Does a broad-spectrum cannabidiol supplement improve performance in a 10-min cycle ergometer performance-test?

Cannabidiol (CBD) is a non-intoxicating phytocannabinoid which has been proposed to possess anti-inflammatory and analgesic properties. Given the potential for perceptions of pain to limit exercise performance, the aim of the present study was to investigate if 3 weeks of daily CBD supplementation (150 mg day-1) improved performance in a 10-min performance-trial on a cycle ergometer. In a randomized, double-blind and placebo-controlled study, 22 healthy participants (n = 11 male and n = 11 female) completed two 10-min performance trials on a WattBike cycle ergometer interspersed with a 3-week supplementation period. Supplementation involved either 150 mg day-1 oral CBD or 150 mg day-1 of a visually identical placebo (PLA). During trials, ratings of perceived exertion (RPE [6-20]), heart rate (HR) and blood lactate (BLa) were collected every 2 min. Mean power (W) was also taken throughout the exercise at each time point. All data were analyzed using two-way ANOVAs. There were no significant differences (P > 0.05) between CBD or PLA groups for mean power (W) during the 10-min performance trial. There were also no significant differences (P > 0.05) in any of the physiological or perceptual parameters (HR, BLa and RPE) between conditions. Three weeks supplementation of a broad-spectrum CBD supplement did not improve performance via any change in RPE during a 10-min time trial on a cycle ergometer, and as such, this evidence does not support the claim that broad-spectrum CBD supplements could be performance-enhancing in this exercise modality.

Formulation Development and Evaluation of Cannabidiol Hot-Melt Extruded Solid Self-Emulsifying Drug Delivery System for Oral Applications.

Cannabidiol (CBD) is a highly lipophilic compound with poor oral bioavailability, due to poor aqueous solubility and extensive pre-systemic metabolism. The aim of this study was to explore the potential of employing Hot Melt Extrusion (HME) technology for the continuous production of Self Emulsifying Drug Delivery Systems (SEDDS) to improve the solubility and in vitro dissolution performance of CBD. Accordingly, different placebos were processed through HME in order to obtain a lead CBD loaded solid SEDDS. Two SEDDS were prepared with sesame oil, Poloxamer 188, Gelucire®59/14, PEO N80 and Soluplus®. Moreover, Vitamin E was added as an antioxidant. The SEDDS formulations demonstrated emulsification times of 9.19 and 9.30 min for F1 and F2 respectively. The formed emulsions showed smaller droplet size ranging from 150-400 nm that could improve lymphatic uptake of CBD and reduce first pass metabolism. Both formulations showed significantly faster in vitro dissolution rate (90% for F1 and 83% for F2) compared to 14% for the pure CBD within the first hour, giving an enhanced release profile. The formulations were tested for stability over a 60-day time period at 4°C, 25°C, and 40°C. Formulation F1 was stable over the 60-day time-period at 4°C. Therefore, the continuous HME technology could replace conventional methods for processing SEDDS and improve the oral delivery of CBD for better therapeutic outcomes.

The effects of a brand-specific, hemp-derived cannabidiol product on physiological, biochemical, and psychometric outcomes in healthy adults: a double-blind, randomized clinical trial.

