Understanding Sources of Heavy Metals in Cannabis and Hemp Consumer Products, Part I: Is the Fractured Nature of State-based Regulations Ignoring the Evidence?

Introduction

In this month’s column, guest contributor, Rob Thomas takes a critical look at the big four heavy metals which are regulated by the vast majority of US states and suggests that there is compelling evidence in the public domain that the panel should be increased because there is not a good understanding of sources of elemental contaminants in the production of cannabis consumer products. As a result of the inadequate nature of these state-based regulations, consumer safety is most likely being compromised.

Part 1 of this column examines the fractured nature of state-based regulations and compares it with the federal limits for pharmaceutical products and dietary supplements. Part 2 will look at specific examples in the public domain of elemental contamination of cannabis consumer products, which shows that other elements are worthy of consideration and should be an integral part of the regulatory framework.

The Regulatory Framework

Even though cannabis is in the process of being rescheduled from a Schedule I to a Schedule III drug by the Drug Enforcement Administration (DEA), uncertainty about federal oversight of cannabis consumer products in the US has left individual states to regulate its use. Cannabis is legal for medicinal purposes in 39 jurisdictions, while 19 states and Washington, D.C. allow its use for adult recreational consumption (1). However, the cannabis plant is known to be a hyper-accumulator of toxic metals in the grow medium and other manufacturing pathways, so it is critical to monitor levels of elemental contaminants to ensure cannabis products are safe to use. Unfortunately, there are many inconsistencies with heavy metal limits in different states where cannabis is legal. The vast majority of these states set limits for the “big four” heavy metals: lead (Pb), arsenic (As), cadmium (Cd), and mercury (Hg). New York State also requires the testing for chromium (Cr), nickel (Ni), copper (Cu), and antimony (Sb), while Michigan requires inorganic As (not total) and also adds Cr, Ni, and Cu to the big four. Maryland and a few other states also include Cr as well as the big four. Some states base their limits directly in the cannabis, while others are related to human consumption per day. Some take into consideration the body weight of the consumer, while other states do not even have heavy metal limits. To complicate the situation, certain states only require heavy metals in the cannabis plant/flower, while some give different limits for the delivery method such as oral, inhalation, or transdermal (2). This review article will provide evidence from publicly-available sources that a wider panel beyond the “big four” heavy metals are worthy of consideration, suggesting that the industry does not have a good understanding of sources of elemental contaminants in the cultivation and production of cannabis consumer products and as a result the fractured nature of state-based regulations could potentially be compromising consumer health and safety.

State Inconsistencies

The inconsistencies of state-based limits would make it extremely complicated to implement at the federal level, unless there was a completely fresh assessment of the regulations. For example, why does New York State currently have action limits for eight elemental contaminants whereas the vast majority of the other states only require the big four? In other words, what do New York regulators know about the toxicological impact of the four additional elements, compared to California that only regulates four? Or why does Michigan require inorganic arsenic while all other states just list total arsenic? Furthermore, how can some states justify no heavy metal action limits at all? It might all become a moot point when federal regulators eventually have oversight of the industry, but what will that regulatory panel look like? The disparity in state-based limits might not be a good indicator, but there could also be clues in the way federally approved cannabidiol (CBD) drug formulations have historically been regulated, together with an understanding of how standards and reference material organizations have approached developing standardized analytical methodology for measuring heavy metals.

Disparity with Federal Limits

To highlight the disparity between state-based limits and federal guidelines for pharmaceutical formulations, the Food and Drug Administration’s (FDA) Botanical Review Team in the Office of New Drug Products recently published a study entitled, “Quality Standards in State Programs Permitting Cannabis for Medical Uses” (3), which compared the maximum allowable limits of the big four heavy metals for states that had Medical Cannabis Programs (MCP) with United States Pharmacopeia (USP) Chapter <232> permitted daily exposure (PDE) concentrations in inhalation and oral drug formulations routes of administration (ROA) and USP Chapter <2232> Elemental Contaminants in Dietary Supplements (4). Although the actual states are not mentioned, it can be seen from Table 1 that in the majority of cases, the eight medical programs reported are very different to the USP limits. In fact, it can be seen by much of the data in bold, that they are significantly higher than the federal limits. There is no obvious reason as to why the state programs action limits are so different, but it was interesting that the researchers’ critique was three-fold:

• Testing for the four heavy metals in inhalation and oral products was lacking in the majority of state medical programs.
• Even when present, it was inconsistent across the different jurisdictions.
• It did not always align with USP recommendations.

How Many Metals are Enough?

So clearly there is a need for more consistency across state lines, particularly as the industry inevitably moves in the direction of federal oversight. This is further compounded by the fact that there is a great deal of evidence in the public domain that only monitoring the big four heavy metals is not enough to ensure consumer safety. But how many metals should there be in an expanded panel, particularly as there is no comprehensive understanding of the sources of elemental contaminants in the cannabinoid cultivation and production processes? Moreover, unlike drug products, there has been no risk assessment studies carried out with regard to heavy metal contaminants in cannabis consumer products and for that reason, consumer health is likely being compromised.

