Regulating Heavy Metal Contaminants in Cannabis: What Can be Learned from the Pharmaceutical Industry? Part 3

Potential sources of contamination: the cannabinoid manufacturing process

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 two focused on how growers and cultivators need to be actively investigating all the potential sources of elemental contamination before they can even hope to minimize them. Part three will examine how the manufacturing process can contribute to the problem.

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.

Manufacturing challenges

With the approval of USP Chapter <232>, Chapter <233>, and ICH Q3D guidelines, the pharmaceutical industry was mandated to fully-understand elemental pathways of the entire drug manufacturing process, including impurities derived from the raw materials, excipients, active ingredients, organic synthesis method, water quality, manufacturing equipment, mixing vessels, containers, and packaging, etc.^1,2,3 To comply with these directives, companies had to show convincing evidence (data and/or risk assessment studies) to the regulatory agency that up to 24 elemental impurities of toxicological concern are below certain maximum permitted daily exposure (PDE) limits for three different drug delivery methods (oral, parenteral, inhalation). The process was challenging, painful, and sometimes confusing, but after a 20-year approval process, they eventually met the challenge by generating the necessary data to show that drugs were safe to use. 

Similarities between production of pharmaceuticals and cannabinoids

Unfortunately, the cannabis and hemp industries are moving so rapidly that few are taking the time to investigate potential sources of heavy metals throughout the entire manufacturing processes of the multitude of cannabinoid products on the market today.

It is well-accepted that cannabis and hemp will absorb heavy metals from the growing medium, soil, nutrients, and fertilizers. However, at present, there is less understanding of what heavy metals contaminants are carried over into the pure cannabinoid extracts from the various purification steps, including preparation, extraction, evaporation, concentration and distillation. It makes sense that there is some degree of transfer from the plant to the extract, but how do the extraction processes and the solvent properties have an impact on the amount carried over?

To better understand all these potential sources of contamination in the production of cannabinoid products, the cannabis plant can be considered very similar to the raw materials used in pharmaceutical manufacturing; while the various cannabinoids can be likened to the active pharmaceutical ingredients (API) used in the drug formulation. The similarities are quite striking, because pharmaceutical manufacturers had to characterize the entire production process to reduce elemental impurities in drug products. Therefore, the cannabis industry clearly has to better understand the entire cannabinoid production process including the cultivation and extraction steps in order to reduce heavy metal contaminants in the final products.

Cannabis extraction

Extraction is necessary to purify and concentrate the essential cannabinoid compounds from the plant while also removing the undesired contaminants. These compounds are mainly contained in the female flower’s trichomes, small glandular hairs protruding from the surface of the plant, which secrete a sticky resin from the cells at the end of the trichome, containing most of the cannabinoids and terpenoids of interest. When the optimum extraction method is employed it can either result in pure, isolated compounds or more natural, full-spectrum extracts containing a wide array of the cannabinoids and terpenoids found in the source material. Most consumers of cannabis are familiar with delta-9- tetrahydrocannabinol (THC) and cannabidiol (CBD) but these are only two of the 100+ cannabinoid compounds found in cannabis. The ability to extract the desired compounds allows medicinal products to be manufactured based on the desired therapeutic effect for the specific ailment being treated. However, cannabis also contains 140+ different terpenes (terpenoids), aromatic compounds best-known for giving cannabis its distinctive fragrances and flavors. Terpenes are currently gaining a great deal of attention not only for their potential therapeutic value, but also because of the so called “entourage effect” when combined with other cannabinoids.

The technology needed to extract bioactive compounds from the flower’s trichomes, or other parts of the plant, clearly depends on medicinal product goals. It’s also important to emphasize that when cannabis is harvested, it contains practically no THC and CBD. There are, however, significant amounts of tetrahydrocannabinolic acid (THCA), and cannabidiolic acid (CBDA). So to convert THCA and CBDA to THC and CBD, the cannabis must first be heated to remove the carboxyl functional group (COOH) from the respective THCA and CBDA molecules. This process is known as decarboxylation, which converts them into THC and CBD respectively. These chemical structures are the gateway molecules to the human endocannabinoid system (ECS) that runs throughout the central nervous system, delivering the desired therapeutic/psychoactive effect.

It’s therefore clear that heat is a very efficient way to increase the bioavailability of certain compounds in cannabis; however, it does not give us the ability to select which compounds we want to activate. This is achieved by carrying out extraction procedures using different organic solvents, often combined with precise control of temperature and pressure, which allows for the optimization and fine-tuning of the products being made. 

