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From The Lab

I Was Wrong… und das ist auch gut so!

By Dr. Markus Roggen
3 Comments

I was wrong. And that’s a good thing! Based on all available data, I assumed that evaporating ethanol from a cannabis oil/ethanol solution would result in terpene loss. As it turns out, it doesn’t. There are so many beliefs and assumptions about cannabis: Cannabis cures cancer!1 Smoking cannabis causes cancer!2 Sativas help you sleep; Indicas make you creative!3,4 CBD is not psychoactive!5 But are these ‘facts’ backed by science? Have they been experimentally tested and validated?

I postulated a theory, designed experiments to validate it and evaluated the results. Simply putting “cannabis backed by science” on your label does not solve the problem. Science is not a marketing term. It’s not even a fixed term. The practice of science is multifaceted and sometimes confusing. It evolved from the traditional model of Inductivism, where observations are used in an iterative process to refine a law/theory that can generalize such observations.6 Closely related is Empiricism, which posits that knowledge can only come from observation. Rationalism, on the other hand, believes that certain truths can be directly grasped by one’s intellect.7 In the last century, the definition of science was changed from the method by which we study something, such as Inductivism or Rationalism, and refocused on the way we explain phenomena. It states that a theory should be considered scientific if, and only if, it is falsifiable.8 All that means is that not the way we study something is what makes it scientific, but the way we explain it.

I wonder how can we use empirical observations and rational deliberations to solve the questions surrounding cannabis? And more importantly, how can we form scientific theories that are falsifiable? Cannabis, the plant, the drug, has long been withheld from society by its legal status. As a result, much of what we know, in fact, the entire industry has thrived in the shadows away from rigorous research. It’s time for this to change. I am particularly concerned by the lack of fundamental research in the field. I am not even talking about large questions, like the potential medical benefit of the plant and its constituents. Those are for later. I’m talking about fundamental, mundane questions like how many lumens per square centimetre does the plant need for optimal THC production? What are the kinetics of cannabis extraction in different solvents? What are the thermodynamics of decarboxylation? Where do major cannabinoids differ or align in terms of water solubility and viscosity?

The lack of knowledge and data in the cannabis field puts us in the precarious position of potentially chasing the wrong goals, not to mention wasting enormous amounts of time and money. Here’s a recent example drawn from personal experience:Certainly, I cannot be the only one who has made an incorrect assumption based on anecdotes and incomplete data?

Some of the most common steps in cannabis oil production involve ethanol solutions. Ethanol is commonly removed from extraction material under reduced pressure and elevated heat in a rotary evaporator. I expected that this process would endanger the terpenes in the oil – a key component of product quality. My theory was that volatile terpenes9 would be lost in the rotary evaporator during ethanol10 removal. The close values of vapor pressure for terpenes and ethanol make this a reasonably assumed possibility.11 In the summer of 2018, I finally got the chance to test it. I designed experiments at different temperatures and pressures, neat and in solution, to quantify the terpene lost in ethanol evaporation. I also considered real life conditions and limitations of cannabis oil manufacturers. After all the experiments were done, the results unequivocally showed that terpenes do not evaporate in a rotary evaporator when ethanol is removed from cannabis extracts.12 As it turns out, I was wrong.

We, as an industry, need to start putting money and effort into fundamental cannabis research programs. But, at least I ran the experiments! I postulated a theory, designed experiments to validate it and evaluated the results. At this point, and only this point, can I conclude anything about my hypothesis, even if that is that my working theory needs to be revised. Certainly, I cannot be the only one who has made an incorrect assumption based on anecdotes and incomplete data?

There is a particular danger when using incomplete data to form conclusions. There are many striking examples in the medical literature and even the casual observer might know them. The case of hormone replacement therapy for menopause and the associated risks of cardiovascular diseases showed how observational studies and well-designed clinical trials can lead to contradicting results.13 In the thirties of the last century, lobotomy became a cure-all technique for mental health issues.14 Dr. Moniz even won the Nobel Prize in Medicine for it.15 And it must come as no surprise when WIRED states “that one generation’s Nobel Prize-winning cure is another generation’s worst nightmare.”16 And with today’s knowledge is impossible to consider mercury as a treatment for syphilis, but that is exactly what it was used as for many centuries.17 All those examples, but the last one in particular should “be a good example of the weight of tradition or habit in the medical practice, […] of the necessity and the difficulties to evaluate the treatments without error.”18 There is the danger that we as cannabis professionals fall into the same trap and believe the old stories and become dogmatic about cannabis’ potential.

We, as an industry, need to start putting money and effort into fundamental cannabis research programs. That might be by sponsoring academic research,19 building in-house research divisions,20 or even building research networks.21 I fully believe in the need for fundamental cannabis research, even the non-sexy aspects.22 Therefore, I set up just that: an independent research laboratory, focused on fundamental cannabis research where we can test our assumptions and validate our theories. Although, I alone cannot do it all. I likely will be wrong somewhere (again). So, please join me in this effort. Let’s make sure cannabis science progresses.

