Regulating Heavy Metal Contaminants in Cannabis: What Can be Learned from the Pharmaceutical Industry? Part 4
Potential sources of contamination: the final products
The first installment of the series gave an overview of why testing cannabis and hemp for heavy metal contaminants is so important and how the pharmaceutical industry can play a critical role in preparing the cannabis industry for federal oversight. Part 2 focused on how growers and cultivators need to actively investigate all potential sources of elemental contamination before they can even hope to minimize them. And, Part 3 highlighted how potential sources from the extraction and manufacturing processes can contribute to the problem. Part four will examine how processors can reduce the chances of elemental contamination, as well as provide examples of how high levels of heavy metals in some CBD products have led to government recalls and litigations because of false advertising of heavy metal content. In addition, we’ll take a look at one CBD manufacturer’s extraction protocols and how it impacted heavy metal levels in its products. Finally, we’ll investigate the effect of smoking/inhaling cannabis products, not only from the perspective of the cannabinoid but also from heavy metal contamination in the smoking/inhaling method/device used.
Note: 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. The book, including its table of contents, is now available for preordering from the publisher’s website.
There is clear evidence in the public domain that heavy metals are not being completely removed from commercially-available cannabinoid products, evidenced by the fact that from time to time we see products recalled for high levels of heavy metals. The following stories, taken from online newspapers and news sites are examples of this.
• There was a case recently where a CBD oil producer from Florida was forced to recall a CBD tincture by the FDA because it had 10x higher Pb levels - 4.7 ppm compared to the maximum allowable limit for Florida which was 0.5 ppm1.
• And there have been other similar stories reported where a CBD manufacturer claimed their product was “heavy metal” free but on further testing, it was found to be over the legal limit for Pb, Cu, and Ni. This case is currently going through the litigation process2.
• Thirteen strains of medical marijuana sold at a licensed medical marijuana center in Michigan were recalled. They failed to meet state maximum allowable limits for heavy metals when tested, because they were contaminated with high levels of Cd and As, according to the Michigan Bureau of Marijuana Regulation MBMR)3.
• Ohio state regulators recently recalled medical marijuana flower because it was packaged for sale at dispensaries before being tested for high levels of heavy metals, in addition to microbes, mycotoxin fungi, and foreign matter4.
• Following an inspection by the California Bureau of Cannabis Control (CBCC) a cannabis testing lab had to give up its business license. The inspection uncovered false results for a group of contaminants during cannabis product testing over a four-month period. This was especially detrimental to the California cannabis industry because they were in the process of putting in stricter limits for toxins, such as heavy metals5.
• Medical cannabis regulators in Maryland expanded testing for heavy metals in marijuana products as they warned the public about the risk for possible lead contamination in popular vaping devices. They issued an advisory to notify patients and other stakeholders of potential lead contamination of cannabis liquids in vape cartridges following exposure to heat inside the device6.
• Lead and ethanol contaminants were found in vape cartridges sold in Hawaii. They don't say where these contaminants come from, but the lead most likely comes from the soldered battery connections inside the vaping device, while the ethanol is a carryover from the cannabinoid extraction process. At vaping temperatures of approx 200°C, who knows what these contaminants are doing to someone's lungs, so it’s not surprising that a local doctor thinks they might be linked to a recent spate of lung illnesses7.
These stories emphasize that there is a continuing trend of products that are testing above maximum allowable levels for heavy metals, which indicates that growers and processors do not fully understand how heavy metals end up in commercially available cannabinoid products. It should also be pointed out that the majority of states that allow for medicinal cannabis only regulate Pb, As, Cd and Hg. In Part 2 of my series, I show convincing evidence in the public domain that there are probably another 10 heavy metals that could potentially be considered when assessing contamination in cannabis and cannabinoid products. Currently, if these metals found their way into cannabis products, they would escape the scrutiny of most state regulators.
There are many over the counter CBD-based drugs/medications on the market for medicinal purposes, but there is only one CBD prescription drug that is regulated by the FDA. Epidiolex™ is a prescription CBD-based drug for seizures in young children, which is manufactured by G.W. Pharmaceuticals. And, because it a prescription drug, it is regulated according to USP Chapter 232/233 in the US and to ICH Q3D guidelines in the ROW for 24 elemental impurities Permitted Daily Exposure (PDE) limits (refer to Part 2 for details). However, as the elemental impurities are not listed on the Epidiolex label, the only evidence I could find that indicates the level of heavy metals in the product is with regard to the company’s patent application for their cannabis extraction process8. A summary of its production/extraction protocol is shown below, which uses CO2 with sub-critical fluid extraction conditions at a temperature of 10° C and a pressure of 60 bar. On further investigation of the patent, the final heavy metal content is in the order of 20 ppm, although they do not mention which heavy metals they found.
