Administration Of Cannabidiol Research Articles

Cannabidiol Treatment Shows Therapeutic Efficacy in a Rodent Model of Social Transfer of Pain in Pair-Housed Male Mice.

Introduction: Prosocial behavior refers to sharing emotions and sensations such as pain. Accumulated data indicate that cannabidiol (CBD), a nonpsychotomimetic component of the Cannabis sativa plant, attenuates hyperalgesia, anxiety, and anhedonic-like behavior. Nevertheless, the role of CBD in the social transfer of pain has never been evaluated. In this study, we investigated the effects of acute systemic administration of CBD in mice that cohabited with a conspecific animal suffering from chronic constriction injury. Furthermore, we assessed whether repeated CBD treatment decreases hypernociception, anxiety-like behavior, and anhedonic-like responses in mice undergoing chronic constriction injury and whether this attenuation would be socially transferred to the partner. Materials and Methods: Male Swiss mice were Housed in pairs for 28 days. On the 14th day of living together, animals were then divided into two groups: cagemate nerve constriction (CNC), in which one animal of each partner was subjected to sciatic nerve constriction; and cagemate sham (CS), subjected to the same surgical procedure but without suffering nerve constriction. In Experiments 1, 2, and 3 on day 28 of living together, the cagemates (CNC and CS) animals received a single systemic injection (intraperitoneally) of vehicle or CBD (0.3, 1, 10, or 30 mg/kg). After 30 min, the cagemates were subjected to the elevated plusmaze followed by exposure to the writhing and sucrose splash tests. For chronic treatment (Exp. 4), sham and chronic constriction injury animals received a repeated systemic injection (subcutaneous) of vehicle or CBD (10 mg/kg) for 14 days after the sciatic nerve constriction procedure. On days 28 and 29 sham and chronic constriction injury animals and their cagemates were behaviorally tested. Results and Conclusion: Acute CBD administration attenuated anxiety-like behavior, pain hypersensitivity, and anhedonic-like behavior in cagemates that cohabited with a pair in chronic pain. In addition, repeated CBD treatment reversed the anxiety-like behavior induced by chronic pain and enhanced the mechanical withdrawal thresholds in Von Frey filaments and the grooming time in the sucrose splash test. Moreover, repeated CBD treatment effects were socially transferred to the chronic constriction injury cagemates.

Cannabidiol as a Modulator of the Development of Alcohol Tolerance in Rats.

The study aimed to explore in vivo the influence of cannabidiol (CBD) on the development of alcohol tolerance in rats. Rats were treated with ethanol (3.0 g/kg, i.p.) and CBD (20 mg/kg, p.o.) for nine successive days, and rectal body temperature, sedation (sleeping time), and blood alcohol concentration (BAC) were measured. In the prefrontal cortex, hippocampus, and striatum, the cannabinoid (CB1R and CB2R) and dopaminergic (DRD1, DRD2, DRD4, DRD5) receptors' mRNA level changes were analyzed using the quantitative RT-PCR method. CBD inhibited the development of tolerance to the hypothermic and sedative action of alcohol, coupled with BAC elevation. On a molecular level, the most pronounced effects of the CBD + ethanol interaction in the striatum were observed, where CBD reversed the downregulation of CB2R gene transcription caused by ethanol. For CB1R, DRD1, and DRD2 mRNAs, the CBD + ethanol interaction produced opposite effects than for CB2R ones. In turn, for the transcription of genes encoding dopaminergic receptors, the most potent effect of alcohol as CBD occurred in the hippocampus. However, the combined CBD and alcohol administration showed the same effect for each substance administered separately. Since tolerance is considered a prelude to drug addiction, obtained results allow us to emphasize the thesis that CBD can inhibit the development of alcohol dependence in rats.

