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.

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 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.

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).

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.

Effects of phytocannabinoids on heart rate variability and blood pressure variability in female post-concussion syndrome patients: case series.

Cannabidiol (CBD) can exert neuroprotective effects without being intoxicating, and in combination with Δ9-tetrahydrocannabinol (THC) CBD has shown to protect against THC psychosis. Acute concussion and post-concussion syndrome (PCS) can result in autonomic dysfunction in heart rate variability (HRV), but less information is available on blood pressure variability (BPV). Furthermore, the effects of phytocannabinoids on HRV and BPV in PCS are unknown. The purpose of this study was to observe the influence of daily administration of CBD or a combination of CBD and THC on HRV and BPV parameters in four female PCS participants. Participants completed a seated 5-min rest followed by six breaths-per-minute paced breathing protocol. Data was collected prior to phytocannabinoid intake and continued over 54 to 70 days. High frequency systolic BPV parameter increased every assessment period, unless altered due to external circumstances and symptoms. HRV parameters showed less consistent and varying responses. These results suggest that CBD can help to improve the altered autonomic dysfunction in those with PCS, and that responses to the drug administration was individualized. Double blinded, randomized controlled trials with greater sample sizes are required to better understand the influences of the varying dosages on human physiology and in PCS.

Effects of cannabidiol in cannabis flower: Implications for harm reduction.

Using a federally compatible, naturalistic at-home administration procedure, the present study examined the acute effects of three cannabis flower chemovars with different tetrahydrocannabinol (THC) to cannabidiol (CBD) ratios, in order to test whether chemovars with a higher CBD content produce different effects. Participants were randomly assigned to ad libitum administration of one of three chemovars (THC-dominant: 24% THC, 1% CBD; THC+CBD: 9% THC, 10% CBD; CBD-dominant: 1% THC, 23% CBD); 159 regular cannabis users (male = 94, female = 65) were assessed in a mobile pharmacology lab before, immediately after, and 1 h after ad libitum administration of their assigned chemovar. Plasma cannabinoids as well as positive (e.g., high, elation) and negative (e.g., paranoia and anxiety) subjective effects were assessed at each time points. Participants who used the CBD-dominant and THC + CBD chemovars had significantly less THC and more CBD in plasma samples compared to participants who used the THC-dominant chemovar. Further, the THC + CBD chemovar was associated with similar levels of positive subjective effects, but significantly less paranoia and anxiety, as compared to the THC-dominant chemovar. This is one of the first studies to examine the differential effects of various THC to CBD ratios using chemovars that are widely available in state-regulated markets. Individuals using a THC + CBD chemovar had significantly lower plasma THC concentrations and reported less paranoia and anxiety while also reporting similar positive mood effects as compared to individuals using THC only, which is intriguing from a harm reduction perspective. Further research is needed to clarify the harm reduction potential of CBD in cannabis products.

Orally administered cannabidiol does not produce false-positive tests for Δ9 -tetrahydrocannabinol on the Securetec DrugWipe® 5S or Dräger DrugTest® 5000.

Many jurisdictions use point-of-collection (POC) oral fluid testing devices to identify driving under the influence of cannabis, indexed by the presence of Δ9 -tetrahydrocannabinol (THC), an intoxicating cannabinoid, in oral fluid. Although the use of the non-intoxicating cannabinoid, cannabidiol (CBD), is not prohibited among drivers, it is unclear whether these devices can reliably distinguish between CBD and THC, which have similar chemical structures. This study determined whether orally administered CBD produces false-positive tests for THC on standard, POC oral fluid testing devices. In a randomised, double-blind, crossover design, healthy participants (n = 17) completed four treatment sessions involving the administration of either placebo or 15-, 300- or 1500-mg pure CBD in a high-fat dietary supplement. Oral fluid was sampled, and the DrugWipe®-5S (DW-5S; 10 ng·ml-1 THC cut-off) and Drug Test® 5000 (DT5000; 10 ng·mL-1 THC cut-off) devices administered, at baseline (pretreatment) and ~20-, ~145- and ~185-min posttreatment. Oral fluid cannabinoid concentrations were measured using ultra-high performance liquid chromatography-tandem mass spectrometry. Median (interquartile range [IQR]) oral fluid CBD concentrations were highest at ~20 min, quantified as 0.4 (6.0), 15.8 (41.6) and 167 (233) ng·ml-1 on the 15-, 300- and 1500-mg CBD treatments, respectively. THC, cannabinol and cannabigerol were not detected in any samples. A total of 259 DW-5S and 256 DT5000 tests were successfully completed, and no THC-positive tests were observed. Orally administered CBD does not appear to produce false-positive (or true-positive) tests for THC on the DW-5S and DT5000. The likelihood of an individual who is using a CBD (only) oral formulation being falsely accused of DUIC therefore appears low.

