Is Phytol Safe to Vape… Or Could There Be Flaws in Canopy’s Paid-For Study?

Is Phytol Safe to Vape… Or Could There Be Flaws in Canopy’s Paid-For Study?

Is Phytol Safe to Vape… Or Could There Be Flaws in Canopy’s Paid-For Study?

In August 2020, a Canopy subsidiary (Tokyo Smoke) announced it would pull all products containing phytol, a terpene derived from cannabis and a common botanical additive to vape liquids, from it’s shelves. This is a story we’ve been following ever since and one which deserves a detailed response. Is phytol safe to vape? 

With another alarmist article published on Leafly, it’s time to set the record straight on phytol’s safety profile and the many problems contained in Canopy’s study.

 

Is Canopy’s Quest to Discredit Phytol due to Competitive Threat? 

After contracting with a controversial for-hire lab to conduct animal-based research, Canopy Growth claimed, “Phytol, not propylene glycol, causes severe pulmonary injury.” But the results of this study are controversial in their own right. [1]

Throughout a six-month smear campaign, Canopy has tried to connect phytol to the 2019 vape crisis, falsely alluded to working with Health Canada, and concealed the true nature of the study’s results behind a paywall. 

Why might phytol have earned the ire of Canopy Growth? In short: it may be perceived as a competitive threat. Phytol has been widely used among many well-known brand manufacturers across the legal vape sector in both the U.S. and Canada as one of the few known terpene based vape diluents that passes the strict restrictions of high compliance states like California, Florida, and Michigan who have zero tolerance policies against non-cannabis centric adulterants used as suspension excipients. Some of the obvious banned ingredients would be the usual suspects such as PG, VG, VEA, Squalene, etc.

Canopy may see these products that contain phytol as rivals to its own vape lines, which still use (according to Canopy) notorious ingredients like propylene glycol (PG). PG is known to convert to formaldehyde at high vape temperatures. Good manufacturers also know that PG makes a poor suspension fluid as it separates from cannabinoids and terpenes having poor homogenization properties with non-polar molecules. PG works much better in nicotine e-cigarette formulations, which is where it originally came from.

Those who still use it have typically chosen either cheap manufacturing costs over quality, or simply have not evolved their formulations for ten plus years from the early days of vape manufacturing. 

When industry players sponsor research through a for-hire lab, it’s critical to question the motive. After purchasing the paper and reviewing what’s hidden behind Canopy’s sensational claims, it appears that their “health concerns” about this terpene are not based on accepted scientific principles. 

There are serious flaws with the study’s structure, the framing of the results, and the claims made throughout Canopy’s media blitz.

 

What is Phytol?

Phytol (2-Hexadecen-1-ol,3,7,11,15-tetramethyl-,(2E,7R,11R)) is a diterpenoid. Diterpenoids are naturally occurring in plants, fungi, and sometimes in marine organisms and insects. They are a subclass of terpenes, defined as having four isoprene units. Unlike most terpenes, this diterpenoid is unique in its relatively mild aroma, often described as earthy or jasmine-tea-like.

Within plants, phytol comes from the degradation of chlorophyll. It’s common in medicinal herbs (Crataeva nurvala Buch-Hum), green tea, and cannabis/hemp cultivars, and is just one of more than 100 known terpenes derived from cannabis.

Although it’s recently earned the attention of the cannabis industry, phytol has a wide range of applications across the consumer world. It’s a food additive found in condiments, seasonings, and more. Amongst those in the know, Phytol is also used in the cannabis sector as a plant-derived, cannabis-centric diluent to improve the viscosity of cannabis extracts for vape products.

The Food and Drug Administration (FDA) has approved phytol for use as a flavoring agent and novel adjuvant in vaccine formulations. The World Health Organization (WHO) has also approved it as a food additive and has found “no safety concern at current levels of intake when used as a flavoring agent.”

Like many terpenes, a growing number of scientific studies have explored phytol’s possible medicinal qualities. Preliminary investigation has examined it as an anxiolytic, anti-inflammatory, antinociceptive, and antitumor agent.[2][3][4]

In one of the most interesting studies, researchers explored phytol’s anti-inflammatory characteristics in a mouse model of acute inflammation. As a secondary measure, they also investigated phytol’s impact on oxidative stress and cytokine levels. 

