The use of cannabis for medicinal purposes dates back thousands of years. Recent research focuses on cannabidiol (CBD), a major phytocannabinoid in cannabis, due to its non-psychoactive properties, making it a more attractive therapeutic option than THC. Growing interest surrounds CBD's potential in treating various brain disorders, including epilepsy, pain, depression, anxiety, and psychosis. The FDA's approval of Epidiolex® for treating refractory epileptic seizures underscores this growing interest. Different administration routes for CBD are being explored to optimize its pharmacokinetics (PK) and systemic delivery to the brain, aiming to improve its low aqueous solubility and bioavailability, currently limited by extensive first-pass metabolism following oral administration.

Existing literature highlights CBD's interaction with numerous central nervous system (CNS) targets. While CBD shows low affinity for CB1 and CB2 receptors and doesn't directly activate them, it acts as a negative allosteric modulator of these receptors and antagonizes CB1/CB2 agonists. CBD also interacts with various non-endocannabinoid receptors, including GPR3, GPR6, GPR12, GPR55, transient receptor potential channels (TRPM8, TRPA1, TRPV1, TRPV2), serotonin receptors, opioid receptors, peroxisome proliferator-activated receptor gamma, and glycine receptors. This interaction with multiple receptors suggests its potential therapeutic applications in diverse CNS conditions. Numerous animal and human studies have explored CBD's therapeutic potential in neurological and psychiatric disorders. Studies demonstrate CBD's antiepileptic, analgesic, neuroprotective, antidepressant, anxiolytic, antipsychotic, and sedative effects.

This review article synthesizes preclinical and clinical data from various studies examining CBD's therapeutic effects and pharmacokinetic profiles across different administration routes. The authors collated and analyzed data from multiple sources, including randomized controlled trials (RCTs), open-label studies, animal studies, and case series. The primary focus is on comparing the pharmacokinetic properties of CBD when administered via various routes, including intravenous, oral, sublingual, buccal, pulmonary (smoking, vaporization, MDI, DPI), intranasal, and transdermal routes. The analysis emphasizes the absorption, distribution, metabolism, and excretion (ADME) parameters such as peak plasma concentration (Cmax), time to reach peak plasma concentration (tmax), area under the concentration-time curve (AUC), bioavailability (F), volume of distribution (Vd), clearance (CL), and mean retention time (MRT). These pharmacokinetic parameters were compared to determine the optimal route for CBD delivery to treat brain disorders.

CBD's mechanism of action involves interaction with various CNS receptors. Clinical trials demonstrate CBD's effectiveness in reducing seizure frequency in drug-resistant epilepsies like Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex. Animal and human studies suggest analgesic effects, particularly in inflammatory pain. In Parkinson's disease, open-label trials showed a reduction in disease severity and movement disorders; however, double-blind studies produced mixed results. Preclinical studies suggest neuroprotective effects in Alzheimer's disease models. Animal and human studies have explored CBD's antidepressant, anxiolytic, and antipsychotic effects, with promising results in some studies but inconsistent findings in others. Regarding substance use disorders, preclinical studies show CBD's potential in reducing craving and attenuating cue-induced drug seeking behavior for opioids, psychostimulants, tobacco, and alcohol, but clinical findings are mixed and require further research. Studies on insomnia have shown potential hypnotic and sedative effects. Oral CBD exhibits low bioavailability (6–19%) due to first-pass metabolism. Intravenous administration provides rapid, high systemic concentration but has rapid clearance. Sublingual/buccal routes offer faster absorption than oral but bioavailability varies. Pulmonary administration (MDI and DPI) demonstrates high bioavailability and rapid onset. Intranasal delivery provides rapid absorption and high bioavailability. Transdermal administration achieves sustained plasma concentration but has slower absorption.

The review highlights CBD's therapeutic potential in various brain disorders. However, the inconsistent findings across studies emphasize the need for further large-scale, well-designed clinical trials with standardized methodologies and outcome measures. The low bioavailability of oral CBD necessitates exploration of alternative delivery routes. The superior pharmacokinetic profiles of intranasal and inhalation delivery warrant further investigation and development of effective formulations for CNS disorders.

CBD shows promise in treating various brain disorders, but its low oral bioavailability necessitates alternative delivery methods. Intranasal and inhalation routes offer advantages in terms of rapid absorption, high bioavailability, and non-invasive self-administration, making them promising avenues for future research and development of CBD formulations for CNS disorders. Larger-scale and longer-term studies are needed to confirm the efficacy and safety of CBD across various applications and delivery methods.

The review relies heavily on existing literature, which may include studies with varying methodologies and sample sizes. The heterogeneity of study designs and outcome measures limits the ability to draw definitive conclusions about the effectiveness of CBD in specific disorders. Further research is needed to optimize CBD formulations for different delivery routes and to fully understand the long-term effects and potential risks of CBD.