• Botanical raw material (dried cannabis) is decarboxylated by heating to approximately 105°C for 15 minutes, followed by approximately 145°C for a minimum of 55 minutes for THCA and 90 minutes for CBDA (Note; refer to Part 3 for information on decarboxylation).
• Extraction with liquid food-grade carbon dioxide (CO2) for up to 10 hours.
- Subcritical extraction conditions: approximately 60 bar pressure at 10°C
• Removal of CO2 by depressurization to recover crude extract
• Winterization of the crude extract by dissolution in ethanol followed by chilling solution (-20°C up to 52 hours) to precipitate unwanted lipids and waxes
• Removal of unwanted waxy material by cold filtration (20 µm filter)
• Removal of ethanol and water from the filtrate by thin-film evaporation under reduced pressure (60°C with vapor at 40°C - 172 mbar and 72 mbar)
• Final botanical drug substance (CBD extract) stored at -20°C.
By reading through the entire patent, the following text gives their reasons for using this extraction procedure.
….the density of sub-critical CO2 is low, and remains low even as pressure is increased until the critical point of the system is reached. Thus, whilst the solvating power of sub-critical CO2 is reduced, a high degree of selectivity can be achieved, as only the most soluble components are efficiently dissolved by the CO2; in this case the cannabinoid fraction. The result is the production of a relatively simple extract containing, as well as the cannabinoids, only a limited number of non-target compounds (inc. heavy metals), many of which can be removed relatively easily by a simple winterization clean-up step. In contrast, at higher temperatures, there is a significant increase in the density of the CO2 as it now exists in a supercritical fluid state. This has the effect of greatly increasing the solvating power of the solvent, which whilst generally advantageous in that more cannabinoids are solubilized, thereby giving high yields, in fact, proves disadvantageous because the decreased selectivity of the more powerful solvent results in increased solubility of a range of non-target compounds which makes the resulting extract more difficult to purify.
Using this process, the resulting product specifications are shown in Figure 1:
Figure 1: Product Specifications for a CBD extract manufacture by GW Pharmaceuticals8.
Anyway, this is the only data I could find which shows heavy metal levels in a CBD extract. But we also must keep in mind that Epidiolex is a prescription drug which is regulated by the FDA. This means that to comply with USP directives and ICH guidelines, they have to show that 24 elemental impurities are below maximum permitted daily exposure (PDE) limits for an orally-delivered drug compound. So clearly they have a strong incentive to ensure elemental contaminant levels are kept at a low level, as this prescription is being used on young, sick children with compromised immune systems…..not too sure the same strict guidelines can be said for cannabinoid-related products that are regulated by the states.
So it’s worth going through a similar exercise to the cultivation process and list potential areas to investigate in order to reduce potential sources of heavy metal contamination from a cannabis preparation, drying, extraction, production, and manufacturing perspective.
• Try to minimize the use of metal-based processing/extraction /manufacturing equipment. Perhaps there is a plastic alternative? In particular, avoid the use of stainless steel mixing vats, processing vessels, cutting blades, and grinding equipment. Depending on the quality/specification of the stainless steel, metals ions and/or fine particulates of iron, chromium, nickel, cobalt, manganese, molybdenum, and silicon could find their way into the processed cannabis flowers and eventually into the extracted oils and concentrates9.
• If possible, use an optimized solvent and extraction/distillation process to minimize the amount of heavy metals ending up in the extracted products8. It would also be useful to characterize the heavy metal content at every step of the manufacturing process from the cannabis plant through to the final product.
• Use ultra-clean solvents, and chemicals (low in heavy metals) for the extraction, distillation, concentration, and infusion of cannabinoids from the plants10.
• Make sure the source of water used in the cannabis production process is contamination-free. Minerals or elemental impurities in the water supply should be below the EPA maximum contaminant levels (MCL), otherwise, the extracted material could pick up heavy metals from the water. A contaminated water supply could be a real concern with older buildings that potentially have lead pipes or copper/iron pipes connected with lead-based solder11.
• Some heavy metals are leached out from delivery devices, such as vaping sticks, inhalation devices and infused transdermal patches. In particular, ensure that internal parts of vaping devices such as battery connections, atomizer, tank, and mouthpiece are not made from metallic components that could corrode at elevated vaping temperatures and deliver elemental contaminants such as Pb, Cr, Ni, Co and Fe to the consumer12.
• Some silicate glasses and inexpensive plastics are notorious for elemental contamination, which could leach out into the product during storage. Even some cannabis rolling papers contain elemental impurities13.
• Raw materials used in cannabinoid tablets, gel caps, creams, oils, edibles, and drinks formulations, that could possibly be contaminated with heavy metals. Examples of this would be fillers, excipients, dissolution raw materials which are added to the tablet formulations, or diluent/mineral oils used in vaping liquids. Historically elemental impurities have been found in some dietary supplements14.
