Regulating Heavy Metals in Cannabis: What Can be Learned from the Pharmaceutical Industry? Part 1
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This article is the first part in a series on the importance of measuring heavy metals in cannabis and hemp. In particular, the series will explore how the cannabis industry can learn a great deal from the pharmaceutical industry, which took over 20 years to bring in meaningful and comprehensive regulations for elemental impurities to ensure the safety and efficacy of drug products.
The series has been summarized from two chapters in Robert Thomas’ upcoming book, Measuring Heavy Metal Contaminants in Cannabis and Hemp: A Practical Guide, which will be published by CRC Press this September. If you are interested in learning more about the book, please visit Robert Thomas’ website where you can download the publisher's marketing flyer. The book, including its table of contents, is now also available for pre-ordering from the publisher.
The cannabis and hemp industry is moving at such an alarming rate that the analytical testing community is struggling to keep up with it. It’s estimated that the demand for medicinal and adult recreational cannabis-based products, containing tetrahydrocannabinol (THC) and cannabidiol (CBD) compounds will exceed $25 billion in the US by 2025. However, because the US Food and Drug Administration (FDA) has only been involved in this process when an investigational new drug has been submitted to conduct human clinical trials (e.g. Epidiolex from GW Pharmaceuticals for treating seizures in young children), regulating the industry to make sure products are safe for human consumption has been left to individual states. In addition, CBD-only products, which are dominating today’s marketplace, are, for all intents and purposes, unregulated by the federal government at this time.
Unfortunately, many of the states where it’s legal don’t have the necessary experience and background to fully-understand all the safety, quality, and toxicological issues regarding the cultivation and production of cannabis and hemp products on the market today. Besides the need to characterize its potency (CBD and THC content), one of the most important contaminants to measure is the level of heavy metals, because cannabis and hemp will avidly accumulate trace elements from the growing medium, the soil, fertilizers, and even the metallic equipment used during the preparation and processing of the various concentrates and oils. For that reason, it’s critically important to monitor heavy metals in cannabis and hemp to ensure that products are safe for human consumption.
Regulating cannabis and hemp
The lack of federal oversight with regard to heavy metals in medicinal cannabis products in the US has left individual states to regulate its use. Medical cannabis is legal in 34 states, while 11 states and Washington, DC allow its use for adult recreational consumption. However, the cannabis plant is known to be a hyper-accumulator of heavy metals in the soil, so it’s 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 states define four heavy metals: lead, arsenic, cadmium, and mercury. Some base their limits directly in the cannabis, while others are based on human consumption per day. Others take into consideration the body weight of the consumer, while some states don’t even have heavy metal limits.
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 transdermal1. This makes it extremely complicated, because currently all regulations apply only in the state where the cannabis is grown, processed, and sold. And since the federal government still considers cannabis a Schedule I drug (same as heroin), there can be no interstate commerce with regard to cannabis products. However in 2020, it will be legal to grow hemp (which contains less than 0.3 percent THC) anywhere in the US for the production of CBD-based and other industrial products, so it will be interesting to see how the Department of Agriculture regulates the industry at the federal level, when cannabis is regulated by the individual states.
What can be learned from the pharmaceutical industry?
So clearly there is a need for more consistency across state lines, particularly as the industry inevitably moves in the direction of federal regulation. The cannabis industry can learn a great deal from the pharmaceutical industry, as it went through this process over 20 years ago when it updated its 100-year old qualitative sulfide precipitation test for an undefined suite of heavy metals2 to eventually arrive at a list of 24 elemental impurities in drug products using plasma spectrochemical techniques3,4.
These procedures were described in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines on elemental impurities5. These new directives defined maximum permitted daily exposure limits based on well-established elemental toxicological data for drug delivery methods (including oral, parenteral, and inhalation), together with the analytical methodology to carry out the analysis. This meant that pharmaceutical manufacturers were required to not only understand the many potential sources of heavy metals in raw materials and active ingredients, but also to know how the manufacturing process contributed to the elemental impurities in the final drug products.
