The World of Cannabis Research

The cannabis field keeps reinventing itself and seems always ripe for innovation

Paola Cubillos, M.D, N.D | Scientific Lead - Procannacol

This is a sector that is maturing rapidly and is always open to create, develop and implement the next best thing, being a new product to open a new market segment or a new process that brings efficiencies and competitive advantage. Such break-neck innovation speed is a consequence of the critical mass: as more consumers and patients globally become aware of cannabis uses, its potential therapeutic benefits and its versatility, the opportunities for companies and developers to deliver, through research and innovation, the products consumers want are endless

Diversifying the Adult-use market 

The term Innovation has obviously penetrated the cannabis space, and companies, both in the medicinal and wellness markets work relentlessly to find and create a niche for their products, appeal to consumers through creative solutions as they respond to the ever-changing regulatory and commercial landscapes. The world has witnessed an explosion of novel and innovative cannabis delivery methods, such as vaping devices, both for dry flower and oil-based, a wide range of edibles, from chocolates, sublingual strips, soft chews, and to sparkling water and infused beverages.

In the adult-market scenario, there is one attribute that companies desire their products to have to ensure consumer loyalty: to deliver a “consistent experience”. Some cannabis companies believe that ensuring a consistent cannabinoid/terpene/flavonoid composition in their final products is sufficient to improve the reliability of the effects their products elicit, however, taking into account issues such as delivery and bioavailability of the different cannabis derived compounds as important variables still scapes most cannabis producers. Industry trends tend to be ahead of science. 

Pushing the frontiers of knowledge  

Addressing issues of pharmacokinetics, bioavailability, and the interplay between compounds of interest and potential genetic polymorphisms are inherent components of the pharmaceutical development processes. Finding ways to optimize absorption, delivery and stability of compounds known to inherently pose challenges in these areas, such as cannabinoids, which are highly lipophilic with very low aqueous solubility, and are susceptible to degradation by light and temperature, is essential to position cannabinoids as legitimate therapeutic agents.  The cannabinoid du jour, cannabidiol or CBD, favoured by new cannabis consumers and used in a wide range of cannabis edibles, is known to have poor bioavailability, slow time to peak plasma concentration after oral administration, and a prominent first-pass metabolism. Therefore, it becomes imperative to problem-solve most of these issues, through innovative approaches, to ensure consistent effects. 

The lipophilic nature of cannabinoids render them suitable for development through nanotechnology, a method already used in traditional medication delivery, which enables increased bioavailability, targeted delivery and a reduction of side effects [1]

Lately, the cannabinoid research world has seen the arrival of nanosized, liposomal, and micellar formulations for both topical and systemic preparations, which contain CBD exclusively, a combination of CBD and delta-9-THC, terpenes, and that are either lipid based or polymer based. Bruni and colleagues provide a comprehensive overview of the publicly known formulations that have utilised this technology, and that are in different stages of development, from stability to clinical studies [2]. 

Many opportunities ahead, many challenges too

In an effort to overcome the challenges when dosing cannabidiol, companies are resorting to strategies such as delivery through self-emulsification, single crystal structures and co-crystals.  In their 2020 paper, Millar et. al. compiled a list of different CBD formulations under development by commercial companies [3]. Self-emulsification delivery systems produce micro-sized droplets that upon contact with the aqueous environment, they emulsify under mild agitation conditions, such as those found in the gut [4]. As explained by Millar and Colleagues, co-crystallization increases bioavailability, solubility, stability and permeability, among other features. Co-crystals include the active pharmaceutical ingredient (API) and other crystalline co-formers, which modifies the material properties but maintains the pharmacological activity [3]

Through pulmonary administration, several of the issues pertaining to oral administrations are circumvented. This delivery route is known to be effective, it has a fast onset of action and high systemic bioavailability, therefore it is thought to play a role in the treatment of certain conditions such as cancer pain. To tackle the unmet pain control needs of patients with cancer cachexia, the canadian biotechnology company, Tetra Bio-Pharma has developed a cannabinoid-derived inhaled medicine that uses synthetic THC and CBD, and has partnered with the device manufacturer Storz & Bickel, to make their vaporizer device part of a kit that is to be evaluated under a clinical trial, and that will be subsequently reviewed by the FDA as a drug/device combination product, a unique move for the medical cannabis industry. 