The Effects of Long-Term Self-Dosing of Cannabidiol on Drowsiness, Testosterone Levels, and Liver Function

Introduction: Previous research indicated that cannabidiol (CBD) may result in low levels of male total testosterone (TT), elevations in liver tests (LTs), and daytime drowsiness (DD). We investigated the prevalences of TT and LT in a large adult sample self-administering CBD and determined the effect self-dosing of CBD has on the severity of DD. Methods: Adult participants (18–75 years of age) who self-dose CBD orally for a minimum of 30 days were recruited for this decentralized observational study from companies that offer CBD products. Participants were sent their usual CBD regimen. A clinical study platform was used on a phone app to obtain consent and collect study data. Data included demographic information, reasons for self-dosing, dosage, current medications and dosage, medical history, adverse effects, effects on DD, and efficacy. After 30 days, LT and TT were obtained and follow-up LT was offered to participants who demonstrated elevated values of alanine transaminase (ALT). Results: A total of 28,121 individuals were contacted, 1,475 met the criteria and were enrolled, and 1,061 (female: 65.2%, male: 34.8%) completed the study. Most of the participants used full-spectrum CBD oil or CBD isolate with the mean ± SD daily dose of CBD for all users of 55.4 ± 37.8 mg. CBD use was associated with a significant decrease in DD and a decrease in the prevalence of low TT in males >40 years of age. The prevalences of elevations in ALT and aspartate aminotransferase were not significantly different from those of the general adult population, and the prevalences of elevated levels of alkaline phosphatase and bilirubin were less than those of a healthy adult population. There was no relationship between LT and CBD dose. Conclusions: In this large-sample study, self-dosing CBD was not associated with an increased prevalence of elevation of LT or low levels of TT in men. Furthermore, CBD administration decreased DD and was associated with a lower prevalence of low testosterone levels in older men as compared to age-adjusted population norms.

Cannabidiol improves muscular lipid profile by affecting the expression of fatty acid transporters and inhibiting de novo lipogenesis

Obesity is one of the principal public health concerns leading to disturbances in glucose and lipid metabolism, which is a risk factor for several chronic diseases, including insulin resistance, type 2 diabetes mellitus, and cardiovascular diseases. In recent years, it turned out that cannabidiol (CBD) is a potential therapeutic agent in the treatment of obesity and its complications. Therefore, in the present study, we used CBD therapy (intraperitoneal injections in a dose of 10 mg/kg of body mass for 14 days) in a rat model of obesity induced by a high-fat diet (HFD). Gas–liquid chromatography and Western blotting were applied in order to determine the intramuscular lipid content and total expression of selected proteins in the white and red gastrocnemius muscle, respectively. Based on fatty acid composition, we calculated de novo lipogenesis ratio (16:0/18:2n-6), desaturation ratio (18:1n-9/18:0), and elongation ratios (18:0/16:0, 20:0/18:0, 22:0/20:0 and 24:0/22:0), in the selected lipid fractions. Two-week CBD administration significantly reduced the intramuscular fatty acids (FAs) accumulation and inhibited de novo lipogenesis in different lipid pools (in the free fatty acid, diacylglycerol, and triacylglycerol fractions) in both muscle types, which coincided with a decrease in the expression of membrane fatty acid transporters (fatty acid translocase, membrane-associated fatty acid binding protein, and fatty acid transport proteins 1 and 4). Moreover, CBD application profoundly improved the elongation and desaturation ratios, which was in line with downregulated expression of enzymes from the family of elongases and desaturases regardless of the metabolism presented by the muscle type. To our knowledge, this study is the first that outlines the novel effects of CBD action on skeletal muscle with different types of metabolism (oxidative vs. glycolytic).

CBD supplementation reduces arterial blood pressure via modulation of the sympatho-chromaffin system: A substudy from the HYPER-H21-4 trial

Data concerning the effects of cannabidiol (CBD) on blood pressure (BP) is controversial. HYPER-H21–4 was a randomized, placebo-controlled, crossover trial which sought to elucidate if 5-week administration of CBD will reduce BP in hypertensive patients. In the substudy of this trial, we aimed to establish the mechanistic background of CBD-induced BP reduction. Specifically, we explored the dynamic of catestatin, a sympathoinhibitory peptide implicated in the pathophysiology of hypertension. In the present analysis, 54 patients with Grade 1 hypertension were included. 5-week administration of CBD but not placebo reduced serum catestatin concentration in comparison to baseline (13.50 [10.85–19.05] vs. 9.65 [6.37–12.26] ng/mL, p < 0.001). Serum catestatin levels at the start of the treatment period demonstrated a negative correlation with the extent of reduction in mean arterial pressure (r = −0.474, p < 0.001). Moreover, the extent of change in catestatin serum levels showed a strong correlation with the extent of mean arterial pressure reduction (r = 0.712, p < 0.001). Overall, the results of the present study imply that the antihypertensive effects of CBD may be explained by its interaction with the sympatho-chromaffin system, although further research is warranted.

