Nanosuspension-Loaded Dissolving Microneedle Patches for Enhanced Transdermal Delivery of a Highly Lipophilic Cannabidiol.

Purpose: Transdermal Drug Delivery System (TDDS) offers a promising alternative for delivering poorly soluble drugs, challenged by the stratum corneum's barrier effect, which restricts the pool of drug candidates suitable for TDDS. This study aims to establish a delivery platform specifically for highly lipophilic drugs requiring high doses (log P > 5, dose > 10 mg/kg/d), to improve their intradermal delivery and enhance solubility. Methods: Cannabidiol (CBD, log P = 5.91) served as the model drug. A CBD nanosuspension (CBD-NS) was prepared using a bottom-up method. The particle size, polydispersity index (PDI), zeta potential, and concentration of the CBD-NS were characterized. Subsequently, CBD-NS was incorporated into dissolving microneedles (DMNs) through a one-step manufacturing process. The intradermal dissolution abilities, physicochemical properties, mechanical strength, insertion depth, and release behavior of the DMNs were evaluated. Sprague-Dawley (SD) rats were utilized to assess the efficacy of the DMN patch in treating knee synovitis and to analyze its skin permeation kinetics and pharmacokinetic performance. Results: The CBD-NS, stabilized with Tween 80, exhibited a particle size of 166.83 ± 3.33 nm, a PDI of 0.21 ± 0.07, and a concentration of 46.11 ± 0.52 mg/mL. The DMN loaded with CBD-NS demonstrated favorable intradermal dissolution and mechanical properties. It effectively increased the delivery of CBD into the skin, extended the action's duration in vivo, and enhanced bioavailability. CBD-NS DMN exhibited superior therapeutic efficacy and safety in a rat model of knee synovitis, significantly inhibiting TNF-α and IL-1ß compared with the methotrexate subcutaneous injection method. Conclusion: NS technology effectively enhances the solubility of the poorly soluble drug CBD, while DMN facilitates penetration, extends the duration of action in vivo, and improves bioavailability. Furthermore, CBD has shown promising therapeutic outcomes in treating knee synovitis. This innovative drug delivery system is expected to offer a more efficient solution for the administration of highly lipophilic drugs akin to CBD, thereby facilitating high-dose administration.

Key Transdermal Patch Using Cannabidiol-Loaded Nanocarriers with Better Pharmacokinetics in vivo.

Purpose: Cannabidiol (CBD) is a promising therapeutic drug with low addictive potential and a favorable safety profile. However, CBD did face certain challenges, including poor solubility in water and low oral bioavailability. To harness the potential of CBD by combining it with a transdermal drug delivery system (TDDS). This innovative approach sought to develop a transdermal patch dosage form with micellar vesicular nanocarriers to enhance the bioavailability of CBD, leading to improved therapeutic outcomes. Methods: A skin-penetrating micellar vesicular nanocarriers, prepared using nano emulsion method, cannabidiol loaded transdermal nanocarriers-12 (CTD-12) was presented with a small particle size, high encapsulation efficiency, and a drug-loaded ratio for CBD. The skin permeation ability used Strat-M™ membrane with a transdermal diffusion system to evaluate the CTD and patch of CTD-12 (PCTD-12) within 24 hrs. PCTD-12 was used in a preliminary pharmacokinetic study in rats to demonstrate the potential of the developed transdermal nanocarrier drug patch for future applications. Results: In the transdermal application of CTD-12, the relative bioavailability of the formulation was 3.68 ± 0.17-fold greater than in the free CBD application. Moreover, PCTD-12 indicated 2.46 ± 0.18-fold higher relative bioavailability comparing with free CBD patch in the ex vivo evaluation. Most importantly, in the pharmacokinetics of PCTD-12, the relative bioavailability of PCTD-12 was 9.47 ± 0.88-fold higher than in the oral application. Conclusion: CTD-12, a transdermal nanocarrier, represents a promising approach for CBD delivery, suggesting its potential as an effective transdermal dosage form.

Medicinal Cannabis (MedCan 3): a randomised, multicentre, double-blind, placebo-controlled trial to assess THC/CBD (1:20) to relieve symptom burden in patients with cancer-a study protocol for a randomised controlled trial.