References

  1. No, it does not. There are preliminary in-situ studies that point at anti-cancer effects, but its more complicated. The therapeutic effects of Cannabis and cannabinoids: An update from the National Academies of Sciences, Engineering and Medicine report, Abrams, Donald I., European Journal of Internal Medicine, Volume 49, 7 – 11
  2. No, it does not. National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. https://doi.org/10.17226/24625.
  3. No, it does not. The chemical profile of the plant dictates the biological effects on humans, not the shape of the leaf.  Justin T. Fischedick, Cannabis and Cannabinoid Research, Volume: 2 Issue 1: March 1, 2017
  4. Indica and Sativa are outdated terms. Piomelli D, Russo EB. The Cannabis sativa versus Cannabis indica debate: An Interview with Ethan Russo, MD. Cannabis Cannabinoid Res 2016; 1: 44–46.
  5. No, it is. CBD’s supposed “calming effects” is indeed a psychoactive effect. However, it is not intoxicating like THC. Russo E.B., Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects.Br. J. Pharmacol. 2011; 163: 1344-1364
  6. As attributed to Francis Bacon.
  7. See the work by philosopher Baruch Spinoza.
  8. As theorized by Karl Popper.
  9. Monoterpenes have a vapor pressure in the low to mid hundreds of Pascals at room temperature.
  10. Vapor pressure of 5.95 kPa at 20˚C.
  11. Furthermore, there is always the possibility of azeotropes in complex mixtures. Azeotropes are mixtures of two or more liquids that have different boiling points individually, but in mixture boil together.
  12. Terpene Retention via Rotary Evaporator Application Note, Heidolph North America
  13. https://www.pharmaceutical-journal.com/research/review-article/establishing-the-risk-related-to-hormone-replacement-therapy-and-cardiovascular-disease-in-women/20202066.article?firstPass=false
  14. https://psychcentral.com/blog/the-surprising-history-of-the-lobotomy/
  15. https://en.wikipedia.org/wiki/António_Egas_Moniz
  16. https://www.wired.com/2011/03/lobotomy-history/
  17. https://www.infezmed.it/media/journal/Vol_21_4_2013_10.pdf
  18. https://www.ncbi.nlm.nih.gov/pubmed/11625051
  19. Canopy Growth funds a professorship of cannabis science at UBC. Tilray collaborates with UCSD on a phase I/II clinical trial.
  20. For examples see: NIBR, PMISCIENCE.
  21. For examples see: CEMI, theAIRnet, Future Sky.
  22. Research that does not lead to short-term stock value spikes but long-term progress

Orange Photonics Introduces Terpenes+ Module in Portable Analyzer

By Aaron G. Biros
No Comments

Last week at the National Cannabis Industry Association’s (NCIA) Cannabis Business Summit, Orange Photonics unveiled their newest product added to their suite of testing instruments for quality assurance in the field. The Terpenes+ Module for the LightLab Cannabis Analyzer, which semi-quantitatively measures terpenes, Cannabichromene (CBC) and degraded THC, adds three new chemical analyses to the six cannabinoids it already reports.

CBC, a cannabinoid typically seen in hemp and CBD-rich plants, has been linked to some potentially impactful medical applications, much like the findings regarding the benefits of CBD. The module that tests for it, along with terpenes and degraded THC, can be added to the LightLab without any changes to hardware or sample preparation.

Dylan Wilks, chief technology officer of Orange Photonics
Dylan Wilks, chief technology officer of Orange Photonics

According to Dylan Wilks, chief technology officer of Orange Photonics, this could be a particularly useful tool for distillate producers looking for extra quality controls. Cannabis distillates are some of the most prized cannabis products around, but the heat used to create them can also create undesirable compounds,” says Wilks. “Distillate producers can see potency drop more than 25% if their process isn’t optimized”. With this new Terpenes+ Module, a distillate producer could quantify degraded THC content and get an accurate reading for their QC/QA department.

We spoke with Stephanie McArdle, president of Orange Photonics, to learn more about their instruments designed for quality assurance for growers and extractors alike.

Stephanie McArdle, president of Orange Photonics
Stephanie McArdle, president of Orange Photonics

According to McArdle, this could help cultivators and processors understand and value their product when terpene-rich products are the end goal. “Rather than try to duplicate the laboratory analysis, which would require expensive equipment and difficult sample preparation, we took a different approach. We report all terpenes as a single total terpene number,” says McArdle. “The analyzer only looks for monoterpenes (some common monoterpenes are myrcene, limonene and alpha-pinene), and not sesquiterpenes (the other major group of cannabis terpenes, such as Beta- Caryophyllene and Humulene) so the analysis is semi-quantitative. What we do is measure the monoterpenes and make an assumption that the sesquiterpenes are similar to an average cannabis plant to calculate a total terpene content.” She says because roughly 80% of terpenes found in cannabis are monoterpenes, this should produce accurate results, though some exotic strains may not result in accurate terpene content using this method.

The LIghtLab analyzer on the workbench
The LIghtLab analyzer on the workbench

As growers look to make their product unique in a highly competitive market, many are looking at terpenes as a source of differentiation. There are a variety of areas where growers can target higher terpene production, McArdle says. “During production, a grower may want to select plants for growing based on terpene content, or adjust nutrient levels, lighting, etc. to maximize terpenes,” says McArdle. “During the curing process, adjusting the environmental conditions to maximize terpene content is highly desirable.” Terpenes are also beginning to get recognized for their potential medical and therapeutic values as well, notably as an essential piece in the Entourage Effect. “Ultimately, it comes down to economics – terpene rich products have a higher market value,” says McArdle. “If you’re the grower, you want to prove that your product is superior. If you’re the buyer, you want to ensure the product you buy is high quality before processing it into other products. In both cases, knowing the terpene content is critical to ensuring you’re maximizing profits.”

Orange Photonics’ LightLab operates very similarly to instruments you might find in a cannabis laboratory. Many cannabis testing labs use High Performance Liquid Chromatography (HPLC) to analyze hemp or cannabis samples. “The primary difference between LightLab and an HPLC is that we operate at lower pressures and rely on spectroscopy more heavily than a typical HPLC analysis does,” says McArdle. “Like an HPLC, LightLab pushes an extracted cannabis sample through a column. The column separates the cannabinoids in the sample by slowing down cannabinoids by different amounts based on their affinity to the column.” McArdle says this is what allows each cannabinoid to exit the column at a different time. “For example, CBD may exit the column first, then D9THC and so on,” says McArdle. “Once the column separates the cannabinoids, they are quantified using optical spectroscopy- basically we are using light to do the final quantification.”

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The Four Pillars of Cannabis Processing

By Christian Sweeney
2 Comments
extractiongraphic

Cannabis extraction has been used as a broad term for what can best be described as cannabis processing. A well-thought-out cannabis process goes far beyond just extraction, largely overlapping with cultivation on the front-end and product development on the back-end1. With this in mind, four pillars emerge as crucial capabilities for developing a cannabis process: Cultivation, Extraction, Analytics and Biochemistry.

The purpose and value of each pillar on their own is clear, but it is only when combined that each pillar can be optimized to provide their full capacities in a well-designed process. As such, it is best to define the goals of each pillar alone, and then explain how they synergize with each other.

