In June 2018, the U.S. Food and Drug Administration (FDA) approved Epidiolex, a CBD oral solution.
Don’t take CBD oil if you’re pregnant or breastfeeding. The American Academy of Pediatrics advises pregnant women to avoid marijuana because of the potential risks to a baby’s development. Although the effects of CBD itself are unclear, CBD does pass through the placenta.
The way that CBD acts in the brain can explain why this happens. In low doses, CBD may act the same as surrounding molecules that normally bind to the receptor, which "turns up" their signaling.
Possible Side Effects
However, CBD affected each type of addiction very differently.
THC is what's responsible for the psychoactive effects of cannabis—in other words, what makes you feel "high." CBD oil generally doesn't have THC, although trace amounts might be in products sold in certain states.
There’s some evidence CBD interacts with seizure medicines like Onfi (clobazam) and boosts their concentration in the blood. More research is needed, though.
Capsules, gummies, and sprays are easier to dose, although they tend to be more expensive.
Results: Eight patients completed the study. On average Cmax was 14 times and AUC0-∞ 4 times higher in the fed state. The 90% CI for the ratio of fed versus fast conditions for Cmax and AUC0-∞ were 7.47-31.86 and 3.42-7.82, respectively. No sequence or period effect for Cmax and AUC0-∞ was observed. No adverse events were reported.
Methods: Adult patients who were prescribed CBD for seizures, had localization-related intractable epilepsy with ≥4 seizures per month, and qualified for Minnesota cannabis were enrolled. A single dose of 99% pure CBD capsules was taken under both fasting (no breakfast) and fed (high fat 840-860 calorie) conditions. Blood sampling for CBD plasma concentrations was performed under each condition between 0 and 72 hours post-dose and measured by a validated liquid chormatography-mass spectometry assay. CBD pharmacokinetic profiles including maximum concentration (Cmax ), area-under-the-curve from zero to infinity (AUC0-∞ ), and time-to-maximum concentration (Tmax ) were calculated. The confidence intervals (CIs) for log-transformed Cmax and AUC0-∞ ratios between fed and fasting states were calculated. Seizure and adverse events information was collected.
Objective: To evaluate the pharmacokinetics of a purified oral cannabidiol (CBD) capsule administered with and without food in adults with refractory epilepsy.
Significance: Administering CBD as a capsule rather than a liquid allows for more precise determination of pharmacokinetics parameters and is more representative of CBD swallowed products. The fat content of a meal can lead to significant increases in Cmax and AUC0-∞ and can account for variability in bioavailability and overall drug exposure within patients with oral products.
Keywords: CBD; cannabidiol; epilepsy; food-effect; pharmacokinetics.
Entresto™ is an example of a drug–drug cocrystal containing monosodium sacubitril and disodium valsartan used to treat chronic heart failure that has obtained FDA approval. PK studies demonstrated a mean relative bioavailability of 161% in the cocrystal form of valsartan compared to reference valsartan tablets . The cocrystal demonstrates high solubility and medium permeability. Suglat ® is another marketed cocrystal, comprised of the sodium glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin and L-proline, approved in Japan for the treatment of diabetes mellitus. The third cocrystal currently on the market is Depakote ® , an anti-convulsant drug, which is comprised of valproate sodium with valproic acid .
Interest and progress in the concept of cocrystallisation have expanded over recent years and is becoming a well-established process in drug development. Cocrystals consist of the API and one or more unique crystalline co-formers which modify the material properties whilst retaining the intrinsic pharmacological drug activity. Cocrystallisation is a useful method for overcoming problematic properties of drugs by increasing the bioavailability, solubility, dissolution rate, physical form, melting point, tableting, stability, or permeability of drug substances [82,83,84]. Further advantages of crystal preparations include the potential for numerous co-molecules including preservatives, other APIs, and pharmaceutical excipients, as well as providing the opportunity to address intellectual property issues by extending API life cycles and fulfilling patent eligibility criteria .
A sublingual formulation by Diverse Biotech Inc., and an oral liquid by Emerald Health Pharmaceuticals containing a pure synthetic CBD are both in early clinical phases (see Table 1 ).