BACKGROUND: Cannabidiol (CBD) is a non-psychoactive phyto-cannabinoid derived from the Cannabis sativa plant. CBD exhibits various interactions at receptor sites, prompting the research of its potential anti-inflammatory, immunomodulatory, psychological, and pain-relieving effects. This study aimed to investigate the physiological, biochemical, and psychometric effects of a brand-specific, hemp-derived CBD product in healthy adults over a 12-week observation period. METHODS: 54 healthy males and females (age = 25 ± 7y; BMI = 24.82 ± 3.25 kg/m2) recruited from a large Southeastern University completed the study. Participants arrived at the laboratory after > 8 h of fasting, and > 48 h without alcohol consumption and vigorous exercise. Following baseline measurements (height, weight, blood pressure, electrocardiogram (ECG), and blood work), participants were stratified by sex and randomized to either CBD or placebo groups. Products were administered double-blinded, with both given in liquid form containing medium-chain triglyceride oil, while the CBD product specifically contained 50 mg/mL of CBD. Participants were instructed to consume 1 mL of their product twice daily and were given enough product to last until their next laboratory visit. Data were collected at baseline and on days 30 ± 3, 60 ± 3, and 90 ± 3. Blood was drawn for analysis of immune and inflammatory biomarkers. Chronic pain among participants was calculated using urine samples according to the foundational pain index (FPI). Self-reported psychometric questionnaires were utilized (Cohen's Perceived Stress Scale, Pittsburgh Sleep Quality Index, Profile of Mood States,10-item Likert scale for perceived pain) to assess stress, sleep quality, mood state, and body discomfort. To determine overall wellbeing, participants completed a daily survey indicating if they missed work or school due to illness. Change from baseline was calculated for each measure, and mixed effects models were used to determine differences between groups over time while adjusting for baseline values (α = 0.05). Data are presented as mean ± standard deviation. RESULTS: There were no Group-by-Time interactions or Group or Time main effects for immune or inflammatory biomarkers (p > 0.05). Analyses revealed no Group-by-Time interactions or main effects observed for perceived stress, sleep quality, overall mood disturbance, and all the profile of mood state subscales (p > 0.05), except "vigor-activity." A Time main effect was found for the sub-score for "vigor-activity" (p = 0.007; Pre CBD = 19.5 ± 5.2, Post CBD = 17.3 ± 5.3; Pre PL = 19.0 ± 5.7, Post PL = 17.9 ± 7.1), which decreased from Visit 3 to Visit 4 (p = 0.025) and from Visit 3 to Visit 5 (p = 0.014). There was a Group main effect for FPI (p = 0.028; Pre CBD = 11.9 ± 14.4, Post CBD = 8.8 ± 10.9; Pre PL = 9.0 ± 14.2, Post PL = 12.9 ± 11.5), indicating that the placebo group had greater increases in pain over the intervention compared to the CBD group. No significant differences were found between groups in the incidence and prevalence of "colds or flus" (p > 0.05). DISCUSSION: CBD was safe and well tolerated in healthy adults. These findings show pain was lower in the CBD group, suggesting a potentially positive effect for consumption of CBD. "Vigor-activity" decreased across the intervention, which may be a confounding effect of the academic semester. While the dosage chosen was safe, more research may be warranted using higher doses as these may be needed to observe further therapeutic effects in healthy populations.

Enhanced brain-targeting and efficacy of cannabidiol via RVG-Exo/CBD nanodelivery system.

This study introduces an innovative brain-targeted drug delivery system, RVG-Exo/CBD, utilizing rabies virus glycoprotein (RVG)-engineered exosomes for encapsulating cannabidiol (CBD). The novel delivery system was meticulously characterized, confirming the maintenance of exosomal integrity, size, and successful drug encapsulation with a high drug loading rate of 83.0 %. Evaluation of the RVG-Exo/CBD's brain-targeting capability demonstrated superior distribution and retention in brain tissue compared to unmodified exosomes, primarily validated through in vivo fluorescence imaging. The efficacy of this delivery system was assessed using a behavioral sensitization model in mice, where RVG-Exo/CBD notably suppressed methamphetamine-induced hyperactivity more effectively than CBD alone, indicating a reduction in effective dose and enhanced bioavailability. Overall, the RVG-Exo/CBD system emerges as a promising strategy for enhancing the therapeutic efficacy and safety of CBD, particularly for neurological applications, highlighting its potential for addressing the limitations associated with traditional CBD administration in clinical settings.

High-loading cannabidiol powders for inhalation.

Limited attempts have been made previously to develop high-loading CBD inhalable powders, which are essential for high dose delivery. Therefore, this study aimed to develop and characterise inhalable powders with ≥ 95 % w/w CBD by wet ball milling. The effects of magnesium stearate (2 % and 5 %) and inhaler resistance (low-resistance and high-resistance RS01 inhalers) on aerosol performance were also compared. Wet ball milling produced CBD powders with > 50 % production yield. The milled particles showed irregular shapes. The powders were crystalline with minimal amorphous content, low residual solvent level (<1%), and low moisture sorption (<4%). Magnesium stearate improved both the emitted and fine particle fractions. The aerodynamic particle size distribution of the formulations differed between the low-resistance and high-resistance RS01 inhalers. The latter decreased throat deposition but increased inhaler retention. The dissolution profiles showed that all three formulations released CBD steadily and plateaued at 30 min. The best scenario was CBD with 5 % magnesium stearate dispersed from the high resistance RS01 inhaler, showing the highest FPF with the lowest throat deposition. This combination may be tested in vivo in the future to investigate its pharmacokinetic profile.