At the intersection of each pillar, specific technology platforms exist that can effectively drive an innovation and discovery cycle towards the development of ideal products.Cultivation is the foundation of any horticultural process, including cannabis production. Whether the goal be to convert pigments, flavors or bioactive compounds into a usable form, a natural process should only utilize what is provided by the raw material, in this case cannabis flower. That means cultivation offers a molecular feedstock for our process, and depending on our end goals there are many requirements we may consider. These requirements start as simply as mass yield. Various metrics that can be used here include mass yield per square foot or per light. Taken further, this yield may be expressed based not only on mass, but the cannabinoid content of the plants grown. This could give rise to a metric like CBD or THC yield per square foot and may be more representative of a successful grow. Furthermore, as scientists work to learn more about how individual cannabinoids and their combinations interact with the human body, cultivators will prioritize identifying cultivars that provide unique ratios of cannabinoids and other bioactive compounds consistently. Research into the synergistic effect of terpenes with cannabinoids suggests that terpene content should be another goal of cultivation2. Finally, and most importantly, it is crucial that cultivation provide clean and safe materials downstream. This means cannabis flower free of pesticides, microbial growth, heavy metals and other contaminants.

Extraction is best described as the conversion of target molecules in cannabis raw material to a usable form. Which molecules those are depends on the goals of your product. This ranges from an extract containing only a pure, isolated cannabinoid like CBD, to an extract containing more than 100 cannabinoids and terpenes in a predictable ratio. There are countless approaches to take in terms of equipment and process optimization in this space so it is paramount to identify which is the best fit for the end-product1. While each extraction process has unique pros and cons, the tunability of supercritical carbon dioxide provides a flexibility in extraction capabilities unlike any other method. This allows the operator to use a single extractor to create extracts that meet the needs of various product applications.

Analytics provide a feedback loop at every stage of cannabis production. Analytics may include gas chromatography methods for terpene content3 or liquid chromatography methods for cannabinoids 3, 4, 5. Analytical methods should be specific, precise and accurate. In an ideal world, they can identify the compounds and their concentrations in a cannabis product. Analytics are a pillar of their own due simply to the efforts required to ensure the quality and reliability of results provided as well as ongoing optimization of methods to provide more sensitive and useful results. That said, analytics are only truly harnessed when paired with the other three pillars.

extractiongraphic
Figure 1: When harnessed together the pillars of cannabis processing provide platforms of research and investigation that drive the development of world class products.

Biochemistry can be split into two primary focuses. Plant biochemistry focuses back towards cultivation and enables a cannabis scientist to understand the complicated pathways that give rise to unique ratios of bioactive molecules in the plant. Human biochemistry centers on how those bioactive molecules interact with the human endocannabinoid system, as well as how different routes of administration may affect the pharmacokinetic delivery of those active molecules.

Each of the pillars require technical expertise and resources to build, but once established they can be a source of constant innovation. Fig. 1 above shows how each of these pillars are connected. At the intersection of each pillar, specific technology platforms exist that can effectively drive an innovation and discovery cycle towards the development of ideal products.

For example, at the intersection of analytics and cultivation I can develop raw material specifications. This sorely needed quality measure could ensure consistencies in things like cannabinoid content and terpene profiles, more critically they can ensure that the raw material to be processed is free of contamination. Additionally, analytics can provide feedback as I adjust variables in my extraction process resulting in optimized methods. Without analytics I am forced to use very rudimentary methods, such as mass yield, to monitor my process. Mass alone tells me how much crude oil is extracted, but says nothing about the purity or efficiency of my extraction process. By applying plant biochemistry to my cultivation through the use of analytics I could start hunting for specific phenotypes within cultivars that provide elevated levels of specific cannabinoids like CBC or THCV. Taken further, technologies like tissue culturing could rapidly iterate this hunting process6. Certainly, one of the most compelling aspects of cannabinoid therapeutics is the ability to harness the unique polypharmacology of various cannabis cultivars where multiple bioactive compounds are acting on multiple targets7. To eschew the more traditional “silver bullet” pharmaceutical approach a firm understanding of both human and plant biochemistry tied directly to well characterized and consistently processed extracts is required. When all of these pillars are joined effectively we can fully characterize our unique cannabis raw material with targeted cannabinoid and terpene ratios, optimize an extraction process to ensure no loss of desirable bioactive compounds, compare our extracted product back to its source and ensure we are delivering a safe, consistent, “nature identical” extract to use in products with predictable efficacies.

Using these tools, we can confidently set about the task of processing safe, reliable and well characterized cannabis extracts for the development of world class products.

[1] Sweeney, C. “Goal-Oriented Extraction Processes.” Cannabis Science and Technology, vol 1, 2018, pp 54-57.

[2] Russo, E. B. “Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects.” British Journal of Pharmacology, vol. 163, no. 7, 2011, pp. 1344–1364.

[3] Giese, Matthew W., et al. “Method for the Analysis of Cannabinoids and Terpenes in Cannabis.” Journal of AOAC International, vol. 98, no. 6, 2015, pp. 1503–1522.

[4] Gul W., et al. “Determination of 11 Cannabinoids in Biomass and Extracts of Different Varieties of Cannabis Using high-Performance Liquid Chromatography.” Journal of AOAC International, vol. 98, 2015, pp. 1523-1528.

[5] Mudge, E. M., et al. “Leaner and Greener Analysis of Cannabinoids.” Analytical and Bioanalytical Chemistry, vol. 409, 2017, pp. 3153-3163.

[6] Biros, A. G., Jones, H. “Applications for Tissue Culture in Cannabis Growing: Part 1.” Cannabis Industry Journal, 13 Apr. 2017, www.cannabisindustryjournal.com/feature_article/applications-for-tissue-culture-in-cannabis-growing-part-1/.

[7] Brodie, James S., et al. “Polypharmacology Shakes Hands with Complex Aetiopathology.” Trends in Pharmacological Sciences, vol. 36, no. 12, 2015, pp. 802–821.

A More Effective and Efficient Approach to Purer Cannabidiol Production Using Centrifugal Partition Chromatography

By Lauren Pahnke
3 Comments

Many physicians today treat their patients with cannabidiol (CBD, Figure 1), a cannabinoid found in cannabis. CBD is more efficacious over traditional medications, and unlike delta-9 tetrahydrocannbinol (THC), the main psychoactive compound in cannabis, CBD has no psychoactive effects. Researchers have found CBD to be an effective treatment for conditions such as cancer pain, spasticity in multiple sclerosis, and Dravet Syndrome, a form of epilepsy.

