WSLCB - Deliberative Dialogue - Cannabis Impairment
(April 27, 2022)

Here are some observations from the Wednesday April 27th Washington State Liquor and Cannabis Board (WSLCB) Deliberative Dialogue on Cannabis Impairment.

My top 4 takeaways:

• The conversation around cannabis impairment grew in prominence during the 2022 legislative session when WSLCB request legislation, HB 1668, and other bills around cannabinoid regulation received criticism for definitions of what constituted an impairing cannabinoid.
  • Policy and Rules Manager Kathy Hoffman welcomed attendees to an “evaluation of [tetrahydrocannabinol] THC compounds” to “begin a discussion around how we may determine and define what is, and is not, impairing today” (audio - 2m, video). Policy Affairs and Outreach Director Justin Nordhorn added more deliberative dialogues were in the works, and the conversation was “not going to be the only session…not everything is going to be covered today” (audio - 1m, video).
  • Nephi Stella, University of Washington Center for Cannabis Research (UW CCR) Director, said he was a professor of “pharmacology, and psychology, and behavioral sciences” (audio - <1m, video).
    • Stella hosted a webinar for UW CCR on April 4th titled “Optimizing the Medical Properties of Cannabis.” The organization planned to host their 2022 retreat on Monday May 9th.
  • Jessica Tonani, Verda Bio CEO, stated her company conducted cannabis research centered around the “molecular biology of the plant and metabolite analysis” (audio - <1m, video).
  • Brad Douglass, The Werc Shop Organic Chemist, mentioned his experience in “regulatory affairs, namely” the U.S. Food and Drug Administration (FDA, audio - <1m, video).
  • David Gang, Washington State University Center for Cannabis Policy, Research, and Outreach (WSU CCPRO) Director, also worked as a professor in the WSU Institute of Biological Chemistry (audio - 1m, video).
  • Previous sessions on cannabis plant chemistry in June and July 2021 featured the same panel, with the exception of Medicine Creek Analytics Science Director Amber Wise who chose not to participate beyond the June event.

• Panelists responded to questions covering cannabinoid impairment; modes of ingestion; binding affinities and function; differing thresholds for products; assessing new compounds; and other topics.
  • What Is and Is Not Impairing. Hoffman led with a question that had come up in talks with lawmakers and commented that she was looking to better understand “what is it about the…brain’s interaction with cannabinoids that we’re trying to get at” (audio - 9m, video).
    • Tonani found the phrase ‘impairing’ wasn’t the ideal “word to define what we all kind of know as the” intoxicating or psychotropic effects felt by someone who “could be high” that regulators hoped to quantify. She further felt “impairing” carried “an immediate negative” connotation, but agreed to use it “even though we know it’s not perfect.” 
    • Douglass wanted to hear from Stella about “what is it on a receptor level, or a pharmacological pathway level, what is happening when THC, or a similar molecule, is making somebody feel high?” Stella viewed impairing as a suitable definition as he explained the interaction between THC molecules being ingested and the body’s cannabinoid receptors throughout the brain. He described this as important due to the fact that THC’s impact on the human brain was “polymodal,” meaning it did “many, many different things.” Because of this, Stella encouraged differentiating the “euphoric effect” of cannabis from its impairment, which varied significantly based on “the type of task that the individual [is] performing.” Specific factors such as "motor impairment," "reaction times," "decision making," or someone’s "ability to focus" could be inconsistently impacted by THC, he explained, “because we have these receptors in the different areas of the brain.”
    • Douglass followed up to ask Stella if the CB1 receptor that “mediates the euphoric effects” also mediated impairment. Stella affirmed that the receptors impacted by THC connected with “neurons that control attention,” sensory perception, and euphoric feelings. The basal ganglia was also affected, with results on “motor coordinations” and precise movements, he added.
