Current Therapeutic Cannabis Controversies and Clinical Trial Design Issues

Content is from Frontiers in Pharmacology as seen on NCBI – PCM

Is there a pathway that will lead to the return of cannabis to mainstream medicine? The answer is clear, inasmuch as it has already commenced. It follows the same time-honored process that any pharmaceutical must attain to receive regulatory approval: proof of biochemical uniformity and stability along with safety and efficacy as proven by randomized clinical trials (RCT).

A prescription cannabis product must be standardized, consistent and display a quality equal to any New Chemical Entity that has passed muster as a pharmaceutical (Russo, 2006a; Russo et al., 2015). It must also possess a practical and suitable delivery system that minimizes patient risk, including intoxication, other aspects of drug abuse liability (DAL) or serious adverse events, such as pulmonary sequelae. An additional requirement is a supply chain that ensures security that it is being distributed to its intended target patients.

The status quo of cannabis medicine for most patients still involves the black market with its myriad risks and inherent lack of quality control. In the future, the desirable alternative would be a safe and effective evidence-based pharmaceutical solution that physicians prescribe with confidence, that pharmacists endorse and supply, and that government health services and third party payers will cover.

Garden variety cannabis as bought on the street cannot meet these criteria nor gain regulatory approval in most nations of the world. The biochemical variability of one chemovar to another is a primary challenge, while unregulated material may harbor pesticide residues, molds, bacteria, or heavy metals that endanger public health. The most common delivery system, smoking, imposes similar risks: chronic cough, phlegm production, bronchitis, and inhalation of pyrolytic by-products (Tashkin, 2013). Cannabis inhalation, whether by smoking or vaporizer produces a rapid peak in serum and brain concentrations that maximizes intoxication and possible reinforcement that are risk factors for DAL (Schoedel et al., 2011). Other routes of administration, e.g., transdermal patches and rectal suppositories have not yet demonstrated practicality in later stage clinical trials (Huestis, 2007).

A cannabis delivery system with reliable intermediate onset, allows dose titration without pulmonary dangers, relieves symptoms, and is biochemically uniform and defined would engender confidence of all parties. The first preparation to fulfill these criteria, currently in 27 nations around the globe, is nabiximols (US Adopted name, also known as Sativex®), an oromucosal spray produced from whole cannabis extracts whose effects begin in 15–40 min, allowing a therapeutic window for control of symptoms without intoxication. In reality, patients are not seeking altered states from their medicine, but rather relief of pain or other complaints. Other cannabis-based medicines that follow will necessarily be required to meet similar benchmarks.

It is the widespread belief of most scientists and many legal scholars that the only viable solution to the issues of medicinal cannabis is a pharmaceutical approach. Only in this way are regulatory standards fulfilled, and patient desires satisfied in safety. Such an approach can remove the current clandestine atmosphere surrounding cannabis and promote the kind of open and mutual therapeutic doctor-patient relationship, while maintaining legal status. Political efforts at legalization in certain American states and various countries will necessitate wrestling with issues of pharmaceutical cannabis preparations as compared to allowable claims in a less regulated market for herbal preparations.

While cannabis is usually thought of in relation to THC content, and its agonistic effects at the CB1receptor, it requires emphasis that humans express individual endocannabinoid tone, that may be deficient under certain conditions, as has been suggested in migraine, fibromyalgia, and irritable bowel syndrome (Russo, 20042016a), or alternatively may be excessive in obesity and metabolic syndrome (Kunos, 2007). Beyond THC, other cannabis components such as cannabidiol and tetrahydrocannabivarin act as neutral antagonists at CB1 (McPartland et al., 2015) that along with dietary manipulations with prebiotics and probiotics portend to provide potential treatment interventions for the latter (Russo, 2016b).

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