BACKGROUND: Distressing symptoms are common in advanced cancer. Medicinal cannabinoids are commonly prescribed for a variety of symptoms. There is little evidence to support their use for most indications in palliative care. This study aims to assess a 1:20 delta-9-tetrahydrocannabinol/cannabidiol (THC/CBD) cannabinoid preparation in the management of symptom distress in patients with advanced cancer undergoing palliative care. METHODS AND DESIGN: One hundred and fifty participants will be recruited across multiple sites in Queensland, Australia. A teletrial model will facilitate the recruitment of patients outside of major metropolitan areas. The study is a pragmatic, multicenter, randomised, placebo-controlled, two-arm trial of escalating doses of an oral 1:20 THC/CBD medicinal cannabinoid preparation (10 mg THC:200 mg CBD/mL). It will compare the efficacy and safety outcomes of a titrated dose range of 2.5 mg THC/50mgCBD to 30 mg THC/600 mg CBD per day against a placebo. There is a 2-week patient-determined titration phase, to reach a dose that achieves symptom relief or intolerable side effects, with a further 2 weeks of assessment on the final dose. The primary objective is to assess the effect of escalating doses of a 1:20 THC/CBD medicinal cannabinoid preparation against placebo on change in total symptom distress score, with secondary objectives including establishing a patient-determined effective dose, the effect on sleep quality and overall quality of life. Some patients will be enrolled in a sub-study which will more rigorously evaluate the effect on sleep. DISCUSSION: MedCan-3 is a high-quality, adequately powered, placebo-controlled trial which will help demonstrate the utility of a THC:CBD 1:20 oral medicinal cannabis product in reducing total symptom distress in this population. Secondary outcomes may lead to new hypotheses regarding medicinal cannabis' role in particular symptoms or in particular cancers. The sleep sub-study will test the feasibility of using actigraphy and the Insomnia Severity Index (ISI) in this cohort. This will be the first large-scale palliative care randomised clinical trial to utilise the teletrial model in Australia. If successful, this will have significant implications for trial access for rural and remote patients in Australia and internationally. TRIAL REGISTRATION: ANZCTR ACTRN12622000083796 . Protocol number 001/20. Registered on 21 January 2022. Recruitment started on 8 August 2022.

An open-label feasibility trial of transdermal cannabidiol for hand osteoarthritis.

Hand osteoarthritis (OA) is an irreversible degenerative condition causing chronic pain and impaired functionality. Existing treatment options are often inadequate. Cannabidiol (CBD) has demonstrated analgesic and anti-inflammatory effects in preclinical models of arthritis. In this open-label feasibility trial, participants with symptomatically active hand OA applied a novel transdermal CBD gel (4% w/w) three times a day for four weeks to their most painful hand. Changes in daily self-reported pain scores were measured on a 0-10 Numeric Pain Rating Scale (NPRS). Hand functionality was determined via daily grip strength measures using a Bluetooth equipped squeeze ball and self-report questionnaire. Quality of life (QoL) ratings around sleep, anxiety, stiffness and fatigue were also measured. All self-report measures and grip strength data were gathered via smartphone application. Urinalysis was conducted at trial end to determine systemic absorption of CBD. Eighteen participants were consented and 15 completed the trial. Pain ratings were significantly reduced over time from pre-treatment baseline including current pain (- 1.91 ± 0.35, p < 0.0001), average pain (- 1.92 ± 0.35, p < 0.0001) and maximum pain (- 1.97 ± 0.34, p < 0.0001) (data represent mean reduction on a 0-10 NPRS scale ± standard error of the mean (SEM)). A significant increase in grip strength in the treated hand (p < 0.0001) was observed although self-reported functionality did not improve. There were significant (p < 0.005) improvements in three QoL measures: fatigue, stiffness and anxiety. CBD and its metabolites were detected at low concentrations in all urine samples. Measured reductions in pain and increases in grip strength seen during treatment reverted back towards baseline during the washout phase. In summary, pain, grip strength and QoL measures, using smartphone technology, was shown to improve over time following transdermal CBD application suggesting feasibility of this intervention in relieving osteoarthritic hand pain. Proof of efficacy, however, requires further confirmation in a placebo-controlled randomised trial.Trial registration: ANZCTR public trials registry (ACTRN12621001512819, 05/11/2021).