    • Tonani spoke to the struggle legislators had defining cannabinoid impairment earlier in the year, and that it wasn’t just “delta-9[-THC], there’s delta-8, delta-10…a wide variety.” Stella agreed those cannabinoids had “comparable activity at the CB1 receptor, according to the results that we have,” though more data were being collected to better understand impacts. He said a “recent hypothesis that’s arisen in the field is that” people using THC resulted in the compound being “metabolized by the liver, and the first metabolite of THC is going to be 11-hydroxy-THC,” a compound frequently used in urinalysis. Researchers had started to question if “the effect of THC is not stopped by its metabolism,” stated Stella, and lingering effects on the body could be attributed to 11-hydroxy-THC continuing to activate CB1 receptors. Moreover, Stella indicated that “we actually have no idea what is the metabolism of delta-8, what is the metabolism of delta-10,” which could also “have some bioactivity.”
  • Modes of Ingestion. Hoffman wondered how modes of ingestion changed the metabolism of cannabinoids (audio - 11m, video).
    • Stella responded that metabolism speed was the main attribute impacted, smoking and vaping being the fastest route for the compounds to the brain. By contrast, he commented that oral ingestion, like infused food, was slower to metabolize, and that less THC reached the brain since “it's already metabolized by the liver.” 
    • Douglass remarked there was literature suggesting that 11-hydroxy-THC could be “significantly more psychotropic, impairing perhaps than delta-9-THC itself.” He asked what the “binding affinity” was for the compounds, to which Stella replied it had been “known since the ‘90s” that 11-hydroxy-THC binds to CB1 receptors. Emerging research suggested that after receptors were “activated, by different compounds, they can do slightly different things, on the neurons” of the brain. This made it possible that 11-hydroxy-THC was “more potent” than delta-9-THC but its effects were drawn out over time, Stella speculated. He felt scientists needed to ask “where are the receptors expressed in the brain, in terms of impairment,” which “molecule that is going to reach the receptor,” and “how precisely is that receptor going to be activated?”
    • Tonani observed that people were “so used to alcohol” as a comparable product to cannabis, but varying cannabinoid compounds could be “difficult to make that direct correlation from level to impairment.”
    • Gang found it important for people to consider that delta-9-THC had a slight difference in binding based on the isomerization, or “the negative optical rotation of the…stereoisomer of it.” Noting the topics had been discussed at the June 3rd deliberative dialogue, he returned to an analogy that the compound was akin to a person’s left or right hand, and the receptor to a glove which differed a bit based on factors like “gut microflora,” organ development, and enzymes. So a person’s response to a cannabinoid—like a hand’s fit in a glove—would be "in general very similar," Gang remarked, yet "different enough" that defining at what point "somebody gets affected enough, that everybody else in society starts to get worried about it” would prove difficult. He found that question was more easily answerable for alcohol, a “very simple molecule” in comparison to cannabinoids. Gang believed it was “very well known that somebody that’s a long time consumer of these compounds has a different response than somebody who's never taken it before.” All of this made a clearcut definition of impairment hard to establish.
    • Hoffman’s takeaway was that the impact was "different enough [it] can be different for every person.” Gang responded that even the methods for evaluating it were debated. Analysis of blood or urine were common, but a consistent and “nice correlation” had yet to be sussed out by officials. 
  • Binding Affinity and Function. Tonani suggested defining which cannabinoids had these effects seemed like the next challenge researchers faced, followed by the concentration in someone at which they’re “deemed impairing.” She commented that a molecule had to have a cannabinoid structure, and be shown to bind to cannabinoid receptors (audio - 8m, video).
    • Agreeing, Gang didn’t think it should be constrained to whether a substance was scientifically classified as a cannabinoid, noting certain alcohol compounds had no intoxicating effects on people. Stella was of the mind that the impairing effect should be less driven by the compounds present than “what activates the CB1 receptor.” He noted that artificial cannabinoids had been used in other products to activate those receptors. Stella then built out the concept by saying that varying effects in people weren’t only based on their genetics but “a history difference” tied to what someone’s liver had previously metabolized. He added that the brain receptors reacted differently as well based on whether the body had previously metabolized a compound, sometimes called “tolerance.” A regular consumer would experience the same compounds differently which could impact their self-titration, or how much would be present in their body before they reacted as though they were impaired.