Complexation of CBD with cyclodextrins (CD) has also been investigated as a potential method to increase the water solubility and subsequently improve the bioavailability of sublingually delivered CBD. Mannila and colleagues demonstrated precipitation complexation of CBD and β-CD at a 1:2 ratio could increase the water solubility of CBD and increase the dissolution rate . The authors noted sublingual delivery of the CBD/β-CD complex produced superior bioavailability compared to oral dosage forms of CBD in rabbits. However, in this study, CBD delivered in an ethanol solution sublingually was comparable to sublingual delivery of the CBD/β-CD complex. Two formulations of CBD and CDs are currently in development by Medexus pharmaceuticals and Vireo health LLC. These companies propose complexes of CBD and CDs will increase the aqueous solubility and subsequently improve bioavailability. However no clinical studies have been performed using these exact formulations to date.
3.2. Solid-State Delivery Formulations
Cannabidiol (CBD) is a phytocannabinoid used globally for a variety of indications, but with few approved medicinal applications. Purified CBD is only licensed in treatment-resistant, rare paediatric forms of epilepsy [1,2,3,4,5]. Ongoing clinical trials are being conducted in potential indications such as anxiety, schizophrenia, addiction, post-traumatic stress disorder, graft-versus-host disease, cancer and inflammatory bowel disease. The United States (US) Food and Drug Administration and the European Medicine Agency approved drug formulations containing CBD include Epidiolex ® (a pure CBD oral solution) and Sativex ® (a CBD and Delta-9-tetrahydrocannabinol (THC, 1:1) oromucosal spray), both developed by GW pharmaceuticals.
Although the methodology is not clear from publicly available information, Echo Pharmaceuticals and Ananda Scientific are also investigating formulations which claim to enhance bioavailability and consistency in PK profiles by increasing CBD’s water solubility; Ananda’s Liquid Structure™ Enhanced CBD and Echo Pharmaceutical’s Arvisol, using their lipophilic compound delivery technology Alitra ® . Both compounds are in preclinical or early clinical phase 1 development (see Table 1 ).
Solid-state oral delivery allows for 100% of the drug to reach the GI tract and has the potential to improve PK characterisation [76,77]. CBD delivered via this route would also further avoid local side effects associated with use of Sativex oromucosal spray (1:1 CBD:THC) or GI discomfort or pain associated with the vehicle itself in oral liquid formulations . Current investigated solid-dose oral formulations of CBD include a 200 mg CBD tablet by Columbia Care called BeneCeed™, which will be used in a UK clinical trial. Elsewhere, a patent by GW pharmaceuticals lists a solid-state CBD as a potential clinical consideration in the treatment of inflammatory bowel disease . Whilst dosing in this fashion ensures a consistent dose, formulations of this nature do not necessarily address problems associated with poor bioavailability.
3.1. Self-Emulsifying Drug Delivery Systems
In order to be successfully utilised as a medicine, it is paramount to identify and overcome the inherent challenges that face CBD’s effective delivery, particularly through the oral route, which is the most preferred route for drug delivery by patients and drug developers. Some of the most significant issues with oral CBD include poor bioavailability, variable pharmacokinetics profiles, and possible polymorphisms , which may have unintended consequences of less predictable efficacy, increased side effects and drug–drug interactions with higher doses. This review will outline some of the current issues with CBD pharmaceutics, the novel CBD formulations under development and under clinical investigation, and the strategies to improve CBD delivery and efficacy.
Some researchers claim to have improved the single crystal form of CBD. For example, one patent listed describes a crystalline CBD of a novel form, including (R,R)-(−)-crystalline cannabidiol . This crystalline form was shown to possess a melting point of 37–50 °C, compared with a melting point of 66–67 °C for CBD. Intramolecular crystal lattice binding between ions within a crystal affects its melting point and reductions in lattice energies may increase aqueous solubility . PureForm CBD™ is described as a molecularly identical, non-hemp-based CBD that has been developed using their Inter-Molecular Stacking Technology to improve solubility and stability . There is no further publicly available information on these products.