An observational time-series study on the behavioral effects of adjunctive artisanal cannabidiol use by adults with treatment resistant epilepsies.

BACKGROUND: For approximately 30% of people with epilepsy, seizures are not well-controlled by anti-seizure medication (ASM). This condition, called treatment resistant epilepsy (TRE), is associated with increased morbidity and mortality, and substantially impacts the quality of life of both the individual and their family. Non-responsiveness to ASMs leads many people with TRE to seek alternative therapies, such as cannabinoid-based medication, particularly cannabidiol (CBD), with or without medical or professional advice. This is due in part to widespread reporting in the media about the benefits of CBD for seizures in some forms of epilepsy. METHODS: Adults with TRE, opting to add CBD to their existing treatment regime, completed this prospective, observational, longitudinal, quasi-experimental, time-series study. We hypothesized that adjunctive CBD use would positively impact participants' quality of life and psychological well-being in comparison to a baseline period without CBD use. Participants were followed for a period of approximately six months - for approximately one month of baseline prior to the initiation of CBD use and approximately five months after the initiation of CBD use. Participants provided urine samples and completed behavioral questionnaires that assessed quality of life, anxiety/depression, and adverse events during baseline and at two times during CBD use. RESULTS: Complete case analyses (n = 10) showed a statistically significant improvement in quality of life, a statistically significant decrease in anxiety symptoms, and a statistically significant decrease in the experience of adverse events over time (p < 0.05). Improvements noted in the experience of depression symptoms did not reach statistical significance. Urinalysis revealed the majority of participants had no CBD/metabolites in their system at the beginning of the study, and confirmed the presence of CBD/metabolites in participants' urine after CBD was added to their treatment regime. Analysis of missing data using multiple imputation supported the findings of the complete case analysis. INTERPRETATION: For a small group of individuals with TRE of varying etiologies, adjunctive use of artisanal CBD was associated with improvements in the behavioral and psychological symptoms of TRE, as well as improved medication tolerability.

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 2.5 mg/kg/day. Primary outcome was change in motor MDS-UPDRS from baseline to final dose. RESULTS: Participants were randomized to CBD/THC (n = 31) or placebo (n = 30). Mean final dose (CBD/THC group) was 191.8 ± 48.9 mg CBD and 6.4 ± 1.6 mg THC daily. Motor MDS-UPDRS was reduced by 4.57 (95% CI, -8.11 to -1.03; P = 0.013) in CBD/THC group, and 2.77 (-4.92 to -0.61; P = 0.014) in placebo; the difference between groups was non-significant: -1.80 (-5.88 to 2.27; P = 0.379). Several assessments had a strong placebo response. Sleep, cognition, and activities of daily living showed a treatment effect, favoring placebo. Overall adverse events were mild and reported more in CBD/THC than placebo group. On 2.5 mg/kg/day CBD plasma level was 54.0 ± 33.8 ng/mL; THC 1.06 ± 0.91 ng/mL. CONCLUSIONS: The brief duration and strong placebo response limits interpretation of effects, but there was no benefit, perhaps worsened cognition and sleep, and there was many mild adverse events. Longer duration high quality trials that monitor cannabinoid concentrations are essential and would require improved availability of research cannabinoid products in the United States. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A randomised, placebo-controlled, double blind, crossover trial on the effect of a 20:1 cannabidiol: Δ9-tetrahydrocannabinol medical cannabis product on neurocognition, attention, and mood.

