomiting (RD 3% (0.4% to 6%)), drowsiness (RD 5% (2% to 8%)), impaired attention (RD 3% (1% to 8%)), and nausea (RD 5% (2% to 8%)), but not diarrhoea; while high certainty evidence shows greater increased risk of dizziness (RD 9% (5% to 14%)) for trials with <3 months follow-up versus RD 28% (18% to 43%) for trials with ≥3 months follow-up; interaction test P=0.003; moderate credibility of subgroup effect). CONCLUSIONS: Moderate to high certainty evidence shows that non-inhaled medical cannabis or cannabinoids results in a small to very small improvement in pain relief, physical functioning, and sleep quality among patients with chronic pain, along with several transient adverse side effects, compared with placebo. The accompanying BMJ Rapid Recommendation provides contextualised guidance based on this body of evidence. SYSTEMATIC REVIEW REGISTRATION: https://osf.io/3pwn2.

Medical cannabis or cannabinoids for chronic pain: a clinical practice guideline.

CLINICAL QUESTION: What is the role of medical cannabis or cannabinoids for people living with chronic pain due to cancer or non-cancer causes? CURRENT PRACTICE: Chronic pain is common and distressing and associated with considerable socioeconomic burden globally. Medical cannabis is increasingly used to manage chronic pain, particularly in jurisdictions that have enacted policies to reduce use of opioids; however, existing guideline recommendations are inconsistent, and cannabis remains illegal for therapeutic use in many countries. RECOMMENDATION: The guideline expert panel issued a weak recommendation to offer a trial of non-inhaled medical cannabis or cannabinoids, in addition to standard care and management (if not sufficient), for people living with chronic cancer or non-cancer pain. HOW THIS GUIDELINE WAS CREATED: An international guideline development panel including patients, clinicians with content expertise, and methodologists produced this recommendation in adherence with standards for trustworthy guidelines using the GRADE approach. The MAGIC Evidence Ecosystem Foundation (MAGIC) provided methodological support. The panel applied an individual patient perspective. THE EVIDENCE: This recommendation is informed by a linked series of four systematic reviews summarising the current body of evidence for benefits and harms, as well as patient values and preferences, regarding medical cannabis or cannabinoids for chronic pain. UNDERSTANDING THE RECOMMENDATION: The recommendation is weak because of the close balance between benefits and harms of medical cannabis for chronic pain. It reflects a high value placed on small to very small improvements in self reported pain intensity, physical functioning, and sleep quality, and willingness to accept a small to modest risk of mostly self limited and transient harms. Shared decision making is required to ensure patients make choices that reflect their values and personal context. Further research is warranted and may alter this recommendation.

Cannabinoids Regulate Sensory Processing in Early Olfactory and Visual Neural Circuits.

Our sensory systems such as the olfactory and visual systems are the target of neuromodulatory regulation. This neuromodulation starts at the level of sensory receptors and extends into cortical processing. A relatively new group of neuromodulators includes cannabinoids. These form a group of chemical substances that are found in the cannabis plant. Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the main cannabinoids. THC acts in the brain and nervous system like the chemical substances that our body produces, the endogenous cannabinoids or endocannabinoids, also nicknamed the brain's own cannabis. While the function of the endocannabinoid system is understood fairly well in limbic structures such as the hippocampus and the amygdala, this signaling system is less well understood in the olfactory pathway and the visual system. Here, we describe and compare endocannabinoids as signaling molecules in the early processing centers of the olfactory and visual system, the olfactory bulb, and the retina, and the relevance of the endocannabinoid system for synaptic plasticity.

Cannabis constituents interact at the drug efflux pump BCRP to markedly increase plasma cannabidiolic acid concentrations.

