Here we examine the history of cannabis in the US, the role the USP played in that field, and the new role the USP is taking with cannabis for medical use.
The cannabis industry has been a hot topic of discussion over the last few years with the push for cannabis legalization around the world. It has been considered the most novel, brand new, and untested agricultural market in decades. But, what has been forgotten is that cannabis is not a new product, nor has it just appeared in the agricultural world. Cannabis was one of the largest agricultural crops in the United States up until its prohibition, and as such was a part of the United States Pharmacopeia (USP) compendium for almost a century. This column examines the history of cannabis in the US and the role the USP played in that field. We also discuss the new role the USP is taking in bringing the research and safety back into its scope including its most recent work and developments for the safety and quality of the cannabis for medical use.
Despite the fact that cannabis is treated like the newest botanical product to come to market in decades, cannabis has a long-standing history going back before 3000 B.C. with the first recorded uses in China. Early cannabis products were hemp fibers and medicinal treatments were prescribed by ancient Greek and Roman physicians. In the 16th and 17th centuries the use of cannabis continued and increased with its expansion to the Americas in the 1600s.
Linnaeus classified Cannabis sativa in 1753 as other scientists and physicians included cannabis in world dispensatories. In the US, cannabis products were part of the history for centuries with even our founding fathers growing cannabis crops (Figure 1). (See upper right for Figure 1, click to enlarge.)
It has only been within the last 100 years that cannabis was consigned to the shadows of illicit and banned materials in the US and around the world. During the 19th century and the early 20th century, cannabis rose to widespread use, but also became the object of restriction around the world.
In 1906, the US Pure Food and Drug Act required labeling products that contained psychogenic substances such as cannabis and alcohol. By 1914, the Harrison Act (US) made the use of marijuana (a variety of cannabis that contains higher levels of tetrahydrocannabinol [THC]) and other narcotic drugs a crime. Starting in 1915 through the 1930s the prohibition and criminalization of cannabis continued all over the world. In 1937, the US Marijuana Tax Act criminalized cannabis without distinguishing between cannabis with psychotropic properties or species used for hemp products (1).
Despite its illicit status, the research into the medicinal uses of cannabis continued. Many medical applications have come to light and have been shown promising by the scientific methods, including its use as an analgesic for glaucoma and cancer patients. Now in the 21st century, countries around the world are rediscovering the beneficial and medicinal properties of cannabis and pushing for legality. Governments and regulatory agencies have begun to introduce or reintroduce cannabis into their catalog of botanical and agricultural products. One of the organizations actively involved in increasing our knowledge and understanding of cannabis is the United States Pharmacopeia (USP).
What is USP?
The USP is an independent, nonprofit organization outside of the US government whose purpose according to their missions statement (1) is “to improve global health through public standards and related programs that help ensure the quality, safety, and benefit of medicines and foods.”
The USP was founded in 1820 by physicians whose intent was to bring a national set of standards to the US that would unify the quality of drugs in the nation. At the time of the initial organization of the USP, most drugs were based on botanical or mineral ingredients. The US needed its own compendium or pharmacopeia (a compilation of standards and quality specifications that can test to confirm: composition, identity, purity, and strength of specified materials for use in medicines and food products) (2). The first national Pharmacopoeia of the United States of America (1820) contained a list of 217 drugs that included 145 botanicals and botanical products.
Subsequent editions of the USP included updates, omissions, and additions of materials as research progressed or regulations changed. This process was observed in the case of cannabis, which first appeared in the 1850 edition of the USP until it was dropped from the pharmacopeia by 1940.
The United States Pharmacopeia started as the primary compendium document produced from the USP Convention, which over the years has changed but persisted since its inception. The modern USP Convention is composed of three principle bodies: The Convention Membership, Board of Trustees (BoT), and the Council of Experts (CoE). The Convention is a group of up to 600 delegates representing academic institutions, health professionals, scientific and public interest organizations, state and national associations, agencies of the federal government, and many others. The Convention is governed by the Board of Trustees and advised by the Council of Experts.