CBD is still considered an unsafe drug under federal law, but to meet the medical demand, 17 states in the US recently passed laws allowing individuals to consume CBD for medical purposes. A recent survey found that half of medicinal CBD users rely on the substance by itself for treatment. As doctors start using CBD to treat more patients, the demand for CBD is only expected to rise, and meeting that demand can pose challenges for manufacturers who are not used to producing such high quantities of CBD. Furthermore, as CBD-based drugs become more popular, the US Food and Drug Administration (FDA) will likely require manufacturers to demonstrate they can produce pure, high-quality products.

cannabidiol
Figure 1. The structure of cannabidiol, one of 400 active compounds found in cannabis.

Most manufacturers use chromatography techniques such as high performance liquid chromatography (HPLC) or flash chromatography to isolate compounds from natural product extracts. While these methods are effective for other applications, they are not, however, ideal for CBD isolate production. Crude cannabis oil contains some 400 potentially active compounds and requires pre-treatment prior to traditional chromatography purification. Both HPLC and flash chromatography also require silica resin, an expensive consumable that must be replaced once it is contaminated due to irreversible absorption of compounds from the cannabis extract. All of these factors limit the production capacity for CBD manufacturers.

Additionally, these chromatography methods use large quantities of solvents to elute natural compounds, which negatively impacts the environment.

A Superior Chromatography Method

Centrifugal partition chromatography (CPC) is an alternative chromatography method that can help commercial CBD manufacturers produce greater quantities of pure CBD more quickly and cleanly, using fewer materials and generating less toxic waste. CPC is a highly scalable CBD production process that is environmentally and economically sustainable.

The mechanics of a CPC run are analogous to the mechanics of a standard elution using a traditional chromatography column. While HPLC, for instance, involves eluting cannabis oil through a resin-packed chromatography column, CPC instead elutes the oil through a series of cells embedded into a stack of rotating disks. These cells contain a liquid stationary phase composed of a commonly used fluid such as water, methanol, or heptane, which is held in place by a centrifugal force. A liquid mobile phase migrates from cell to cell as the stacked disks spin. Compounds with greater affinity to the mobile phase are not retained by the stationary phase and pass through the column faster, whereas compounds with a greater affinity to the stationary phase are retained and pass through the column slower, thereby distributing themselves in separate cells (Figure 2).

Figure 2- CPC
Figure 2. How CPC isolates compounds from complex, natural mixtures. As the column spins, the mobile phase (yellow) moves through each cell in series. The compounds in the mobile phase (A, B, and C) diffuse into the stationary phase (blue) at different rates according to their relative affinities for the two phases.

A chemist can choose a biphasic solvent system that will optimize the separation of a target compound such as CBD to extract relatively pure CBD from a cannabis extract in one step. In one small-scale study, researchers injected five grams of crude cannabis oil low in CBD content into a CPC system and obtained 205 milligrams of over 95% pure CBD in 10 minutes.

Using a liquid stationary phase instead of silica imbues CPC with several time and cost benefits. Because natural products such as raw cannabis extract adhere to silica, traditional chromatography columns must be replaced every few weeks. On the other hand, a chemist can simply rinse out the columns in CPC and reuse them. Also, unlike silica columns, liquid solvents such as heptane used in CPC methods can be distilled with a rotary evaporator and recycled, reducing costs.

Environmental Advantages of CPC

The solvents used in chromatography, such as methanol and acetonitrile, are toxic to both humans and the environment. Many environmentally-conscious companies have attempted to replace these toxic solvents with greener alternatives, but these may come with drawbacks. The standard, toxic solvents are so common because they are integral for optimizing purity. Replacing a solvent with an alternative could, therefore, diminish purity and yield. Consequently, a chemist may need to perform additional steps to achieve the same quality and quantity achievable with a toxic solvent. This produces more waste, offsetting the original intent of using the green solvent.

CPC uses the same solvents as traditional chromatography, but it uses them in smaller quantities. Furthermore, as previously mentioned, these solvents can be reused. Hence, the method is effective, more environmentally-friendly, andeconomically feasible.

CPC’s Value in CBD Production

As manufacturers seek to produce larger quantities of pure CBD to meet the demand of patients and physicians, they will need to integrate CPC into their purification workflows. Since CPC produces a relativelyduct on a larger scale, it is equipped to handle the high-volume needs of a large manufacturer. Additionally, because it extracts more CBD from a given volume of raw cannabis extract, and does not use costly silica or require multiple replacement columns, CPC also makes the process of industrial-scale CBD production economically sustainable. Since it also uses significantly less solvent than traditional chromatography, CPC makes it financially feasible to make the process of producing CBD more environmentally-friendly.

Suggested Reading:

CPC 250: Purification of Cannabidiol from Cannabis sativa

Introduction to Centrifugal Partition Chromatography

UniversalSymbolCOMED2

Colorado Debuts Universal THC Symbol

By Aaron G. Biros
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UniversalSymbolCOMED2

Yesterday, the Colorado Marijuana Enforcement Division issued a bulletin unveiling their universal symbol for all cannabis products. According to the bulletin, the State Licensing Authority adopts the universal symbol for all packaging, labeling and on-product marking for medical and recreational cannabis products, effective immediately.

UniversalSymbolCOMED“The State Licensing Authority’s adoption of a Single Universal Symbol is intended to further protect public health and safety by enhancing consumers’ ability to identify products containing marijuana,” reads the bulletin, signed by James Burack, director of the Marijuana Enforcement Division. “Further, by eliminating distinctions between Universal Symbols for medical and retail marijuana, the Single Universal Symbol works to simplify and improve compliance regarding packaging, labeling, and product marking requirements.”

On January 1st, 2019, use of the universal symbol on packaging will be mandatory for all products, with a few exceptions for medical center sales with existing inventory. There is an optional use period that lasts until the end of 2018 where producers and retailers can use the previous universal symbols. After July 1st, 2019, every product sold in the state of Colorado must have the updated universal symbols, according to the bulletin.UniversalSymbolCOMED2

On packaging and labeling, the red and white symbol is required whereas on single servings, the symbol must be on one side but doesn’t need to have the colors.