    • Alcohol had a “well established relationship between” concentration in the bloodstream and “behavioral impairment,” Stella reiterated. He claimed his lab had been studying the effects of cannabinoids on animals with the hopes to “translate that and have a better understanding of what’s happening” in humans. Stella mentioned that surveys to understand the effects of THC had progressed from “how do you feel? Do you feel high right now” to more complex questions focusing on cannabinoid properties. Stella next mentioned another barrier to an equivalency for quantifying impairment was that since cannabinoid compounds were “hydrophobic” compared to alcohol, they were “greasier” and “not evacuated by the lungs” in a way amenable to breath analysis. He expected that the most relevant method to determine impairment for cannabis products would be the presence of “THC or their metabolites in blood.”
  • Animal Models of Impairment. Douglass asked “with the advances now in functional impairment and tying that to THC levels, or metabolites in the blood,” if Stella believed animal models to assess impairment would continue to be a useful “proxy” for people (audio - 2m, video).
    • Stella said studies with animal models and those with human subjects were continuing and that researchers were in communication on “what is impairment in humans” compared to animals. He felt there were clearly limitations on what one could infer from animal studies, bringing up one study he knew was using functional magnetic resonance imaging to see what areas of the brain were impacted by THC. Stella pointed out how this work focused on the prefrontal cortex, an area of the brain harder to test on lab animals like mice.
  • Per Se Blood Level Tests. As there was a per se driving under the influence (DUI) standard for delta-9-THC in Washington state, Douglass wondered whether officials knew there was “not good correlation between blood levels, breath levels…and any sort of functional impairment in humans?” (audio - 2m, video)
    • Stella confirmed this take, saying studies continued but the existing correlation around blood levels and human impairment was “not actually validated.” Not wanting to be ahead of the research, he expected "it's always about the dose" of something “and what’s the prior history?”
  • Thresholds for Differentiating Impairing Products. Nordhorn said agency officials were regularly asked how WSLCB staff “differentiate an impairing product versus a non-impairing product.” For alcohol, he told the group the limit of 1.5% by volume was used, and asked if a comparable scale for cannabis and its “entourage effect” could even be measured (audio - 7m, video).
    • Tonani believed that once “impairing cannabinoid” was quantified that serving sizes could be established. But she cautioned that since people could be “pretty creative with chemistry” a definition should encompass “how much of that leads to impairment.”
    • Knowing “structure-activity relationships,” Douglass relayed how minor changes can be made to compounds which “either enhances effects or can decrease effects.” He stated that some cannabinoids could be altered without changing their overall binding affinity “or impairing activity.”
    • Gang indicated that the “vast majority of the other cannabinoids” didn’t have a measurable impairing effect, “and they don’t function the same way” as delta-9-THC.
  • Consumer Understanding of Impairing Products (audio - 5m, video). Nordhorn considered how the “general public” might look at packaging to comprehend whether the contents were likely to “cause impairment for me.” His impression was that regulatory bodies couldn’t just name a compound and expect consumers to appreciate the effects, and instead wanted to find “a commonality in that range” so WSLCB staff weren’t left regulating “non-impairing products.”
    • Tonani felt that defining the affinity point at which “people will get high” from a cannabinoid could lead to improved packaging and labeling. Stella concurred and hypothesized that the “diversity in behavioral impairment that we’re going to get with THC is going to be broader” than for equivalent impairment from alcohol. He further pointed out roadside DUI tests for alcohol typically combined a breathalyzer and attention-based motor skill testing, but the latter hadn’t been adapted for cannabinoid impairment so far.
      • Check out the Washington State Patrol impaired driving training and discovery materials, including a March 2013 guide to “DWI Detection and Standardized Field Sobriety Testing.”
  • Assessing New Cannabis Compounds. Nordhorn’s last question was on the “molecular structure” of emerging cannabinoids and how they fit “into this equation on being able to identify” their impairing effect (audio - 7m, video).