Regulatory Evidence

So, assuming that only monitoring the big four heavy metals is inadequate to ensure consumer safety, what is a realistic panel of elemental contaminants that should be used for state regulatory purposes? The only solid evidence we have at this current time for what could be a federally regulated panel is with the FDA approved CBD-based drug Epidiolex, which is available in the US to treat childhood seizures. Manufactured by UK-based GW Pharmaceuticals (now a division of Jazz Pharmaceuticals), it went through the regulatory process prior to its introduction in 2018 to get it approved in the US (5) and had to show compliance by meeting permitted daily exposure (PDE) limits for up to 24 elemental impurities as defined in USP Chapter <232> (3) and International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q3D guidelines (6). In practice, because eight of those metals are associated with the drug synthesis process using platinum group catalysts which was not used in the Epidiolex manufacturing process, only 16 were used for manufacturing quality assurance purposes.

Furthermore, USP recently published a draft monograph for CBD as an active pharmaceutical ingredient (API) for a federally approved drug formulations which stated that (7):

“Elemental impurities in official drug products are controlled according to the principles defined and requirements specified in Elemental Impurities—Limits, Chapter <232>, as presented in the General Notices 5.60.30.”

In the long term, this could possibly indicate that the FDA will regulate CBD products for up to 24 elemental contaminants when it eventually has oversight of the cannabis industry. But more importantly, in the short term it implies that CBD being manufactured in the US for recreational or medicinal purposes does not meet the purity requirements for federally approved drugs, because currently it only has to comply with the state’s maximum limits for heavy metal contaminants, which in most US states is typically only Pb, Cd, As, and Hg.

However, it’s important to stress that a panel generated by pharmaceutical regulators isn’t necessarily one that should be used by the cannabis industry, as the process for manufacturing cannabinoids is very different to drug products. In addition, many consumer products are not intended for medicinal purposes, but can be classified as foods, beverages, candies, or snacks so perhaps an argument could be made that they should be treated more like food products than drug substances. However, based on recent reports, it is clear the FDA is not doing such a good job of keeping us safe from the effects of toxic metals in our food supply as exemplified by a reprimand from Congress in 2021 for failing to identify processed baby food cereals with elevated levels of heavy metals (8) and more recently, for not flagging a case of intentional adulteration of cinnamon with lead chromate (Pb CrO4) for economic gain (9). So, until there is a mandatory requirement for food manufacturers to test their products on supermarket shelves, there is always the potential for incidents like this. So irrespective of what regulated limits are used, at some point the cannabis industry needs to carry out a comprehensive risk assessment study of its own to provide evidence as to what metals should be monitored, similar to what regulators did to characterize elemental impurities in drug products and formulations (10). To better understand this risk assessment process and how it might have a bearing on a cannabis panel of heavy metal contaminants, let’s take a detailed look at how regulations for pharmaceutical and supplements came into existence, which eventually became the basis for state-based oversight of the cannabis industry.

Federal Regulations for Drug Substances

The pharmaceutical industry began the process to overhaul regulations and methodology for elemental impurities over 20 years ago when it updated its 100-year-old semi-quantitative sulfide precipitation colorimetric test for lead and a small suite of heavy metals to eventually arrive at a method to monitor 24 elemental impurities in drug products using plasma spectrochemistry. Moreover, they completely reassessed the toxicological impact of these elemental contaminants based on well-established animal models and defined them by permitted daily exposure (PDE) limits according to the mode of administration (oral, parenteral, inhalation, transdermal) and classified them by toxicity and the probability of finding them in the drug manufacturing process.

These limits were described in USP <232> - Elemental Impurities (4) and ICH Q3D Guidelines (6), together with USP Chapter <2232> for dietary supplements (4). While the measurement procedures were defined in USP Chapter <233> which describes the plasma spectrochemistry methodology (inductively coupled plasma optical emission spectroscopy [ICP-OES] or inductively coupled plasma mass spectrometry [ICP-MS]), microwave digestion procedure and a full set of validation protocols (11). Table 2 represents the full list of USP/ICH elemental PDE limits in microgram per day (µg/day) per delivery method and toxicological classification, which are explained in greater detail in Table 3.