The research team behind this study theorized that phytol functioned by reducing oxidative stress, white blood cell (neutrophil) migration, and tumor necrosis factor-α (TNFα) levels. In the end, they reasoned, “These results suggest that phytol attenuates the inflammatory response.”

 

Canopy’s Anti-Phytol Media Blitz

On July 31st, 2020, Tokyo Smoke, a Canopy-owned retailer, issued a request to all vape manufacturers that they provide a complete ingredient listing. Canopy gave manufacturers a 48-hour deadline to comply or threatened to place a stop-sale order on their vape carts and filled vape pens.

Soon after, publications like Marijuana Business Daily, Stratcann, and the oz. published pieces on the dangers of phytol, based on a “soon-to-be-published study” scheduled for release “in the coming weeks.” Every article copied the same series of quotes from Dr. Mark Ware (“Dr. Ware”), the Chief Medical Officer at Canopy Growth, but failed to cite a single fact, finding, or result from the forthcoming study. 

By August 7th, 2020, Canopy announced it was pulling most third-party vape products from their store shelves based on these yet-unpublished or unclarified study results. According to Google’s Way Back Machine, Canopy’s Tokyo Smoke retail locations had formerly sold many third-party vape pen brands including Dosist, Canaca, Soleil, and more. Six months after Tokyo Smoke threatened third-party vape manufacturers, the retail locations and online stores still seem to sell many of the same brands. It’s unclear what changes, if any, were made.

Canopy’s August media blitz seems perfectly crafted to play into the vape-related lung disease fears that linger from the Fall 2019 crisis. According to a quote attributed to Dr. Ware and copied throughout the published articles, “New information underscores the need for consistent, science- and evidence-based regulations for cannabis products so people have access to safe cannabis products they can trust, made by producers that act with integrity.” 

But at no point did Ware or any other member of the Canopy team share details about this new information.

 

False Associations with Health Canada

Several of the publications suggested that Canopy was working with Health Canada about these concerns. While it is true that Health Canada sent requests for clarification to several vape manufacturers, this was already under development as far back as 2019. 

Canopy’s attempts to pull Health Canada into their media onslaught seemed designed to fortify their claims and incite fear in the average consumer.

In a statement to the Okanagan Z, Health Canada explained:

“To clarify, the requests sent to select license holders in mid-July were not related to phytol but are part of the Department’s ongoing requests for additional information that began in November 2019 to better understand the composition and makeup of vaping and inhalable products that are going to be released into the marketplace.”

According to the Stratcann coverage, Canopy claimed to have shared the results of their 14-day inhalation toxicology study with Health Canada. Canopy presumably shared this before their media campaign in August, well before the study’s publication, which would also mean before completing the peer-review process.

It has been six months since Canopy shared its findings with Health Canada, but notably, the government department has yet to release any recall or public health warning about phytol. This suggests the study results showed little to no risk to the public or that there was a fault within the study design. 

As a reminder, Health Canada quickly responded to the actual vaping crisis in the Fall of 2019. By September 4th, 2019, it had released an Important Safety Update warning “of potential risk of pulmonary illness associated with vaping products.” Considering it’s been almost twelve months since Canopy attempted to incite phytol fear, one would assume Health Canada would have released a warning should these fears have been based on facts.

We contacted Health Canada’s Vaping Inquiry for comment on phytol and the claims made by Canopy Health for this story on two occasions. From the first request, it seemed clear through the department’s internal back and forth that they were unaware of any claims, positive or negative, about phytol. We did not receive any response by the deadline of our second request.

Health Canada made no acknowledgment or endorsement of Canopy’s claims or the study results in both cases. The most recent Leafly article was based around a request made to Health Canada under the Access to Information Act (AIA). On June 23, 2020, Health Canada released information, but — it seems to have only released Canopy’s study. A study that was already available, albeit through a paywall.

Based on the Leafly article, it appears as if no other documents, communications, or reports were released, which would strongly suggest Health Canada has not acknowledged, endorsed or further researched the claims made within the study. 

To date, phytol is still legal in cannabis vape cartridges in Canada. Although Leafly may cite sources that claim it’s “shadow-banned in the country,” we can report otherwise.

