Strategies to Improve Cannabidiol Bioavailability and Drug Delivery.

The poor physicochemical properties of cannabidiol (CBD) hamper its clinical development. The aim of this review was to examine the literature to identify novel oral products and delivery strategies for CBD, while assessing their clinical implications and translatability. Evaluation of the published literature revealed that oral CBD strategies are primarily focused on lipid-based and emulsion solutions or encapsulations, which improve the overall pharmacokinetics (PK) of CBD. Some emulsion formulations demonstrate more rapid systemic delivery. Variability in the PK effects of different oral CBD products is apparent across species. Several novel administration routes exist for CBD delivery that may offer promise for specific indications. For example, intranasal administration and inhalation allow quick delivery of CBD to the plasma and the brain, whereas transdermal and transmucosal administration routes deliver CBD systemically more slowly. There are limited but promising data on novel delivery routes such as intramuscular and subcutaneous. Very limited data show that CBD is generally well distributed across tissues and that some CBD products enable increased delivery of CBD to different brain regions. However, evidence is limited regarding whether changes in CBD PK profiles and tissue distribution equate to superior therapeutic efficacy across indications and whether specific CBD products might be suited to particular indications.

The therapeutic potential of purified cannabidiol.

The use of cannabidiol (CBD) for therapeutic purposes is receiving considerable attention, with speculation that CBD can be useful in a wide range of conditions. Only one product, a purified form of plant-derived CBD in solution (Epidiolex), is approved for the treatment of seizures in patients with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. Appraisal of the therapeutic evidence base for CBD is complicated by the fact that CBD products sometimes have additional phytochemicals (like tetrahydrocannabinol (THC)) present, which can make the identification of the active pharmaceutical ingredient (API) in positive studies difficult. The aim of the present review is to critically review clinical studies using purified CBD products only, in order to establish the upcoming indications for which purified CBD might be beneficial. The areas in which there is the most clinical evidence to support the use of CBD are in the treatment of anxiety (positive data in 7 uncontrolled studies and 17 randomised controlled trials (RCTs)), psychosis and schizophrenia (positive data in 1 uncontrolled study and 8 RCTs), PTSD (positive data in 2 uncontrolled studies and 4 RCTs) and substance abuse (positive data in 2 uncontrolled studies and 3 RCTs). Seven uncontrolled studies support the use of CBD to improve sleep quality, but this has only been verified in one small RCT. Limited evidence supports the use of CBD for the treatment of Parkinson's (3 positive uncontrolled studies and 2 positive RCTs), autism (3 positive RCTs), smoking cessation (2 positive RCTs), graft-versus-host disease and intestinal permeability (1 positive RCT each). Current RCT evidence does not support the use of purified oral CBD in pain (at least as an acute analgesic) or for the treatment of COVID symptoms, cancer, Huntington's or type 2 diabetes. In conclusion, published clinical evidence does support the use of purified CBD in multiple indications beyond epilepsy. However, the evidence base is limited by the number of trials only investigating the acute effects of CBD, testing CBD in healthy volunteers, or in very small patient numbers. Large confirmatory phase 3 trials are required in all indications.

A zinc fixative for 3D visualization of cerebral capillaries and pericytes.

BACKGROUND: A large volume of data indicates that disturbances in the morphology and function of the capillary wall may play a causal role in several types of neurodegenerative disorders. We present a highly reproducible staining method for investigating the cerebral capillary network and the pericyte cells within the basement membrane in mice - a specie specific challenging task when uniform staining in thick sections was needed for confocal microscopy or a quantitative analysis, e.g. stereological investigation using 3D probes. NEW METHOD: We perfused C57BL6/Jbom mice and immersion fixated the brains with an aldehyde free zinc fixative, which is normally used for paraffin embedded tissues, and stained for CD31 and Collagen Type IV positive capillaries in 100µm thick sections. RESULTS: Using the milder zinc fixative allowed complete immunohistochemical visualization of the cerebral capillary network in 100µm thick sections using CD31 or Collagen Type IV antibodies. Moreover CD31 or Collagen Type IV staining revealed the presence of pericytes, which was confirmed by a fluorescent co-localization with the NG2 pericyte marker. COMPARISON WITH EXISTING METHODS: Compared with conventional aldehyde-based fixative, this method resulted in a homogeneous staining through the entire depth of thick sections with very limited background staining and well-preserved morphology. CONCLUSIONS: This method is suitable for 3D stereological analysis of capillary networks and pericytes within thick brain sections using CD31 or Collagen Type IV antibodies.

Quantitative analysis of the capillary network of aged APPswe/PS1dE9 transgenic mice.

A combination of immunohistochemical and stereological techniques were used to investigate the capillary network in the cerebral cortex of 18-month-old APPswe/PS1dE9 transgenic (Tg) mice and control littermates. Data regarding total capillary length, segment number, diffusion radius, and pericyte number are presented. The total length was 60 meters and there was a one-to-one relationship between the number of capillary segments and pericytes in both groups. Significant differences were not observed in the Tg and wild-type controls indicating that the Alzheimer's-like amyloidosis produced in this Tg mouse has a minimal affect on the structural integrity of the cerebral capillary network.

Cholinergic axon length reduced by 300 meters in the brain of an Alzheimer mouse model.

Modern stereological techniques have been used to show that the total length of the cholinergic fibers in the cerebral cortex of the APPswe/PS1deltaE9 mouse is reduced by almost 300 meters at 18 months of age and has a nonlinear relationship to the amount of transgenetically-induced amyloidosis. These data provide rigorous quantitative morphological evidence that Alzheimer's-like amyloidosis affects the axons of the cholinergic enervation of the cerebral cortex.