Activation of GPR55 attenuates cognitive impairment and neurotoxicity in a mouse model of Alzheimer's disease induced by Aß1-42 through inhibiting RhoA/ROCK2 pathway.

The accumulation of amyloid-ß (Aß) peptides in the brain is considered to be the initial event in the Alzheimer's disease (AD). Neurotoxicity mediated by Aß has been demonstrated to damage the cognitive function. In the present study, we sought to determine the effects of O-1602, a specific G-protein coupled receptor 55 (GPR55) agonist, on the impairment of learning and memory induced by intracerebroventricular (i.c.v.) of Aß1-42 (400 pmol/mouse) in mice. Our results showed that i.c.v. injection of aggregated Aß1-42 into the brain of mice resulted in cognitive impairment and neurotoxicity. In contrast, O-1602 (2.0 or 4.0 µg/mouse, i.c.v.) can improve memory impairment induced by Aß1-42 in the Morris water maze (MWM), and novel object recognition (NOR) tests. Besides, we found that O-1602 reduced the activity of ß-secretase 1 (BACE1) and the level of soluble Aß1-42 in the hippocampus and frontal cortex. Importantly, O-1602 treatment reversed Aß1-42-induced GPR55 down-regulation, decreased pro-inflammatory cytokines, and the level of malondialdehyde (MDA), increased the levels of glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT), as well as suppressed apoptosis as indicated by decreased TUNEL-positive cells, and increased the ratio of Bcl-2/Bax. O-1602 treatment also pronouncedly ameliorated synaptic dysfunction by promoting the upregulation of PSD-95 and synaptophysin (SYN) proteins. Moreover, O-1602 concurrently down regulated the protein levels of RhoA, and ROCK2, the critical proteins in the RhoA/ROCK2 pathway. This study indicates that O-1602 may reverse Aß1-42-induced cognitive impairment and neurotoxicity in mice by inhibiting RhoA/ROCK2 pathway. Taken together, these findings suggest that GPR55 could be a novel and promising target for the treatment of AD.

Cannabidiol Product Dosing and Decision-Making in a National Survey of Individuals with Fibromyalgia.

Many people with fibromyalgia use cannabidiol (CBD) products despite limited rigorous evidence of benefit. In the current study, we conducted a secondary analysis of a cross-sectional survey of N = 878 people with fibromyalgia to investigate naturalistic decision making around CBD product choices, use patterns, and dosing. We subgrouped participants based on use of high-THC cannabis (HTC) in the past year (yes/no) as previous studies have shown that HTC use influences CBD use patterns. The study population was largely female (93.6%), white (91.5%) and 55.5 years old on average. Participants typically purchased CBD products online or at dispensaries, with purchasing driven by personal research (63%) rather than endorsement from medical professionals (16%). Overall, tinctures and topicals were the most common administration routes endorsed. However, participants in the past-year HTC group used inhalation routes far more frequently than those who did not (39.8% vs 7.1%). Among participants using CBD tinctures or edibles, the average dose per session was 16 mg and 24 to 27 mg per day, although approximately one-third of participants did not know what dose of CBD they used. Participants using both inhalation and non-inhalation administration routes reported greater symptom relief than those using non-inhalation routes alone. However, there was no consistent relationship between CBD dose and reported effects, possibly due to expectancy effects around CBD products or interindividual variability. Our granular investigation reveals variability of CBD product dosing practices for fibromyalgia, and how past-year HTC use influences CBD product use. Future clinical trials should investigate the potential benefits of low-dose (<50mg) botanical CBD products. PERSPECTIVE: This article shows that past-year HTC use strongly influences how people with fibromyalgia choose and use CBD products. Participants typically used <50 mg/d of CBD, and there was no relationship between higher CBD dose and reported therapeutic benefit. Future clinical trials should investigate therapeutic benefits of low dose CBD.