Transdermal Delivery of Cannabidiol for the Management of Acute Inflammatory Pain: A Comprehensive Review of the Literature.

The emerging field of nanotechnology has paved the way for revolutionary advancements in drug delivery systems, with nanosystems emerging as a promising avenue for enhancing the therapeutic potential and the stability of various bioactive compounds. Among these, cannabidiol (CBD), the non-psychotropic compound of the Cannabis sativa plant, has gained attention for its therapeutic properties. Consequently, researchers have devoted significant efforts to unlock the full potential of CBD's clinical benefits, where various nanosystems and excipients have emerged to overcome challenges associated with its bioavailability, stability, and controlled release for its transdermal application. Therefore, this comprehensive review aims to explain CBD's role in managing acute inflammatory pain and offers an overview of the state of the art of existing delivery systems and excipients for CBD. To summarize this review, a summary of the cannabinoids and therapeutical targets of CBD will be discussed, followed by its conventional modes of administration. The transdermal route of administration and the current topical and transdermal delivery systems will also be reviewed. This review will conclude with an overview of in vivo techniques that allow the evaluation of the anti-inflammatory and analgesic potentials of these systems.

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.

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).

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.

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.

Cannabidiol and its application in the treatment of oral diseases: therapeutic potentials, routes of administration and prospects.

Cannabidiol (CBD), one of the most important active ingredients in cannabis, has been reported to have some pharmacological effects such as antibacterial and analgesic effects, and to have therapeutic potential in the treatment of oral diseases such as oral cancer, gingivitis and periodontal diseases. However, there is a lack of relevant systematic research and reviews. Therefore, based on the etiology and clinical symptoms of several common oral diseases, this paper focuses on the therapeutic potential of CBD in periodontal diseases, pulp diseases, oral mucosal diseases, oral cancer and temporomandibular joint diseases. The pharmacological effects of CBD and the distribution and function of its receptors in the oral cavity are also summarized. In order to provide reference for future research and further clinical application of CBD, we also summarize several possible routes of administration and corresponding characteristics. Finally, the challenges faced while applying CBD clinically and possible solutions are discussed, and we also look to the future.

Spray freeze dried cannabidiol with dipalmitoylphosphatidylcholine (DPPC) for inhalation and solubility enhancement.

Pulmonary delivery is an efficient route of administration to deliver cannabidiol (CBD) due to the high bioavailability and fast onset of action. The major formulation challenge is the poor aqueous solubility of CBD. This study aimed to produce inhalable CBD powders with enhanced solubility and characterise their solid-state properties. CBD was spray freeze dried with mannitol or trehalose dihydrate with and without dipalmitoylphosphatidylcholine (DPPC). All four powders had acceptable yields at > 70 % with porous and spherical particles. The two crystalline mannitol powders contained less residual solvent than both amorphous trehalose ones. The addition of DPPC did not affect the crystallinity and residual solvent level of the powders. Instead, DPPC made the particles more porous, decreased the particle size from 19-23 µm to 11-13 µm, and increased CBD solubility from 0.36 µg/mL to over 2 µg/mL. The two DPPC powders were dispersed from a low resistance RS01 inhaler, showing acceptable aerosol performance with emitted fractions at 91-93 % and fine particle fractions < 5 µm at 34-43 %. These formulations can be used as a platform to deliver CBD and other cannabinoids by inhalation.

Harnessing therapeutic deep eutectic solvents in self-emulsifying systems to improve CBD delivery.