Canopycontinues to allude to Health Canada’s involvement in their scheme against phytol, but from our inquiries, the department is not involved in any way. Health Canada’s clear lack of involvement is suggestive about Canopy’s objectives and perhaps even about the scientific protocols of the study itself.

 

Canopy’s Study Results: Problems and Limitations

What was not effectively addressed in the media reports is that Canopy paid for this study on phytol. As per the study’s disclosure statement, “The study was commissioned by Canopy Growth USA, LLC (C.G.) with the intent of comparing two potential excipients for their potential product portfolio. Experiments were designed, performed, and interpreted independently by Lovelace Biomedical scientists without influence from C.G.”

First and foremost, the actual results of this study remain frustratingly hidden behind a paywall. A paywall effectively excludes the average consumer or journalist from exploring the results for themselves. The abstract leaves much to the imagination regarding dose, exposure technique, and application for humans.

Even the document linked to in the most recent Leafly study is heavily redacted, from details on doses delivered to the methodology used. Both of which are essential to determining this study’s design, scientific protocols, and relevance for human health.

The abstract dramatically warns against the use of phytol, concluding “its use as an excipient in vaping product is not recommend[sic],” based on the low observed adverse effect level (LOAEL) of 109.0/ 10.9 mg/kg/day presented/deposited dose. But these numbers mean nothing unless the details are examined.  

How were the rats exposed? How much phytol were they exposed to? What does that translate to for an average consumer with a vape pen? Does this study answer the question, “‘Is phytol safe to vape?”

As a reminder, all these details are hidden behind a paywall, with nothing outlined in the publicly available abstract. Canopy’s initial media blitz didn’t include any study results, only blanket statements. Even after the paper’s publication six months later, all of the reporting relied solely on the abstract. 

After purchasing the paper and digging into the actual results, several major critiques of this study are warranted. 

First, what is the comparable dose when you translate the numbers from rat to human? The researchers dosed animals using a compressed air jet nebulizer with a nose-only inhalation system. The average phytol aerosol concentration on day one was 5.935 mg/L and 5.059 mg/L on day two. This method resulted in “estimated presented/deposited dose ranges of 129.5/12.9mg/kg to 1549.8/155.0mg/kg for 0.5 to 6h exposure duration on Day 1.”

phytol concentration table

These are meaningless numbers, unless you translate this into a vape pen and a human consumer. What is the equivalency for phytol exposure from a standard vape liquid in a vape pen? 

We estimate for a person to match the dosage of phytol presented/deposited with the rats in the Canopy study, it would require an average 200-lb man to smoke 281 vape pens in six hours. That means consuming 47 vape pens in an hour, or almost one vape pen per minute.

According to the experts interviewed in the Leafly article, even they confirmed that the amount of phytol the animals in the Canopy study were exposed to was “orders of magnitude” more than any human would receive from a vape pen. Shawna Vreeke, a safety chemist from a terpene manufacturer, calculated it would be like “hitting a vape 250 times in 30 minutes.”

Jeffrey Raber, the founder of The Werc Shop, was also asked to comment by Leafly, and he again confirmed the rat dosing was too high to mimic human exposure to phytol within a vape pen. Raber also stated that the vaporization temperature was too low to make an effective comparison with real-life vape pens.

How many humans could survive exposure to any terpene at this level of concentration and exposure? Even in the most drastic of imaginary scenarios, it would be physically impossible for a human to consume vape pens at that rate. 

The study’s authors don’t elucidate on this point at all. While the authors explain that “ “The PG concentration administered in the present study was about ten times higher than the amount of PG that is assumed to be delivered per puff during vaping,” They don’t provide similar calculations for phytol.

In the study’s discussion section, they cite the limitation,” That the same aerosol characteristics used for PG were targeted for Phytol and therefore the effects observed in this study are assumed to be translated to higher doses than the expected human dose.

But, this doesn’t provide any specifics on phytol dose. Did the researchers know how much phytol is contained within a standard vape pen? Or do they not care to accurately compare their results to real-world applications? This is a glaring admission and demonstrates study bias.

A second major issue contained in the details was the method of delivery, a limitation outlined by the authors themselves. As the study stated, “Aerosols were generated using compressed air jet nebulizers, which does not reflect aerosol generation through vape pens.” The method of aerosolization would immediately affect both the particle size and any by-products produced. Compressed air nebulizers deliver a different end product than any of the thousands of vape pens on the market today.