Cannabidiol repairs behavioral and brain disturbances in a model of fetal alcohol spectrum disorder

Fetal alcohol spectrum disorder (FASD) includes neuropsychiatric disturbances related to gestational and lactational ethanol exposure. Available treatments are minimal and do not modulate ethanol-induced damage. Developing animal models simulating FASD is essential for understanding the underlying brain alterations and searching for efficient therapeutic approaches. The main goal of this study was to evaluate the effects of early and chronic cannabidiol (CBD) administration on offspring exposed to an animal model of FASD. Ethanol gavage (3 g/kg/12 h, p.o.) was administered to C57BL/6 J female mice, with a previous history of alcohol consumption, between gestational day 7 and postnatal day 21. On the weaning day, pups were separated by sex, and CBD administration began (30 mg/kg/day, i.p.). After 4–6 weeks of treatment, behavioral and neurobiological changes were analyzed. Mice exposed to the animal model of FASD showed higher anxiogenic and depressive-like behaviors and cognitive impairment that were evaluated through several experimental tests. These behaviors were accompanied by alterations in the gene, cellular and metabolomic targets. CBD administration normalized FASD model-induced emotional and cognitive disturbances, gene expression, and cellular changes with sex-dependent differences. CBD modulates the metabolomic changes detected in the hippocampus and prefrontal cortex. Interestingly, no changes were found in mitochondria or the oxidative status of the cells. These results suggest that the early and repeated administration of CBD modulated the long-lasting behavioral, gene and protein alterations induced by the FASD model, encouraging the possibility of performing clinical trials to evaluate the effects of CBD in children affected with FASD.

Cannabidiol inhibits lung proliferation in monocrotaline-induced pulmonary hypertension in rats

Cannabidiol (CBD) is a safe and well-tolerated plant-derived drug with anti-proliferative properties. Pulmonary hypertension (PH) is a rapidly progressive and still incurable disease. CBD diminishes monocrotaline (MCT)-induced PH, including reduced right ventricular systolic pressure, pulmonary vascular hypertrophy, and right ventricular remodeling. The aim of our study was to investigate the effect of chronic administration of CBD (10 mg/kg once daily for 21 days) on selected remodeling parameters in the lung of MCT-induced PH rats. In MCT-induced PH, we found an increase in profibrotic parameters, e.g., transforming growth factor β1 (TGF-β1), galectin-3 (Gal-3), procollagen I, collagen I, C-propeptide, matrix metalloproteinase 9 (MMP-9) and an increased number of mast cells. In our study, we observed that the TGF-β1, Gal-3, procollagen I, collagen I, C-propeptide, and mast cell levels in lung tissue were decreased after CBD administration to MCT-treated rats. In summary, CBD treatment has an anti-proliferative effect on MCT-induced PH. Given the beneficial multidirectional effects of CBD on PH, we believe that CBD can be used as an adjuvant PH therapy, but this argument needs to be confirmed by clinical trials.

Systematic literature review of human studies assessing the efficacy of cannabidiol for social anxiety.

The current review evaluates the potential of cannabidiol (CBD) as a promising pharmacotherapy for social anxiety disorder (SAD). Although a number of evidence-based treatments for SAD are available, less than a third of affected individuals experience symptom remission after one year of treatment. Therefore, improved treatment options are urgently needed, and CBD is one candidate medication that may have certain benefits over current pharmacotherapies, including the absence of sedating side effects, reduced abuse liability, and rapid course of action. The current review provides a brief overview of CBD's mechanisms of action, neuroimaging in SAD, and evidence for CBD's effects on the neural substrates of SAD, as well as systematically reviewing literature directly examining the efficacy of CBD for improving social anxiety among healthy volunteers and individuals with SAD. In both populations, acute CBD administration significantly decreased anxiety without co-occurring sedation. A single study has also shown chronic administration to decrease social anxiety symptoms in individuals with SAD. Collectively, the current literature suggests CBD may be a promising treatment for SAD. However, further research is needed to establish optimal dosing, assess the timecourse of CBD's anxiolytic effects, evaluate long-term CBD administration, and explore sex differences in CBD for social anxiety.

