Phytocannabinoids: Regulators Turn to Science

Background

After the enactment of the Controlled Substance Act (CSA) in 1970 [3], for many years it was very simple for researchers, as well as law officers, to determine which cannabis materials were DEA Schedule I (C-I), as practically all parts of the cannabis plant, as well as all cannabinoids and their derivatives, were controlled under those regulations. Although cannabis roots and stems are specifically excluded from the CSA definition of “marijuana,” when the state of Oregon began issuing licenses in 2009 to cultivate fiber-type cannabis plants within the state, the legality of those activities began to be questioned as that state law was at odds with federal law [4]. In an earnest effort to allow states to develop industrial hemp programs, Congress subsequently enacted the 2014 Farm Bill to allow the cultivation of hemp varieties of cannabis plants under pilot programs by institutions of higher learning to develop agricultural and processing methods that could enable commercial production of industrial hemp products, such as fiber for textiles, as well as seeds and oil as foods. However, the language of the 2014 Farm Bill was subject to contradictory interpretations that led to clashes between federal and state regulators [5]. To address those issues that were hindering the growth of a major agricultural industry, the 2018 Farm Bill established a specific definition of hemp and removed it from the list of DEA controlled substances [6].

The 2018 Farm Bill defined hemp as cannabis plants and all derivatives containing less than 0.3% delta-9 THC based on dry weight. This precise legal definition of hemp did indeed spur increased hemp production in the US, but not only did the law increase production of industrial hemp for traditional uses, it also opened the doors for development of novel hemp products that contain cannabinoids intended for therapeutic purposes. The first hemp-based cannabinoid products to appear on the market were cannabidiol (CBD) preparations, as this cannabinoid was well characterized for its therapeutic properties and low potential for abuse. Following the growing market for non-intoxicating CBD products, the hemp industry utilized the language of the 2018 Farm Bill to also justify marketing intoxicating products, such as those containing substantial amounts of delta-8 THC, a cannabinoid that provides a user very similar psychoactive effects as delta-9 THC. It is quite reasonable that the authors of the 2018 Farm Bill may have disregarded the possibility of a psychoactive cannabinoid that occurs naturally in the plant in very small concentrations, such as delta-8 THC, could be utilized commercially. The word “derivatives” in the 2018 Farm Bill, though, unintentionally provided a convenient loophole because CBD isolated from hemp can be readily converted to delta-8 THC through chemical processes. Thus, the new definition of hemp and the regulatory specifics of FY2026 AAA are intended to clarify the regulatory status of cannabis products based on the intrinsic characteristics of their cannabinoid ingredients.

Purpose

Representatives of federal agencies must consider many factors to determine the regulatory status of various cannabinoids so that research may progress as directed in the Executive Order (EO-14370) issued in December 2025 [7]. This directive mandates an update to the statutory definition of final hemp-derived cannabinoid products that will eventually provide a regulatory pathway to improve access to safe therapies while restricting the sale of products that pose serious health risks. A key factor in the regulatory process is valid scientific evidence about the identity of cannabinoids that occur naturally in the plant, and which cannabinoids may or may not have significant potential for abuse.

The term “phytocannabinoids” distinguishes the class of cannabinoids that occur naturally in the plant from other compounds that have similar molecular structures, such as synthetic analogs of the natural cannabinoids, and the endogenous cannabinoids that may be present in the human body. At this time, over 130 phytocannabinoids have been reported by researchers worldwide over the past sixty years. While the major phytocannabinoids such as THC and CBD are well known, minor phytocannabinoids such as cannabinol (CBN), cannabichromene (CBC), cannabigerol (CBG), cannabidivarin (CBDV) and tetrahydrocannabivarin (THCV) are now gaining attention as possible candidates for treatments of various disorders with products that may provide safer and more effective treatments with the least potential for abuse. Furthermore, those traditionally known “minor” cannabinoids may appear at much higher concentrations in selected chemovars which have been developed by selective breeding or genetic modifications.

The regulations resulting from the recent legislative actions will definitively clarify the regulatory status of cannabinoids and cannabis-based final products because it is well known that the DEA regulatory status of materials used in research studies is a major factor in the design and execution of studies involving cannabis. Researchers can readily abide by the controlled substance regulations for any type of study if those regulations are clear, whether involving Schedule I or Schedule III materials, or materials not DEA controlled.

Fundamental Challenges

Scientists and officials may face challenges when interpreting the findings in technical literature due to the complex chemistry of the cannabis plant and the intrinsic characteristics of cannabinoids. In an ideal world governed by chemists, the nomenclature that describes any chemical compound would reflect the chemical structure of the compound without ambiguity. But in the real world of cannabis chemistry the complexity of the molecular structures of cannabinoids presents challenges to chemists and laymen alike as various systems of chemical nomenclature have been utilized in scientific literature to describe and characterize cannabinoids and related compounds. Today’s chemists who compile information on cannabinoids for scientific review must present their findings systematically to avoid any confusion.