Back in 2016, Colorado began using a THC universal symbol, requiring it on infused product servings, essentially as a warning symbol on edibles. With this newly implemented rule, all products, including packaging for flower and concentrates, must have the symbol on it. Licensees are encouraged to visit the MED’s website for more information.

extraction equipment

The Ever-Growing Importance of Protecting Cannabis Extraction Innovations

By Alison J. Baldwin, Brittany R. Butler, Ph.D., Nicole E. Grimm
1 Comment
extraction equipment

With legalization of cannabis for medicinal and adult use occurring rapidly at the state level, the industry is seeing a sharp increase in innovative technologies, particularly in the area of cannabis extraction. Companies are developing novel extraction methods that are capable of not only separating and recovering high yields of specific cannabinoids, but also removing harmful chemicals (such as pesticides) from the concentrate. While some extraction methods utilize solvents, such as hydrocarbons, the industry is starting to see a shift to completely non-solvent based techniques or environmentally friendly solvents that rely on, for example, CO2, heat and pressure to create a concentrate. The resulting cannabis concentrate can then be consumed directly, or infused in edibles, vape pens, topicals and other non-plant based consumption products. With companies continually seeking to improve existing extraction equipment, methods and products, it is critical for companies working in this area to secure their niche in the industry by protecting their intellectual property (IP).

extraction equipment
Extraction can be an effective form of remediating contaminated cannabis

Comprehensive IP protection for a business can include obtaining patents for innovations, trademarks to establish brand protection of goods and services, copyrights to protect logos and original works, trade dress to protect product packaging, as well as a combination of trade secret and confidentiality agreements to protect proprietary information and company “know-how” from leaking into the hands of competitors. IP protection in the cannabis space presents unique challenges due to conflicting state and federal law, but for the most part is available to cannabis companies like any other company.

Federal trademark protection is currently one of the biggest challenges facing cannabis companies in the United States. A trademark or service mark is a word, phrase, symbol or design that distinguishes the source of goods or services of one company from another company. Registering a mark with the U.S. Patent and Trademark Office (USPTO) provides companies with nationwide protection against another company operating in the same space from also using the mark.

As many in the industry have come to discover, the USPTO currently will not grant a trademark or service mark on cannabis goods or services. According to the USPTO, since cannabis is illegal federally, marks on cannabis goods and services cannot satisfy the lawful use in commerce requirement of the Lanham Act, the statute governing federal trademark rights. Extraction companies that only manufacture cannabis-specific equipment or use cannabis-exclusive processes will likely be unable to obtain a federal trademark registration and will need to rely on state trademark registration, which provides protection only at the state-level. However, extractors may be able to obtain a federal trademark on their extraction machines and processes that can legitimately be applied to non-cannabis plants. Likewise, companies that sell cannabis-infused edibles may be able to obtain a federal trademark on a mark for non-cannabis containing edibles if that company has such a product line.

Some extraction companies may benefit from keeping their innovations a trade secretSince the USPTO will not grant marks on cannabis goods and services, a common misconception in the industry is that the USPTO will also not grant patents on cannabis inventions. But, in fact, the USPTO will grant patents on a seemingly endless range of new and nonobvious cannabis inventions, including the plant itself. (For more information on how breeders can patent their strains, see Alison J. Baldwin et al., Protecting Cannabis – Are Plant Patents Cool Now? Snippets, Vol. 15, Issue 4, Fall 2017, at 6). Unlike the Lanham Act, the patent statute does not prohibit illegal activity and states at 35 U.S.C. § 101 that a patent may be obtained for “any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof.”

For inventions related to extraction equipment, extraction processes, infused products and even methods of treatment with concentrated formulations, utility patents are available to companies. Utility patents offer broad protection because all aspects related to cannabis extraction could potentially be described and claimed in the same patent. Indeed, there are already a number of granted patents and published patent applications related to cannabis extraction. Recently, U.S. Patent No. 9,730,911 (the ‘911 patent), entitled “Cannabis extracts and methods of preparing and using same” that granted to United Cannabis Corp. covers various liquid cannabinoid formulations containing very high concentrations of tetrahydrocannabinolic acid (THCa), tetrahydrocannabinol (THC), cannabidiol (CBD), THCa and cannabidiolic acid, THC and CBD, and CBD, cannabinol (CBN), and THC. For example, claim 1 of the ‘911 patent recites:

A liquid cannabinoid formulation, wherein at least 95% of the total cannabinoids is tetrahydrocannabinolic acid (THCa).Properly crafted non-disclosure agreements can help further ensure that trade secrets remain a secret indefinitely.

Although the ‘911 patent only covers the formulations, United Cannabis Corp. has filed a continuation application that published as US2017/0360745 on methods for relieving symptoms associated with a variety of illnesses by administering one or more of the cannabinoid formulations claimed in the ‘911 patent. This continuation application contains the exact same information as the ‘911 patent and is an example of how the same information can be used to seek complete protection of an invention via multiple patents.

An example of a patent application directed to solvent-based extraction methods and equipment is found in US20130079531, entitled “Process for the Rapid Extraction of Active Ingredients from Herbal Materials.” Claim 1 of the originally filed application recites:

A method for the extraction of active ingredients from herbal material comprising: (i) introducing the herbal material to a non-polar or mildly polar solvent at or below a temperature of 10 degrees centigrade and (ii) rapidly separating the herbal material from the solvent after a latency period not to exceed 15 minutes.

Claim 12, covered any equipment designed to utilize the process defined in claim 1.

Although now abandoned, the claims of this application were not necessarily limited to cannabis, as the claims were directed to extracting active ingredients from “herbal materials.”

Other patents involve non-toxic extraction methods utilizing CO2, such as Bionorica Ethics GMBH’s U.S. Patent No. 8,895,078, entitled “Method for producing an extract from cannabis plant matter, containing a tetrahydrocannabinol and a cannabidiol and cannabis extracts.” This patent covers processes for producing cannabidiol from a primary extract from industrial hemp plant material.

There have also been patents granted to cannabis-infused products, such as U.S. Patent No. 9,888,703, entitled “Method for making coffee products containing cannabis ingredients.” Claim 1 of this patent recites:

A coffee pod consisting essentially of carbon dioxide extracted THC oil from cannabis, coffee beans and maltodextrin.