As cannabinoid-based medications gain popularity in the treatment of refractory medical conditions, it is crucial to examine the neurocognitive effects of commonly prescribed products to ensure associated safety profiles. The present study aims to investigate the acute effects of a standard 1 mL sublingual dose of CannEpil®, a medicinal cannabis oil containing 100 mg cannabidiol (CBD) and 5 mg Δ9-tetrahydrocannabinol (THC) on neurocognition, attention, and mood. A randomised, double-blind, placebo-controlled, within-subjects design assessed 31 healthy participants (16 female, 15 male), aged between 21 and 58 years, over a two-week experimental protocol. Neurocognitive performance outcomes were assessed using the Cambridge Neuropsychological Test Automated Battery, with the Profile of Mood States questionnaire, and the Bond-Lader Visual Analogue Scale used to assess subjective state and mood. CannEpil increased Total Errors in Spatial Span and Correct Latency (median) in Pattern Recognition Memory, while also increasing Efficiency Score (lower score indicates greater efficiency) relative to placebo (all p < .05). Subjective Contentedness (p < .01) and Amicability (p < .05) were also increased at around 2.5 h post dosing, relative to placebo. Drowsiness or sedative effect was reported by 23 % of participants between three to six hours post CannEpil administration. Plasma concentrations of CBD, THC, and their metabolites were not significantly correlated with any observed alterations in neurocognition, subjective state, or adverse event occurrence. An acute dose of CannEpil impairs select aspects of visuospatial working memory and delayed pattern recognition, while largely preserving mood states among healthy individuals. Intermittent reports of drowsiness and sedation underscore the inter-individual variability of medicinal cannabis effects on subjective state. (ANZCTR; ACTRN12619000932167; https://www.anzctr.org.au).

Cytogenotoxicity and inflammatory response in liver of rats exposed to different doses of cannabis nano emulsions.

Cannabis is the most used illicit substance for recreational purposes around the world. However, it has become increasingly common to witness the use of approved cannabis preparations for symptoms management in various diseases. The aim of this study was to investigate the effects of cannabis nano emulsion in the liver of Wistar rats, with different proportions of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). For this, a total of 40 male Wistar rats were distributed into 5 groups, as follows (n = 8 per group): Control: G1, Experimental group (G2): treated with cannabis nano emulsion (THC and CBD) at a dose of 2.5 mg/kg, Experimental group (G3): treated with cannabis nano emulsion (THC and CBD) at a dose of 5 mg/kg, Experimental group (G4): treated with cannabis nano emulsion (CBD) at a dose of 2.5 mg/kg; Experimental group (G5): treated with cannabis nano emulsion (CBD) at a dose of 5 mg/kg. Exposure to the nano emulsion was carried out for 21 days, once a day, orally (gavage). Our results showed that cannabis nano emulsions at higher doses (5 mg/kg), regardless of the composition, induced histopathologic changes in the liver (G3 and G5) in comparison with the control group. In line with that, placental glutathione S-transferase (GST-P) positive foci increased in both G3 and G5 (p < 0.05), as well as the immune expression of Ki-67, vascular endothelial growth factor (VEGF) and p53 (p < 0.05). Also, the nano emulsion intake induced an increase in the number of micronucleated hepatocytes in G5 (p < 0.05) whereas G3 showed an increase in binucleated cells (p < 0.05). As for metanuclear alterations, karyolysis and pyknosis had an increased frequency in G3 (p < 0.05). Taken together, the results show that intake of cannabis nano emulsion may induce degenerative changes and genotoxicity in the liver in higher doses, demonstrating a clear dose-response relationship.

The acute effects of cannabis, with and without cannabidiol, on attentional bias to cannabis related cues: a randomised, double-blind, placebo-controlled, cross-over study.

RATIONALE: Attentional bias to drug-related stimuli is hypothesised to contribute towards addiction. However, the acute effects of Δ9-tetrahydrocannabinol (THC) on attentional bias to cannabis cues, the differential response in adults and adolescents, and the moderating effect of cannabidiol (CBD) are unknown. OBJECTIVES: Our study investigated (1) the acute effects of vaporised cannabis on attentional bias to cannabis-related images in adults and adolescents and (2) the moderating influences of age and CBD. METHODS: We conducted a randomised, double-blind, placebo-controlled, cross-over study where three weight-adjusted vaporised cannabis preparations: 'THC' (8 mg THC for a 75-kg person), 'THC + CBD' (8 mg THC and 24 mg CBD for a 75-kg person) and PLA (matched placebo). Cannabis was administered on 3 separate days to 48 participants, who used cannabis 0.5-3 days/week: 24 adolescents (12 females, aged 16-17) and 24 adults (12 females, aged 26-29). Participants completed a visual probe task with cannabis cues. Our primary outcome was attentional bias to cannabis stimuli, measured using the differential reaction time to a cannabis vs. neutral probe, on 200-ms trials. RESULTS: In contrast to hypotheses, attention was directed away from cannabis cues on placebo, and there was a main effect of the drug (F(2,92) = 3.865, p = 0.024, η2p = 0.077), indicating THC administration eliminated this bias. There was no significant impact of CBD nor an age-by-drug interaction. CONCLUSIONS: Acute THC intoxication eliminated attentional bias away from cannabis cues. There was no evidence of differential response in adolescents compared to adults and no evidence that a moderate vaporised dose of CBD altered the impact of cannabis on attentional bias. TRIAL REGISTRATION: This study was listed with the US National Library of Medicine and registered on ClinicalTrials.gov, URL: Do Adolescents and Adults Differ in Their Acute Response to Cannabis?-Full Text View-ClinicalTrials.gov, registration number: NCT04851392.