In this study, Cannabidiol crystals (CBD) were used as a BCS class II model drug to generate a novel therapeutic deep eutectic solvent (THEDES) with easy preparation using caprylic acid (CA). The hydrogen bonding interaction was confirmed by different techniques such as FT-IR and NMR, resulting in a hydrophobic system suitable for liquid formulations. The CBD-based THEDES, combined with a specific mixture of surfactants and co-surfactants, successfully formed a self-emulsifying drug delivery system (SEDDS) that generated uniform nano-sized droplets once dispersed in water. Hence, the THEDES showed compatibility with the self-emulsifying approach, offering an alternative method to load drugs at their therapeutic dosage. Physical stability concerns regarding the unconventional oily phase were addressed through stress tests using multiple and dynamic light scattering, demonstrating the robustness of the system. In addition, the formulated SEDDS proved effective in protecting CBD from the harsh acidic gastric environment for up to 2 h at pH 1.2. Furthermore, in vitro studies have confirmed the safety of the formulation and the ability of CBD to permeate Caco-2 cells when formulated. This investigation highlights the potential incorporation of THEDES in lipid-based formulations like SEDDS, expanding the avenues for innovative oral drug delivery approaches.

Evaluation of the efficacy, safety, and pharmacokinetics of nanodispersible cannabidiol oral solution (150 mg/mL) versus placebo in mild to moderate anxiety subjects: A double blind multicenter randomized clinical trial.

BACKGROUND: Anxiety disorders, an increasingly prevalent global mental health illness, affected approximately 301 million individuals worldwide in 2019. There is an unmet need for the treatment of anxiety disorders, as current therapies are associated with limited response rates, residual symptoms, and adverse effects. OBJECTIVES: To evaluate the efficacy, safety, and pharmacokinetics of nanodispersible cannabidiol (CBD) oral solution versus placebo for the treatment of mild to moderate anxiety disorders. METHODS: This phase 3 prospective, randomized, double blind, parallel group, placebo-controlled, 15-week cohort study took place at multiple sites across India. Eligible participants were randomly assigned to one of the two treatment arms (CBD or placebo) in a 1:1 ratio. RESULTS: 178 participants were randomized to receive CBD (n=89) or placebo (n=89). The study met both primary (GAD-7 and HAM-A scores) and secondary outcomes (CGI-I, CGI-S, PHQ-9 and PSQI scores). The GAD-7 score difference between the end of treatment and baseline for the CBD versus the placebo was -7.02 (S.E: 0.25, 95% CI -7.52; -6.52), p<0.0001. Similarly, the HAM-A score difference at the end of treatment compared to baseline for the CBD versus the placebo was -11.9 (S.E: 0.33, 95% CI -12.6; -11.3), p<0.0001. CONCLUSIONS: Nanodispersible CBD was therapeutically safe with no serious adverse events, well tolerated, and effective for the treatment of mild to moderate anxiety disorders, as well as associated depression and sleep quality disturbances. These results pave way for probable prospective use of nanodispersible CBD formulation for various psychiatry disorders alone or in conjunction with other drugs.

Infant formula as a solid lipid dose form for enhancement of the oral bioavailability of cannabidiol for paediatric patients.

Cannabinoids can save paediatric patients from harmful psychological conditions caused by epilepsy. However, the limited aqueous solubility of the drug presents a limitation to oral absorption and bioavailability. Previous studies have shown the enhancement of oral bioavailability for poorly water-soluble drugs using milk or milk-based products like infant formula as a novel lipid-based formulation, due to digestion of the lipids to enhance drug solubility that is particularly well suited to infants and in low economy settings. Therefore, this study has investigated the in vitro solubilisation enhancement of cannabidiol (CBD) in milk-based products during digestion using synchrotron small angle X-ray scattering, followed by pharmacokinetic studies to determine the relative oral bioavailability. The in vitro results, coupled with in vivo data, demonstrate a two-fold increase in the oral bioavailability of CBD in bovine milk as well as infant formula. The results of this study indicate the potential for infant formula to be considered as a novel formulation approach for CBD. Further study is encouraged for more drugs with infant formula to strengthen the correlation between the solubilisation of drug and their oral bioavailability.

Formulation and In Vitro-Ex vivo Evaluation of Cannabidiol and Cannabidiol-Valine-Hemisuccinate Loaded Lipid-Based Nanoformulations for Ocular Applications.