Despite the USPTO’s willingness to grant cannabis patents, there is an open question currently regarding whether they can be enforced in a federal court (the only courts that have jurisdiction to hear patent cases). However, since utility patents have a 20-year term, extractors are still wise to seek patent protection of the innovations now.

Another consideration in seeking patent protection for novel extraction methods and formulations is that the information becomes public knowledge once the patent application publishes. As this space becomes increasingly crowded, the ability to obtain broader patents will decline. Therefore, some extraction companies may benefit from keeping their innovations a trade secret, which means that the secret is not known to the public, properly maintained and creates economic value by way of being a secret. Properly crafted non-disclosure agreements can help further ensure that trade secrets remain a secret indefinitely.

Regardless of the IP strategy extractors choose, IP protection should be a primary consideration for companies in the cannabis industry to ensure the strongest protection possible both now and in the future.

Microbiology 101 Part One

By Kathy Knutson, Ph.D.
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I have been studying microorganisms for over 35 years, and the elusive critters still fascinate me! Here in Microbiology 101, I write about the foundation of knowledge on which all microbiologists build. You may have a general interest in microbiology or have concerns in your operation. By understanding microbiology, you understand the diversity of microorganisms, their source, control of microorganisms and their importance.

Part 1

The term microbiology covers every living being we cannot see with the naked eye. The smallest microbe is a virus. Next in size are the bacteria, then yeast and mold cells, and the largest microbes are the protozoans. The tiny structure of a virus may be important in the plant pathology of cannabis, but will not grow in concentrates or infused products. A virus is not living, until it storms the gate of a living cell and overtakes the functions within the cell. Viruses are the number one cause of foodborne illness, with the number one virus called Norovirus. Think stomach flu. Think illness on cruise ships. Viruses are a food service problem and can be prevented by requiring employees to report sickness, have good personal hygiene including good hand washing, and, as appropriate, wear gloves. Following Good Manufacturing Practices (GMPs) is critical in preventing the transfer of viruses to a product where the consumer can be infected.

The petri dishes show sterilization effects of negative air ionization on a chamber aerosolized with Salmonella enteritidis. The left sample is untreated; the right, treated. Photo courtesy of USDA ARS & Ken Hammond

The largest microbial cell is the protozoan. They are of concern in natural water sources, but like viruses, will not grow in cannabis products. Control water quality through GMPs, and you control protozoans. Viruses and protozoans will not be further discussed here. Bacteria, yeast and mold are the focus of further discussion. As a food microbiologist, my typical application of this information is in the manufacturing of food. Because Microbiology 101 is a general article on microbiology, you can apply the information to growing, harvesting, drying, manufacture of infused products and dispensing.

It is not possible to have sterile products. Even the canning process of high temperature for an extended time allows the survival of resistant bacterial spores. Astronauts take dehydrated food into space, and soldiers receive MREs; both still contain microbes. Sterility is never the goal. So, what is normal? Even with the highest standards, it is normal to have microbes in your products. Your goal is to eliminate illness-causing microorganisms, i.e. pathogens. Along the way, you will decrease spoilage microbes too, making a product with higher quality.

Petri dish containing the fungus Aspergillus flavus. It produces carcinogenic aflatoxins, which can contaminate foods and cause an invasive fungal disease.
Photo courtesy of USDA ARS & Peggy Greb.

Yeast and mold were discussed on CIJ in a previous article, Total Yeast & Mold Count: What Cultivators & Business Owners Need to Know. Fuzzy mold seen on the top of food left in the refrigerator too long is a quality issue, not a safety issue. Mold growth is a problem on damaged cannabis plants or cuttings and may produce mycotoxin, a toxic chemical hazard. Following Good Agricultural Practices (GAPs) will control mold growth. Once the plant is properly dried, mold will not grow and produce toxin. Proper growing, handling and drying prevents mycotoxins. Like mold, growth of yeast is a quality issue, not a safety issue. As yeast grow, they produce acid, alcohol and carbon dioxide gas. While these fermentation products are unwanted, they are not injurious. I am aware that some states require cannabis-infused products to be alcohol-free, but that is not a safety issue discussed here.

What are the sources of microorganisms?

People. Employees who harvest cannabis may transfer microorganisms to the plant. Later, employees may be the source of microbes at the steps of trimming, drying, transfer or portioning, extract processing, infused product manufacture and packaging.

Ingredients, Supplies and Materials. Anything you purchase may be a source of microorganisms. Procure quality merchandise. Remember the saying, “you get what you pay for.”

Environment. Starting with the outdoors, microbes come from wind, soil, pests, bird droppings and water. When plants are harvested outdoors or indoors, microbes come from the tools and bins. Maintain clean growing and harvesting tools in good working condition to minimize contamination with microbes. For any processing, microbes come from air currents, use of water, and all surfaces in the processing environment from dripping overhead pipes to floor drains and everything in between.

In Part 2 I will continue to discuss the diversity of microorganisms, and future articles will cover Hazard Analysis and Critical Control Points (HACCP) and food safety in more detail. What concerns do you have at each step of operations? Are you confident in your employees and their handling of the product? As each state works to ensure public health, cannabis-infused products will receive the same, if not more, scrutiny as non-cannabis food and beverages. With an understanding and control of pathogens, you can focus on providing your customers with your highest quality product.

California Manufacturing Regulations: What You Need To Know

By Aaron G. Biros
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In late November, California released their proposed emergency regulations for the cannabis industry, ahead of the full 2018 medical and adult use legalization for the state. We highlighted some of the key takeaways from the California Bureau of Cannabis Control’s regulations for the entire industry earlier. Now, we are going to take a look at the California Department of Public Health (CDPH) cannabis manufacturing regulations.

According to the summary published by the CDPH, business can have an A-type license (for products sold on the adult use market) and an M-type license (products sold on the medical market). The four license types in extraction are as follows:

  • Type 7: Extraction using volatile solvents (butane, hexane, pentane)
  • Type 6: Extraction using a non-volatile solvent or mechanical method
    (food-grade butter, oil, water, ethanol, or carbon dioxide)
  • Type N: Infusions (using pre-extracted oils to create edibles, beverages,
  • capsules, vape cartridges, tinctures or topicals)
  • Type P: Packaging and labeling only

As we discussed in out initial breakdown of the overall rules, California’s dual licensing system means applicants must get local approval before getting a state license to operate.