• Any products or ingredients that come from Asia can potentially be a source of contamination. Think melamine in infant formula/pet food, lead-paint on toys, and lead in fake silver jewelry. In particular, it has been shown that inexpensive vaping cartridges that are sourced in China, contain metallic components that corrode when vaped15.
The smoking/inhaling of cannabisIt’s worth pointing out that historically, most consumers of recreational cannabis have used it by the inhalation/smoking route. Smoke chemistry has been predominantly investigated in tobacco products but many studies over the past ten years have highlighted the qualitatively similar carcinogenic chemicals contained within both tobacco and cannabis smoke16. In a recent study, the International Organization for Standardization and Health Canada analyzed tobacco and cannabis cigarettes. The heavy metals contained in both smoked products included: mercury, cadmium, lead, chromium, nickel, arsenic, manganese, and selenium17. Quantitatively, there were lower heavy metal concentrations in cannabis smoke condensates, due mainly to the fact that the cannabis supply was grown hydroponically. In addition, the soilless growth medium of the cannabis plants required water and water-soluble hydroponic vegetable fertilizers which contain nitrogen in the form of nitrates. So, with no soil-based heavy metals to be extracted during the growth cycle of the cannabis, it was the liquid fertilizers used in the hydroponic systems that contributed most to the heavy metal levels. There is a great deal of information in the public domain about heavy metals in tobacco and tobacco products, such as nicotine and electronic nicotine delivery (END) devices18.
However, the more common way of inhaling cannabis products today is via vaping sticks or pens. These devices are being marketed to the younger consumer by giving them fruit and peppermint flavors. The demand for these vaping devices is almost out of control and as a result, very loosely regulated, which is attracting manufacturers with very little regard for safety. There are literally thousands of these devices in the marketplace where the cannabis extract or oil is heated up to about 15-200 °C and the aerosol is vaporized into the consumer’s mouth, very much like an inhaler for an asthma sufferer. The problem with this mode of delivery is that many of the components inside these vaping devices are typically metal, including the liquid tank, coil, mouthpiece and battery terminals, which are usually made from materials such as stainless steel (Fe, Cr, Ni, Co), brass (Cu, Zn), chromel (Cr, Ni), inconel (Ni, Cr, and Fe), Nichrome (Ni, Cr) and soldered battery connectors (Pb, Sb, Sn). This means that at these kinds of temperatures, dissolved metals or even fine metallic particles will almost certainly be delivered to the consumer’s air pathways and lungs via the mouth19.
This is of great concern, because unlike oral delivery through the mouth and gastro intestinal digestion system, the lungs and respiratory system were designed to allow us to breathe. They bring oxygen from the air into our bodies and send carbon dioxide out. Air enters the respiratory system through the nose or the mouth. If it goes in through the nostrils there are tiny hairs called cilia that protect the nasal passageways and other parts of the respiratory tract, filtering out dust and other particles that enter the nose. There is no such filtering system in the mouth, so if any metal particulates are inhaled, there is no mechanism to stop them entering through the respiratory system into the lungs, where they can do serious damage, particularly if vaping is carried out on a regular basis over extended periods of time.
The recent nationwide outbreak of lung injuries and deaths by consumers using e-cigarettes, and/or cannabis vaping products that contain vitamin E acetate is a tragic testament to this fact. It’s also worth pointing out that most state-based regulations only specify Pb, As, Cd and Hg, and as a result, would not identify the other elements (Fe, Cu, Zn, Cr, Ni, Sb, and Sn) if they were present in the vaping liquid because there is no requirement to test for them.
It took the pharmaceutical industry almost 25 years to fully-understand all the sources of elemental impurities in the manufacture of drug products. The cannabis industry has a great deal to learn about this process. The way to minimize heavy metals in cannabis and cannabis products is to first understand and characterize the cultivation process. Unfortunately, this is often very challenging, particularly if the plants are being grown outdoors. However, by carefully selecting the right cultivars and optimizing the extraction method, processors have the ability to reduce levels of heavy metals in the final cannabinoid extracts. Very often there are many choices when selecting an extraction technology, depending on the desired extract or the products being made for a therapeutic outcome. It is clear that elemental contaminants can be minimized by optimizing the entire production process including extraction solvent, temperature/pressure conditions, and the other techniques used including evaporation/distillation/filtration. This can also be extended to include the packaging and delivery systems, which are all important to characterize heavy metals in order to ensure that all cannabis products are safe for consumption.
One final thought to consider. The New England Journal of Medicine published a letter recently from a group of cannabis researchers who were very concerned that they could not find good quality cannabis free of contaminants for their studies into the human endocannabinoid system. The major reason being that the DEA limits the number of licenses they give out to cultivators/processors because cannabis is still categorized as a Schedule 1 drug. As a result, researchers are limited to a small number of sources of cannabis, which does not reflect the wide variety of products and cannabinoid formulations that patients obtain from commercial dispensaries. So, this is a problem that highlights cannabis contamination from a slightly different perspective...not from a consumer safety perspective, but from investigators who just cannot find good quality cannabis for medical research20.