Extraction approaches

The methods used to extract cannabinoids are as varied as the compounds themselves. Some techniques use temperature and pressure, relying on thermal and mechanical forces to remove valuable compounds from the plant’s trichomes; others rely on organic solvents to carry the desired compounds into another solution, which is then processed again to remove the solvent. Some even use microwave- and ultrasonic-assisted extraction methods⁴. Whatever extraction technique is employed, they all use a combination of solvent, temperature, pressure, and time, in a precise, controlled manner, to access one or many of the cannabinoids, flavonoids, and terpenes present in the cannabis plant. There are a myriad of different extraction techniques, all with their own strength and weaknesses. Let’s take a closer look at three of the most common approaches⁵.

Alcohol extraction

Alcohol extraction is one of the most efficient extraction methods for processing large batches of cannabis flower, and can be done in hot, cold, or room temperature conditions. Typically carried out using hot ethanol (or propanol), extraction is generally accomplished using the Soxhlet extraction technique, which cycles the hot solvent through the solid cannabis flower, stripping the cannabinoids and terpenes from the flower in the process. However, the method can be difficult to scale up to large batches, and often extracts unwanted chlorophyll and plant waxes from the cannabis flower due to the polarity of the ethanol solvent that often requires several additional post-processing steps (filtering, distillation, evaporation etc.). Cold ethanol or even room temperature helps to avoid this problem, as the cooler temperatures make it a little more difficult for the unwanted polar plant waxes and chlorophylls to dissolve in a polar ethanol solvent.

Hydrocarbon extraction

Hydrocarbon extraction, normally achieved using butane or propane, is able to extract a greater variety of terpenes from the cannabis material than the ethanol extraction method. For products such as vape oils or oral tinctures, where the cannabis extract is unlikely to be masked by other flavors, preserving these terpenes helps to give the extract a specific flavor and aroma.

This improved extraction comes as a result of the low boiling point of the hydrocarbon, (butane, -0.5°C) at standard pressure. After cold butane solvent has washed over the cannabis plant material and extracted its oils, the solvent can be easily cold-boiled off to leave oil which is more representative of the entire plant as more of the temperature-sensitive terpenes will be retained.

However, like the ethanol method, hydrocarbon extraction cannot be so easily scaled up to deal with large single batches of cannabis material. While the low boiling point of butane is advantageous when the solvent needs to be removed without removing any other organic compounds, these flammable solvents also present a safety hazard to workers. Hydrocarbon extraction is a very hands-on process and is rarely automated, meaning that there is almost always an operator in close proximity to the extraction vessel. In the interest of safety, hydrocarbon extraction is done on a much smaller scale, though the speed and efficiency of this extraction method means its overall output still makes it suitable for large-scale operations.

Super/subcritical CO₂ fluid extraction

Super- or sub-critical CO₂ fluid extraction is relatively new to the cannabis industry, but it’s already becoming a popular choice. In brief, the method involves using specialist pressure and temperature control equipment to turn gaseous CO₂ into a super or sub-critical fluid. When passed over cannabis material, the fluid can easily extract plant waxes and oils from the cannabis. Super-critical fluid extraction refers to a higher temperature and pressure, which is good for THC/CBD yield, but tends to extract more of the non-targeted compounds including contaminants. While the subcritical method uses a much lower temperature and pressure, which sacrifices yields, but leaves many of the contaminants behind

When cannabis is processed under relatively low pressures and temperature conditions over a longer period of time, the amount of post-processing that’s required after extraction is minimized, and can usually be used without any further processing. When using higher temperature and pressure conditions, winterization is often used to clean up the extract and remove unwanted waxes and fatty acids. This is achieved by soaking the extract in cold ethanol (-20°C) for approximately 24 hours and then filtering out the unwanted solid waxes and lipids.

The major downside of CO₂ extraction is the high initial equipment cost which can be prohibitive for start-ups or small businesses.  However, unlike ethanol or butane, CO₂ is a very flexible and tunable solvent, which can pull unique compounds from botanicals using different pressures and temperatures. In addition, CO₂ is far safer than the flammable hydrocarbon methods. It is also worth noting that butane extraction often results in a more concentrated product, which can be detrimental if the cannabis material contains toxins or contaminants from the cultivation process. 