Single cannabidiol administration affects anxiety-, obsessive compulsive-, object memory-, and attention-like behaviors in mice in a sex and concentration dependent manner

RationaleThe behavioral effects of cannabidiol (CBD) are understudied, but are important, given its therapeutic potential and widespread use as a natural supplement. ObjectiveThe objective of this study was to test whether a single injection of CBD affected anxiety-like or attention-like behavior, or memory in wildtype mice or mice with reported trait anxiety due to a targeted gene-deletion in a voltage-dependent potassium channel, Kv1.3. MethodsWildtype C57BL/6 J and Kv1.3−/− mice of both sexes were reared to adulthood and then administered an intraperitoneal injection of 10 or 20 mg/kg CBD. Mice were behaviorally-phenotyped using the marble-burying test, the light-dark box (LDB), short (1 h) and long-term (24 h) object memory test, the elevated-plus maze (EPM), and the object-based attention task in order to assess obsessive compulsive-, anxiety-, and attention-like behaviors, and memory. ResultsWe discovered that acute CBD treatment reduced marble burying in male, but not female mice. CBD was effective in lessening anxiety-like behaviors determined by the LDB test in both male and female wildtype mice, whereby the effective dose required to observe the effect in females was less. In Kv1.3−/− mice, CBD increased anxiety-like behaviors in the LDB in both sexes at the higher concentration of CBD and it similarly increased anxiety-like behavior in females in the EPM at the lower concentration of CBD. Long-term object memory was reduced in male wildtype mice at the lower concentration of CBD. Finally, ADHD- or attention-like behaviors were not altered by CBD in wildtype mice, but in Kv1.3−/− mice, females were observed to have a loss in attention while males demonstrated improved attention. ConclusionsWe conclude that administration of a single dose of CBD has immediate effects on mouse behavior that is dose, sex, and anxiety-state dependent – and that these behavioral outcomes are important to examine in parallel human trials.

Adverse Effects of Oral Cannabidiol: An Updated Systematic Review of Randomized Controlled Trials (2020-2022).

(1) Background: With the massive demand for the use and commercialization of medicinal cannabidiol (CBD) products, new randomized clinical trials (RCTs) are being published worldwide, with a constant need for safety and efficacy evaluation. (2) Methods: We performed an update on a systematic review published in 2020 that focused on analyzing the serious adverse effects (SAEs) of CBD in RCTs and its possible association with drug interactions. We also updated the report of the most prevalent CBD adverse effects (AEs). We systematically searched EMBASE, MEDLINE/PubMed, and Web of Science without language restriction for RCTs that reported adverse effects after repeated oral CBD administration for at least one week in healthy volunteers or clinical samples published from January 2019 to May 2022. The included studies were assessed for methodological quality by the Quality Assessment of Controlled Intervention Studies tool. The present review is registered on PROSPERO, number CRD42022334399. (3) Results: Twelve studies involving 745 randomized subjects analyzed were included (range 1.1-56.8 y). A total of 454 participants used CBD in the trials. The most common AEs of CBD were mild or moderate and included gastrointestinal symptoms (59.5%), somnolence (16.7%), loss of appetite (16.5%), and hypertransaminasemia (ALT/AST) (12.8%). Serious adverse effects include mainly hypertransaminasemia with serum levels elevations greater than three times the upper limit of the normal (6.4%), seizures (1.3%), and rash (1.1%). All SAEs reported in the studies were observed on CBD as an add-on therapy to anticonvulsant medications, including clobazam and valproate. (4) Conclusion: Recent RCTs involving oral CBD administration for at least a week suggest that CBD has a good safety and tolerability profile, confirming previous data. However, it can potentially interact with other drugs and its use should be monitored, especially at the beginning of treatment.