2. Lawsuit over heavy metals in CBD products raises more questions than answers, E. Watson, Food Navigator, May 11, 2020, https://www.foodnavigator-usa.com/Article/2020/05/11/Lawsuit-over-heavy-metals-in-CBD-products-raises-more-questions-than-answers-says-attorney-Hemp-Authority-seal-gains-traction#
3. Marijuana contaminated with heavy metals, pesticide recalled in testing lab investigation, A. Biolchini, Michigan live, August, 30, 2019, https://www.mlive.com/news/2019/08/marijuana-contaminated-with-heavy-metals-pesticide-recalled-in-testing-lab-investigation.html
4. Ohio medical marijuana program issues first mandatory product recall, L. Hancock, Cleveland Online, November 15, 2019, https://www.cleveland.com/open/2019/12/state-regulators-issue-second-mandatory-recall-of-ohio-medical-marijuana-product.html
5. California Testing Lab Falsification Might Cause Huge Cannabis Product Recall, December 4, 2018, EcoWaste, https://ecowasteservices.com/california-cannabis-testing-lab-falsification-recall
6. Maryland cannabis regulators warn of lead contamination risk as they expand tests for heavy metals D. Donovan, The Baltimore Sun, June 4, 2019, https://www.baltimoresun.com/health/marijuana/bs-md-cannabis-heavy-metals-20190605-story.html
7. Hawaiian Cannabis Vape Cartridges Are Contaminated With Ethanol and Lead, Tests Find, L. Bear-McGuiness, June 9, 220, Analytical Cannabis, https://www.analyticalcannabis.com/news/hawaiian-cannabis-vape-cartridges-are-contaminated-with-ethanol-and-lead-tests-find-312447
8. Extraction of Pharmaceutically Active Components from Plant Materials, G. Whittle et. al., United States Patent, Number: 7,344.736, March 18, 2008, https://patentimages.storage.googleapis.com/8b/d5/bb/9c377f6598f6a2/US7344736.pdf
9. Cannabis contaminants: sources, distribution, human toxicity and pharmacologic effects, L. Dryburgh et.al., Br J Clin Pharmacol 2018 Nov; 84(11): 2468–2476, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177718/
10. Cannabis Contaminants: Regulating Solvents, Microbes, and Metals in Legal Weed, N. Seltenrich, Environmental Health Perspectives, 20 August 2019, https://doi.org/10.1289/EHP5785
11. America’s Clean Water Crisis Goes Far Beyond Flint. There’s No Relief in Sight. J. Moorland, Time Magazine, Feb 20, 2020, https://time.com/longform/clean-water-access-united-states/
12. Metal Concentrations in e-Cigarette Liquid and Aerosol Samples: The Contribution of Metallic Coils. P. Olmedo et. al., Environmental Health Perspectives, February, Feb 21; 126 (2), 2018.
13. Heavy Metals Contamination: Is Cannabis Packaging to Blame? R. Newman, Analytical Cannabis, Feb 20, 2020, https://www.analyticalcannabis.com/articles/heavy-metals-contamination-is-cannabis-packaging-to-blame-312246
14. Facing the Problem of Dietary-Supplement Heavy-Metal Contamination: How to Take Responsible Action, R. Liva, Integrative Medicine, Vol. 6, No. 3, Jun/Jul 2007, http://www.imjournal.com/resources/web_pdfs/0607_liva.pdf
15. Journey of a Tainted Vape Cartridge: from China’s Labs to Your Lungs, D. Downs, D. Howard, B. Barcott, Leafly, September 24, 2019, https://www.leafly.com/news/politics/vape-pen-injury- supply-chain-investigation-leafly
16. Toxic Metal Concentrations in Mainstream Smoke from Cigarettes Available in the USA, R. Pappas et al. al. Journal of Analytical Toxicology; 38:204–211, 2014
17. Analysis of Heavy Metals in Cigarette Tobacco, J. Pariati, Journal of Medical Discovery, March 2017.
18. Toxic Metal Concentrations in Mainstream Smoke from Cigarettes Available in the USA, R. Pappas et al. Journal of Analytical Toxicology; 38:204–211, 2014
19. Toxic Metals Found in E-Cigarette Vapor, A Moses, WebMD, Feb 26, 2018, https://www.webmd.com/smoking-cessation/news/20180226/toxic-metals-found-in-e-cigarette-vapor#1
20. The State of Cannabis Research Legislation in 2020 by A.J. Zarrabi, et.al., .New England Journal of Medicine, HHS Public Access, June 16, 2020,