Rigorous testing

As mentioned in part one and part two of this series of articles, cannabis plants are avid accumulators of heavy metal contaminants in the growing medium, soil, fertilizer and other environmental pathways, which can end up being concentrated in the final extract. This can be significantly compounded if further preparation, distillation, evaporation, or concentration steps are required, using metal processing equipment and storage containers, which are potential additional sources of contamination. For this reason, extraction and processing techniques must be supported by rigorous scientific testing from the very start of the production cycle. This means that the best practices in cannabis extraction often start at the growing stage.

Cannabis that is grown in controlled environments and under strict quality control usually produces the purest extracts. In other words, if the cultivation of the plant is carried out indoors using clean, uncontaminated growing medium, high purity nutrients and fertilizers and ultra clean water, it’s probably going to result in low levels of elemental contaminants in the plant. Of course, this is not always going to happen, but will likely be the case when compared to plants cultivated outdoors, which could pick up significant levels of heavy metals if grown in, near or around contaminated soil or if low quality fertilizers are used (refer to part two on sources of contamination in the cultivation process). 

Extraction objectives

The optimum extraction method is often selected based on what cannabinoid/terpenoid combination is required, which is typically chosen based on the required medicinal product or desired therapeutic/psychoactive outcome. In other words, a processor doesn’t decide on whether they are going to use CO₂, butane, ethanol, or another extraction process. Instead it’s driven by what isolate/concentrate they are trying to make, based on the desired finished product. Whether it’s a vape pen, a gummy, a cookie, a tincture or an oil, it begins with the final product and then it’s “reverse engineered” to get the ingredients for those products and then finally selection of the extraction method that will best provide those ingredients.

This fundamental “reverse engineering” principle can even be related back to the cultivar as it’s important to select the plant that will provide the desired molecular profile or to manipulate the chemistry to get the desired ingredients. David Hodes wrote an excellent review of the major commercial extraction methods and the pros and cons of using each approach, which is highly recommended reading for any current or new processor who wants to optimize their extraction procedures⁶.

Heavy metal absorption mechanisms

Part two of the series looked at how cannabis plants take up heavy metals through their roots from the growing medium, where it’s eventually stored in the shoots, leaves, and flowers. Khan and coworkers wrote a very informative paper on tracing the movement of heavy metals from the soil into the cannabis plant and investigating which part of the plant they eventually ended up in⁷. Let’s just recap how this mechanism takes place.

The transport of minerals from the growing medium into the cannabis root is an active process that is energy dependent. We know that the concentration of essential minerals in root tissue is significantly higher than the surrounding soil, making this concentration difference unfavorable for passive transport. By pumping protons out of the root cells, the positive charge of the soil increases creating a gradient that drives desirable cations into the plant cells. Unfortunately, these transport channels don’t exclude chemically similar ions making them a possible entry point for heavy metals in the soil.

Once they have entered the plant tissue, these minerals and/or heavy metals are secreted into the xylem by nearby cells. The xylem is mainly used for transporting water from roots to stems and leaves but will also transport other metal ions in solution. Once these metal ions have entered the xylem, they are swept up by the transpiration process and distributed throughout the plant, in many cases, bound up with chlorophyll molecules. Some of the ions will move laterally throughout the roots and stems, while others will continue on to the leaves where they are released into the atmosphere through the stomata. However, most of the metal ions will be actively transferred to the phloem, which is responsible for transporting food produced from photosynthesis to other parts of the plant, including the reproductive organs, the flowers, and the trichome cells⁸.

Traditional pathways

Unfortunately, many of the heavy metals found in the soil, exist in different oxidation states, metalloid forms, organo-metallic species, and possibly nanoparticles. Some are impacted by nitrogen phosphorus and potassium (NPK) from the nutrients/fertilizers. Others are dependent on the soil pH, while some end up being complexed with natural chelating agents in the soil, like humic acid or bound up with other transition metals such as iron and manganese.

Additionally, the plant’s own polyamine compounds will strengthen its natural defense mechanism against diverse environmental stressors such as metal toxicity and oxidative stress. The journey of elemental contaminants from the growing medium to the cannabis flower isn’t completely understood – it’s an area of research that has not been fully explored. We can only go on what is known about traditional agricultural plants and botanicals, and make the assumption that they are very similar, which means that the elemental movement via the cells and other biochemical pathways are varied and diverse based on the growing conditions and the individual metal species. However, it can be fair to assume that the trichomes of the female cannabis flower, which are home to 100+ cannabinoid compounds, also contain many heavy metal contaminants derived from the growing process. 

