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cbd oil clinical trials

Cannabidiol (CBD) has been recently covered in the media, and you may have even seen it as an add-in booster to your post-workout smoothie or morning coffee. What exactly is CBD? Why is it suddenly so popular?

CBD may offer an option for treating different types of chronic pain. A study from the European Journal of Pain showed, using an animal model, CBD applied on the skin could help lower pain and inflammation due to arthritis. Another study demonstrated the mechanism by which CBD inhibits inflammatory and neuropathic pain, two of the most difficult types of chronic pain to treat. More study in humans is needed in this area to substantiate the claims of CBD proponents about pain control.

How is cannabidiol different from marijuana?

Side effects of CBD include nausea, fatigue and irritability. CBD can increase the level in your blood of the blood thinner coumadin, and it can raise levels of certain other medications in your blood by the exact same mechanism that grapefruit juice does. A significant safety concern with CBD is that it is primarily marketed and sold as a supplement, not a medication. Currently, the FDA does not regulate the safety and purity of dietary supplements. So, you cannot know for sure that the product you buy has active ingredients at the dose listed on the label. In addition, the product may contain other (unknown) elements. We also don’t know the most effective therapeutic dose of CBD for any particular medical condition.

CBD is readily obtainable in most parts of the United States, though its exact legal status is in flux. All 50 states have laws legalizing CBD with varying degrees of restriction, and while the federal government still considers CBD in the same class as marijuana, it doesn’t habitually enforce against it. In December 2015, the FDA eased the regulatory requirements to allow researchers to conduct CBD trials. Currently, many people obtain CBD online without a medical cannabis license. The government’s position on CBD is confusing, and depends in part on whether the CBD comes from hemp or marijuana. The legality of CBD is expected to change, as there is currently bipartisan consensus in Congress to make the hemp crop legal which would, for all intents and purposes, make CBD difficult to prohibit.

CBD stands for cannabidiol. It is the second most prevalent of the active ingredients of cannabis (marijuana). While CBD is an essential component of medical marijuana, it is derived directly from the hemp plant, which is a cousin of the marijuana plant. While CBD is a component of marijuana (one of hundreds), by itself it does not cause a "high." According to a report from the World Health Organization, "In humans, CBD exhibits no effects indicative of any abuse or dependence potential…. To date, there is no evidence of public health related problems associated with the use of pure CBD."

Through a series of discussions, six (6) common challenges were identified as the main barriers/issues faced when submitting clinical trials involving cannabis medicines to Human Research Ethics Committees (HREC) and regulatory authorities (such as Research Governance Offices (RGO) in Australia) for review and approval. These include (1) considerations when selecting cannabis medicines products, (2) accurate dosing and administration, (3) adverse events, (4) drug-drug interactions, (5) consent and (6) post-trial access to cannabis medicine products.

Does the product meet Good Manufacturing Practice (GMP) and current Federal and State regulations (such as the Therapeutic Goods (Standard for Medicinal Cannabis) (TGO 93) in Australia [3, 4])?

Considerations when selecting cannabis medicines products in the trial setting

Therapeutic Goods Administration. Guidance for the use of medicinal cannabis in Australia: overview 2017 [updated December 2017. 21/12/2017:[Available from: https://www.tga.gov.au/publication/guidance-use-medicinal-cannabis-australia-overview.

Therapeutic Goods Administration. Access to medicinal cannabis products [Internet]. 2020. [cited 07 August 2020]. Available from: https://www.tga.gov.au/access-medicinal-cannabis-products-1.

Special Access Scheme

While this review’s focus is on the current uses of Epidiolex and similar formulations, there is a wide-spread issue of private companies forming nutraceutical blends of CBD with various carrier oils, terpene mixtures, and additives that are being used to treat various conditions without any clinical evaluation. While the main ingredient, CBD, has been proven numerous times to be well-tolerated in a wide range of patients suffering from various ailments, there still presents a public danger of unregulated products being distributed without any clinical information about these mixtures.