Cannabis is a complex mixture of hundreds of bioactive molecules. This provides the potential for pharmacological interactions between cannabis constituents, a phenomenon referred to as "the entourage effect" by the medicinal cannabis community. We hypothesize that pharmacokinetic interactions between cannabis constituents could substantially alter systemic cannabinoid concentrations. To address this hypothesis we compared pharmacokinetic parameters of cannabinoids administered orally in a cannabis extract to those administered as individual cannabinoids at equivalent doses in mice. Astonishingly, plasma cannabidiolic acid (CBDA) concentrations were 14-times higher following administration in the cannabis extract than when administered as a single molecule. In vitro transwell assays identified CBDA as a substrate of the drug efflux transporter breast cancer resistance protein (BCRP), and that cannabigerol and Δ9-tetrahydrocannabinol inhibited the BCRP-mediated transport of CBDA. Such a cannabinoid-cannabinoid interaction at BCRP transporters located in the intestine would inhibit efflux of CBDA, thus resulting in increased plasma concentrations. Our results suggest that cannabis extracts provide a natural vehicle to substantially enhance plasma CBDA concentrations. Moreover, CBDA might have a more significant contribution to the pharmacological effects of orally administered cannabis extracts than previously thought.

Influence of Cannabinoid Receptor 1 Genetic Variants on the Subjective Effects of Smoked Cannabis.

As many jurisdictions consider relaxing cannabis legislation and usage is increasing in North America and other parts of the world, there is a need to explore the possible genetic differences underlying the subjective effects of cannabis. This pilot study investigated specific genetic variations within the cannabinoid receptor 1 (CNR1) gene for association with the subjective effects of smoked cannabis. Data were obtained from a double-blinded, placebo-controlled clinical trial studying the impact of cannabis intoxication on driving performance. Participants randomized to the active cannabis group who consented to secondary genetic analysis (n = 52) were genotyped at the CNR1 rs1049353 and rs2023239 polymorphic areas. Maximum value and area under the curve (AUC) analyses were performed on subjective measures data. Analysis of subjective effects by genotype uncovered a global trend towards greater subjective effects for rs1049353 T-allele- and rs2023239 C-allele-carrying subjects. However, significant differences attributed to allelic identity were only documented for a subset of subjective effects. Our findings suggest that rs1049353 and rs2023239 minor allele carriers experience augmented subjective effects during acute cannabis intoxication.

The why behind the high: determinants of neurocognition during acute cannabis exposure.

Acute cannabis intoxication may induce neurocognitive impairment and is a possible cause of human error, injury and psychological distress. One of the major concerns raised about increasing cannabis legalization and the therapeutic use of cannabis is that it will increase cannabis-related harm. However, the impairing effect of cannabis during intoxication varies among individuals and may not occur in all users. There is evidence that the neurocognitive response to acute cannabis exposure is driven by changes in the activity of the mesocorticolimbic and salience networks, can be exacerbated or mitigated by biological and pharmacological factors, varies with product formulations and frequency of use and can differ between recreational and therapeutic use. It is argued that these determinants of the cannabis-induced neurocognitive state should be taken into account when defining and evaluating levels of cannabis impairment in the legal arena, when prescribing cannabis in therapeutic settings and when informing society about the safe and responsible use of cannabis.

Seizure and Interictal Electroencephalographic (EEG) Changes with Cannabinoid Concentrate Use.

BACKGROUND The electroencephalographic (EEG) findings associated with tetrahydrocannabinol (THC) use, particularly in concentrated form, are not well-described, despite the current widespread availability of these products. There is a lack of prior research describing the EEG findings in adolescent cannabis users, and the effects of THC on the seizure threshold have been variably reported. CASE REPORT A 17-year-old girl with no prior history of seizures or known seizure risk factors presented to an Emergency Department with acutely abnormal behavior in the setting of daily vaping of highly concentrated THC marijuana ("wax"). On admission, she had a witnessed generalized tonic-clonic seizure. Urine toxicology was positive for THC, and an extensive evaluation for other etiologies of her encephalopathy was unrevealing. Extended EEG on admission showed mild diffuse background slowing with occasional bifronto-centrally predominant sharp and spike wave discharges. Seven days later, without interim antiseizure medications, a repeat extended EEG showed resolution of the previously seen interictal findings. CONCLUSIONS The clinical and EEG findings were temporally associated with the patient's use of concentrated THC and may represent a constellation of symptoms of a THC wax toxidrome. In this case, THC was associated with lowering the seizure threshold and triggering a provoked seizure in an adolescent with no prior evidence of seizure tendency. This case also suggests the possibility of THC concentrate itself generating epileptiform discharges, as has previously been described with synthetic cannabinoid use.