Effects of cannabidiol on vacuous chewing movements, plasma glucose and oxidative stress indices in rats administered high dose risperidone

Atypical antipsychotics, despite their rapid dissociation from dopamine receptors and reduced tendency to induce oxidative stress, have been associated with difficult-to-manage movement disorders, including tardive dyskinesia (TD). The study set out to investigate the effects of cannabidiol (CBD), a potent antioxidant, on risperidone-induced behavioural and motor disturbances; namely vacuous chewing movements (VCM), and oxidative stress markers (e.g. superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), malondialdehyde (MDA), Nitric oxide (NO), and DPPH (2,2-diphenyl-1-picrylhydrazyl)). Oral risperidone (10 mg/kg) or oral CBD (5 mg/kg) were administered to six experimental groups. While risperidone alone was administered for 28 days, CBD concomitantly or in sequential order with risperidone, was administered for 28 days; and CBD alone was administered for 21 days. Behavioural, motor, and specific biochemical parameters, which included VCM, muscle tone, fasting blood sugar (FBS), and oxidative stress markers were assessed at different time points after the last dose of medication. Oral CBD (5 mg/kg) significantly reduced risperidone-induced elevated FBS when given after the administration of risperidone. Oral CBD also had effects on VCM when administered before risperidone and similarly, attenuated risperidone-induced increased muscle tone. It was also established that concomitant or sequential administration of CBD and risperidone did not have any adverse effects on cognition or locomotion. Both CBD and risperidone increased the activity of antioxidant enzymes and decreased the activity of pro-oxidant enzymes. This study suggests CBD could mitigate metabolic dysregulation and extrapyramidal side effects associated with risperidone without producing cognitive impairments.

Cannabidiol attenuates fear memory expression in female rats via hippocampal 5-HT1A but not CB1 or CB2 receptors

Growing evidence from male rodent and human studies suggests that cannabidiol (CBD) modulates the expression of aversive memories and anxiety-related responses. The limited data on whether and how CBD influences these aspects in females could have therapeutic implications given the increased susceptibility of women to anxiety- and stress-related disorders relative to men. Female studies are also essential to examine inherent aspects that potentially contribute to differences in responsiveness to CBD. Here we addressed these questions in adult female rats. Contextually fear-conditioned animals acutely treated with CBD (1.0–10 mg/kg) were tested 45 min later. In subsequent experiments, we investigated the estrous cycle effects and the contribution of dorsal hippocampus (DH) serotonin 1A (5-HT1A) and cannabinoid types 1 (CB1) and 2 (CB2) receptors to CBD-induced effects on memory retrieval/expression. The effects of pre-retrieval systemic or intra-DH CBD administration on subsequent fear extinction were also assessed. Lastly, we evaluated the open arms avoidance and stretched-attend postures in females exposed to the elevated plus-maze after systemic CBD treatment. CBD 3.0 and 10 mg/kg administered before conditioned context exposure reduced females' freezing. This action remained unchanged across the estrous cycle and involved DH 5-HT1A receptors activation. Pre-retrieval CBD impaired memory reconsolidation and lowered fear during early extinction. CBD applied directly to the DH was sufficient to reproduce the effects of systemic CBD treatment. CBD 3.0 and 10 mg/kg reduced anxiety-related responses scored in the elevated plus-maze. Our findings demonstrate that CBD attenuates the behavioral manifestation of learned fear and anxiety in female rats.

Pharmacokinetics of escalating single-dose administration of cannabidiol to cats.

This study aimed to assess the single-dose pharmacokinetics and tolerability of a cannabidiol (CBD) isolate in sunflower oil with escalating oral doses in eight healthy, purpose-bred cats. Eight cats were randomized into six dosing groups of four cats each. Cats were administered a single 2.5, 5, 10, 20, 40, or 80 mg/kg dose orally with at least a two-week washout in between doses. Behavior scoring, complete blood count, serum biochemistry analysis, physical examination, and CBD plasma levels were evaluated before and after dosing. All cats successfully completed the study. CBD was measured in the plasma of all cats dosed with CBD oil. The Cmax and AUC increased in a dose-proportional fashion across all dosing groups. There were no major bloodwork or behavioral changes although the BUN and creatinine values decreased after treatment across all doses. No adverse effects were observed, and behavioral changes were limited to head shaking, lip smacking, and hypersalivation immediately following dose administration. Single orally administered CBD doses up to 80 mg/kg were safe and well tolerated in this cohort of cats and display dose-proportional pharmacokinetics across a broad concentration.