Real life retrospective study of cannabidiol therapy in alternating hemiplegia of childhood.

BACKGROUND: Many alternating hemiplegia of childhood (AHC) patients have received Cannabidiol (CBD) but, to our knowledge, there are no published data available. GOALS: Test the hypothesis that CBD has favorable effects on AHC spells. METHODS: Retrospective review of available data of AHC patients who received CBD. Primary analysis: Clinical Global Impression Scale of Improvement (CGI-I) score for response of AHC spells to CBD with calculation of 95% confidence interval (CI) for rejection of the null hypothesis. Secondary analyses, performed to achieve an understanding of the effect of CBD as compared to flunarizine, were CGI-I scores of 1) epileptic seizures to CBD, 2) AHC spells to flunarizine, 3) epileptic seizures to flunarizine. Also, Mann-Whitney test was done for comparison of CGI-I scores of CBD and flunarizine to both AHC spells and seizures. RESULTS: We studied 16 AHC patients seen at Duke University and University of Lyon. CI of CGI-I scores for AHC spells in response to CBD and to flunarizine, each separately, indicated a positive response to each of these two medications: neither overlapped with the null hypothesis score, 4, indicating significant positive responses with p < 0.05 for both. These two scores also did not differ (p = 0.84) suggesting similar efficacy of both: CBD score was 2 ± 1.1 with a 95% CI of 1.5-2.6 and flunarizine score was 2.3 ± 1.3 with a 95% CI of 1.7-3.1. In patients who had seizures, CI calculations indicated a positive effect of CBD on seizure CGI scores but not of flunarizine on seizure scores. CBD was well tolerated with no patients discontinuing it due to side effects and with some reporting positive behavioral changes. CONCLUSION: Our study indicates a real-life positive effect of CBD on AHC type spells.

Cannabidiol for moderate-severe insomnia: a randomized controlled pilot trial of 150 mg of nightly dosing.

STUDY OBJECTIVES: Low-dose cannabidiol (CBD) has become readily available in numerous countries; however, little consensus exists on its efficacy as a sleep aid. This trial explored the efficacy of 150 mg of CBD (n = 15) compared with placebo (n = 15) as a sleep aid in primary insomnia. CBD supplementation was hypothesized to decrease insomnia symptoms and improve aspects of psychological health, relative to placebo. METHODS: Using a randomized, placebo-controlled, parallel design featuring a single-blind placebo run-in week followed by a 2-week double-blind randomized dosing phase, participants consumed the assigned treatment sublingually 60 minutes before bed nightly. Wrist-actigraphy and sleep diaries measured daily sleep. Sleep quality, sleep effort, and well-being were measured weekly over 4 in-laboratory visits. Insomnia severity and trait anxiety were measured at screening and study conclusion. RESULTS: Insomnia severity, self-reported sleep-onset latency, sleep efficiency, and wake after sleep onset did not differ between treatments throughout the trial (all P > .05). Compared with placebo, the CBD group reported greater well-being scores throughout the trial (trial end mean difference = 2.60; standard error: 1.20), transient elevated behavior following wakefulness scores after 1 week of treatment (mean difference = 3.93; standard error: 1.53), and had superior objective sleep efficiency after 2 weeks of treatment (mean difference = 6.85; standard error: 2.95) (all P < .05). No other significant treatment effects were observed. CONCLUSIONS: Nightly supplementation of 150 mg CBD was similar to placebo regarding most sleep outcomes while sustaining greater well-being, suggesting more prominent psychological effects. Additional controlled trials examining varying treatment periods and doses are crucial. CLINICAL TRIAL REGISTRATION: Registry: Australian New Zealand Clinical Trials Registry; Name: Cannabidiol (CBD) treatment for insomnia; URL: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12620000070932; Identifier: ACTRN12620000070932. CITATION: Narayan AJ, Downey LA, Rose S, Di Natale L, Hayley AC. Cannabidiol for moderate-severe insomnia: a randomized controlled pilot trial of 150 mg of nightly dosing. J Clin Sleep Med. 2024;20(5):753-763.