The rules dictate a close-loop system certified by a California-licensed engineer when using carbon dioxide or a volatile solvent in extraction. They require 99% purity for hydrocarbon solvents. Local fire code officials must certify all extraction facilities.

In the realm of edibles, much like the rule that Colorado recently implemented, infused products cannot be shaped like a human, animal, insect, or fruit. No more than 10mg of THC per serving and 100mg of THC per package is allowed in infused products, with the exception of tinctures, capsules or topicals that are limited to 1,000 mg of THC for the adult use market and 2,000 mg in the medical market. This is a rule very similar to what we have seen Washington, Oregon and Colorado implement.

On a somewhat interesting note, no cannabis infused products can contain nicotine, caffeine or alcohol. California already has brewers and winemakers using cannabis in beer and wine, so it will be interesting to see how this rule might change, if at all.

CA Universal Symbol (JPG)

The rules for packaging and labeling are indicative of a major push for product safety, disclosure and differentiating cannabis products from other foods. Packaging must be opaque, cannot resemble other foods packaged, not attractive to children, tamper-evident, re-sealable if it has multiple servings and child-resistant. The label has to include nutrition facts, a full ingredient list and the universal symbol, demonstrating that it contains cannabis in it. “Statute requires that labels not be attractive to individuals under age 21 and include mandated warning statements and the amount of THC content,” reads the summary. Also, manufacturers cannot call their product a candy.

Foods that require refrigeration and any potentially hazardous food, like meat and seafood, cannot be used in cannabis product manufacturing. They do allow juice and dried meat and perishable ingredients like milk and eggs as long as the final product is up to standards. This will seemingly allow for baked goods to be sold, as long as they are packaged prior to distribution.

Perhaps the most interesting of the proposed rules are requiring written standard operating procedures (SOPs) and following good manufacturing practices (GMPs). Per the new rules, the state will require manufacturers to have written SOPs for waste disposal, inventory and quality control, transportation and security.

Donavan Bennett, co-founder and CEO of the Cannabis Quality Group

According to Donavan Bennett, co-founder and chief executive officer of the Cannabis Quality Group, California is taking a page from the manufacturing and life science industry by requiring SOPs. “The purpose of an SOP is straightforward: to ensure that essential job tasks are performed correctly, consistently, and in conformance with internally approved procedures,” says Bennett. “Without having robust SOPs, how can department managers ensure their employees are trained effectively? Or, how will these department managers know their harvest is consistently being grown? No matter the employee or location.” California requiring written SOPs can potentially help a large number of cannabis businesses improve their operations. “SOPs set the tempo and standard for your organization,” says Bennett. “Without effective training and continuous improvement of SOPs, operators are losing efficiency and their likelihood of having a recall is greater.”

Bennett also says GMPs, now required by the state, can help companies keep track of their sanitation and cleanliness overall. “GMPs address a wide range of production activities, including raw material, sanitation and cleanliness of the premises, and facility design,” says Bennett. “Auditing internal and supplier GMPs should be conducted to ensure any deficiencies are identified and addressed. The company is responsible for the whole process and products, even for the used and unused products which are produced by others.” Bennett recommends auditing your suppliers at least twice annually, checking their GMPs and quality of raw materials, such as cannabis flower or trim prior to extraction.

“These regulations are only the beginning,” says Bennett. “As the consumer becomes more educated on quality cannabis and as more states come online who derives a significant amount of their revenue from the manufacturing and/or life science industries (e.g. New Jersey), regulations like these will become the norm.” Bennett’s Cannabis Quality Group is a provider of cloud quality management software for the cannabis industry.

“Think about it this way: Anything you eat today or any medicine you should take today, is following set and stringent SOPs and GMPs to ensure you are safe and consuming the highest quality product. Why should the cannabis industry be any different?”

Soapbox

Terpene Reconstitution: This Oak Barrel Is Not Your Answer

By Dr. Zacariah Hildenbrand
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I’m not much of an oenophile but I recently came across a very interesting set of documentaries about sommeliers, which are experts on the science of wine and, most importantly, how wines are to be paired with food. What struck me as the most fascinating topic pertained to how mistakes made in the vineyard could be concealed by the barrel in which the wine is stored. For example, if the weather conditions throughout the season had been particularly tumultuous, and you end with sub-optimal grapes that are lacking complexity, then you can compensate for this by aging the wine in a variety of different oak barrels to enhance the flavor. To me, this is synonymous with the way that I’ve seen cannabis concentrates being handled, particularly with respect to terpenes. More specifically, it has recently become somewhat fashionable to supplement cannabis extracts with commercially available terpenes to reestablish an aroma profile that is most representative of the original stock material. Taken one step further, I have even heard of hemp extracts being supplemented with terpenes to achieve a particular strain phenotype, which I cannot imagine pans out very well. In my opinion, this is a very bad idea for two reasons:

One, cannabis is incredibly complex and can contain over 100 different terpene molecules, which can collectively act as anti-inflammatories (Chen et al., 2014), anti- microbial agents (Russo, 2011), sleep aids (Silva et al., 2007), bronchodilators (Falk et al., 1990), and even insulin regulators (Kim et al., 2014). So let’s say that you get your stock material tested and the laboratory screens the product for the top 25 most-prevalent terpenes: alpha- and beta-pinenes, linalool, limonene, beta-myrcene, etc. At that point you utilize this information to supplement your extraction product with these terpenes. However, you still may be missing information about other important molecules such as trans-2-pinanol, alpha-bisabolene and alloaromadendrene that are produced at extremely low, yet therapeutically relevant concentrations in the plant. So essentially with the limited information of the terpenes actually present in your stock material, you would be trying to rebuild a puzzle with only a small fraction of the pieces. Even Ben Affleck’s character in the movie ‘The Accountant’ can’t effectively pull this off.

An example of some commercially available terpenes on the market

Secondarily, not all commercially available terpenes are created equal. I’ll be the first to admit that I don’t have decades of experience vetting the quality of terpenes currently on the market; however, the several times that I have thrown samples into the GC-FID (Gas Chromatograph equipped with a Flame Ionization Detector) I have been unpleasantly surprised. Expecting beta-caryophyllene and detecting caryophyllene oxide is frustrating and in my opinion, such inaccuracies are wrong and should not be accepted as colloquialisms.

