Re: Breeding Cannabis Chemovars for Patients Requiring Distinct Chemical Profiles for Optimum Efficacy

Lewis MA, Russo EB, Smith KM. Pharmacological foundations of cannabis chemovars. Planta Med. March 2018;84(4):225-233. doi: 10.1055/s-0043-122240. Proper exposition requires definition, certainly the case in the longstanding debate over cannabis (Cannabis sativa, Cannabaceae) speciation. Authors briefly introduce the ongoing dispute between followers of Fuchs (1542 CE) and Linnaeus (1753) and those of Lamarck (1783) and Schultes (1974). Lamarck described the putative "C. indica" and has been followed by proposed “compromise” naming like "C. afghanica,' "C. ruderalis," etc. If one holds that a species includes all plants capable of reproduction with each other, there is no debate. Cannabis is quite variable in height, branch density, leaf width, seed size, organoleptic and chemical traits, but all cannabis plants can interbreed. Nonetheless, "Sativa" and "Indica," especially, have entered the popular lexicon, used even in medical cannabis dispensaries to denote the reputed differences in effect. A plethora of "strain" names – more properly varieties or cultivars, despite the illegality of the plant in the United States* – from old-school "Acapulco Gold" to the newer "Cinderella 99" are sought for both medical and recreational use. Division into cannabinoid profile types (Type I, predominantly containing tetrahydrocannabinol [THC]; Type II, with both major cannabinoids, and Type II, predominantly containing cannabidiol [CBD]) has become widespread but lacks specificity. Other methods of reliably distinguishing among cannabis plants have been proposed but none have found broad acceptance. The authors recommend the term "chemovars" for cannabis plants, and introduce a patent-pending method, PhytoFacts, to distinguish among them. In furtherance of this, they conducted an advanced Mendelian breeding program to maximize yields of cannabinoids and terpenoids, and thus cannabis' efficacy. Samples of about two dozen established, hybridized genotypes from this program were analyzed for appearance, content, and, by patient panels, subjective qualities including aroma, flavor, and "entourage" (synergistic) effects of cannabis terpenoids. As many as 200 terpenoids in cannabis occur in the same glandular trichomes of unfertilized female flowers that produce phytocannabinoids. Their production is based on genetic rather than environmental factors. Cannabis terpene synthases are reported to be "promiscuous" in creating substrates, but mechanisms of terpene regulation in cannabis remain to be described. About 50 terpenoids are routinely found in North American chemovars, with 17 common and eight predominant (myrcene, terpinolene, ocimene, limonene, α-pinene, humulene, linalool, and β-caryophyllene.). All of those discussed are generally recognized as safe (GRAS) for human consumption and/or are approved as food additives. Many have been extensively studied for pharmacological effects. Myrcene, for example, "far and away" the most prevalent terpene in chemovars in the United States and Europe at the time of this report, produces sedating effects. α-Pinene, with energizing effects, inhibits acetylcholinesterase, possibly benefiting learning and memory. It is possible to grow Type I, II, and III plants with almost the same terpenoid content but varying effects due to different cannabinoid levels. Sequential trials could offer optimal symptom control with the least adverse effects (AEs). It is noted that many potential indicators of specific chemovars may be cited but have not been studied in randomized controlled clinical trials (RCTs) and require further study. For example, α-pinene's inhibition of acetylcholinesterase may be enhanced, negated, or overshadowed by THC's anticholinergic effects; in the presence of 1,8-cineole and camphor it may be enhanced synergistically. If shown in well-designed RCTs to reduce negative effects of THC on short-term memory, α-pinene could find use in cannabis treatment for dementia, where THC is already known to reduce agitation. A chemovar with linalool, limonene, and β-caryophyllene might be used in conditions as diverse as burns and epilepsy. PhytoFacts reports assign an alpha-numeric heading to each chemovar. A bar graph shows relative proportions of the top three terpenes in the sample. Below that, another graph shows proportions of total cannabinoids, total terpenoids, and moisture, alongside basic data like plant part ("Type") tested, harvest and test dates, and sample and test identifiers. The next panel shows proportions of the top two cannabinoids in a circle graph, a photo of unfertilized female flowering parts for authentication, and a list of all cannabinoids detected to ±0.05% of dry weight. The next panel shows results of patient groups in a spider graph of 10 aromas and flavors (e.g., sweet, spicy, piney) and a pie chart of five entourage effects (e.g., energy, calm, relaxation). The final panel shows percentages of all terpenoids detected to ±0.01%. Developed to help the cannabis industry analyze, sort, and recommend chemovars using laboratory results, PhytoFacts will not resolve the speciation dispute but could render it practically irrelevant. It will be interesting to see how the system develops, including access to and criteria for inclusion, and resolving identification of duplicate chemical profiles. —Mariann Garner-Wizard *Under international plant nomenclature rules, cultivars must be registered varieties, but most cannot be registered since they are illegally grown in the United States. Similarly, voucher specimens of cannabis may not be deposited in US herbaria except under stringent licensing and storage conditions.