In 2015 the American Chemical Society (ACS) started their cannabis subdivision aptly called the Cannabis Chemistry Subdivision (CANN). Since that time, the CANN has been one of the world’s most trusted sources for up-to-date cannabis research. Covering topics ranging from cannabinoid pharmacokinetics, testing and analytical methods, dosage, formulation, risk assessment and many others. The regular symposia given by the society are highly attended professional gatherings where cannabis scientists from around the world are given the opportunity to showcase the research that their labs have been conducting. Here we will cover the first 4 of the 16 topics covered in the Fall 2020 symposia. 

Topics 1-4

Dr. Douglas spoke about the variety of compounds that are derived from cannabis and how an approach to safety and regulation could be achieved. The rapid expansion of the cannabis industry has led to the business and science of cannabis to outpace legislation in a lot of areas. No longer is it just Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD), product manufacturers are now including a wide range of cannabinoids such as cannabigerol (CBG), cannabinol (CBN), and Δ⁸-tetrahydrocannabinol (D8) in product formulation. This is just a short list as there are a wide number of cannabis derived compounds being introduced into products and many of them have yet to be fully evaluated in terms of safety. This leads to the question of how to regulate the growing number of compounds. 

The system that Dr. Douglas proposed is quite intuitive suggesting that classes of compounds be broken down in the following manner. 

• The least dangerous categories
  • Compounds made by the cannabis plant
    • This includes the acidic forms of the cannabinoids that are actually biosynthesized by the plant such as THCA, CBDA, CBGA, THCVA ect.
  • Compounds that are found in the cannabis plant
    • These are the “degradation” forms of the compounds that are the decarboxylated forms of the cannabinoids found in the plant in small quantities including THC, CBD, CBG and THCV
• The moderately dangerous categories
  • Compounds that are the same as the cannabis plant compounds that were fully synthesized in a lab
    • This group of compounds are synthetically produced versions of plant cannabinoids such as CBG, CBGA, THCV, CBL, CBC
    • Another group of compounds in this like plant category are cannabinoid salts that are plant cannabinoids that have been converted into ionic salts such as potassium tetrahydrocannabinolate KTHC and disodium cannabidiolate Na₂CBD
  • Another group of compounds in this category are the human metabolites
    • These are the compounds that the human body makes in metabolizing cannabinoids such as 11-hydroxy-tetrahydracannabinol (11-OH-THC) and 11-nor-9-carboxy-tetrahydracannabinol (THCCOOH)
• The most dangerous category
  • This category is reserved for all of the non plant cannabinoid analogues that are synthesized
    • These are compounds that started as plant cannabinoids but were synthetically altered in the lab in ways that create cannabinoid like compounds not found in plants or during normal human metabolism such as tetrahydrocannabinol acetate (THC-O-Ac) and hexahydrocannabinol (HHC)

This generalized breakdown of the variety of cannabinoids is useful in cataloging the vast number of cannabinoid compounds and their analogues. It also applies a systemic approach for researchers and regulation advisors to use when making strides towards advancing understanding and regulation of this rapidly growing industry. 

Doctors Rice and Lewandowski spoke about the analytical analysis of cannabis products and the importance of product testing protocols to ensure safety and proper regulation. Another effect of the cannabis industry outpacing the regulation of the industry shows in the area of cannabinoid testing. As the cannabis industry grows so do the number of products found on shelves as well as the number of different cannabinoids being marketed within these products. The 2018 US Agriculture and Improvement Act aka the 2018 Farm Bill has led to a flood of cannabinoids such as tetrahydrocannabivarin (THCV), cannabigerol (CBG), cannabichromene (CBC), and cannabidivarian (CBDV), being purified from hemp and used in various cannabis products. 

This growing list of cannabinoids when added to THC, CBD and the various acidic forms of the cannabinoids is becoming quite long as are the variety of products to which these cannabinoids are being added. Different products such as gummies, tinctures, edibles, vapes, salves etc. have wide ranging ingredients in them which affect the analytical process of testing the potency of these products. Each product will often need a specific approach to sample test prep in order to ensure reliable potency data. The combination of the varieties of cannabinoids along with the varieties of products creates varieties of problems for the analytical chemist. 

In addition to these problems however are the considerations of different test compounds. Potency testing is the most obvious need in the cannabis industry however it is only but one of many such testing needs. As cannabis plants are bioaccumulators testing for metals that may have come from the soil is also a very important test. As are tests for pesticides, microbes, mycotoxins which are important tests for agricultural crops. Also depending on the methods of extraction and purification used in the workup of the cannabinoids used during product manufacturing, residual solvents tests could be critical. 