The BoT assesses the proposed resolutions and shares the findings with The Convention. The BoT also makes the decisions about policy, finances, and the strategic direction of the organization. The CoE is elected to membership by the convention. Each CoE member serves as a chair for an expert committee for five years. The members share their knowledge, develop standards, and review the work plans for their committee. There are many groups and subgroups within the USP CoE working on a range of topic groups for chemical analysis and dietary supplements (Figure 2). (See upper right for Figure 2, click to enlarge.)
The work cycle for the organization begins with the need for guidance, methodology, or standards for a new industry, product, or process (Figure 3). USP scientists and industry collaborate to draft a standard or guidance document. The draft is reviewed by experts and upon agreement posted for public review, which lasts 90 days. The comments and draft are then reviewed by the CoE and either approved or sent back for revision. Once approved the monographs, chapters, and other standards are published. Editions of the United States Pharmacopeia - National Formulary (USP-NF) are published on an annual basis. USP standards are reviewed regularly and revisions are published frequently. (See upper right for Figure 3, click to enlarge.)
The USP-NF contains two primary types of standard or information: monographs and general chapters. A monograph is a document that explains the expectations for a food, drug, or material to ensure its identity, purity, strength, and performance. Monographs contain the chemical information for the ingredient or material and outline the tests and procedures that must occur to meet quality criteria and limit impurities. There are more than 4500 monographs for prescription drugs, over-the-counter drugs, dietary supplements, medical devices, and other products found in the USP-NF.
A general chapter is a document that provides information on accepted processes, tests, and methods to support industry in product development and manufacturing quality controls. General chapters must be referenced in a specific monograph to be enforceable on a legal basis. Otherwise, general chapters contain the best practices and methods for common processes or groups of analytical targets.
While the early editions of USP were always considered authoritative they were not officially or legally recognized in the US until a series of legislative acts: 1848 Drug Importation Act, the 1906 passage of the Food and Drug Act, and the 1938 Food, Drug and Cosmetic Act. The final act decreed that all medicines sold in the US must meet USP quality standards in what is now known as the USP-NF.
USP refers to both the United States Pharmacopeial Convention and the United States Pharmacopeia. The primary document produced from the USP is the compendium called United States Pharmacopeia. The United States Pharmacopeial Convention is the organizational body enacting the workings and standards of USP. In 1888 the National Formulary (NF) was created to complement and supplement the pharmacopeia. It is a compendium of formulations and includes standards for botanicals, excipients, and other preparations not found in the pharmacopeia. Over the decades the two compendia United States Pharmacopeia and the National Formulary merged in 1975 to be published under one cover called the USP-NF.
The full library of the USP documents, in addition to the USP-NF, include: the USP Compounding Compendium, Herbal Medicines Compendium, Dietary Supplements Compendium, and Food Chemicals Codex. Additional guidance materials are frequently published and disseminated by USP to cover emerging topics. These documents are publications such as general notices, articles, white papers, and informational guides.
More than 150 countries around the world recognize and use the standards published by USP. Despite its legal recognition by US agencies, the USP is an independent organization. The USP is an “organization of organizations” with its own governance and membership and broad stakeholder engagement that direct and inform their activities and produce guidance documents for food, pharmaceutical, and dietary supplement and herbal medicine industries which include botanicals.
The USP began in the early 19th century with the idea of standardizing substances and materials used medicinally in that time, which of course meant medicines based mostly upon natural botanical, biological, and mineral ingredients. It was recognized very early in history that agricultural and botanical products are prone to adulteration or substitution. In particular, it was believed that the US was often the recipient from world suppliers of low quality or counterfeited medicinal products which had little to no efficacy. Some botanicals were often adulterated or replaced for economic gain while other materials were unintentionally or intentionally misidentified or substituted (practices which still persist to modern times).
The Drug Importation Act (1848) was enacted to control the adulterated medicinal products entering the US. Later acts, as mentioned previously, continued to attempt to control the import, sale, and use of fraudulent and adulterated medicines. It became essential that standards and testing processes be implemented to confirm identity, potency, and safety of medications. Test procedures and physical reference materials developed over the history of USP became important benchmarks and industry standards for identity and quality of botanical products and dietary supplements in addition to the pharmaceutical products.