Caregivers' Perspectives on the Impact of Cannabidiol (CBD) Treatment for Dravet and Lennox-Gastaut Syndromes: A Multinational Qualitative Study.

OBJECTIVE: To increase understanding of the impact of cannabidiol (CBD) on outcomes beyond seizure control among individuals with Dravet syndrome or Lennox-Gastaut syndrome. METHODS: Qualitative interviews were conducted with caregivers of individuals with Dravet syndrome or Lennox-Gastaut syndrome treated with plant-derived, highly purified CBD medicine (Epidiolex in the USA; Epidyolex in Europe; 100 mg/mL oral solution). Symptoms and impacts of Dravet syndrome and Lennox-Gastaut syndrome on individuals were explored, as were the effects of CBD. Data were analyzed using thematic analysis. RESULTS: Twenty-one caregivers of individuals with Dravet syndrome (n = 14) and Lennox-Gastaut syndrome (n = 7) aged 4-22 years participated. Health-related quality of life improvements associated with CBD included cognitive function, communication, behavior, mobility, and participation in daily activities. Seizure frequency reduction was commonly reported (n = 12), resulting in caregivers having greater freedom and family life being less disrupted. Adverse events were reported by 10 caregivers. CONCLUSION: In addition to reduced seizure frequency, CBD may have a wide range of beneficial effects beyond seizure control that warrant further investigation.

Quantity of Melatonin and CBD in Melatonin Gummies Sold in the US.

This study assesses the actual measured quantities of melatonin and cannabidiol (CBD) in products marketed and sold in the US as melatonin gummies compared with the quantities declared on their labels.

Cannabidiol for the Treatment of Brain Disorders: Therapeutic Potential and Routes of Administration.

The use of cannabidiol (CBD) for treating brain disorders has gained increasing interest. While the mechanism of action of CBD in these conditions is still under investigation, CBD has been shown to affect numerous different drug targets in the brain that are involved in brain disorders. Here we review the preclinical and clinical evidence on the potential therapeutic use of CBD in treating various brain disorders. Moreover, we also examine various drug delivery approaches that have been applied to CBD. Due to the slow absorption and low bioavailability with the current oral CBD therapy, more efficient routes of administration to bypass hepatic metabolism, particularly pulmonary delivery, should be considered. Comparison of pharmacokinetic studies of different delivery routes highlight the advantages of intranasal and inhalation drug delivery over other routes of administration (oral, injection, sublingual, buccal, and transdermal) for treating brain disorders. These two routes of delivery, being non-invasive and able to achieve fast absorption and increase bioavailability, are attracting increasing interest for CBD applications, with more research and development expected in the near future.

Pharmacokinetics of Cannabidiol in Sprague-Dawley Rats After Oral and Pulmonary Administration.