Cannabidiol in low back pain: scientific rationale for clinical trials in low back pain.

INTRODUCTION: The pooled worldwide prevalence of low-back pain-related presentations in primary care varies between 6.8% and 28.4% in the high-income countries rendering it a major healthcare/economy problem. To best manage this complex bio-psycho-social condition a 360-degree approach is needed, as the psycho-social components are often more important than the scant pathophysiology. Pattern analysis of cannabis users suggested that attempts to alleviate musculo-skeletal pain is often seen as a major drive to use cannabinoids. AREAS COVERED: Unlike NSAIDs/opioids, cannabidiol might directly affect more than one modality of pain signaling/perception. The 2019 guideline of the National Institute for Clinical Excellence recommended further studies with cannabidiol in pain medicine because of its excellent safety profile and presumed therapeutic potential. Therefore, we have researched relevant databases for pharmaco-physiological papers published between 2000 and 2021 to collate evidence in a narrative fashion to determine the clinical rationale for this cannabinoid in low-back pain. EXPERT OPINION: Observational research reported good results with CBD in pain and fear reduction, which are both key factors in low-back pain. Given the paucity of high-quality evidence, further research is needed to determine the efficacy/non-inferiority of CBD in primary/emergency care setting, using multimodal assessment of various patient-reported outcomes.

Oral CBD-rich Cannabis Induces Clinical but Not Endoscopic Response in Patients with Crohn's Disease, a Randomised Controlled Trial.

AIMS: Despite reports that medical cannabis improves symptoms in Crohn's disease [CD], controlled studies evaluating disease response are lacking. This study assessed the effect of cannabidiol [CBD]-rich cannabis oil for induction of remission in CD. METHODS: In a double-blind, randomised, placebo-controlled, single-centre trial, patients received orally either cannabis oil containing160/40 mg/ml cannabidiol/tetrahydrocannabinol [CBD/THC] or placebo for 8 weeks. Disease parameters, including the CD activity index [CDAI], and simple endoscopic score for CD [SES-CD], were assessed before and after treatment. In a subgroup of patients, blood samples were collected for CBD and THC plasma levels. RESULTS: The study included 56 patients, age 34.5 ± 11 years, men/women 30/26 [54/46%],30 in cannabis and 26 in placebo groups. CDAI at recruitment and after 8 weeks was 282 (interquartile range [IQR] 243-342) and 166 [IQR 82-226], and 264 [IQR 234-320] and 237 [IQR 121-271] [p <0.05] in the cannabis and placebo groups, respectively. Median quality of life [QOL] score improved from 74 for both groups at baseline to 91 [IQR 85-102] and 75 [IQR 69-88] after 8 weeks in the cannabis and placebo groups, respectively [p = 0.004]. SES-CD was 10 [IQR 7-14] and 11 [IQR7-14], and 7 [4-14] and 8 [IQR 4-12] [p = 0.75] before and after treatment, in the cannabis and placebo groups, respectively. Inflammatory markers (C-reactive protein [CRP], calprotectin) remained unchanged. CONCLUSIONS: Eight weeks of CBD-rich cannabis treatment induced significant clinical and QOL improvement without significant changes in inflammatory parameters or endoscopic scores. The oral CBD-rich cannabis extract was well absorbed. Until further studies are available, cannabis treatment in Crohn's disease should be used only in the context of clinical trials.

Efficacy of cannabinoids against glioblastoma multiforme: A systematic review.