The beginning of the journey to regulate elemental impurities in pharmaceuticals in the late 1990s can be likened to the production of cannabis and hemp derived products today, where the source of elemental contaminants is not fully understood. In particular, the elemental toxicological guidelines to regulate the cannabis industry are being taken very loosely from a combination of methods and limits derived by the pharmaceutical, dietary supplements, food, environmental and cosmetics industries. Even though the process of manufacturing cannabis products might be similar in some cases to drugs and herbal medicines, the consumers of cannabis and hemp products are using them very differently and in very different quantities, particularly compared to pharmaceuticals, which typically have a maximum daily dosage. The bottom line is that heavy metal toxicological data generated for pharmaceuticals over a number of decades cannot simply be transferred to cannabis, hemp, and their multitude of products.
An added complication is that the cannabis and hemp plant can not only absorb heavy metals from the soil, but also from contaminants in fertilizers, nutrients, pesticides and the growing medium as well as from other environmental pathways. Additionally, the process of cutting, grinding, and preparing the cannabis/hemp flowers for extraction can often pick up elemental contaminants from the stainless steel manufacturing equipment. Finally, the cannabinoid extraction process will extract different amounts of heavy metals, depending on the solvent and/or the temperature and pressure used in the extraction/distillation process which could potentially end up in the finished products. In addition, some cultivators will use nutrients containing metal-based bud/flower enhancers, which would not be picked up by the state regulatory process. It’s also worth pointing out that the equipment used to deliver these products to consumers, such as inhalers and vaporizers, can mean the user is exposed to additional sources of elemental contaminants from inside these devices, apart from what’s in the cannabinoid compound itself.
Phytoremediation properties of cannabis and hemp
Cannabis and hemp are known to be hyper-accumulators of contaminants in the soil. That is why they have been used to clean up toxic waste sites where other kinds of remediation attempts have failed. In the aftermath of the Chernobyl nuclear melt down in the Ukraine in 1986, industrial hemp was planted to clean up the radioactive isotopes that had leaked into the soil and ground waters. Of course Chernobyl is an extreme example of heavy metal and radionuclide contamination, but as a result of normal anthropogenic activities over the past few decades, including mining, smelting, and the spread of pesticides, heavy metal pollution has become one of the most serious environmental problems today. And with all the diverse and varied conditions used for growing cannabis, it will be very difficult to eliminate all these potential sources of pollution in order to reduce their impact on the plant’s biology.
So there is no question that the current suite of four heavy metals being required by state-based regulators is totally inadequate to ensure cannabis products are fit for human consumption. Based on evidence in the public domain6, there are about 15 heavy metals found in natural ecosystems and contamination from industrial activities that could be potential sources of contaminants in the plant, including nickel, vanadium, cobalt, copper, selenium, barium, silver, antimony, chromium, molybdenum, manganese, zinc, and iron. They might not all have a negative impact on the health of the plant during cultivation, but the chances that they will end up in the flowers and the final manufactured products are very high. Their levels of toxicity would need to be investigated further, but there is a case to be made that the majority of them could be the future basis of a federally regulated panel of elemental contaminants in cannabis and hemp6. For this reason, it’s critically important to characterize all the potential sources of elemental contamination, including the cultivation of the cannabis/hemp plant, as well as the cannabinoid manufacturing process.
As heavy metals are likely to appear in some hemp and cannabis products, the correct sampling and testing procedures is absolutely critical, so the analytical result of the sample is actually indicative of the cannabis plant. The most suitable and widely used technique is considered to be inductively coupled plasma mass spectrometry (ICP-MS), which is a very sophisticated multielement analytical technique that can easily measure down to parts per trillion detection levels. However, it requires an analytical chemist with a high level of knowledge and expertise to fully understand the nuances of ultra-trace elemental analysis, including lab cleanliness, sources of contamination, sample preparation, digestion techniques, instrumental method development, interference corrections, calibration routines, use of reference materials, and validation procedures. In other words, in the hands of an inexperienced user, it could easily generate erroneous results. For that reason, the expertise of the testing lab and the people running the instrumentation is of prime importance.