While Dr. Leehey’s study suggested improvements in cognition, depression, and emotional issues associated with PD, another group investigated the anti-psychotic effects of CBD in a small group of PD patients with psychosis (n=6) (Zuardi, 2008; Zuardi et al., 2009). Zuardi’s group investigated the efficacy, tolerability and safety of CBD in psychotic patients with PD through an open-label 4-week pilot study. They gave a first dose of 150 mg/day and then increased the dose by 150 mg/day each week for the remaining three weeks for a maximum dose of 600 mg/day during the fourth week. Serial neurological and physical assessments in the study found that CBD did not worsen motor symptoms or contribute any notable side effects, but it did significantly decrease psychosis symptoms (Zuardi, 2008; Zuardi et al., 2009).

Pre-clinical research has reported that there may be promise in patients with treatment-resistant seizure disorders, the CDKL5 deficiency disorder, or Aicardi, Dup15q, and Doose syndromes; however, due to the variability in dosage between these studies, we aim to focus only on completed clinical trial data (Devinsky et al., 2018; Szaflarski et al., 2018). Another company, INSYS Therapeutics Inc. (Phoenix, AZ), has also funded Phase 1 and 2 clinical trials to investigate a non-plant-based cannabidiol oral solution at various dosages to treat resistant seizure disorders in pediatric patients (ages 1–17). Dosages of 10, 20, and 40 mg/kg/day were provided to 20, 20, and 21 patients, respectively. This study mainly aimed to provide the pharmacokinetics of CBD, as well as the safety and dosing information; however, they did report decreases from the baseline number of seizures. Specifically, there was a reduction of tonic seizures per day and a reduction of atonic seizures per day for the respective dosing groups. While there were no serious adverse effects and non-serious adverse events were observed including anemia (10%, 25%, and 19.05%), somnolence (15%, 15%, and 33.3%), and flatulence (14.29%) in the 40 mg/kg/day dosing group (INSYS Therapeutics Inc, 2016; Parikh, 2018).

Table 1

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

CBD is one of more than 120 naturally occurring cannabinoids found in Cannabis sativa L. (ElSohly and Slade, 2005; Brenneisen, 2007; Radwan et al., 2009; Fischedick et al., 2010; Andre et al., 2016; Park et al., 2019) Various CBD formulations have been tested in pre-clinical studies to have diverse medicinal properties, such as anti-nausea, anti-emetic, anti-tumor, anti-inflammatory, anti-depressant, anti-psychotic, and anti-anxiolytic; however, the variance in drug formulations used and limited sample sizes reduce the applicability of these studies in clinical applications (Costa et al., 2006; Parker et al., 2011; Micale et al., 2013; Kucerova et al., 2014; Micale et al., 2015; Bogdanović, 2017; Rock and Parker, 2017; Sumanasekera et al., 2018; Fonseca et al., 2018; Stark et al., 2019). Epidiolex (GWP42003-P) is a colorless to yellow strawberry-flavored tincture that contains 100 mg/ml of plant-derived CBD and less than 0.3% of THC(A) (Guy et al., 2014). This low-abuse and addiction potential formulation is generally well tolerated in most patients, and has a proven long-term safety profile (Schoedel et al., 2018; Laux et al., 2019). The most common side effects of Epidiolex include “somnolence; decreased appetite; diarrhea; transaminase elevations; fatigue, malaise, and asthenia; rash; insomnia, sleep disorder, and poor quality sleep; and infections”, in addition to causing mild to severe hepatic impairment in some trials (GW Biosciences, 2018; Taylor et al., 2018).

Clinical trials results from epidiolex-focused studies.

Clinical trial results from Epidiolex-focused studies: The table summarizes the results from the currently completed clinical trials that have tested Epidiolex’s efficacy against various conditions. The % symptom reduction is reported as the percentage of patients in the treatment group to report improvement in the treatment of their condition. Similarly, the % of adverse effects refers to the total percentage of treatment group patients that reported any adverse effect. The sample size describes the number of patients that have completed the clinical trial currently.