USP and Cannabis
As the botanical and dietary supplement industry changes and grows, additional methods, procedures, chapters, and monographs are added to the information provided by USP. In the last decade, one of the “newest” markets has been cannabis. But, as we have said previously, cannabis is neither a new product to the world or USP. During the 90 years that cannabis was documented in the USP, it appeared in many forms and iterations.
The first entry in 1850 was titled: “Extractum Cannabis. Extract of Hemp.” This form was an alcohol based extract of “Cannabis sativa – variety Indica” composed of the dried tops of the plants. USP V (1870) separated cannabis species into the flowering tops of C. sativa grown in North America and the flowering tops of C. sativa var. indica from India. Cannabis extracts remained in the USP up until USP XII (1940) when it was criminalized by the 1937 US Marijuana Tax Act (Figure 4). (See upper right for Figure 4, click to enlarge.)
Now, in the US on the state level, cannabis has returned for medicinal use for more than 30 states, districts, and territories with more being added each year despite the continued federal status as a Drug Enforcement Administration (DEA) schedule I substance. The individual states have each applied their own differing approaches to the regulation of cannabis. Safety of the products is a goal, but one with lack of guidance from the usual governmental sources. Standards organizations, such as USP, have started to work to include cannabis into a dietary supplements and botanical guidance framework.
Since the reemergence of cannabis as a “medicinal” product, the goal for the USP is to help ensure the quality of cannabis intended for medical purposes and the development of quality parameters for authentication and identification. These will have to include: laboratory verification of cannabis identity; quantitative analysis of cannabinoids and terpenes; and limit exposure from contaminants such as mycotoxins, pesticides, and heavy metals.
The USP organized a multistakeholder roundtable in 2016 to discuss the path forward and subsequently formed a Cannabis Expert Panel to evaluate the specifications needed to define cannabis quality attributes and characteristics. Given the complex legal and regulatory landscape, it was decided early on not to focus on publication in an official compendium, but to ensure that scientific underpinnings of cannabis quality were disseminated as quickly as possible in a broadly accessible format. One of the first goals of the panel was the characterization and definition of a heterogeneous group of species and strains generally recognized as Cannabis indica or Cannabis sativa. Many scientists believe that the separation or designation of two species is not accurate in expressing the variation of chemotypes and characteristics found in the currently studied cannabis species and strains (3).
The panel published it’s recommendations in a peer-reviewed journal (5) and suggested that cannabis should be viewed as a single plant species, Cannabis sativa, with different strains (varieties) or subtypes differentiated based on chemotype profiles. The profiles divide cannabis into three main chemotypes based on amounts of THC and cannabidiol (CBD) with the groups being classified as THC dominant, CBD dominant, or intermediate with both THC and CBD (3,4).
The first step in proper description and control of quality is to establish a standardized nomenclature and identifying characteristics, then establish quantifiable concentrations or limits. Ideally, standardization of medical cannabis would be derived from plants of similar or identical characteristics and chemotypes. Over the centuries and with the advent of agriculture and selective cultivation and breeding, cannabis plants have evolved to produce variations of cannabinoid profiles which USP has suggested be placed into one of the three chemotype groups discussed.
The use of scientific analytical procedures is employed to identify and quantify the chemical marker compounds such as THC, CBD, and other cannabinoids or terpenes. Chromatographic methods such as high performance thin-layer chromatography (HPTLC), high performance liquid chromatography (HPLC), and gas chromatography (GC) are the most frequent tools for the separation, identification, and quantification of the cannabis marker compounds. Reference materials or physical standards, such as the ones currently produced by USP, can be used to confirm the identity of various cannabinoids by chromatographic techniques.