Despite the wide range of testing considerations that must be undertaken, the lack of federal regulation in this regard leaves standardization difficult. States are often responsible for implementing testing regulations which can vary greatly from one state to the next. The overall lack of standards within the industry caused by this leaves many labs to develop their own lab techniques for the various tests that they perform. Developing a consensus approach to cannabis regulation opens the door for consistent nationwide testing standards and procedures. In time it will show that this is a necessary step to ensure the safety and reliability of the products manufactured in this industry. 

Doctors Mercolini and Protti discussed the changing European cannabis market and how it has driven analytical considerations for consumer products. The European cannabis market, like many cannabis markets around the world, is a rapidly expanding cannabis market. Also like many other cannabis markets around the world, the rapid growth is generating problems for regulators and product testing procedures alike. Having gotten to witness the expansion of the cannabis product market in the U.S., Europe is able to prepare for the growth of product variability with a sense of what might be coming as Europe is expected to become one of the world’s largest legal cannabis markets within the next five years. 

Yet despite the continual growth of the legal and medicinal cannabis markets in Europe, seizures of cannabis still account for over ⅓ of all drug seizures in the EU. While currently the majority of the European cannabis market is still raw cannabis flower and hashish, refined extraction methods leading to higher purity concentrates are becoming more popular for use in a range of cannabis products. To optimize therapies utilizing cannabis it is important to have a strong approach to analytical quantification of the active ingredients is imperative. 

The best way to obtain accurate analytical information is to combine advanced separation strategies along with state of the art testing instrumentation. The overall chemical matrix of each product will determine the effectiveness of extracting the cannabinoids from the product into the test sample for proper quantification of the active ingredients. For this, procedures for sample development must take into consideration not only all of the active ingredients within the sample matrix, but all of the inactive ingredients as well since they will be important in separating the cannabinoids from the rest of the chemical mixture. 

Advanced separation is just part of the problem and must be paired with quality instrumentation as well. Typical sample analytical practices will use some type of chromatography, usually high pressure liquid chromatography. When these chromatography practices are combined with a process called mass spectrometry however the results become more detailed and reliable. The addition of mass spectrometry allows for further delineation between the analytes present in the test sample. When combining the best instrumentation with the best analytical procedures allows for consistency and reliability which in turn lead to the safest cannabis products. 

Dr. Sarma presented on the United States Pharmacopeia USP considerations with regards to the varieties of cannabis inflorescence used in medical studies. The increased use of cannabis based therapies presents a wide range of regulation and quality control considerations. As such the FDA recently drafted a guidance to help drive the industry called “Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research.” Similarly the USP has also formed a Cannabis Expert Panel to evaluate the obstacles facing the growing industry from a science and regulatory standpoint. One of the key obstacles that industry professionals, scientists, and regulators alike must deal with stems from the fact that cannabis is a highly varied species with a large number of different strains.  

As the botanical names for the Cannabis species were being developed, the biologist Jean Baptiste Lamark divided the Cannabis species into two subspecies C. sativa subsp. sativa and C. sativa subsp. indica, where the fiber types of cannabis grown primarily in Europe were designated as C. sativa subsp. sativa,  and the psychoactive types grown throughout Afghanistan as well as the central and southern parts of Asia were designated C. sativa subsp. indica. While the terms sativa and indica stuck, a consistent use of the words did not. Currently indica and sativa are used very commonly but with no consistent meaning. This problem is further exacerbated by the fact that many cannabis strains are hybrid strains that have not been fully backcrossed to create genotypically or phenotypically reliable cultivars. What this means is that two different plants that even have the same strain name can have wildly different characteristics. As you can imagine, when it comes time to designate precise therapeutic values it becomes nearly impossible. 

In light of these complications, the USP has proposed a new method of classifying the various subtypes of cannabis. The method suggested by the USP is a rather intuitive classification system when considering the current industry climate and regulations. It is a chemotype method of classifying cannabis varieties that relies on categorizing cannabis types by their major chemical components. The three main subcategories suggested by the USP are: CBD Dominant, THC Dominant, and CBD:THC mixtures. These three categories would then be further broken down based on their relative ratios of other key compounds such as other cannabinoids, terpenes, and flavonoids. There is a clear benefit to this methodology when trying to group the different cannabis varieties based on the overall effect that the cannabis type might display on the body. Problems with this method however arise when looking at newer cannabis strains that have been developed to express CBG primarily instead of CBD or THC. 

Arora, Nigam B., and Jacqueline L. von Salm. “Fall 2020 Proceedings of the Cannabis Chemistry Subdivision.” ACS Chemical Health & Safety (2021).