Introduction: Cannabidiol (CBD) is primarily consumed through ingestion and inhalation. Little is known about how CBD pharmacokinetics differ between routes of administration, and duration of pulmonary exposure. Methods: Pharmacokinetics, brain distribution, and urinary elimination of CBD and its major metabolites (6-hydroxy-cannabidiol [6-OH-CBD], 7-hydroxy-cannabidiol [7-OH-CBD], 7-carboxy-cannabidiol [7-COOH-CBD], and CBD-glucuronide) were evaluated in adult Sprague-Dawley rats following a single oral CBD ingestion (10 mg/kg in medium chain triglyceride oil; 24 male animals), and 1 or 14 days of repeated inhalation (0.9-13.9 mg/kg in propylene glycol [41%/59% by weight]; 5 male and 5 female animals per dose). Blood and brain tissue were collected at a single time point from each animal. Collection times were staggered from 5 min to 24 h postoral gavage or first (blood only) and final inhalation. Urine was collected 24 h postoral gavage or final inhalation. Samples were analyzed through liquid chromatography-mass spectrometry (LC-MS/MS). Results: CBD was more rapidly absorbed following inhalation than ingestion (Tmax=5 min and 2 h, respectively). Inhalation resulted in a dose-responsive increase in CBD Cmax and AUClast. CBD Cmax was 24-fold higher following the highest pulmonary dose (13.9 mg/kg) versus an oral dose of comparable concentration (10 mg/kg). Cmax and AUClast (0-16 h) trended higher following repeated exposure. Elimination was notably faster with repeated CBD inhalation (t1/2=5.3 and 2.4 h on days 1 and 14, respectively). While metabolites were detectable in plasma, AUClast (0-2 h) was at least 10- (7-OH-CBD, 7-COOH-CBD) to 100- (6-OH-CBD) fold lower than the parent compound. Metabolite concentration trended higher following repeated inhalation (6.7 mg/kg CBD); AUClast (0-16 h) was ∼1.8-, ∼1.4-, and ∼2.4-fold higher following 14 days of exposure for 6-OH-CBD, 7-OH-CBD, and 7-COOH-CBD, respectively. CBD was detectable in brain homogenate tissue 24-h after 14-day inhalation (>3.5 mg/kg deposited dose) or a single oral administration. CBD metabolites were only measurable in brain tissue following the highest inhaled dose (13.9 mg/kg CBD). CBD, but not metabolites, was detectable in urine for all dose groups following 2 weeks of CBD inhalation. Neither CBD nor metabolites were present in urine after oral administration. Conclusion: CBD pharmacokinetics differ across oral and pulmonary routes of administration and acute or repeated dosing.

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).

NAbiximols Clinical Translation To the treatment of Pain and Agitation In Severe Dementia (NACTOPAISD): Clinical trial protocol.

Up to 80 % nursing home residents with dementia experiences chronic pain. Contextually, 97 % presents fluctuant neuropsychiatric symptoms (NPS). Among the most challenging is agitation, connected with undertreated pain and managed through neuroleptics doubling death risk. Evidence is accumulating in favor of the involvement of the endocannabinoid system in nociception and NPS. This double-blind, placebo-controlled, randomized trial (NAbiximols Clinical Translation To the treatment of Pain and Agitation In Severe Dementia [NACTOPAISD]) aims at investigating efficacy and safety of oral spray nabiximols, containing Δ9-tetrahydrocannabinol and cannabidiol (Sativex®), for pain and agitation treatment in severe dementia patients (Mini-Mental State Examination ≤ 12) over 65. The coprimary endpoints are efficacy on pain and agitation, assessed through the recently validated Italian Mobilization-Observation-Behavior-Intensity-Dementia and the Cohen-Mansfield Agitation Inventory. The secondary endpoint is the evaluation of efficacy duration after wash-out and the assessment of quality of life through the DEMQOL. Any adverse events will be reported. The results undergo statistical analysis plan. NACTOPAISD might provide rationale for a translational safer pain and agitation treatment in severe dementia. It is approved by Calabria Region Ethics Committee and follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) and the Consolidated Standards of Reporting Trials (CONSORT) statements.

Cannabidiol Treatment Improves Glucose Metabolism and Memory in Streptozotocin-Induced Alzheimer's Disease Rat Model: A Proof-of-Concept Study.

