There is no dispute that cannabis is a complex plant often used as a botanical drug, food, food ingredient, and textile. With no federal oversight, regulatory bodies of the now 29 United States and the District of Columbia where cannabis is legal in some form, are tasked with ensuring product safety to their constituents. Most states require finished product testing by the International Organization for Standardization and the International Electrotechnical Commission (ISO/IEC) 17025 accredited laboratories. Laboratory accreditation to ISO/IEC 17025 represents a laboratory’s commitment to develop protocols to ensure quality practices are implemented and includes the attestation of their competence by an independent third party. Whenever possible or when mandated, analytical labs rely on published consensus and standard test methods or to validate their modifications to such methods to perform the necessary work. Although standard methods are in development by scientific organizations such as AOAC International and ASTM, as of this writing there is not a single published compendial or consensus method for the most typical assays used in the cannabis industry. This article discusses basic principles of quality assurance and laboratory accreditation, and the current status of voluntary methods in development. A final intent of this article is to provide unique insight into the challenges associated with testing cannabis amidst the federal prohibition.
Although the FDA has approved Marinol and Syndros, which are single-compound synthetic forms of Δ9-tetrahydrocannabinol, for certain medical conditions including nausea from chemotherapy and weight loss associated with AIDS (20), they have also clearly stated that there is no medical condition approved for the prescription of cannabis and there are no (botanical) cannabis or cannabis-derived drugs available to date (20). The FDA does, however, provide a pathway forward for cannabis drug development by supporting the Agricultural Act of 2014, which permits universities and state agriculture departments to cultivate cannabis for the explicit purpose to research its industrial potential (17). This paper refrains from discussion on cannabis drug development and the medical utility or medical safety of cannabis, and instead focuses on the characteristics of the raw or finished product.
Of the 29 states and the District of Columbia, all but five require some degree of laboratory analysis of finished products, including dried flower. Unlike other commodities such as food and feed, cannabis is afforded no federal regulatory oversight and hence, no regulated target values of analytes. Where cannabis use is legal, most regulatory divisions or jurisdictions require some degree of third-party testing ranging from minimal to exhaustive analytical profiles. Typical protocols include, for example, identification and quantitation of select cannabinoids, determination of solvent residues, qualitative or quantitative determination of mycotoxins, as well as the identification and quantitation of pesticide residues, quantitation of moisture, water activity, heavy metals analysis, identification of microorganisms, and various fungi. Product testing such as this is not new to analytical laboratories. In fact, many large-scale manufacturers (for example, food, feed, pharmaceutical, and tobacco) have quality assurance labs within their production facilities tasked to ensure that products are developed and manufactured according to specification before release for public distribution. In industries like pharmaceuticals and food, however, testing is required by a regulatory body like the FDA or the Food Safety and Inspection Service (FSIS) under the US Department of Agriculture to ensure products are accurately tested without bias, providing consumers confidence in their products.
Challenges to Ensuring Cannabis Product Safety
Laboratories testing cannabis and cannabis-infused products are challenged on several fronts. First and perhaps foremost, this complex (15) plant itself comprises nearly 500 compounds, at least 100 of which are cannabinoids, 120 terpenes, and dozens of flavonoids (22-24). By their very nature, many of the cannabis compounds are likely to interact with one another (15), requiring keen attention to component stabilities. Concentrations of constituents are inconsistent between structures within a single plant (such as flower, leaf, or stem) (22,25), which is further complicated when different cannabis strains are commingled and (theoretically) homogenized. This implies that sampling and subsampling are the most critical steps in testing. Further, cannabis plant material is prone to degradation and subsequent reactions (24), thus representing a dynamic and complex system where identification of single constituents is challenging at best, even under ideal conditions. Depending on the extraction technology used, the process may facilitate sample-product degradation. For example, cannabinoids are carboxylated in their natural state and may decarboxylate when processed in a mechanical grinder. Furthermore, Hazecamp and colleagues reported that some cannabinoids may be oxidized and isomerized while in the gas chromatography (GC) injector port and column, well before the sample reaches the oven (25).
The Lack of Certified Reference Standards for Laboratory Proficiency Tests
Analytical testing laboratories in most industries rely on the use of high-purity and well-characterized reference materials, preferably certified reference materials (CRM) accredited to the International Organization for Standardization and the International Electrotechnical Commission (ISO/IEC) 17034 (formerly ISO/IEC Guide 34) to validate analytical test methods. Currently there are more than a dozen cannabinoid CRMs available through several providers. The rigor of CRM formulation is susceptible, however, to timely and strict environmental conditions and processing to avoid in situ deterioration during manufacture, and then in the laboratory following purchase.
In most industries, third-party testing laboratories participate in commercially available proficiency test (PT) or interlaboratory comparison (ILC) programs as indicators of analytic competence. Many industries, including food and feed, purchase commercially available PT schemes that are accredited to ISO/IEC 17043, representing the most rigorous material characterization. Although there are differences between PT and ILC schemes, the intent of both is to provide a laboratory the opportunity to compare test results of a specified sample with the results of other participating laboratories. Presently, there are no accredited PT schemes available for the cannabis industry, nor is there an ILC program that utilizes a representative cannabis sample. Simply stated, this void exists because cannabis products cannot be legally shipped across state boundaries. Consequently, cannabis laboratories resort to purchasing commercial products that are essentially reference materials prepared at concentrations to accommodate legal transfer across state lines. With no method guidelines and no real extraction to perform, these samples are often referred to as “dilute and shoot” mixed proficiency samples. The resulting data represent an interlaboratory comparison of each laboratory’s skill at recovering the analytes of interest. It is noteworthy that there is no cannabis plant reference material with well characterized analytes and no clean surrogate that could be enhanced with cannabinoid CRMs to provide a realistic determination of laboratory proficiency.