The moral of the story here is that in order to produce premium cannabis extracts/concentrates, the stock material needs to be handled with extreme care in order to retain the bouquet of terpenes in their natural ratios. This is incredibly important given the volatile nature of terpenes and their seemingly ephemeral, yet vital, nature in cannabis. Thankfully in this bourgeoning industry there are a number of extraction professionals who are delicately navigating the balance between art and science to produce premium products that are incredibly terpene-rich. However, for every alchemyst there is also someone trying to circumvent nature and while as a scientist I am inherently in favor of experimentation, I am also an admirer of natural processes.

References:

L. Chen et al., “Protective effect of p-cymene on lipopolysaccharide-induced acute lung injury in mice,” Inflammation 37(2), 2014. 

A.A. Falk et al., “Uptake, distribution and elimination of alpha-pinene in man after exposure by inhalation,” Scandinavian Journal of Work and Environmental Health 16, 1990.

S. Kim et al., “Dietary camphene attenuates hepatic steatosis and insulin resistance in mice,” Obesity 2, 2014.

E.B. Russo, “Taming THC: Potential cannabis synergy and phytocannabinoid-terpenoid entourage effects,” British Journal of Pharmacology 163, 2011.

M.I. Silva et al., ” Central nervous system activity of acute administration of isopulegol in mice,” Pharmacol. Biochem. Behav. 88(2), 2007.

Soapbox

The Problem With Puerto Rico’s Medical Cannabis

By Dr. Ginette M. Collazo
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Recently Puerto Rico approved the law that regulates the production, manufacturing, dispensing and consumption of medical cannabis. Although medical cannabis was already “legal” through an executive order and was “supervised” by local regulation, there was no law to back up the industry and protect investors.

The creation and approval of laws resides in the hands of elected individuals. Expecting absolute knowledge is unrealistic, especially when we refer to cannabis as a medicine. Sadly, the lack of knowledge is affecting the patients, and an emerging industry that can be the solution to the Island’s current economic crisis.

I am in no way insinuating that Puerto Rico is the only example. I have seen this type of faulty thinking in many places, but cannabis is the perfect manifestation of this human defect. Check some of your laws, and you will find a few that nearly qualify for the same characterization.

As we can see, lack of knowledge can be dangerous. Objective, factual information needs to be shared, and our leaders need a formal education program. Patients need them to have a formal education program to better understand and regulate the drug.

The approval of this law is a significant step for the Island. Still, many Puerto Ricans are not happy with the result. The lack of legitimate information coupled with conservative views made the process an excruciating one. It took many hearings, lots of discussions and created tensions between the government and population, not because of the law, but for the reasons behind the proposed controls. Yes, it was finally approved, but with onerous restrictions that only serve as a detriment to the patient’s health, proving the need for an education program designed specifically to provide data as well as an in-depth scientific analysis of the information, then, you address the issue at hand.

Let’s take a look at some of the controls implemented and the justification for each one as stated by some members of the government.

  1. Patients are not allowed to smoke the flower in its natural state unless it is a terminal patient, or a state-designated committee approves it. Why? Because the flower is not intended for medical use (just for recreational) and the risks associated with lung cancer are too high. Vaporize it.
  2. It was proposed to ban edibles because the packaging makes it attractive for children. Edibles made it, but with the condition that the packaging is monochromatic (the use of one color), yes, insert rolling eyes here.
  3. It only allows licensed pharmacists to dispense medical cannabis at the dispensary (bud tending). The rationale? Academic Background.
  4. The new law requires a bona fide relationship between the doctor and the patient to be able to recommend medical cannabis, even if the doctor is qualified by the state and is a legitimate physician. This is contrary to their policy with other controlled substances, where a record is not required.

When there are different beliefs on a particular topic like it is with medical cannabis, you are not only dealing with the technical details of the subject; there is an emotional side to it too. Paradigms, stigma, stereotypes, beliefs and feelings affect the way we think. We let our judgment get in the way of common sense. When emotions, morals and previous knowledge are hurting objectivity, then we have to rely on scientific data and facts to issue resolution. However, when the conflict comes from opinions, we rely on common sense, and this one is scarce.

Now education: what can education do with beliefs, morals and emotional responses?

David Burns in his book “Feeling Good: The New Mood Therapy” discusses ten thinking errors that could explain, to those like me that want to believe this is a legitimate mistake, that there are cognitive distortions that affect the result of ours thoughts.

Now let’s analyze …

  1. There are many things wrong with this prohibition. First, the flower is natural and organic. It is the easiest to produce and the cheapest alternative for patients; there are more than 500 compounds all interdependent to make sick people feel better. There are seas of data, anecdotal information, serious studies collecting information for decades and opinions of highly educated individuals that support the consumption of flower in its natural state for medical purposes. The benefits are discarded, and personal opinions take the lead. Based on Burns’s work this is a textbook case of Disqualifying the Positive: dismissing or ignoring any positive facts. Moreover, let’s not forget the benefit for illegal growers and distributors.
  2. Keep out of reach of children, does it ring a bell? For years and years, we have consumed controlled substances, have manipulated detergent pods, bleach and so many other products that can be fatal. The warning is enough, just like is done with other hazardous Here we can notice how we can fall into the Fortune Teller Error, which believes that they know what will happen, without evidence.
  3. Not even the largest drug stores in the USA have this requirement. There is one pharmacist per shift, and a licensed pharmacist supervises pharmacy technicians. Medical cannabis is not even mentioned in current Pharmacy’s BA curricula. Most pharmacists take external courses in training institutes. On the other hand, bud tenders go through a very comprehensive certification process that covers from customer service to cash management and safety and of course all technical knowledge. If anything, a botanist (plant scientist) makes more sense. What a splendid example of magnification (make small things much larger than they deserve). This is an unnecessary requirement.
  4. The relationship between a certified doctor and patient has to be bona fide (real, honest). In practical terms, the doctor has to treat the patient for some time (sometimes six months) and have a history of the patient. Even though this sounds logical, not all doctors are certified to recommend cannabis, but all can diagnose. Are we penalizing the doctor or the patient? The only thing that you need to qualify as a patient is the condition. Besides, I had prescriptions filled for controlled medications at the drug store with no history. Why are we overgeneralizing Do we think that all doctors are frauds?