Environmental factors during the growing cycle of the cannabis plant certainly affect cannabinoid metabolism within the plant, as does the genetic predisposition of cannabis varieties which may be manipulated to increase the concentrations of certain cannabinoids for commercial use. Additionally, the normal plant processing procedures, such as drying and storage, can alter the cannabinoid profile of bulk plant material. For example, the rate of conversion of delta-9 THC-acid to delta-9 THC that occurs after harvest over time will occur more rapidly under high temperature conditions. Although the compounds normally present in harvested and processed plant materials are considered as naturally occurring cannabinoids, artifacts that may occur in minute quantities during laboratory analysis may be very difficult to characterize as such.

While the chemical synthesis of new cannabinoid-like compounds will inevitably occur in institutional research laboratories (as well as in backroom clandestine labs), the scheduling of synthetic cannabinoids is not directly addressed by the FY2026 AAA. The regulatory status of cannabinoids produced synthetically, both novel molecules and duplicates of phytocannabinoids, will be addressed during the rule making processes scheduled by the April Final Rule issued by DEA [8]. Perhaps as analytical technologies evolve and new cannabinoids are discovered, the results of the current rule making processes will provide a basis for informed decisions by regulators.

Sources of Data

Considering that classical records of the medicinal and psychoactive properties of cannabis were recorded first over 3,000 years ago, the enormity of information on cannabis science that has been recorded since THC was identified in 1964 as the major psychoactive compound in the plant is not surprising [9]. Because review articles on cannabis chemistry and pharmacology present comprehensive overviews of relevant literature, these peer-reviewed publications are often the starting point for a research project, such as the assessment of known cannabinoids for regulatory evaluation. The 2021 review, “Cannabinoids, Phenolics, Terpenes and Alkaloids of Cannabis,” is a thorough literature review article that includes graphical chemical structures and discussions of the methods of identification for 125 phytocannabinoids, as well as 42 phenolics, 34 flavonoids, 120 terpenes, and 2 alkaloids that naturally occur in the cannabis plant [10]. Each of the 113 references cited in the paper was validated by the authors to ensure the accuracy of the reported compounds and to standardize the nomenclature and chemical structures. The authors present 2D diagrams that indicate stereochemical orientations and group the compounds by chemical classes and subclasses to convey similarities in molecular structures. Since the publication of Radwan, et al in 2021, several additional phytocannabinoids have been reported [11,12,13].

While the intrinsic nature of individual cannabinoids and their molecular structures may be readily demonstrated through valid chemical data reported in peer-reviewed articles, the evaluation of the psychoactive effects of individual cannabinoids may require the judicious review of data from multiple sources, including reports of interventional clinical studies in humans, observational studies in humans, studies in laboratory animals, and in-vitro receptor binding assays [14]. In the 2024 review article, “A critical assessment of the abuse, dependence and associated safety risks of naturally occurring and synthetic cannabinoids,” the authors collated evidence from published clinical and non-clinical studies to evaluate the abuse, dependence, and associated safety risks of many cannabinoids [15]. The authors present data that includes benefit/risk analyses, relative receptor affinities, and pharmacological profiles to confirm that THC and other psychoactive cannabinoids have moderate reinforcing effects, including withdrawal syndrome as well as intoxicating and cognitive properties.

An example of the extensive effort required to identify and characterize a newly discovered phytocannabinoid is demonstrated in the 2019 study, “A novel phytocannabinoid isolated from Cannabis sativa L. with an in vivo cannabimimetic activity higher than Δ9-tetrahydrocannabinol: Δ9-Tetrahydrocannabiphorol.” [16] The authors report the discovery of naturally occurring tetrahydrocannabiphorol (THCP) that they found to be much more psychoactive than delta-9 THC. The scientists isolated and purified THCP from dried plant material, elucidated the structure by spectroscopic methods, and replicated the THCP molecule through chemical synthesis to unambiguously confirm the chemical structure as a long side-chain analog of THC. The team then utilized in-vitro assays to measure the binding affinity to human receptors CB1 and CB2 which was followed by in-vivo behavioral assays in mice.

Conclusion

The enactment of the FY2026 AAA in November 2025, which was intended to address public health concerns by amending the statutory definition of hemp, was followed in December by EO-14370, which reiterates the need for a regulatory framework that will improve access to hemp-derived products and to inform standards of care for the safe use of those products. Federal agencies proceeded to gather the relevant scientific information necessary to go forward with rule making processes that will potentailly impact the hemp industry while protecting public health and safety.

While the catalogs of naturally occurring cannabinoids that are generated through federal agency collaborations are currently accurate, new developments must be reported to the agencies. R3CR will fulfill its role as a comprehensive repository of information for cannabis researchers and regulators by continuing to disseminate to federal agencies and to the research community any new cannabinoid discoveries and experimental findings that are relevant to regulatory issues.

Acknowledgements

We extend special thanks to Dr. Mahmoud ElSohly, Dr. Mohamed Radwan, and Dr. Suman Chandra for sharing insights into cannabis chemistry and pharmacology for this commentary.