- M. Booth, Cannabis: A History (St. Martin’s Press, New York, 2005).
- E. Russo, H.E. Jiang, X. Li, A. Sutton, A. Carboni, F. del Bianco, G. Mandolino, D.J. Potter, Y. Zhao, S. Bera, Y. Zhang, E. Lu, D.K. Ferguson, F. Hueber, L. Zhao, C. Liu, Y. Wang, and C. Li, J. Exp. Bot. 59(15), 4171-4182 (2008).
- L.L. Iversen, The Science of Marijuana (Oxford University Press, New York, 2008).
- E.B. Russo, in Handbook of Cannabis, R.G. Pertwee, Ed. (Oxford University Press, New York, 2014), pp. 23-43.
- V. Angelova, R. Ivanova, V. Delibaltova, and K. Ivanov, Industrial Crops and Products 19(3), 197-205 (2004).
- S. Mukherjee, The Public Domain Review, Retrieved January 15, 2018 from https://publicdomainreview.org/2017/04/19.
- US Pharmacopeia, 3rd Edition. Retrieved January 15, 2018, from http:antiquecannabisbook.com/view.timeline.php.
- D.F. Musto, Scientific American 20-27 (July 1991). Retrieved from https://faculty.unlv.edu.
- Federal Food and Drugs Act of 1906 (The “Wiley Act”), Public Law Number 59-384, 34 STAT.768 (1906), 21 USC Sec 1-15 (1934). Retrieved from www.fda.gov/regulatoryinformation/lawsenforcedbyFDA/ucm148690.
- H.R. 18583, 91st Congress of the United States (1970).
- United States Drug Enforcement Administration. Drug Scheduling. Retrieved from www.dea.gov/druginfo/ds.
- National Academies of Sciences, Engineering, and Medicine, The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research (The National Academies of Press, Washington, DC, 2017). Doi:10.17226/24625.
- V. DiMarzo, D. Melck, T. Bisogno, and L. De Petrocellis, Trends in Neurosciences 21, 521-528 (1998).
- J.M. Cole, Deputy Attorney General. Memorandum for all United States Attorneys (August 29, 2013). Retrieved January 10, 2018 from www.mpp.org/federal/cole-memo.
- B.T. Yeh, The Controlled Substances Act: Regulatory Requirements (2012). Retrieved January 15, 2018 from https://fas.org/sgp/crc/mis.
- Federal Drug Administration Food Safety Modernization Act of 2011. Retrieved January 15, 2018 from https://www.fda.gov/food/guidanceregulations/fsma.
- US Food and Drug Administration, Good Laboratory Practices. Retrieved January 30, 2018: www.fda-glp.com (FDA, Rockville, Maryland).
- US Food and Drug Administration, Facts about Current Good Manufacturing Practices. Retrieved January 30, 2018: www.fda.gov/drugs/development/approvalprocess/manufacturing (FDA, Rockville, Maryland).
- International Conference on Harmonization, Harmonised Tripartite Guideline, Guideline for Good Clinical Practice, E6(R1) (ICH, Geneva, Switzerland, 1996).
- US Food and Drug Administration, FDA and Marijuana: Questions and Answers. Retrieved January 30, 2018: www.fda.gov/newsevents/publichealthfocus (FDA, Rockville, Maryland).
- H.R. 2642, 130th Congress of the United States, 2nd Session (2014).
- M.A. ElSohly, and D. Slade, Life Sciences 78, 539-548 (2005).
- G.A. Cabral, E.S. Raborn, and G.A. Ferreira, “Phytocannabinoids and the Immune System,” in Handbook of Cannabis, R.G. Pertwee, Ed. (Oxford University Press, New York, 2014), pp. 261-274.
- U. Pagotto, G. Marsicano, D. Cota, B. Lutz, and R. Pasquali, Endocrine Reviews 27(1), 73-100 (2006).
- M.A. ElSohly, in Emerging Issues in Analytical Chemistry, B.F. Thomas, Ed. (Elsevier, Amsterdam, The Netherlands, 2016).
- A. Thompson and V. Langfield, in Handbook of Cannabis, R.G. Pertwee, Ed. (Oxford University Press, New York, 2014), pp. 356-372.
- M. Backes, Cannabis Pharmacy (Black Dog & Leventhal Publishers, New York, 2014).
- M. Starks, Marijuana Chemistry (Ronin Publishing, Inc., Berkeley, California, 1990).
- A. Hazecamp, A. Peltenburg, R. Verpoorte, and C. Giroud, Journal of Liquid Chromatography & Related Technologies 28, 2361-2382 (2005).
- International Laboratory Accreditation Cooperation (ILAC). Retrieved January 20, 2018 from www.ILAC.gov.
- International Organization for Standardization. (1994). Quality management and quality assurance - vocabulary (ISO Standard No. 8402).
- E. Pritchard and V. Barwick, Quality Assurance in Analytical Chemistry (Wiley Publishers, West Sussex, UK, 2007).
- M.E. Swartz and I.S. Krull, Handbook of Analytical Validation (CRC Press, Boca Raton, Florida, 2012).
- AOAC International. Retrieved January 29, 2018: www.aoac.org/aoac_prod_imis/APAC/AB/AOAC.
- ASTM International, The History of ASTM International. Retrieved January 29, 2018: www.astm.org/about/history_book.
- American Oil Chemists’ Society, History of AOCS. Retrieved January 29, 2018: www.aocs.org/info/about-aocs/history-of-aocs.
- US Pharmacopeia, Our History. Retrieved January 29, 2018: www.usp.org/about.
How to Cite This Article
S. Audino, Cannabis Science and Technology 1(1), 14-20 (2018),