Cannabis and cannabinoid drug development: evaluating botanical versus single molecule approaches
Marcel O. Bonn-Miller, Mahmoud A. ElSohly, Mallory J. E. Loflin, Suman Chandra and Ryan Vandrey
International Review of Psychiatry, 2018, VOL. 30, NO. 3, 277–284
Doi : 10.1080/09540261.2018.1474730
Accumulating evidence suggests that the endocannabinoid system is a promising target for the treatment of a variety of health conditions. Two paths of cannabinoid drug development have emerged. One approach is focused on developing medications that are directly derived from the cannabis plant. The other utilizes a single molecule approach whereby individual phytocannabinoids or novel cannabinoids with therapeutic potential are identified and synthesized for pharmaceutical development. This commentary discusses the unique challenges and merits of botanical vs single molecule cannabinoid drug development strategies, highlights how both can be impacted by legalization of cannabis via legislative processes, and also addresses regulatory and public health considerations that are important to consider as cannabinoid medicine advances as a discipline.
KEYWORDS : Cannabis; marijuana; drug development; THC; CBD; medical marijuana
Cannabis has a long history of use in medicine, dating back thousands of years, and has been used historically to treat a variety of ailments such as asthma, depression, epilepsy, fatigue, glaucoma, insomnia, migraine, nausea, pain, rheumatism, and tetanus (Doyle & Spence, 1995; Zuardi, 2006). However, a wide-spread political movement in the early 20th century resulted in prohibition of cannabis use throughout the developed world. Subsequent to this prohibition, western medical practices transitioned from reliance on botanical extracts and tinctures to a pharmacopeia predominantly comprised of single molecule therapeutics and the establishment of rigid regulations regarding the review and approval of new medications in a highly competitive and lucrative drug marketplace.
In the time since cannabis prohibition, a lot has been discovered with regards to the chemical
constituents of the cannabis plant and their pharmacology. Researchers in Israel identified D9-Tetrahydrocannabinol (D9-THC) as the primary psychoactive agent in the cannabis plant in the mid- 1960s (Mechoulam & Gaoni, 1967). This discovery led to extensive research on cannabinoids in the 1970s, which also coincided with renewed interest in potential therapeutic effects of cannabinoids. In 1985, a synthetic formulation of THC (dronabinol) and a synthetic analogue of THC (nabilone) were approved by the US Food and Drug Administration for the treatment of nausea and vomiting associated with cancer chemotherapy. They were subsequently also approved for the treatment of anorexia associated with weight loss in patients with acquired immunodeficiency syndrome (AIDS). This progression followed the established model of western medicine in which individual chemical constituents of plants historically used in medicine are isolated and then developed into proprietary medications.
In 1996, however, a twist in this saga began when the US state of California legalized the medicinal use of botanical cannabis by its residents. Over the past 20 years, an increasing number of countries, states, and territories have followed suit, legalizing the medicinal use of cannabis for a variety of health conditions. This is important because it is a unique example in medicine where: (1) a new medication is introduced to the market via legislation rather than through formal drug development practices, and (2) we see a reversal of the trend towards single molecule drug development in favour of the use of raw botanical products. The caveat here is that cannabis has long been used as an intoxicating drug in the absence of medical need, and most of the organizations that successfully lobbied to legalize medicinal use of cannabis have since acknowledged that medical cannabis legalization was a stepping stone to getting cannabis legalized for non-medicinal purposes as well. However, at the time of this writing, a British pharmaceutical company (GW Pharmaceuticals, Cambridge, UK) has successfully brought a medication derived from raw cannabis (SativexVR ; a blend of extracts high in THC and high in cannabidiol (CBD) in a roughly 1:1 ratio) to market in several countries through the currently accepted drug development process, rather than via legislation, and a second product (EpidiolexVR ; a botanically derived CBD extract) is currently in review for US regulatory approval as a new therapeutic in the treatment of rare seizure disorders. Thus, it seems clear that both cannabis and isolated cannabinoids hold tremendous therapeutic promise, but it also begs the question: Should medication development efforts be focused on botanical or single molecule drug development?
This question is of interest because there are several important nuances to each approach that complicate the answer from both regulatory and scientific perspectives. Moreover, in conversations related to the medicinal use of cannabis/cannabinoids there seem to be strong ideological beliefs among patients, physicians, and caregivers where there is a heavy bias towards only considering use of either botanical cannabis products or pharmaceutical cannabinoids. There are also a number of popular misconceptions (detailed below) associated with the two approaches that require better public education as cannabinoid medicines becomes more commonplace. The aim of this paper is to provide a broad commentary on cannabinoid drug development. It is not intended to serve as a systematic review, nor will we be making recommendations for the use of cannabinoids for specific health conditions. Rather, we will detail why we believe there is renewed interest in cannabis as a botanical medication, as well as specifically discuss the merits and drawbacks of both single molecule and botanical drug development approaches as means of maximizing the promise of therapeutics targeting the cannabinoid system in medicine. To achieve this, contributors on this paper include world experts in cannabinoid drug development. Dr Marcel Bonn-Miller and Dr Mallory Loflin contributed from the perspective of clinical development of single molecule cannabinoid medications. Dr Bonn Miller is a cannabinoid researcher at the University of Pennsylvania Perelman School of Medicine with expertise in single molecule cannabinoid drug development. Dr Loflin is a clinical psychologist and cannabinoid researcher at the San Diego Veterans Affairs Healthcare System. From the perspective of botanical drug development, Dr Mahmoud ElSohly and Dr Suman Chandra of the National Center for Natural Products Research at the University of Mississippi have contributed, each of whom have spent decades researching the cannabis plant and its therapeutic potential. As editor of the issue, Dr Vandrey conceptualized this paper, helped integrate the input of the other contributors, and also contributed to content related to both perspectives.