The pharmaceutical industry went through this learning curve when it was first required to use plasma spectrochemistry after 100 years of the qualitative colorimetric sulfide precipitation test for heavy metals. As the leader of the heavy metals task force on the American Chemical Society’s (ACS) reagent chemicals committee, I had become very familiar with the demands of the pharmaceutical community. My committee had worked very closely with the United States Pharmacopeia (USP) to align the ACS test for heavy metals using plasma spectrochemistry with the new USP methodologies, described in Chapters 232 and 2333,4. It was very clear that pharmaceutical manufacturers were unfamiliar with working at the ultra-trace level required by techniques like ICP-MS. So this became the incentive to write my last book, Measuring Elemental Impurities in Pharmaceutical Materials: A Practical Guide, which was published in the spring of 20187. Once it was in the public domain, I then turned my attention to the cannabis and hemp industry and started talking to cultivators, growers, producers, processors regulators, and testing labs to get a better understanding of what the industry needed with regard to its heavy metals’ testing requirements. As a result of that background research, in early 2019 I began the process of writing a new book, which focused on heavy metals in cannabis and hemp, which is currently on target to become available in the late summer of 20208. This article represents an overview of some of the initial findings of my research.
Our environment has been severely polluted by heavy metals, which has compromised the ability of our natural ecosystems to foster life and render its intrinsic values. Heavy metals are known to be naturally occurring compounds, but anthropogenic activities introduce them in extremely large quantities into our agricultural ecosystems. Nowhere is this more evident than in the delicate balance of growing and cannabis and hemp for commercial, medicinal, and recreational uses. Unfortunately, the demand for cannabinoid-based products is moving so fast that the scientific community is not keeping up with it; whether it’s the testing of the products to make sure they are safe for human consumption, or the medical research required to understanding the biochemistry that is fundamental to treating a particular disease or ailment.
The industry is both exciting and chaotic at the same time, but, because of its unparalleled growth, there appears to be very little incentive to bring in sensible regulations. There clearly needs to be a more comprehensive suite of elemental contaminants tested and to set the toxicological maximum limits on based on the manner and the quantity that cannabis products are consumed. For that reason, I firmly believe that researchers who are trying to raise the bar now will be rewarded when the FDA eventually starts to regulate the industry. However, in the meantime, I’m firmly committed to educating state regulators to better understand the potential sources of heavy metals in cannabis and hemp and to helping testing labs improve the quality of their data.
You can read part 2 of this article series from Rob Thomas by clicking here.
- Marijuana Policy by State: https://www.mpp.org/states/
- United States Pharmacopeia General Chapter <231> Heavy Metals Test in USP National Formulary (NF), https://www.usp.org/chemical-medicines/elemental-impurities-updates
- ICH Guideline Q3D on Elemental Impurities: Step 5, European Medicine Agency Website: https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-13.pdf)
- United States Pharmacopeia General Chapter <232> Elemental Impurities – Limits: First Supplement to USP 40–NF 35, 2017, https://www.usp.org/chemical-medicines/elemental-impurities-updates
- 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
- Marijuana Toxicity: Heavy Metal Exposure Through State-Sponsored Access to “la Fee Verte”, D. Gauvin et.al., Pharmaceutical Reg Affairs, 7:1, 2018
- Measuring Elemental Impurities in Pharmaceuticals: A Practical Guide, R. J. Thomas, CRC Press, Boca Raton. FL, US, 2018, ISBN: 9781138197961
- Measuring Heavy Metal Contaminants in Cannabis and Hemp: A Practical Guide, R. J. Thomas, CRC Press, Boca Raton, FL, ISBN: 9780367417376, Available September, 2020
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