Brian F. Thomas, Ph.D., Principal Scientist, RTI International

Cannabinoid pharmaceutical preparations are available in the United States and are regulated by the Food and Drug Administration (FDA) and the Drug Enforcement Administration (DEA). However, patients and recreational users can also obtain cannabinoid-containing medications and recreational products in herbal form or in Cannabis-derived dosage formulations through dispensaries and statewide programs. Medicinal Cannabis or Cannabis-derived products available in these dispensaries have not been approved for use by the FDA and are still considered Schedule I controlled substances by the DEA. Due to a lack of registration, documentation, inspection, and approval of these products by the FDA, there is public concern about their quality, reliability, and safety. Indeed, these products have been distributed without safety packaging, tamper resistance, or clear unit doses and have been inadvertently consumed by both children and adults who have become intoxicated or suffered adverse effects.^1,2

Individuals who visit dispensaries typically have access to several varieties of Cannabis that are distinguished through the use of popular names or a plethora of Cannabis-derived dosage formulations. It is often difficult to distinguish whether their relatively informal nomenclature and labeling are accurate or reflect any significant differences in chemical composition. If best practices are followed, the quality and reproducibility of the Cannabis plant material has been optimized through control of the seeds or rooted clones used and the growth conditions employed. For example, when grown indoors, systematic control of soil conditions, water, nutrients, temperature, and lighting conditions is possible and advantageous for maximizing yields and consistency in the content of chemical constituents. Specific methods used for harvesting, drying, manicuring, processing, and storing the inflorescence may vary but should be documented and adhered to as this can also have a significant impact on the chemical constituents. Even under ideal conditions, the cannabinoid acids undergo slow degradation to their decarboxylated forms and the terpenes and flavonoids can also isomerize, degrade, or suffer loss through evaporation.^3,4 While the product label cannot contain all of the relevant analytical information that is required to reflect that appropriate selection, processing, manufacturing, analytical characterization, and quality control of Cannabis-based dosage formulations has occurred, this information should be documented and retained in the form of a batch production record and certificate of analysis.

Proper analytical characterization and labeling is particularly important for the final Cannabis-derived products because many of the chemical constituents within the Cannabis plant may interact and contribute to their pharmacological activity and therapeutic potential. It has even been proposed that the development and therapeutic application of Cannabis-based medicines containing multiple cannabinoids, in defined ratios, and other non-cannabinoid fractions can provide better clinical utility than the single synthetic cannabinoid pharmaceuticals currently available.⁵ In this case, all clinically relevant constituents, and any excipients that have been added to the formulation or plant, should be analytically characterized, quantitated, and clearly identified and described on the label. Furthermore, since Cannabis is a natural product that can harbor a variety of pests and microbes, including harmful bacteria and fungi, careful analytical monitoring and quality control to preclude these potentially harmful contaminants from medicinal products is also a necessity. Unfortunately, even when chemical contents are provided on the label, the accuracy of the label has been questioned, and the nomenclature that is used to describe the chemical constituents can be unclear or lacking in sufficient detail. ⁶ For example, the phytocannabinoids in edible products may be referred to as “activated cannabinoids” to indicate that the biosynthetically-derived carboxylic acid forms of the phytocannabinoids in the product have undergone decarboxylation during manufacture. It is also often the case that a single dispensary distributes such a wide variety of products that it presents a considerable challenge for analytical characterization and proper quality control.

In order to ensure therapeutic utility and safety, the analytical methods used for the characterization of medicinal or recreational Cannabis products should ideally follow good manufacturing practices and use analytical reference standards and internal standardization to control for the recovery and quantitation of active ingredients. The analytical methods must be accurate, reproducible, stability indicating, and suitable for their intended use. The quantitative information on active ingredients should be provided in a clear and concise form on a properly reviewed and approved product label. Finally, the packaging should be appropriately secured and include a product insert with more detailed information regarding the ingredients, excipients, and the product’s pharmacology.

References

1. Berger, E. Biochim. Ann. Emerg. Med. 64(4), A19-21 (2014).

2. Potera, C. Am. J. Nurs. 115(9), 15 (2015).

3. Clarke, R.C. Ronin Publishing (1981).

4. Upton, R., Craker, L., ElSohly, M., et al. American Herbal Pharmacopoeia (2013).

5. Russo, E.B. Br. J. Pharmacol. 163(7), 1344-1364 (2011).

6. Vandrey, R., Raber, J.C., Raber, M.E., et al. JAMA 313(24), 2491-2493 (2015).