How Analytical Testing Can Help Optimize Cannabis as a Medicine

Many parts of the world have used cannabis as a medicine for thousands of years, but we have only truly begun to understand the mechanisms by which cannabis provides relief in the last century. Much of the evidence currently available is anecdotal or preclinical, which is insufficient for demonstrating true efficacy in humans. Furthermore, while we now have a decent grasp of the basics of cannabis pharmacology there are still many areas that are severely lacking. In order for cannabis to gain mainstream acceptance by medical practitioners, we will still need to answer many questions with human trials for a number of conditions.

A Brief History of Cannabis Chemistry and Endocannabinoid System Pharmacology

Our fundamental understanding of the chemistry of cannabis came about from the research of Roger Adams and Professor Raphael Mechoulam. Mechoulam was the first to isolate and structurally identify tetrahydrocannabinol (THC) while Adams was the first to achieve this for cannabidiol (CBD)^1-2. The next leap in our understanding came from the work of Dr. Allyn Howlett and Dr. William Devane who identified the first cannabinoid receptor CB1^3. The work of Munro et al. followed which identified the second cannabinoid receptor CB2 based on the similarity of its amino acid sequence to CB1⁴. Naturally, the discovery of the endogenous ligands for these receptors, the endocannabinoids, followed⁵.

Knowing the principal psychoactive components and their primary targets then led researchers to question why different cannabis varieties produced certain effects that could not be explained by cannabinoid content. The first clue came from the work of Dr. Ben-Shabat et al. who observed that inactive fatty acid glycerol esters had a significant effect on enhancing the effects of the endocannabinoid 2-AG at cannabinoid receptors⁶.

In line with this idea, researchers Dr. John McPartland and Dr. Ethan Russo postulated that there are other compounds in cannabis besides the cannabinoids that contribute to its overall effects. McPartland and Russo’s 2001 paper “Cannabis and Cannabis Extracts: Greater than the sum of their parts” set the stage and “Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects” followed offering possible pharmacological mechanisms by which terpenes and other compounds could augment the effects of cannabinoids^7-8. Their theories seem to have merit based on the bulk of cannabis sold at dispensaries today. The majority of it is dominant in THC with minuscule amounts of CBD and other cannabinoids, yet each type can vary wildly in terms of effect with some producing couch-lock and sedation while others are energetic and upbeat.

However, this still doesn’t complete the picture. There are other responses elicited by cannabis that we cannot ascribe to the pharmacological actions of CB1 and CB2. This prompted researchers to search for additional clues. Specifically, in the last two decades, researchers have identified additional receptors where cannabinoids exert action such as GPR3, GPR6, GPR18, GPR55, and GPR119 ^9-12.

What is still missing from the picture?

Many cannabis companies have tried to harness these insights to recreate the effects of cannabis flower in other products. A classic example of this is cannabis vape pens where a bouquet of terpenes, often from non-cannabis sources, are added to blank slate THC distillate in an attempt to reintroduce what is naturally found in the flower. While these vape pens are flavorful, they are often limited to a handful of the dominant terpenes and often fail to reproduce the full therapeutic effects of the flower.

There is mounting evidence that still more compounds exist that produce additional therapeutic benefits such as flavonoids, some of which are unique to cannabis¹³. There may even be other compounds that have not yet been characterized that may contribute to the ensemble. Other compounds of potential interest include steroids, esters, spiroindans, and unique nitrogenous compounds. More in-depth metabolomic work across numerous cannabis varietals is likely to provide some additional insight as to which agents in cannabis are responsible for these subtleties.

How does this translate into medical practice?

With all of the new information that is being gleaned about the science of cannabis, it is tempting to jump to conclusions based on preliminary evidence and anecdotes. However, in medicine, therapies must be proven in clinical trials using relevant populations before cannabis as a medicine can gain wide acceptance. At present, there is a lack of such trials due to the legal status of cannabis in the US at the federal level and in most other developed countries.