A double-blind, randomized, placebo-controlled test of the effects of cannabidiol on fear elicited by a 10% carbon dioxide-enriched air breathing challenge.

A single administration of cannabidiol (CBD) can reduce anxiety during social anxiety inductions. No study, however, has evaluated the impact of CBD on fear responding among humans. A double-blind, randomized, placebo-controlled trial was undertaken to address this gap in the literature. Specifically, the current study tested a single oral administration of CBD (either 150mg, 300mg, or 600mg), compared to placebo, for reducing fear reactivity to a well-established 5-min administration of 10% carbon dioxide (CO2)-enriched air biological challenge. CBD was administered 90min prior to the challenge. Participants were 61 healthy young adults who self-reported fear continuously during the challenge. Heart rate also was continuously monitored, and panic symptoms were self-reported using the Diagnostic Sensations Questionnaire immediately following the procedure. Results indicated no effect of condition on self-reported fear, panic symptoms, or heart rate. This is the first study to document that CBD does not reduce fear reactivity in humans, thereby representing an important extension to research on the effects of CBD.

Mitofusin-2 mediates cannabidiol-induced neuroprotection against cerebral ischemia in rats.

Cannabidiol (CBD) reportedly exerts protective effects against many psychiatric disorders and neurodegenerative diseases, but the mechanisms are poorly understood. In this study, we explored the molecular mechanism of CBD against cerebral ischemia. HT-22 cells or primary cortical neurons were subjected to oxygen-glucose deprivation insult followed by reoxygenation (OGD/R). In both HT-22 cells and primary cortical neurons, CBD pretreatment (0.1, 0.3, 1 μM) dose-dependently attenuated OGD/R-induced cell death and mitochondrial dysfunction, ameliorated OGD/R-induced endoplasmic reticulum (ER) stress, and increased the mitofusin-2 (MFN2) protein level in HT-22 cells and primary cortical neurons. Knockdown of MFN2 abolished the protective effects of CBD. CBD pretreatment also suppressed OGD/R-induced binding of Parkin to MFN2 and subsequent ubiquitination of MFN2. Overexpression of Parkin blocked the effects of CBD in reducing MFN2 ubiquitination and reduced cell viability, whereas overexpressing MFN2 abolished Parkin's detrimental effects. In vivo experiments were conducted on male rats subjected to middle cerebral artery occlusion (MCAO) insult, and administration of CBD (2.5, 5 mg · kg-1, i.p.) dose-dependently reduced the infarct volume and ER stress in the brains. Moreover, the level of MFN2 within the ischemic penumbra of rats was increased by CBD treatment, while the binding of Parkin to MFN2 and the ubiquitination of MFN2 was decreased. Finally, short hairpin RNA against MFN2 reversed CBD's protective effects. Together, these results demonstrate that CBD protects brain neurons against cerebral ischemia by reducing MFN2 degradation via disrupting Parkin's binding to MFN2, indicating that MFN2 is a potential target for the treatment of cerebral ischemia.

Development of cannabidiol nanoemulsion for direct nose to brain delivery: statistical optimization, in vitro and in vivo evaluation