    • Stella compared this with how the U.S. Drug Enforcement Agency (DEA) approached drug scheduling. He said staff tried to “figure out the chemical structure,” whether it could “bind and activate the CB1 receptor,” and if animal testing showed mice responded as though "this molecule feel like THC or not." This didn’t signify impairment, clarified Stella, only that a compound “feels like THC for a mouse.” He wanted an improved process for a “behavioral readout.”
    • “Each one of these molecules is a different chemical entity,” stressed Gang, making it costly to determine more than a “general chemical class” for each cannabinoid. Once defined, regulatory processes for compounds were more clear cut, he observed.
    • Finding a “functional test” for cannabinoids would be a way to “future proof” rules from emerging compounds, Douglass mentioned, saying the federal Analogue Act was one example of a structural test for compounds which hasn’t been shown to be applicable for cannabinoids so far.
    • Tonani further clarified that this conversation focused on cannabinoids that “naturally occur,” and not artificial cannabinoids which were “in their own little bucket” and not allowed.

• Experts and staff next fielded five questions from attendees on topics like minor cannabinoids and drug interactions, and a foreign regulator joined in to suggest a “THC equivalency factor.”
  • Shawn DeNae Wagenseller, Washington Bud Company Co-Owner and Washington Sun and Craft Growers Association (WSCA) Board Member (audio - 4m, video). 
    • In the event chat box, Wagenseller asked about “minor cannabinoids,” and whether there’d been “research on how minor cannabinoids [Cannabigerol (CBG), Cannabinol (CBN), and others] consumed in isolates at significant levels (10%>) effect the endocannabinoid system?"
    • Stella replied that CBN mainly impacted the CB2 receptor in humans and looked to possess “more therapeutic/antiinflammatory properties.” CBG was getting more attention from researchers as a “new, fascinating compound” in the plant, he reported. It didn’t interact with CB1 or CB2 receptors and studies were just beginning to consider “what is the receptor that it’s interacting with, and what are the biological functions” it regulated, Stella indicated. At the time, more was known about “what it doesn't do” as experts had yet to identify what “endogenous pathway is affected by that,” he commented.
    • Douglass asked if CBG and CBN could be classified as “not impairing in a THC-like way.” Stella concurred, considering their impacts more akin to cannabidiol (CBD), which scientists theorized “binds to another binding site, which is called a negative allosteric binding site” and “tunes down the activity” of a CB1 receptor before it can interact with THC compounds. A second hypothesis he identified was that CBD “acts on another receptor, and that receptor has a signal transduction pathway that downregulates the CB1 receptor,” he explained, deeming it a “fascinating area of research.”
  • Jim MacRae, Straight Line Analytics (audio - 5m, video). 
    • MacRae asked a question with “multiple parts” in the chat window:
      • "You mentioned the variation across INDIVIDUALS in their reported experience with ‘cannabis’. What of the well-known and very wide variation in effects across different strains of cannabis?  Does the breadth of impact across 20+ % delta-9 THC strains not suggest complex cross-cannabinoid impact on drug effect?"
      • "To expand on where my question was targeted --- while reductionism is convenient (e.g., saying it's all CB1), is it not possible that the ‘entourage’ effects often mentioned in describing the medicinality of cannabis are also at play in the expression of ‘impairment’ in cannabis. Might not some cannabinoids, for example, be PROTECTIVE of delta-9-mediated impairment?---"
    • Stella considered the "entourage effect" to be a cannabis-centric branding of “drug-drug interactions" wherein effects differ between taking any single compound, or several of them. Research around the “tempering effect of CBD on the THC/CB1 response” was “exciting” for him because of the potential to discover a “therapeutic effect” which scientists could “optimize” to be more potent.
    • Gang noted that for other cannabinoids or compounds like terpenes and flavonoids in the plant, “we don't know what any of those do.” He theorized there were near “infinite possibilities" of drug interactions, especially for naturally occurring plant material with “hundreds, or thousands of compounds."
    • “Jim’s question recognizes the layers of complexity” in the broad question of cannabis impairment, Douglass said, feeling the discussion could get even deeper on this one point alone. It was difficult to stay centered on “what is impairment, how do we define that functionally for policy purposes,” he observed.