Trials that have been conducted typically use isolated compounds and refined formulations rather than whole plant medicines or botanical drug substances. And, cannabis medicines from whole plants have often been demonstrated to be superior in the context of many maladies^14-15. A caveat to this is that cannabinoid pharmacokinetics is complex and not easily predicted in highly variable and complex mixtures such as tinctures and extracts¹⁶. In light of this, it is crucial that cannabis medicines be produced in a standardized and repeatable fashion to obtain the desired clinical outcome.

In the absence of such validation, patients and practitioners alike are left to piece together the currently available information to make educated guesses. While not ideal, this is acceptable for minor ailments. But, when dealing with severe illness, a treatment misstep can be a matter of life and death. This makes it extremely urgent that such trials take place.

The lack of product standardization further compounds the difficulties of using cannabis as a medicine. Analytical testing can help pinpoint products that are likely to be safe and have a beneficial effect. However, it’s not always as cut and dry as reading a COA (certificate of analysis) to arrive at these conclusions. Special attention must be paid to those whose immune systems are compromised to ensure complications do not arise. Moreover, at this point in time, we still don’t know all of the details of every variable that contributes to cannabis’ efficacy as a medicine, therefore, more research is needed.

References

1. Adams, R., Hunt, M., and Clark, J. (1940) Structure of cannabidiol, a product isolated from the marihuana extract of Minnesota wild hemp. I. J. Am. Chem. Soc. 62, 196–199.
2. Gaoni, Y. and Mechoulam, R. (1964) Isolation, structure and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc. 86, 1646–1647.
3. Devane WA, Dysarz FA, Johnson MR, Melvin LS, Howlett AC. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol. 1988;34(5):605-13.
4. Munro S, Thomas KL, Abu-shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365(6441):61-5.
5. Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258(5090):1946-9.
6. Ben-shabat S, Fride E, Sheskin T, et al. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur J Pharmacol. 1998;353(1):23-31.
7. John M. McPartland DO, MS & Ethan B. Russo MD (2001) Cannabis and Cannabis Extracts, Journal of Cannabis Therapeutics, 1:3-4, 103-132, DOI: 10.1300/J175v01n03_08
8. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163(7):1344-64.
9. Laun AS, Song ZH. GPR3 and GPR6, novel molecular targets for cannabidiol. Biochem Biophys Res Commun. 2017;490(1):17-21.
10. Mchugh D, Page J, Dunn E, Bradshaw HB. Δ(9) -Tetrahydrocannabinol and N-arachidonyl glycine are full agonists at GPR18 receptors and induce migration in human endometrial HEC-1B cells. Br J Pharmacol. 2012;165(8):2414-24.
11. Lauckner JE, Jensen JB, Chen HY, Lu HC, Hille B, Mackie K. GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proc Natl Acad Sci USA. 2008;105(7):2699-704.
12. Irving A, Abdulrazzaq G, Chan SLF, Penman J, Harvey J, Alexander SPH. Cannabinoid Receptor-Related Orphan G Protein-Coupled Receptors. Adv Pharmacol. 2017;80:223-247.
13. Appendino, G, et al. Cannflavins from hemp sprouts, a novel cannabinoid-free hemp food product, target microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase, PharmaNutrition, Volume 2, Issue 3, 2014, Pages 53-60
14. Gallily, R., Yekhtin, Z., and Hanuš, L. (2015) Overcoming the Bell-Shaped Dose-Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol. Pharmacology & Pharmacy, 6, 75-85. 
15. Pamplona FA, Da silva LR, Coan AC. Potential Clinical Benefits of CBD-Rich Extracts Over Purified CBD in Treatment-Resistant Epilepsy: Observational Data Meta-analysis. Front Neurol. 2018;9:759.
16. Eichler M, Spinedi L, Unfer-grauwiler S, et al. Heat exposure of Cannabis sativa extracts affects the pharmacokinetic and metabolic profile in healthy male subjects. Planta Med. 2012;78(7):686-91.