Cannabidiol (CBD) is a prescribed drug for epilepsy but has low oral bioavailability and gastric instability. Because of the direct link between the nasal cavity and the central nervous system, intranasal administration of CBD as nanoemulsions which are the small sized lipid carriers seem to improve the bioavailability. CBD-nanoemulsions (NEs) were made using Capryol 90, Tween 80, and Transcutol P as oil, surfactant, and co-surfactant, respectively, following aqueous titration approach. Then, using the Box–Behnken design, CBD-NE was statistically optimised for the selection of desirable excipient concentrations in order to create the optimal CBD-NE formulation. As independent variables in the statistical design, Capryol 90 (oil; coded as A), Tween 80 (surfactant; coded as B), and Transcutol P (co-surfactant; coded as C) were used. The dependent variables were droplet size (DS; coded as R 1) and polydispersity index (PDI; coded as R 2). The average DS, PDI, and the zeta potential of the optimized CBD-NEs were observed to be 88.73 ± 2.67 nm, 0.311 ± 0.015, and −2.71 ± 0.52 mV respectively. Pure CBD and lyophilized CBD-NE Fourier-transform infrared spectra demonstrated no physicochemical interaction between excipients and the drug. Furthermore, differential scanning calorimetry and x-ray diffraction measurements revealed the amorphous CBD in the NE. As compared to pure CBD, the optimised CBD-NE showed considerably better in vitro drug release as well as ex vivo nasal permeability. The drug targeting efficiency and direct transport percentage of the optimised CBD-NEs were found to be 419.64% and 76.17%, respectively, in this research. Additionally, pharmacokinetic investigations after intranasal administration of CBD-NE revealed considerably higher drug concentrations in the brain with better brain targeting efficiency. As a result, the development of CBD-NE may be an excellent alternative for better intranasal delivery.

Design of Liposomal Lidocaine/Cannabidiol Fixed Combinations for Local Neuropathic Pain Treatment.

The administration of drug fixed combinations by nanocarriers is a new attractive approach since it can allow improvements in both the skin penetration of cargo compounds and their synergistic effects. The cutaneous administration of lidocaine (LD) and cannabidiol (CBD) combination can be useful for the local treatment of neuropathic pain. In fact, these drugs might exert a complementary effect on pain acting on sodium and calcium channels. In this study, the feasibility to deliver this combination in the deeper layers of the skin using deformable liposomes was studied. Based on a study of the drug affinity for lipid components performed by DSC, CBD was loaded in the lipid bilayer for limiting the leakage, while LD was loaded in the inner core by a pH gradient method (G-liposomes) or after previous encapsulation in micelle (DiMiL). The effect of the presence of Tween 80 in the liposome membrane was also evaluated. DiMiL increased both the skin permeation and the retention in the dermis of CBD and LD with respect to G-liposomes (R24dermis: 11.52 ± 2.4 against 4.51 ± 0.8 µg/cm2 for CBD; 19.6 ± 2.9 against 3.2 ± 0.1 µg/cm2 for LD). Moreover, both DiMiL and G-liposomes were more efficient than control formulations carrying free drugs in improving drug skin permeation. Interestingly, in the presence of a drug exerting a fluidizing effect such as CBD, the removal of Tween 80 from the composition led to an improved control of drug release and a higher extent of drug retention in the dermis layer.

Social stress under binge-like alcohol withdrawal in adolescence: evidence of cannabidiol effect on maladaptive plasticity in rats.

Alcohol binge drinking may compromise the functioning of the nucleus accumbens (NAc), i.e. the neural hub for processing reward and aversive responses. As socially stressful events pose particular challenges at developmental stages, this research applied the resident-intruder paradigm as a model of social stress, to highlight behavioural neuroendocrine and molecular maladaptive plasticity in rats at withdrawal from binge-like alcohol exposure in adolescence. In search of a rescue agent, cannabidiol (CBD) was selected due to its favourable effects on alcohol- and stress-related harms. Binge-like alcohol exposed intruder rats displayed a compromised defensive behaviour against the resident and a blunted response of the stress system, in addition to indexes of abnormal dopamine (DA)/glutamate plasticity and dysfunctional spine dynamics in the NAc. CBD administration (60 mg/kg) was able to: (1) increase social exploration in the binge-like alcohol exposed intruder rats, at the expenses of freezing time, and in control rats, which received less aggressive attacks from the resident; (2) reduce corticosterone levels independently on alcohol previous exposure; (3) restore DA transmission and (4) facilitate excitatory postsynaptic strength and remodelling. Overall, the maladaptive behavioural and synaptic plasticity promoted by the intersection between binge-like alcohol withdrawal and exposure to adverse social stress can be rescued by a CBD détente effect that results in a successful defensive strategy, supported by a functional endocrine and synaptic plasticity. The current data highlight CBD's relevant therapeutic potential in alcohol- and stress-related harms, and prompt further investigation on its molecular targets.