  • Gabriel Picard, Health Canada Controlled Substances and Cannabis Branch Office of Cannabis Science and Surveillance Scientific Evaluator (audio - 5m, video). 
    • Picard stated that Canadian regulators were looking at similar questions as their WSLCB counterparts, in particular due to a strict THC limit “in the edible cannabis.” In toxicology, he said a single molecule that was “well understood” could be used “as the baseline,” making him wonder if there was a way to “derive an equivalency factor for” cannabinoids specifically. “As a regulator, that would be perfect,” he remarked.
      • In 2019, Health Canada released drafts of updated guidance on Generic Drug Equivalence: Medicinal Ingredients and Identifying and Labelling Medicinal Ingredients.
    • Douglass commented that “ if we have a solid, functional test, then we can have relative ratios” or the equivalency Picard sought. Gang observed that it was dependent upon compounds that “function similarly.” Stella considered it a good idea to use a "benchmark for bioactivity" for cannabinoids and that the process could be viable “once we have, actually, the entire equation.”
      • Determining drug equivalencies, or bioequivalence, is part of the regulation of controlled substances and a standard used by regulators in pharmaceutical development. The FDA publishes Approved Drug Products with Therapeutic Equivalence Evaluations (commonly known as the Orange Book). The book’s preface states it covers “therapeutic equivalence evaluations for approved multisource prescription drug products” compiled to “serve as public information and advice to state health agencies, prescribers, and pharmacists to promote public education in the area of drug product selection and to foster containment of health care costs.”
      • Take a look at an opioid equivalency table from the Stanford School of Medicine.
  • Annie Rothrock, ATREG, Inc. Vice President (audio - 3m, video). 
    • "If a cannabinoid is naturally occurring in cannabis, but not at high enough levels needed for products in the market, but it can be artificially synthesized from a different cannabinoid and is the exact same molecule as the naturally derived molecule (CBN for example) - how is it that ‘artificial’ requires it to be in a ‘separate bucket’ and not allowed when it is the same molecule with the same affect or impairment?"
    • Hoffman and Gang noted the question over artificial and synthetic cannabinoids had been raised before. Tonani found it comparable to winemaking, where grapes could be converted into something “naturally occurring,” versus some grape candy, whose constituent elements “have never seen a grape plant.” Naturally occurring cannabinoids could be produced through synthesis, she attested, but artificial compounds had never been seen in the plant.
    • Stella mentioned that artificial and synthetic cannabinoids could be produced in a lab, meaning “synthesis” was an insufficient determinant for which compounds should be permitted. He preferred contrasting “phytocannabinoids” with “artificial cannabinoids.”
  • Shannon Vetto, Evergreen Market Chief Strategy Officer and Washington CannaBusiness Association (WACA) Trustee (audio - 2m, video). 
    • "Can this panel define ‘impairment’ for regulatory purposes at an individual cannabinoid level for the following list of CBD, CBG, Delta 8, Delta 9, others?"
    • Douglass said they could for the “known cannabinoids” which Vetto mentioned, but applying a definition to new or undiscovered compounds in the plant was challenging. Gang felt this had been the situation with delta-8-THC, “we knew it existed,” but it wasn’t well studied until it was generated in a lab, at which point the compound was “very available.” Being concerned with the safety of children and the consuming public, Douglass claimed their conversation was about “how do we make sure that we can do that, and how do we give the authority to those that need to regulate it, the authority so that they can.”

• Policy and Rules Manager Kathy Hoffman concluded the event by promising to follow up with the panelists on additional questions and mentioned upcoming dialogues on the subject (audio - 3m, video).
  • She reported that the next dialogues would be on May 31st and June 21st. Further questions for the panel or agency staff should be emailed to Hoffman’s office, she said, as well as suggestions for prospective panelists who might have insight on the topic.
  • The panelists thanked attendees and staff. Douglass chimed in to say he appreciated the discussion and felt public conversations were the best way of “learning from each other” to achieve consensus and good policy.