For these chromatographic methods, the USP has general chapters addressing the use of these techniques: USP General Chapter <203> “High-Performance Thin-Layer Chromatography Procedure for Identification of Articles of Botanical Origin;” USP<1064> “Identification of Articles of Botanical Origin by High-Performance Thin-Layer Chromatography Procedure;” and USP <561> “Articles of Botanical Origin” (see Table I). (See upper right for Table I, click to enlarge.)
Chromatography methods are also applicable in the determination of terpene compounds and ratios, which can be used in the identification of cannabis varieties (4). The USP Cannabis panel is suggesting analysis of the five most prevalent terpenes found in cannabis (one sesquiterpene: Î²-caryophyllene and four monoterpenes: D-limonene, Î²-myrcene, Î±-pinene, and Î³-terpinolene) can provide valuable identity information. Each of these terpenes has appeared as the dominant or codominant terpene in various varieties of cannabis, which could aid in confirmation of identity.
The ultimate goals for USP standards are to establish guidelines that ensure safety and create analytical limits for each type of possible contamination: pesticides, heavy metals, aflatoxins, and so on. General chapters give instruction on all aspects of testing and manufacturing quality control practices. These chapters are guidelines for the methodology, limits, and practices for pharmaceuticals, supplements, and botanicals to ensure safety of products.
There have been multiple recalls of cannabis products over the past few years because of contamination issues. Cannabis products are subject to all the same types of contamination found in other botanical and dietary supplement products: pesticides, heavy metals, aflatoxins, microorganisms, and so on. Pesticides are an often cited reason for cannabis product recall due to exceeding state limits or presence of restricted pesticides.
Cannabis plants are highly susceptible to infestations of a variety of pests including several molds, insects, and vertebrates (5). In the past and with the absence of legal guidance, cannabis growers used an assortment of pesticides, many not intended for use with food and medicinal crops. More recently, some cannabis product recalls have been cited for using unauthorized or banned pesticides not listed for cannabis use.
Typically, in the US, pesticides are regulated by the Environmental Protection Agency (EPA), but the restricted federal status of cannabis limits their involvement in cannabis pesticide applications. In this background, the USP presents guidance in the form of general chapters intended for botanical products. USP General Chapter <561> “Articles of Botanical Origin” establishes pesticide limits based on acceptable daily exposure, body weight, amount consumed, and a safety margin for oral exposure that can be used as a starting point for further development of pesticide residue standards for inhaled cannabis materials.
Toxic elements and heavy metals are another source of contamination in dietary supplements and botanical products. Cannabis is an effective concentrator of heavy metals. Impurities from environmental and other sources accumulate in the plant and then pose health risks for patients and consumers. For elemental impurities, USP has several chapters pertaining to heavy metal limits and testing, including limits for both dietary supplements (USP <2232>) and pharmaceuticals (USP <232>) (Table I).
Other chapters include standards for monitoring microorganisms and aflatoxins, which can be used to create limits and methodologies for cannabis testing around the world.
It has often been discussed and written that cannabis, especially at the start of the resurgence, was like the wild west with few rules and no guidance. The truth is that cannabis is a botanical product, like many other products, with a few unique challenges. Cannabis is neither a new botanical nor a totally unique one. The work of the USP over the past 200 years proves that fact. The analytical test methodologies, limits, and best practice guidance are being established by several standards organizations (USP, AOAC, ASTM, and others). These organizations often work in conjunction with each other, industry, and government to provide guidelines and standards to ensure the key components of identity, purity, and safety are met around the world for a wide range of products. Cannabis is only the latest product in need of guidance. USP has once again restarted the process to guide the cannabis industry into compliance as it has done in the past and will continue to do in the future. Additional work to research quality parameters for cannabis and derived products is currently ongoing at USP.
For more information on any of the USP chapters listed, or to volunteer to be involved in the workings of the USP process, please visit the USP website: www.usp.org/dietary-supplements-herbal-medicines/cannabis.
Patricia Atkins is a Senior Applications Scientist with SPEX CertiPrep and a member of both the AOAC and ASTM committees for cannabis.
P. Atkins, Cannabis Science and Technology, 3(5), 17-22 (2020).