An early and persistent sign of Alzheimer's disease (AD) is glucose hypometabolism, which can be evaluated by positron emission tomography (PET) with 18F-2-fluoro-2-deoxy-D-glucose ([18F]FDG). Cannabidiol has demonstrated neuroprotective and anti-inflammatory properties but has not been evaluated by PET imaging in an AD model. Intracerebroventricular (icv) injection of streptozotocin (STZ) is a validated model for hypometabolism observed in AD. This proof-of-concept study evaluated the effect of cannabidiol treatment in the brain glucose metabolism of an icv-STZ AD model by PET imaging. Wistar male rats received 3 mg/kg of STZ and [18F]FDG PET images were acquired before and 7 days after STZ injection. Animals were treated with intraperitoneal cannabidiol (20 mg/kg-STZ-cannabidiol) or saline (STZ-saline) for one week. Novel object recognition was performed to evaluate short-term and long-term memory. [18F]FDG uptake in the whole brain was significantly lower in the STZ-saline group. Voxel-based analysis revealed a hypometabolism cluster close to the lateral ventricle, which was smaller in STZ-cannabidiol animals. The brain regions with more evident hypometabolism were the striatum, motor cortex, hippocampus, and thalamus, which was not observed in STZ-cannabidiol animals. In addition, STZ-cannabidiol animals revealed no changes in memory index. Thus, this study suggests that cannabidiol could be an early treatment for the neurodegenerative process observed in AD.

Antioxidant and anti-apoptotic effects of cannabidiol in model of ischemic stroke in rats.

One of the main non-psychoactive phytocannabinoids of cannabis is cannabidiol (CBD), which has attracted much attention for its neuroprotective roles. The present study was designed to assess whether pretreatment of CBD can attenuate two of the destructive processes of cerebral ischemia, including oxidative stress and cell death. The male rats were randomly divided into 6 main groups (control, MCAO, vehicle, and CBD-treated groups). Using stereotaxic surgery, a cannula was inserted into the right lateral ventricle of the rat brain. CBD was injected at doses of 50, 100 and 200 ng/rat for five consecutive days. After pretreatment, middle cerebral artery (MCA) was blocked for 60 min using the intraluminal filament technique. 24 h after reperfusion, each main group was considered for measurement of infarct volume, superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), p53 gene expression, pathological alterations, and expression of Bax, Bcl-2, cytochrome C, and caspase-3 proteins. The results revealed that CBD at dose of 100 ng/rat reduced the infarction volume and MDA level in cortical and striatal areas of rat brain compared with vehicle group. In addition, the CBD at dose of 100 ng/rat elevated the activity of SOD enzyme in cortex and striatum. The increase in the activity of CAT was also seen at dose of 100 ng/rat in cortex. Furthermore, the Bcl-2/Bax ratio was significantly diminished by the dose of 100 ng/rat CBD in cortex. Moreover, a decrease in expression of cytosolic cytochrome C was observed by CBD at doses of 100 and 200 ng/rat in cortex. CBD at doses 100 and 200 ng/rat also reduced the expression of caspase-3 in cortical and striatal areas, respectively. P53 was downregulated following administration of CBD at dose of 100 ng/rat. Moreover, histological analysis showed the decrease in the percentage of pyknotic neurons in 100 and 200 ng/rat CBD-received groups. CBD played the anti-apoptosis and anti-oxidant roles in cerebral ischemia by affecting the pathways of intrinsic apoptosis, endogenous antioxidant enzymes, and lipid peroxidation.

Early-life stress induces emotional and molecular alterations in female mice that are partially reversed by cannabidiol.

Gender is considered as a pivotal determinant of mental health. Indeed, several psychiatric disorders such as anxiety and depression are more common and persistent in women than in men. In the past two decades, impaired brain energy metabolism has been highlighted as a risk factor for the development of these psychiatric disorders. However, comprehensive behavioural and neurobiological studies in brain regions relevant to anxiety and depression symptomatology are scarce. In the present study, we summarize findings describing cannabidiol effects on anxiety and depression in maternally separated female mice as a well-established rodent model of early-life stress associated with many mental disorders. Our results indicate that cannabidiol could prevent anxiolytic- and depressive-related behaviour in early-life stressed female mice. Additionally, maternal separation with early weaning (MSEW) caused long-term changes in brain oxidative metabolism in both nucleus accumbens and amygdalar complex measured by cytochrome c oxidase quantitative histochemistry. However, cannabidiol treatment could not revert brain oxidative metabolism impairment. Moreover, we identified hyperphosphorylation of mTOR and ERK 1/2 proteins in the amygdala but not in the striatum, that could also reflect altered brain intracellular signalling related with to bioenergetic impairment. Altogether, our study supports the hypothesis that MSEW induces profound long-lasting molecular changes in mTOR signalling and brain energy metabolism related to depressive-like and anxiety-like behaviours in female mice, which were partially ameliorated by CBD administration.