Low heavy metals or high potency yield

It’s well-recognized that many metal ions and species are only partially soluble in organic solvents, but this is going to be dependent on a combination of the specific metal ion, species, and oxidation state, the polarity and boiling point of the solvent, and the extraction temperature and pressure used. This begs the question, what is the optimum extraction technique to minimize the heavy metals carried over but to maximize the cannabinoid yield? It’s well-accepted that most cannabinoids are not very water-soluble, so what is the right balance with regard to solvent choice and polarity to optimize this extraction process. Unfortunately, there is very little information in the public domain on this topic. I thought there might be a comparison between heavy metal levels in cannabis flowers and the resulting extracted concentrate, but unfortunately, my research was not fruitful. For that reason, I suspect there has been no such study carried out and processors have not fully investigated the problem. It appears that everything is geared towards maximum potency yield and they just hope that most of the heavy metals are left behind in the extraction/distillation process and are not being co-extracted/co-distilled with the cannabinoid.

This is probably a sound strategy if the plants have been cultivated indoors, where the growing conditions are far more controlled and the heavy metals in the plant should be relatively low. However, that is not always the case. For example, some indoor growers are now using organic fish emulsion/hydrolysates, which are notorious for containing high levels of mercury⁹. This is predominantly a result of bioaccumulation up the food chain from the smaller bottom feeders to the large predatory fish. The mercury is typically environmental fallout from industrial activity (power plants, metal refineries etc.), which ends up in the sediment of ponds, rivers and lakes and often gets converted to methyl mercury (CH₃Hg), which is even more toxic than the elemental form^{10, 11}.

We are also now beginning to see CBD products derived from hemp in the marketplace, which is predominantly grown outdoors, where the cultivation conditions are less controlled. This leads to the conclusion that heavy metals in plants grown outdoors are potentially going to be much higher. For these reasons, there clearly needs to be a scientifically driven investigation to better understand the level of heavy metal movement from the plant through each step of the preparation/extraction/distillation/concentration process. I’m very hopeful that a concerned processor, university, or research organization will take up this challenge. 

Final thoughts

In this part we’ve covered how common processing and production steps can influence the incidence of heavy metals found in cannabis products in the marketplace. This was a similar predicament to the pharmaceutical industry over 20 years ago until regulators mandated them to fully understand all the potential sources of elemental impurities in their drug products.

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 state and government recalls and in some cases lawsuits filed 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.

You can read Part 4 of this article series from Rob Thomas by clicking here. 

Further reading

1. 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
   
2. 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
3. ICH Website: http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html (Q3D)
4. Cannabis Concentrates: Differences Between Microwave and Ultrasonic Assisted Extraction, A. Mayfield, Extraction Magazine, March 22, 2018, https://extractionmagazine.com/2018/03/22/cannabis-concentrates-differences-between-microwave-and-ultrasonic-assisted-extraction/
5. Advances in Cannabis Extraction, A Beadle, Analytical Cannabis, June 15, 2019, https://www.analyticalcannabis.com/articles/advances-in-cannabis-extraction-techniques-311772
6. New Extraction Technologies Lining Up to Be Game-Changers, D. Hodes, Cannabis Science and Technology, Vol 3, Issue 4, May, 2020, https://www.cannabissciencetech.com/extraction/new-extraction-technologies-lining-be-game-changers
7. Effect of Soil Contamination on Some Heavy Metals Content of Cannabis Sativa, Khan Et.al., J. Chem. Soc. Pak., Vol. 30, No.6, 2008.
8. Back to the Root—The Role of Botany and Plant Physiology in Cannabis Testing, Part I: Understanding Mechanisms of Heavy Metal Uptake in Plants, G. Bode, Cannabis Science and Technology, Vol 3, No 2, March 2020, https://www.cannabissciencetech.com/metals/back-root-role-botany-and-plant-physiology-cannabis-testing-part-i-understanding-mechanisms-heavy
9. The Presence and Transmission of Heavy Metals in Plant Fertilizers, L. Macri, Maximum Yield, September 1, 2016, https://www.maximumyield.com/the-presence- and-transmission-of-heavy-metals-in-plant-fertilizers/2/2640
10. Mercury Contamination of Aquatic Ecosystems, USGS Fact sheet, Fact Sheet 216-95, https://pubs.usgs.gov/fs/1995/fs216-95/
11. Mercury in the Food Chain, Health Canada, https://www.canada.ca/en/environment-climate-change/services/pollutants/mercury-environment/health-concerns/food-chain.html

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