Third, the study also repeats the false relationship between phytol and vitamin E acetate on several occasions. The authors attempt to tie phytol into the ongoing controversies surrounding vitamin E acetate in vape liquids. First in the introduction, and again in the discussion section, they mention vitamin E. 

But as we will get into below, chemically speaking, these are entirely different compounds. Phytol doesn’t transform into vitamin E through vaping, and their attempts at the association are incredibly misleading.

Finally, there seems to be a serious issue around the methods used in this study. Under the description of “aerosol generation, characterization, and dose calculation,” the authors outline the various methods used to expose the animal test subjects to either phytol or PG. They note that both methods were “aerosolized using compressed air jet nebulizers” and “delivered into 3-tier rodent nose-only inhalation systems.” But they then explain, “Two separate exposure systems were used during this study, one for PG and one for Phytol exposures.”

There is no discussion about what these exposure systems were, how they differed, and if that would impact the comparison of the substances. Why were two exposure systems used in a study designed to compare two substances in a controlled setting? Why was this never discussed? We may never know.

 

Failed Attempts to Connect the Vape Crisis with Phytol

In several blogs published in the August anti-phytol campaign, there were statements connecting phytol with vitamin E acetate. It seems like Canopy is attempting to connect “Is vitamin E safe to vape?” with “Is phytol safe to vape?”— when these are two completely unrelated compounds.

As per a brief section in Canopy’s study:

Phytol is used as a precursor for Vitamin E synthesis, and Vitamin E 

acetate is assumed to be related to a series of death and severe lung 

injury after inhalation from vaping products (Blount et al. 2020). Such 

relation and the lack of data on Phytol toxicology after inhalation, 

support the necessity of research on this topic and assess its safety 

before the use in vaping pens becomes more popular.” Similar 

statements appeared several times across Caopy’s August media 

blitz. 

While this statement is technically correct, it misleads the reader, especially a layperson with no chemistry background. The assumption is that phytol, as a chemical precursor, will have the same dangerous effects as Vitamin E acetate. But, this is not how chemistry works.

Of course a precursor chemical “may be” used to form a secondary chemical under forced conditions for chemical synthesis in a lab, but individual components are not equivalent to the final compound. Technically, it is also isophytol that is more commonly used as the intermediate precursor to vitamin E acetate, not phytol. 

While there may be an association between chemicals — like phytol, isophytol, and vitamin E acetate — this association doesn’t predict each compound’s characteristics. For example, oxygen is a requirement for rocket fuel, which means there is an association. But, clearly, oxygen by itself isn’t rocket fuel. 

Another example is that of mustard gas, a deadly chemical. This toxin is created through the combination of bleach and ammonia, but both of these substances are widely used in households around the world. 

Just like in these examples, phytol may be a precursor to creating other chemicals, but it would never transform into these other compounds naturally. A precursor chemical doesn’t instantly mean there is a correlation. Canopy’s attempt to connect the dots between these chemicals is not just technically inaccurate, lazy, and irresponsible, it’s intentionally misleading.

 

A Controversial For-Hire Laboratory: Lovelace Biomedical

“This decision is based on the results of a soon-to-be published study on the safety of 

added phytol in vaping oils. This new information underscores the need for consistent, science and evidence-based regulations for cannabis products so people have access to safe cannabis products they can trust, made by producers that act with integrity.”

 

— Dr. Mark Ware, Chief Medical Officer, Canopy Growth, reported in Stratcann

emphasis added.

 

Canopy’s commissioned study came from Lovelace Biomedical, located in Albuquerque, New Mexico. This lab is a “contract research organization with a rich history of helping its [sic] pharmaceutical and biotechnology partners achieve great things.” The facility (and therefore the study) is unaffiliated with any academic institution. Industry-sponsored pieces commonly do not have academic affiliations due to the inherent conflicts of interest. 

Lovelace Biomedical is a for-hire laboratory with a checkered past. In 2008, the U.S. Department of Agriculture repeatedly found the facility had violated the Animal Welfare Act. In a single year, between 2008 and 2009, it violated the Act on nine occasions. Violations included the death of a monkey used in research, as well as one who escaped. 

