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.

Adolescent behavioral abnormalities in a Scn1a+/- mouse model of Dravet syndrome.

Dravet syndrome is an intractable pediatric epilepsy associated with SCN1A mutations. In addition to having a large seizure burden and a reduced lifespan, patients with Dravet syndrome also exhibit delays in reaching normal developmental milestones in attentional, emotional, and cognitive function. These developmental delays manifest in autistic-like social withdrawal and compulsive behavior. Additionally, cognitive impairments including deficits in sensorimotor processing and memory function are present. Several mouse models utilizing heterozygous deletion of Scn1a (Scn1a+/- mice) have been generated that recapitulate many aspects of Dravet syndrome. Studies in these mouse models of Dravet syndrome have characterized behavioral phenotypes in adult mice. In the present study, we characterized the behavioral phenotype of Scn1a+/- mice generated by targeted deletion of Scn1a exon 1 (Scn1atm1Kea) during adolescence. Identifying behavioral deficits in adolescent mice would more closely model the early onset of attentional, emotional, and cognitive delays observed in patients with Dravet syndrome. The behaviors of adolescent Scn1a+/- and wildtype (WT) mice were compared across several behavioral domains. We assessed motor function (open-field test), sociability and social recognition memory (three-chambered social preference and social interaction tests), memory function (novel object recognition, Barnes maze, fear conditioning paradigm), anxiety-related behavior (elevated plus maze and open-field thigmotaxis), startle reflex and sensorimotor gating (prepulse inhibition of startle (PPI) tests), and repetitive compulsive behavior (marble burying test). Adolescent Scn1a+/- mice exhibited normal locomotor activity, marble burying behavior, sociability, and sensorimotor gating. However, adolescent Scn1a+/- mice displayed increased anxiety-related thigmotactic behavior, atypical fear expression, blunted acoustic startle responses, and impaired social recognition and spatial memory. Our results show that Scn1a+/- mice display various behavioral impairments during adolescence, which provides a foundation for testing early intervention therapies targeting developmental delays modeled in Dravet syndrome mice.

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.

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.