A road towards synthetic?

Researching and bringing to market plant derived cannabinoids continue to be a challenge, due to the already highlighted issues as well as the many regulatory hurdles producers have to face. One way to mitigate some of these issues, while maintaining the desired pharmacological effects of cannabinoids is through the development of synthetic cannabinoids. While some cannabis connoisseurs hold the view that “natural is always better”, the science does not support the view that naturally derived, single-molecule cannabinoids act any differently that their synthetic counterparts [5]. Dr. Raphael Mechoulam, during a scientific conference in 2019, announced having pioneered a production method of fully stable synthetic cannabinoid acid-based molecules. According to the research conducted by Mechoulam and colleagues, the methyl ester form of cannabidiolic acid has a greater therapeutic potential than the conventional plant derived cannabinoids. A recent study showed that initiating treatment of a peripheral nerve injury with cannabidiolic acid methyl ester at an early stage post‐surgery provides anti‐nociception in Sprague–Dawley males rats. [6]

The path forward

As the market grows, so do the opportunities and obligations to utilize all the tools at our disposal to create top-quality cannabis and cannabinoid based products. Whether naturally-derived or synthetic, these must respond to the wishes of the seasoned and inexperienced cannabis consumers, and must also satisfy patients’ needs for consistent, targeted products that meet all safety and efficacy requirements. It is only this way that the capabilities of cannabinoids, including the rare and minor cannabinoids like CBN and CBG, as therapeutic or recreational agents will be fully realized. Fostering the creation of safe products that are based on sound science, products that exceed the regulatory challenges, and creative products that follow relentless ingenuity, the industry will reach the next frontier. 

Conflict of Interest declaration

Dr Cubillos received an unrestricted research grant from Bwellmed Colombia SAS, received travel fees and speaker’s fees from Canopy Growth, and received honorarium as a contractor from CB2 Insights.

References 

1. Conte R, Marturano V, Peluso G, Calarco A, Cerruti P. Recent Advances in Nanoparticle-Mediated Delivery of Anti-Inflammatory Phytocompounds. Int J Mol Sci. 2017;18. doi:10.3390/ijms18040709

2. Bruni N, Della Pepa C, Oliaro-Bosso S, Pessione E, Gastaldi D, Dosio F. Cannabinoid Delivery Systems for Pain and Inflammation Treatment. Molecules. 2018;23. doi:10.3390/molecules23102478

3. Millar SA, Maguire RF, Yates AS, O’Sullivan SE. Towards Better Delivery of Cannabidiol (CBD). Pharmaceuticals . 2020;13. doi:10.3390/ph13090219

4. Knaub K, Sartorius T, Dharsono T, Wacker R, Wilhelm M, Schön C. A Novel Self-Emulsifying Drug Delivery System (SEDDS) Based on VESIsorb Formulation Technology Improving the Oral Bioavailability of Cannabidiol in Healthy Subjects. Molecules. 2019;24. doi:10.3390/molecules24162967

5. Bonn-Miller MO, ElSohly MA, Loflin MJE, Chandra S, Vandrey R. Cannabis and cannabinoid drug development: evaluating botanical versus single molecule approaches. Int Rev Psychiatry. 2018;30: 277–284.

6. Zhu YF, Linher-Melville K, Niazmand MJ, Sharma M, Shahid A, Zhu KL, et al. An evaluation of the anti-hyperalgesic effects of cannabidiolic acid-methyl ester in a preclinical model of peripheral neuropathic pain. Br J Pharmacol. 2020;177: 2712–2725.