In 2011, the lab was fined $22,000 for more violations. Then, in 2015, regulators determined a dog had died at the hands of an untrained Lovelace technician. Between 2012 and 2014, there were reports of even more animal deaths. During this time, the USDA investigated nine animal deaths, which led to another six violations of the Animal Welfare Act.

In 2012, animal rights groups also raised the alarms about a drastic decrease in animals reported at the facility, mainly primates and dogs. The Albuquerque Journal investigated and determined the facility had removed or destroyed close to 300 primates and more than 100 dogs. Lovelace Biomedical did not provide reasoning or specifics on the case.

The lab’s latest run-in with regulators came when the New Mexico Environment Department fined the company $225,000 for failure to adhere to two orders: maintaining accurate records of disposal for radioactive material and committing sufficient funds to the proper removal.

The Administrative Order outlines the state department’s frustrations in dealing with Lovelace over the last seven years. In one section, the order declares, “Despite numerous attempts by the Bureau to verify Respondent’s removal and disposal activities from 2015 to 2020, the Bureau has been unable to verify Respondent’s reduction in inventory due to incomplete records associated with the disposal of the radionuclides.”

In an interview with the Santa Fe New Mexican, Dr. Robert Rubin, CEO of Lovelace Biomedical, called the actions of the department “crazy.”

 

The Fundamental Issue with Industry-Sponsored Research

One of the most outrageous reports about Lovelace came in 2018 from the New York Times. According to their reporting, Volkswagen used Lovelace Biomedical to prove that their newer vehicles emitted healthier diesel fumes than other models. It has since come to light that Volkswagen faked their way through these tests. The New York Times noted that this experiment offers “a rare window into the world of industry-backed academic research.”

As the New York Times highlights, there are undeniable historical examples of biased industry-based research. From Volkswagen’s attempts to prove diesel emissions are safe to the tobacco industry funding research downplaying cigarettes as carcinogenic, there is a long line of suspect industry-funded research. 

In 2017, the Cochrane Database of Systematic Reviews Review Methodology updated the results of a previous review on industry bias in research. “Industry sponsorship and research outcome” included a total of 75 papers (27 new).[5]

The revised results continue to prove that industry-sponsored studies routinely have more favorable efficacy results and conclusions than non-industry-funded studies. As the authors concluded, “Sponsorship of drug and device studies by the manufacturing company leads to more favorable efficacy results and conclusions than sponsorship by other sources. Our analyses suggest the existence of an industry bias that cannot be explained by standard ‘Risk of bias’ assessments.”

Canopy’s study may state, “Experiments were designed, performed, and interpreted independently by Lovelace Biomedical scientists without influence” in the Disclosure Statement, but the problem with industry-funded study bias is often not found in the numbers—it’s in the intent.

Canopy specifically sought a for-hire research group with perceivable motive of discrediting competitor products. This study is yet another in a long line of industry-sponsored research that favors the sponsor. It was designed to demonstrate outcomes pursued by the investor. 

 

Canopy’s War Against Phytol is Misleading, Inaccurate, and Appears to be Solely for Competitive Advantage

Phytol made the news this year, but not because it was linked to any health scares or respiratory conditions. Instead, phytol made the news because of a media blitz pushed by Canopy Growth.

Canopy used a misleading industry-sponsored study designed by a for-hire laboratory with issues of its own, plausibly to discredit competitor products containing phytol. 

Throughout Canopy’s campaign, it has failed to release any of the study’s detailed results and relied on vague statements to scare up media coverage. Some of the tactics used include falsely connecting phytol to the vape crisis and alluding to a connection with Health Canada, which according to our research and direct communications with Health Canada, doesn’t seem to exist.

All of the media coverage thus far has relied on statements from the company or the vague claims made in the study abstract. The real results are hidden behind a paywall, inaccessible to the average consumer. Even Leafly seems only to have accessed a heavily redacted study for it’s most recent article on phytol.

So, is phytol safe to vape?

The study is scientifically problematic in several ways. The most blatant is the amount of phytol the lab rats were given. The exposure rate translates to a human consuming one vape pen per minute, an impossibility even in the most extreme hypothetical scenario of reckless consumption. 

Other concerns include the two different exposure methods used for PG and phytol, and air-jet nebulizers, and temperatures that do not replicate real-world vape pens, nullifying any controls in the experiment.