Intrapallidal injection of cannabidiol or a selective GPR55 antagonist decreases motor asymmetry and improves fine motor skills in hemiparkinsonian rats.

Cannabidiol (CBD) presents antiparkinsonian properties and neuromodulatory effects, possibly due to the pleiotropic activity caused at multiple molecular targets. Recently, the GPR55 receptor has emerged as a molecular target of CBD. Interestingly, GPR55 mRNA is expressed in the external globus pallidus (GPe) and striatum, hence, it has been suggested that its activity is linked to motor dysfunction in Parkinson’s disease (PD). The present study aimed to evaluate the effect of the intrapallidal injection of both CBD and a selective GPR55 antagonist (CID16020046) on motor asymmetry, fine motor skills, and GAD-67 expression in hemiparkinsonian rats. The hemiparkinsonian animal model applied involved the induction of a lesion in male Wistar rats via the infusion of the neurotoxin 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle via stereotaxic surgery. After a period of twenty days, a second surgical procedure was performed to implant a guide cannula into the GPe. Seven days later, lysophosphatidylinositol (LPI), CBD, or CID16020046 were injected once a day for three consecutive days (from the 28th to the 30th day post-lesion). Amphetamine-induced turning behavior was evaluated on the 14th and 30th days post-injury. The staircase test and fine motor skills were evaluated as follows: the rats were subject to a ten-day training period prior to the 6-OHDA injury; from the 15th to the 19th days post-lesion, the motor skills alterations were evaluated under basal conditions; and, from the 28th to the 30th day post-lesion, the pharmacological effects of the drugs administered were evaluated. The results obtained show that the administration of LPI or CBD generated lower levels of motor asymmetry in the turning behavior of hemiparkinsonian rats. It was also found that the injection of CBD or CID16020046, but not LPI, in the hemiparkinsonian rats generated significantly superior performance in the staircase test, in terms of the use of the forelimb contralateral to the 6-OHDA-induced lesion, when evaluated from the 28th to the 30th day post-lesion. Similar results were also observed for superior fine motor skills performance for pronation, grasp, and supination. Finally, the immunoreactivity levels were found to decrease for the GAD-67 enzyme in the striatum and the ipsilateral GPe of the rats injected with CBD and CID16020046, in contrast with those lesioned with 6-OHDA. The results obtained suggest that the inhibitory effects of CBD and CID16020046 on GPR55 in the GPe could be related to GABAergic overactivation in hemiparkinsonism, thus opening new perspectives to explain, at a cellular level, the reversal of the motor impairment observed in PD models.

Pharmacokinetics of cannabidiol in a randomized crossover trial in senior horses.

To determine the pharmacokinetics, bioavailability, and pharmacological effects of cannabidiol (CBD) in senior horses. 8 university-owned senior horses. In this randomized, crossover study, horses were assigned to receive either a single oral dose of 2 mg/kg CBD in oil or a single IV dose of 0.1 mg/kg CBD in DMSO between August 10 and September 4, 2020. Blood samples were collected before and then 0.5, 1, 4, 8, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, and 264 hours after CBD administration. Serum biochemical analyses and CBCs were performed. Plasma concentrations of CBD and its metabolites were determined with the use of liquid chromatography-tandem mass spectrometry. Concentrations of CBD and metabolites (7-COH CBD and 7-COOH CBD) were detected in all plasma samples up to 8 hours after dosing (oral and IV), with 7-COOH CBD being the most predominant metabolite. Pharmacokinetic results for CBD oral dosing at 2 mg/kg were mean ± SD half-life of 7.22 ± 2.86 hours, maximum concentration of 18.54 ± 9.80 ng/mL, and time to maximum concentration of 2.46 ± 1.62 hours. For both oral and IV administrations, 7-COOH CBD did not fall below the limit of quantification for the times reported. Oral bioavailability for CBD was 7.92%. There was no meaningful effect of CBD on results for CBC, serum biochemical analyses, or vital signs for any horse. Pharmacokinetics and bioavailability of CBD in senior horses were determined, and there were no adverse effects of administering either the oral or IV dose of CBD evaluated.