Cannabis vs cannabinoids
This section provides an important background with respect to important definitions, nomenclature, and pharmacology that will be referenced later. The cannabis plant has been shown to be chemically rich,
with 565 known constituents belonging to 23 classes of compounds (ElSohly & Gul 2014; ElSohly & Slade, 2005; Radwan, Wanas, Chandra, & ElSohly. 2017). Perhaps the most recognized class of compounds in cannabis are the namesake cannabinoids. At the time of this writing, 120 different phytocannabinoids, plant-derived molecules unique to cannabis, have been identified in the cannabis plant, many of which directly modulate the endogenous cannabinoid system. These naturally occurring cannabinoids are distributed among 10 sub-classes, including D9- and D8-THC, cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), Cannabinodiol (CBND), cannabielsoin (CBE), cannabicyclol (CBL), cannabitriol (CBT), and miscellaneous type (30 known). THC is produced as an acid (D9-Tetrahydrocannabinolic acid, D9-THCA) in the glandular trichomes of the leaves and inflorescence bracts of the plant and undergoes decarboxylation with age or heating to form D9-THC (Turner, ElSohly, & Boeren, 1980). THC is typically the most abundant chemical constituent of the cannabis flower, and is by far the most studied and well-understood cannabinoid. However, cannabinoids are not the only active components of cannabis. Other constituents that might contribute in some way to the effects of cannabis include Terpenes (120 known); Nitrogenous compounds (33 known); Amino acids (18 known); Proteins, enzymes, and glycoproteins (11); Sugars and related compounds (34); Hydrocarbons (50 known); Simple alcohols (7 known); Simple aldehydes (12 known); Simple ketones (13 known); Simple acids (20 known); Fatty acids (27 known); Simple esters and lactones (13 known); Steroids (15 known); Non-cannabinoid phenols (25 known); Flavonoids (27 known); Vitamins (1 known); Pigments (2 known); Elements (9 known); Phenanthrenes (4 known); Spiroindans (2 known); Xanthones (1 known), and Biphenyls (1 known).
In addition to plant-derived phytocannabinoids, hundreds of exogenous synthetic cannabinoids have
been synthesized and characterized. These include pharmaceutical-grade synthetically derived substances that are chemically identical to the phytocannabinoids found naturally in the cannabis plant (e.g. dronabinol, an oral formulation of synthetically derived D9-THC, and ZYN002, a transdermal synthetic CBD gel produced by Zynerba Pharmaceuticals), in addition to novel molecules not found in nature (e.g. WIN 55,212-2, JWH-018, AM-2201, AMB-FUBINACA). There are two common mis-conceptions we often hear related to synthetic vs naturally occurring phytocannabinoids.
One is that there are differences in the effects of a single molecule phytocannabinoid (e.g. CBD)
based on whether it is synthetic vs plant derived. This should not be the case, as chemistry is an exact science with respect to chemical composition and structure. The circumstances under which this could be true with respect to botanical cannabinoid products vs synthetic products would be limited to cases in which one of the two substances contains impurities that contribute to the overall pharmacological or toxicological effect, or due to inappropriate designation of synthetically derived isomers as being true replications of naturally derived cannabinoids. In these cases, the differences would be due to impure extraction of botanically sourced cannabinoids or missteps in the synthesis of the cannabinoid.
The other common misconception is that synthetic cannabinoids not found naturally in cannabis are more harmful than phytocannabinoids. This largely stems from the ongoing problems associated with illicit sales of synthetic CB1 full agonists (Fattore & Fratta, 2011; Vandrey, Dunn, Fry, & Girling, 2012). The potential harm associated with any newly-synthesized drug is directly tied to its pharmacological effects (pharmacology, receptor specificity and affinity, potency) in the body. Indeed, one advantage of pursuing drug development of botanical cannabis or synthesized phytocannabinoids is that the cannabis plant has a very well established and positive safety profile.
Both phytocannabinoids and synthetic cannabinoids can directly impact the endocannabinoid system
via a variety of pharmacological mechanisms, including agonism, antagonism, and allosteric modulation (for detailed reviews of cannabinoid pharmacology see Pertwee, 2008; Pertwee et al., 2010). Although 120 phytocannabinoids have been identified, they are finite and somewhat limited with respect to pharmacological interaction with the endocannabinoid system. Because of this, there are clear advantages of focusing on single molecule synthetic cannabinoid drug development, simply due to the fact that medicinal chemists are able to systematically modify known cannabinoid molecules in order to target very specific pharmacological effects. This type of ‘fine tuning’ has the potential to yield medications that have a very specific mechanism of action (e.g. full agonism of CB1 receptors outside the CNS), which might both improve therapeutic efficacy and reduce adverse effects compared with phytocannabinoids such as THC, which is neither selective to a specific cannabinoid receptor subtype, nor limited with respect to crossing the blood–brain barrier.