It’s also important to emphasize that the data in Table 2 are maximum limits per day. So, for a suggested daily dosage of 10 g, these limits should be divided by ten to calculate the maximum allowable limits in the drug products in microgram per gram (µg/g). However, even though 10 g is a typical maximum daily dosage for drugs, we have no way of knowing in what quantities consumers use cannabis products. So, if larger or smaller quantities are being used these PDE limits will be different, based on the weight consumed. Furthermore, the mode of administration will also impact the regulated limit, so inhalation PDEs in most cases are significantly lower than the oral ones. In addition, the classification number will impact the frequency of testing with Class 1 and 2A metals of higher priority than the Class 2B and 3 metals. In fact, the classification can offer clues as to what elements from this list would be worthy of inclusion in an expanded panel to regulate cannabis and hemp consumer products. For example, Class 1 and 2A would warrant inclusion in any regulated panel, whereas Class 2B metals would likely not be required at all, because they are not used in the cannabinoid manufacturing process. On the other hand, Class 3 metals may not be required for all oral products but would definitely be required for inhalation products such as vaping devices.

Final Thoughts

Part 1 was essential background information to the topic of this review article. Part 2 of the column takes a closer look at some of the evidence in the public domain, which underscores that the industry does not have a thorough understanding of heavy metal contaminants in consumer products which could support the measurement of a wider panel of elemental contaminants in cannabis materials.

Further Reading

1. Marijuana Policy by State https://www.mpp.org/states.
2. Thomas, R., The Importance of Measuring Heavy Metal Contaminants in Cannabis and Hemp, Analytical Cannabis, 2021, https://cdn.technologynetworks.com/ac/Resources/pdf/the-importance-of-measuring-heavy-metal-contaminants-in-cannabis-and-hemp-312957.pdf
3. Pruyn, S.A.; Wang, Q.; Wu, C.G.; and Taylor, C.L., Quality Standards in State Programs Permitting Cannabis for Medical Uses, Cannabis and Cannabinoid Research, 2022, https://doi.org/10.1089/can.2021.0164
4. United States Pharmacopeia (USP) General Chapter <232> Elemental Impurities in Drug Products and Chapter <2232> Elemental Contaminants in Dietary Supplements, https://www.usp.org/chemical-medicines/elemental-impurities-updates
5. FDA Approves First Drug Comprised of an Active Ingredient Derived from Marijuana to Treat Rare, Severe Forms of Epilepsy, FDA News Release, 2018, https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-comprised-active-ingredient-derived-marijuana-treat-rare-severe-forms
6. ICH Guideline Q3D on Elemental Impurities (R1), European Medicine Agency https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-32.pdf
7. USP Draft Monograph for CBD, Pharmacopeial Forum (PF) 48(1), January 2022, https://www.gmp-compliance.org/gmp-news/usp-draft-monograph-for-cbd
8. Thomas, R. Regulating Heavy Metals in Baby Food: The Challenges of Food Manufacturers and the FDA Being on the Same Page, AP Column, Spectroscopy Magazine, 2021, 36 (7), 10-16, https://www.spectroscopyonline.com/view/regulating-heavy-metals-in-baby-food-the-challenges-of-food-manufacturers-and-the-fda-being-on-the-same-page
9. FDA Takes Steps to Ensure Safety of Cinnamon Products Sold in the US, FDA News Release, 2024, https://www.fda.gov/news-events/press-announcements/fda-takes-steps-ensure-safety-cinnamon-products-sold-us
10. Thomas, R.; Destefano, A. Understanding Sources of Heavy Metals in Cannabis and Hemp: Benefits of a Risk Assessment Strategy, Analytical Cannabis, https://www.analyticalcannabis.com/articles/how-to-better-understand-sources-of-heavy-metal-contaminants-in-cannabis-part-1-what-can-we-learn-313862
11. United States Pharmacopeia General Chapter <233> Elemental Impurities – Procedures: Second Supplement to USP 38–NF 33, 2015, https://www.usp.org/chemical- medicines/elemental-impurities-updates

About the Guest Columnist

Robert (Rob) Thomas is the principal scientist at Scientific Solutions, a consulting company that serves the educational needs of the trace ele­ment user community. He has worked in the field of atomic and mass spectroscopy for almost 50 years, including 24 years for a manufacturer of atomic spectroscopic instrumentation. Rob has written over 100 technical publications, including a 15-part tutorial series entitled, A Beginner’s Guide to ICP-MS. He is also the editor and frequent contributor of the "Atomic Perspectives" column in Spectroscopy magazine, as well as serving on the editorial advisory board of Technology Networks. In addition, Rob has authored six textbooks on the fundamental principles and applications of ICP-MS. His most recent book is entitled A Practical Guide to ICP-MS and Other AS Techniques, which was published in September 2023. Rob has an advanced degree in analytical chemistry from the University of Wales, UK, and is also a Fellow of the Royal Society of Chemistry (FRSC) and a Chartered Chemist (CChem).

How to Cite this Article

Thomas, R. Understanding Sources of Heavy Metals in Cannabis and Hemp Consumer Products, Part I: Is the Fractured Nature of State-based Regulations Ignoring the Evidence? Cannabis Science and Technology, 2024, 7(3), 18-22.