INTRODUCTION: The increased incidence of Glioblastoma Multiforme, the most aggressive and most common primary brain tumour, is evident worldwide. Survival rates are reaching only 15 months due to its high recurrence and resistance to current combination therapies including oncotomy, radiotherapy and chemotherapy. Light has been shed in the recent years on the anticancer properties of cannabinoids from Cannabis sativa. OBJECTIVE: To determine whether cannabinoids alone or in combination with radiotherapy and/or chemotherapy inhibit tumour progression, induce cancer cell death, inhibit metastasis and invasiveness and the mechanisms that underlie these actions. METHOD: PubMed and Web of Science were used for a systemic search to find studies on the anticancer effects of natural cannabinoids on glioma cancer cells in vitro and/or in vivo. RESULTS: A total of 302 papers were identified, of which 14 studies were found to fit the inclusion criteria. 5 studies were conducted in vitro, 2 in vivo and 7 were both in vivo and in vitro. 3 studies examined the efficacy of CBD, THC and TMZ, 1 study examined CBD and radiation, 2 studies examined efficacy of THC only and 3 studies examined the efficacy of CBD only. 1 study examined the efficacy of CBD, THC and radiotherapy, 2 studies examined the combination of CBD and THC and 2 more studies examined the efficacy of CBD and TMZ. CONCLUSION: The evidence in this systematic review leads to the conclusion that cannabinoids possess anticancer potencies against glioma cells, however this effect varies with the combinations and dosages used. Studies so far were conducted on cells in culture and on mice as well as a small number of studies that were conducted on humans. Hence in order to have more accurate results, higher quality studies mainly including human clinical trials with larger sample sizes are necessitated urgently for GBM treatment.

Safety and tolerability of escalating cannabinoid doses in healthy cats.

OBJECTIVES: The aim of this study was to determine the safety and tolerability of escalating doses of orally delivered cannabis oils predominant in cannabidiol (CBD), tetrahydrocannabinol (THC), or both CBD and THC in healthy cats. METHODS: In this placebo-controlled, blinded study, 20 healthy adult cats were randomized to one of five treatment groups (n = 4 per group): two placebo groups (sunflower oil [SF] or medium-chain triglyceride oil [MCT]), or three plant-derived cannabinoid oil groups (CBD in MCT, THC in MCT or CBD/THC [1.5:1] in SF). Up to 11 escalating doses of each formulation were delivered orally via syringe to fasted subjects, with at least 3 days separating doses. Safety and tolerability were determined from clinical observations, complete blood counts (CBCs) and clinical chemistry. Plasma cannabinoids (CBD, THC) and metabolites (7-COOH-CBD, 11-OH-THC) were assessed. RESULTS: Titration to maximum doses of 30.5 mg/kg CBD (CBD oil), 41.5 mg/kg THC (THC oil) or 13.0:8.4 mg/kg CBD:THC (CBD/THC oil) was safely achieved in all subjects. All observed adverse events (AEs) were mild, transient and resolved without medical intervention. Gastrointestinal AEs were more common with formulations containing MCT. Constitutional (lethargy, hypothermia), neurologic (ataxia) and ocular (protrusion membrana nictitans) AEs were more common with oils containing THC (CBD/THC and THC oils). There were no clinically significant changes in CBC or clinical chemistry across treatment groups. Higher plasma levels of the cannabinoids and their metabolites following administration of the CBD/THC combination product are suggestive of a pharmacokinetic interaction. CONCLUSIONS AND RELEVANCE: This is the first feline study to explore the safety and tolerability of CBD and THC, alone and in combination, in a controlled research setting. These findings will inform veterinarians of the safety profile of cannabinoids, particularly when considering the potential therapeutic use of CBD in cats or recognizing clinical signs associated with accidental exposure to THC-containing products.

Therapeutic and Cosmetic Uses of Cannabis: Cannabinoids for Acne Treatment and Skin -Rejuvenation.

Cannabinoids can be endogenous (endocannabinoids), plant-derived (phytocannabinoids), or synthesized (synthetic cannabinoids). They are being used for the management of several medical conditions. Laboratory and preliminary clinical studies suggest that topical cannabinoids may be beneficial for the treatment of acne and for skin rejuvenation. (SKINmed. 2021;19:-0).