Understanding Sources of Heavy Metals in Cannabis and Hemp: Benefits of a Risk Assessment Strategy – Part 3

Part 3: The extraction of cannabinoids?

Part 1 of this series of articles highlighted the pharmaceutical risk assessment approach from a historical perspective to better understand sources of heavy metal contaminants in drug products. Part 2 explored why the cannabis industry could benefit from a similar strategy and in particular how the cultivation process likely contributed to sources of metal uptake from the soil and growing environment.

Part 3 will examine the critically important step of extracting cannabinoids from the biomass, the flower, and other parts of the plant.

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 that secrete a sticky resin that contains 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-plus 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-plus 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 is 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, known as decarboxylation, converts the compounds 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 is therefore clear that heat is a very efficient way to increase the bioavailability of certain compounds in cannabis. However, heat alone 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 a precise control of temperature, pressure and flow, which allows for the optimization and fine-tuning of the products being made.

Note: Although not the focus of this article, delta-8-THC is another compound of concern. It is manufactured synthetically from CBD¹ and has only recently entered the marketplace. The potential for elevated levels of contaminants is much higher than with delta-9-THC or CBD because of the manufacturing process, which uses solvents such as toluene and sulfonic acid as a catalyst. This results in an impure product that requires further clean-up to purify, which often does not happen because of the higher cost of production.

Extraction approaches

The methods used to extract cannabinoids are as varied as the compounds themselves. Some techniques use temperature, pressure, and flow, 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 methods. 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 multitude of different extraction techniques, all with their own strength and weaknesses. Let us take a closer look at three of the most common approaches².

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. The process also often extracts unwanted chlorophyll and plant waxes from the cannabis flower due to the polarity of the ethanol solvent. The mixture then 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 that 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 is already becoming a popular choice. In brief, the method involves using special pressure, temperature, and flow control equipment to turn gaseous CO₂ into a super or sub-critical nonpolar fluid. When passed over cannabis material, the fluid can easily extract plant waxes and oils from the cannabis. Super-critical fluid extraction employs higher temperature, pressure, and flow, which is good for THC/CBD yield, but tends to extract more of the non-targeted compounds including contaminants. The subcritical method employs a much lower temperature, pressure, and flow, which sacrifices yields, but leaves many of the contaminants behind. When cannabis is processed under relatively low pressure, temperature and flow conditions over a longer time, the amount of post-processing that is required after extraction is minimized and can usually be used without any further processing. When using higher temperature, pressure and flow 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 and can pull unique compounds from botanicals using different pressures, temperatures, and flows. In addition, the gas 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.

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 does not decide on whether they are going to use CO₂, butane, ethanol, or another extraction process. Instead, their decision is driven by what isolate/concentrate they are trying to make, based on the desired finished product. Whether it is a vape pen, a gummy, a cookie, a tincture, or an oil, it begins with the final product and then it is “reverse engineered” to get the ingredients for those products. There is then a final 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 is 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 procedures³.

Production of cannabis consumer products

So, with this as background information, here are some suggestions to reduce the likelihood of metals contaminating the cannabinoids during the cannabis preparation, extraction, and purification process:

• Minimize the use of metal-based processing/extraction/blending equipment. Perhaps there is a polymer alternative that could be used? In particular, avoid the use of stainless-steel mixing vats, processing vessels, cutting blades, scissors and grinding equipment. Depending on the quality/specification of the stainless steel, metals ions could find their way into the processed cannabis flowers and eventually into the extracted oils and concentrates⁴.
• If possible, use an optimized solvent and extraction/distillation process to minimize the amount and number of metals ending up in the extracted products. It would also be useful to characterize the metal content at every step of the manufacturing process from the extraction and purification to the final consumer product⁵.
• Some extraction processes are known to be better for low carry-over of metals. For example, a patent application by GW Pharmaceuticals (manufacturer of Epidiolex for childhood seizures) in 2008 for the extraction of pharmaceutically active components from plant materials showed the benefits of a sub-critical, low pressure/low temperature fluid extraction process using carbon dioxide to minimize the carryover of metals into the cannabinoid extracts⁶.
• Use ultra-clean solvents and chemicals low in heavy metals for the extraction, distillation, concentration, and infusion of cannabinoids from the plants⁷.
• 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 Environmental Protection Agency (EPA) maximum contaminant levels (MCL), otherwise the extracted material could pick up 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 solder. If in doubt, use pharmaceutical-grade water as per ICH Q3D guidelines^{8, 9, 10}.

The balance between low heavy metals or high potency yield

It is well-recognized that many metal ions and species are only slightly soluble in organic solvents, but this is dependent on a combination of the specific metal ion, its 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 is 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. We thought there might be a comparison between heavy metal levels in cannabis flowers and the resulting extracted concentrate but there does not seem to be any published literature on this topic, indicating that if it has been studied, the information remains proprietary. As a general rule, it appears that everything is geared towards maximum potency yield, and much of the literature just assumes 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 mercury¹¹. 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 form¹². We are also now beginning to see more CBD products derived from hemp in the marketplace, which is predominantly grown outdoors, where the cultivation conditions and, in particular, the quality of the fertilizers are far less controlled¹³. 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 am very hopeful that a concerned processor, university, or research organization will take up this challenge.

Final thoughts

Part 3 has taken a closer look at the cannabis extraction process and what potential elemental contaminants could find their way into cannabinoid products. The final part of the series will focus on the rest of production process, including the manufacturing of specific cannabinoid infused products, such as edibles, tincture, oils and vapes, and emphasize how a meaningful risk assessment approach is critically important to  reduce the likelihood of heavy metal contaminants ending up in these consumer products.

References

1. It’s time to hold cannabinoid products to the highest standard: USP Cannabis Panel statement on delta8-THC, https://www.usp.org/sites/default/files/usp/document/our-science/usp-delta-8-final-12-2-21.pdf
2. Advances in Whole Plant Cannabis Extraction, A Beadle, Analytical Cannabis, June 15, 2019, https://www.analyticalcannabis.com/articles/advances-in-whole-plant-cannabis-extraction-312087
3. 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
4. Cannabis Contaminants: Sources, Distribution, Human Toxicity and Pharmacologic Effects, L. Dryburgh et.al., Journal of Clinical Pharmacology Nov; 84(11): 2468– 2476, 2018,  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177718/
5. Cannabis Contaminants: Regulating Solvents, Microbes, and Metals in Legal Weed, N. Seltenrich, Environmental Health Perspectives, 20 August 2019, https://doi.org/10.1289/EHP5785
6. 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
7. Processing and Extraction Methods of Medicinal Cannabis: A Narrative Review, M. Lazajarni et.al., Journal of Cannabis Research., 3: 32, Published online 2021 Jul 19. Doi:10.1186/s42238-021-00087-9
8. ICH Guideline Q3D on Elemental Impurities (R1), European Medicine Agency Website: https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-32.pdf
9. 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/
10. Flint Drinking Water Response, EPA Continues to Oversee State and City Action to Protect Public Health, The U.S. Environmental Protection Agency (EPA), https://www.epa.gov/flint
11. Mercury Contamination of Aquatic Ecosystems, USGS Fact sheet, Fact Sheet 216-95, https://pubs.usgs.gov/fs/1995/fs216-95/
12. Mercury in the Food Chain, Health Canada, https://www.canada.ca/en/environment-climate-change/services/pollutants/mercury-environment/health-concerns/food-chain.html
13. 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