Phytol remains legal for use in cannabis vape products in Canada and the US. There have been no further communications about phytol released (even from within the AIA) from Health Canada. Licensed producers on both sides of the border continue to use phytol in their products. 

Most importantly, there have been zero reported hospital admissions, health issues, or reported adverse events from consumers themselves.

As is the case with any research paid for by a private company, it’s critical to examine the motive. Why did Canopy go out of its way to pay for research into phytol? Why did it launch a media campaign against a substance it doesn’t use in any of its products?

Based on our findings, it seems Canopy Growth had one goal in mind: to create a public outcry against a natural terpene, phytol, which happens to be used by its competitors, many of whom are known to focus on high quality manufacturing. 

As a reminder, Canopy still admittedly uses PG in its vape formulations. It has been widely established that PG converts to formaldehyde at higher temperatures, like those in electronic cigarettes and vape pens. Propylene glycol is also a poor excipient to use in formulation due to its poor homogenization characteristics and is likely to separate from natural cannabinoids and terpenes. [6] [7]

What was the motive behind Canopy’s study? Where there is a motive, there is potential for bias.

As stated by Canopy’s Chief Medical Officer, Dr. Ware, “Canopy Growth has ceased sales of third-party vape cannabis products with added phytol in its corporate owned retail stores and confirms that all franchise retail locations have done the same.” There is no indication why Canopy would have paid a company like Lovelace to conduct this study on phytol beyond seeking an advantage over their competitors. 

Third-party vape companies use phytol, while Canopy continues to use PG. What would be an easy way to remove this competition than to stigmatize it?

By no means are we stating or assuming any conclusions about Canopy’s motive, but with a careful review of the timeline of publication and action to remove phytol from their shelves, many questions remain. We may never know the answer to the question, but the seeds of stigma have already been planted.

While the anti-phytol propaganda continues to disseminate through blogs and forums, the real results of the study remain hidden behind a paywall. Based on our research, these results speak for themselves — they are in no way relevant to real-world use of terpenes in vape pens as they are manufactured today.

Researching the safety of any ingredient like phytol is a positive thing if there is good reason for its investigation. The problem with this study is that it was not a reaction to real and reported health concerns. The study was driven in a direction by its sponsors and left a trail of misinformation in its wake. 

 

Citations

[1] Schwotzer, Daniela et al. “Phytol, not propylene glycol, causes severe pulmonary injury after inhalation dosing in Sprague-Dawley rats.” Inhalation toxicology vol. 33,1 (2021): 33-40. doi:10.1080/08958378.2020.1867260

[2] Costa, Jéssica Pereira et al. “Anxiolytic-like effects of phytol: possible involvement of GABAergic transmission.” Brain research vol. 1547 (2014): 34-42. doi:10.1016/j.brainres.2013.12.003

[3] Santos CC, Salvadori MS, Mota VG, Costa LM, de Almeida AA, de Oliveira GA, Costa JP, de Sousa DP, de Freitas RM, de Almeida RN. Antinociceptive and Antioxidant Activities of Phytol In Vivo and In Vitro Models. Neurosci J. 2013;2013:949452. doi: 10.1155/2013/949452. Epub 2013 Jun 11. PMID: 26317107; PMCID: PMC4437258.

[4]Pejin, Boris et al. “An insight into the cytotoxic activity of phytol at in vitro conditions.” Natural product research vol. 28,22 (2014): 2053-6. doi:10.1080/14786419.2014.921686

[5]Lundh, Andreas et al. “Industry sponsorship and research outcome.” The Cochrane database of systematic reviews vol. 2 MR000033. 16 Feb. 2017, doi:10.1002/14651858.MR000033.pub3

[6] Salamanca, J.C., Meehan-Atrash, J., Vreeke, S. et al. E-cigarettes can emit formaldehyde at high levels under conditions that have been reported to be non-averse to users. Sci Rep 8, 7559 (2018). https://doi.org/10.1038/s41598-018-25907-6

[7] Lestari, K. S., Humairo, M. V., & Agustina, U. (2018). Formaldehyde Vapor Concentration in Electronic Cigarettes and Health Complaints of Electronic Cigarettes Smokers in Indonesia. Journal of environmental and public health, 2018, 9013430. https://doi.org/10.1155/2018/9013430

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