The goal of this investigation is to develop stable ophthalmic nanoformulations containing cannabidiol (CBD) and its analog cannabidiol-valine-hemisuccinate (CBD-VHS) for improved ocular delivery. Two nanoformulations, nanoemulsion (NE) and nanomicelles (NMC), were developed and evaluated for physicochemical characteristics, drug-excipient compatibility, sterilization, thermal analysis, surface morphology, ex-vivo transcorneal permeation, corneal deposition, and stability. The saturation solubility studies revealed that among the surfactants tested, Cremophor EL had the highest solubilizing capacity for CBD (23.3 ± 0.1 mg/mL) and CBD-VHS (11.2 ± 0.2 mg/mL). The globule size for the lead CBD formulations (NE and NMC) ranged between 205 and 270 nm while CBD-VHS-NMC formulation had a particle size of about 78 nm. The sterilized formulations, except for CBD-VHS-NMC at 40 °C, were stable for three months of storage (last time point tested). Release, in terms of CBD, in the in-vitro release/diffusion studies over 18 h, were faster from the CBD-VHS nanomicelles (38 %) compared to that from the CBD nanoemulsion (16 %) and nanomicelles (33 %). Transcorneal permeation studies revealed improvement in CBD permeability and flux with both formulations; however, a greater improvement was observed with the NMC formulation compared to the NE formulation. In conclusion, the nanoformulations prepared could serve as efficient topical ocular drug delivery platforms for CBD and its analog.

Evaluation of amorphous and lipid-based formulation strategies to increase the in vivo cannabidiol bioavailability in piglets.

Cannabidiol (CBD) suffers from poor oral bioavailability due to poor aqueous solubility and high metabolism, and is generally administered in liquid lipid vehicles. Solid-state formulations of CBD have been developed, but their ability to increase the oral bioavailability has not yet been proven in vivo. Various approaches are investigated to increase this bioavailability. This study aimed to demonstrate the enhancement of the oral bioavailability of oral solid dosage forms of amorphous CBD and lipid-based CBD formulation compared to crystalline CBD. Six piglets received the three formulations, in a cross-over design. CBD and 7 - COOH - CBD, a secondary metabolite used as an indicator of hepatic degradation, were analyzed in plasma. A 10.9-fold and 6.8-fold increase in oral bioavailability was observed for the amorphous and lipid formulations, respectively. However, the lipid-based formulation allowed reducing the inter-variability when administered to fasted animals. An entero-hepatic cycle was confirmed for amorphous formulations. Finally, this study showed that the expected protective effect of lipids against hepatic degradation of the lipid-based formulation did not occur, since the ratio CBD/metabolite was higher than that of the amorphous one.

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.

Cannabidiol - an effective analgesic for toothache?

