Cannabinoid Vaping Products Present Novel Challenges for Assessment of Respiratory Health Effects

Cannabinoid vaping products, including Δ9-tetrahydrocannabinol (Δ9-THC), Δ8-tetrahydrocannabinol (Δ8-THC), and cannabidiol (CBD) products, are rapidly gaining popularity. There are growing concerns for the adverse health effects of cannabinoid vaping products due to recent outbreaks of e-cigarette, or vaping, product use-associated lung injury (EVALI) which, as of February 2020, included 2807 hospitalized cases and 68 deaths (CDC, 2020). Within EVALI patients, 82% reported use of THC vaping products and 16% reported use of CBD vaping products (Ellington et al., 2020). To date, there has been limited research on THC- and CBD-containing vaping products both due to regulatory barriers and the rapid evolution of the cannabinoid market. THC is currently classified as a Schedule 1 substance under the U.S. Drug Enforcement Agency Controlled Substances Act, which has restricted investigators’ access to THC-containing products for research. Although the Agriculture Improvement Act of 2018 legalized hemp-derived CBD containing less than 0.3% Δ9-THC, the U.S. cannabinoid market is still new and there are limited data on the health effects of these products, particularly in the context of vaping and inhalational exposures.

The prevalence of THC and CBD vaping product use has been reviewed in multiple populations and demographics, although it is most studied in adolescents. A recent meta-analysis of 17 studies found that lifetime use of THC vaping products in adolescents increased from 6.1% to 13.6% between 2013 and 2020, and that adolescents preferred THC vaping oil over cannabis flower (Lim et al., 2022). In a 2020 survey of U.S. adults (n = 30 288), 26.1% reported CBD use in the past year, and 18.9% reported using CBD vaping oils (Goodman et al., 2020). These rates may be higher among adolescents and young adults; however, there is a need for more comprehensive surveillance and meta-analysis of CBD vaping product use.

Cannabinoid vaping products can be categorized as either concentrated “oils,” which typically range in concentration from 700 to 1200 mg/ml and are most used with pen-type devices, or diluted “vape juice,” which typically ranges in concentration from 15 to 50 mg/ml and can be used with a wide variety of refillable vaping devices. Both THC and CBD vaping products have been found to contain terpenes, flavorants, humectants, silicones, pesticides, vitamins, and metals, illustrating a clear need for federal guidance over manufacturing practices. Toxicological assessment of cannabinoid vaping products including assessment of additives and diluents, relevant dose-response patterns, and inhalational exposures will be necessary to inform federal policy.

Studies investigating the health effects of cannabinoid vaping products are limited. In a sample of U.S. adolescents, participants who had ever vaped cannabis had increased odds of multiple respiratory symptoms including wheezing and dry cough (Boyd et al., 2021). Several recent studies have also shown that in vitro exposure of airway epithelial cells to CBD vaping product aerosols upregulates markers of toxicity including cellular reactive oxygen species levels, inflammation, and cytotoxicity (Leigh and Goniewicz, 2020; Muthumalage and Rahman, 2019). Although these biological effects may be driven by the initial constituents of vaping products, there is also potential for chemical conversion of these constituents to reactive byproducts through heated aerosolization, oxidation, or cellular metabolism. Cannabinoid vaping products may also cause systemic effects beyond the lung, particularly in the brain and vasculature, as prenatal THC use has been shown to alter brain development.

In addition to transformation by oxidation or metabolism, CBD is being intentionally converted to psychoactive Δ8-THC by acid catalysis. Commonly referred to as “delta-8” or “D8,” Δ8-THC emerged on the market in September 2019 and is now sold legally in many U.S. states. Like its isomer, Δ9-THC, which produces the “high” associated with marijuana use, Δ8-THC produces somatic, perceptual, and psychoactive effects (Hollister and Gillespie, 1973). Consumers of Δ8-THC report that the effects are less potent than Δ9-THC (Hollister and Gillespie, 1973); however, the current availability of Δ8-THC in states where marijuana and Δ9-THC are prohibited has led to a surge in demand and consumption. In a recent study using Google Trends, searches for Δ8-THC increased in popularity nearly 7-fold since August 2020, with searches for “Δ8-THC” being 35% as frequent as those for “marijuana” (Livingston et al., 2022).

Although Δ8-THC is only a minor constituent of hemp and cannot be obtained in sufficient quantities to make extraction financially attractive, it is easily manufactured through acid-catalyzed intramolecular cyclization of CBD (Meehan-Atrash and Rahman, 2022). Protocols for the isomerization of CBD to Δ8-THC are broadly circulated online. However, acid catalysis of CBD can also produce Δ9-THC, Δ10-THC, and other cannabinoids. Furthermore, improper chemical conversion may lead to product contamination with solvents, metals, and catalysts such as heptane and toluene. A recent independent test commissioned by the U.S. Cannabis Council examined 16 over-the-counter Δ8-THC vaping cartridges for their chemical content (US Cannabis Council, 2021). All samples contained more Δ9-THC than the 0.3% federal limit, and 7 of the 16 samples had high concentrations of copper, chromium, or nickel. Additionally, unknown cannabinoid-like compounds were identified in most of the samples. Synthetic cannabinoids are of particular concern as they have been shown to produce anxiety, panic, dysphoria, psychosis, and accidental deaths in users. In states where marijuana and Δ-9-THC are currently illegal to purchase or possess, consumer interest in Δ8-THC products and emerging “legal” psychoactive cannabinoids will likely continue to increase, making understanding of the inhalational toxicity a public health imperative.

To prevent another public health crisis like EVALI, further research is needed on the pulmonary toxicity of emerging cannabinoid vaping products containing THC, Δ8-THC, Δ10-THC, and other THC metabolites like tetrahydrocannabivarin, THC acetate ester, and hexahydrocannabinol. Toxicological assessment will be critical for understanding the effects of inhalational exposures, dose effects relevant to vaping products, and the toxicity of diluents and additives, such as terpenes, medium-chain triglycerides, flavorings, and pesticides. Systemic effects following inhalation of cannabinoid vaping products including cardiovascular and neurological toxicity should also be investigated. The rising popularity of cannabinoid vaping products especially in adolescents, the rapidly evolving product market, and federal restrictions imposed on THC research present unique challenges for comprehensive assessment of the inhalation toxicity of these products.

FUNDING

This work was supported by a T32 Training grant (CAL; National Research Service Award T32 ES007126), a pilot grant from P30ES010126 (PWC) from the National Institute of Environmental Health Sciences, and an administrative supplement to R01HL139369-S2 (IJ and PWC) from the National Heart, Lung, and Blood Institute.

DECLARATION OF CONFLICTING INTERESTS

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.