DESIGN: The study by Chrepa et al. is a randomised, placebo-controlled, triple-arm, phase IIA clinical trial with double masking which investigates the effectiveness and safety of Cannabidiol (CBD) as an analgesic for acute dental pain. The intervention drug, Epidiolex is an FDA-approved CBD oral solution (100 mg/ml) derived from the cannabis plant. The psychoactive ingredient tetrahydrocannabinol (THC) is not included. The maximum recommended daily dose of Epidiolex is 20 mg/kg. 64 patients with moderate-severe odontogenic pain participated in the study and REDCap software was utilised to randomly assign participants into groups: CBD10 (10 mg/kg), CBD20 (20 mg/kg) and placebo. A single dose of the respective oral solution was administered, and participants monitored for 3 h. Patients remained blinded to group assignment, as did the outcome assessor. The provider was not blinded. The primary outcome measure was VAS (visual analogue scale) pain difference, compared to baseline and recorded at 7 subsequent marked times following administration (15, 30, 45, 60, 90, 120, 180 min). Additional outcome measures were also recorded: changes in bite force, pain intensity differences, the onset of significant pain relief, the maximum pain relief, psychoactive effects, mood changes and adverse events. CASE SELECTION: 40 female and 21 male patients with moderate-severe odontogenic pain (defined as ≥30 on a 100 mm VAS) with a diagnosis of irreversible pulpitis or pulp necrosis and symptomatic apical periodontitis were included. Participation required a negative test for recent drug and alcohol use, a negative pregnancy test and no use of analgesics within 6 h of the trial. Pregnancy, breastfeeding, hepatic impairment, recreational cannabis users and patients taking CBD metabolising drugs were excluded along with those with an ASA classification above III. Patient characteristics recorded included: age, gender, race, tooth type affected, weight and BMI. DATA ANALYSIS: Mixed model analysis was used to compare numerical variables among the cohorts at the marked time intervals. VAS, bite force, Bowdle and Bond/Lader questionnaires were recorded. Inter-group analysis was completed using parametric and non-parametric post-hoc tests, including Holm-Bonferroni adjustment and the Shapiro-Wilk test, to evaluate data normality. NNTs were calculated for both CBD doses- the number of patients needing treatment before one patient experiences a minimum of 50% pain relief. X² tests were used to analyse categorical variables: pain intensity and adverse events. JMP software was used for the statistical analysis. RESULTS: 64 participants had originally enroled in the study, but three were excluded from data analysis due to 'unrealistic results', reporting complete pain relief within the first 15 min. 20 participants were given CBD10, 20 were given CBD20 and 21 placebo. 68% of the participants were Hispanic/Latino whilst 11% were white. The average age was 44 +/- 13.7. There was equal distribution of age, sex, race, tooth type, weight and body mass index (p > 0.05). No subject required rescue pain relief during the 3-h observation period. Compared to baseline VAS, significant pain relief was seen 30 min after drug administration for CBD10, versus after 15 min for CBD20 (p < 0.05). Pain reduction reached 50% at 60 min for CBD10 and at 120 min for CBD20. Both reported maximum pain reduction of 73% of baseline at 180 min. 33% pain reduction from baseline was seen in the placebo group, with a median VAS pain of 67% at 180 min. 45.4% of CBD10 and 46.6% of CBD20 required pain relief after 1-6 h, versus 37.5% of placebo (p > 0.05). Bite force increase was seen in both CBD10 and CBD20 groups at 90 and 180 min, versus no significant differences between time points in the placebo group. On assessing pain intensity, pain reduction was significantly associated with increasing time in the CBD groups (p < 0.001), versus no significant association with the placebo group (p = 0.0521). No statistically significant differences were seen between and within the groups for Bowdle or Bond/Lader questions (p > 0.05). In the 3 h observation period, CBD10 experienced 14 times more sedation symptoms versus placebo (p < 0.05), whilst CBD20 experienced this 8 times more (p < 0.05). Within the 3 h, CBD20 were 10-fold more likely to have diarrhoea and abdominal pain (p < 0.05), with some experiencing pain beyond the 3 h but resolving within the day. CONCLUSIONS: Based on this randomised clinical trial, pure CBD drug Epidiolex demonstrates effective analgesia against acute toothache.

3D DLP-printed cannabinoid microneedles patch and its pharmacokinetic evaluation in rats.

OBJECTIVE: The objective of the present study was to enhance the bioavailability of cannabidiol (CBD) using 3D Digital Light Processing (DLP)-printed microneedle (MN) transdermal drug delivery system. METHODS: CBD MN patch was fabricated and optimized using 3D DLP printing using CBD (8% w/v), Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) (0.49% w/v), distilled water (20% w/v), and poly (ethylene glycol) dimethacrylate 550 (PEGDAMA 550) (up to 100% w/v). CBD MNs were characterized for their morphology, mechanical strength, in vitro release study, ex vivo permeation study, and in vivo pharmacokinetic (PK) profile. KEY FINDINGS: Microscopic images showed that sharp CBD MNs with a height of ~800 µm, base diameter of ~250 µm, and tip with a radius of curvature (RoC) of ~15 µm were successfully printed using optimized printing parameters. Mechanical strength studies showed no significant deformation in the morphology of CBD MNs even after applying 0.5N/needle force. Ex vivo permeation study showed significant (P < .0001) permeation of CBD in the receiving media as compared to CBD patch (control). In vivo PK study showed significantly (P < .05) enhanced bioavailability in the case of CBD MN patch as compared to CBD subcutaneous inj. (control). CONCLUSION: Overall, systemic absorption of CBD was significantly enhanced using 3D-printed MN drug delivery system.