Introduction ARTICLE SECTIONS Jump To

Legalization and increasing social acceptance of cannabis in the United States and worldwide has led to a proliferation of novel cannabis administration methods. Advancement of cannabis extract (CE) production and processing has placed these at the forefront of novel cannabis inhalation methods, and sales of CEs now make up more than 20% of the retail market share in the Washington state. (1) Despite their popularity, little work has been done to assess the safety of these novel consumption methods.

9-tetrahydrocannabinolic acid (THCA, mp 75 ± 3 °C 2 ) are used to extract acid cannabinoids in an oleoresin that includes terpenes, waxes, fatty acids, steroids, lignins, etc. Cannabinoids, the constituents responsible for cannabis’ psychoactive and medicinal effects, are biosynthesized in trichomes of female cannabis inflorescences. (2−4) Figure 1 displays the pharmacologically active cannabinoids THC (mp: <25 °C (5) ) and cannabidiol (CBD, mp: 62–63 °C (6) ), which are biosynthesized as the acid cannabinoids Δ-tetrahydrocannabinolic acid (THCA, mp 75 ± 3 °C (7) ) and cannabidiolic acid (CBDA, mp 68 ± 3 °C (8) ) that readily decarboxylate upon heating. (9) Nonpolar solvents (e.g., butane (10−12) and supercritical CO (13,14) ) are used to extract acid cannabinoids in an oleoresin that includes terpenes, waxes, fatty acids, steroids, lignins, etc. (15) While butane hash oil (BHO, an amber or gold solid (10,16) ) contains primarily acid cannabinoids, (10,11) superfluid cannabis extract (SFE) may contain acid or neutral cannabinoids depending on processing methods. Vacuum distillation affords purified neutral cannabinoids allowing manufacturers to tailor cannabinoid and terpene content in the final product commonly referred to as a distillate. (17) Distillates are often amended with terpenes at 5–15% (m/m). (18)

Figure 1 Figure 1. Relevant cannabinoids.

Three consumption methods/devices for CEs have predominated: dabbing, cartridge vaporizers (CVs), and top-loading vaporizers (TLVs). Dabbing involves flash vaporizing a small amount of CE, a dab, on a hot surface, a nail, which is connected to a pipe or water pipe, an oil rig or rig. (19) A user quickly and immediately inhales aerosol generated when the dab is placed onto the nail, which may require up to an entire vital capacity for complete capture. (11) BHO, distillate, and SFE are amenable to dabbing, though BHO is most common. (11,20) CVs are small electronic cigarette-like devices that use battery-powered resistive heating to aerosolize CEs. A button-activated battery powers an atomizer located in a cartridge preloaded with CE to generate aerosol a user inhales through a mouthpiece; reliance on wicking necessitates extracts containing neutral THC with added terpenes to decrease viscosity. (21) TLVs also use a battery to power a resistively heated coil but differ in that users manually place the CE directly onto exposed heating coils in the atomizer ad libitum. (22) Any extract may be used in TLV. (22) Both TLV and CV are colloquially referred to as vape pens, and no surveys to date distinguish between the two, categorizing them together as cannabis e-cigarettes or cannabis electronic vapor products (CEVPs). In all these CE consumption methods, carrier liquids such as glycerol, propylene glycol, and medium-chain triglycerides are not typically included as they are considered to be undesirable. (23)

Vaporizing (or vaping) cannabis by any method has gained popularity among recreational and medical users, particularly young adults and teens, (24) as a less detectable method of using marijuana compared to smoking that is also perceived to be healthier. (25−27) Vaporizers for cannabis inflorescences (28,29) have existed long before popularization of CEs, (30) and terminology used to refer to these (e.g., vaporizers and vapes) has been applied for TLV and CV, which has led to some confusion in the literature. Several studies have investigated prevalence of CEVPs specifically, though many others exist for inflorescence vaporizers. The 2016 National Youth Tobacco Survey (31) reported that nearly 1 in 11 respondents reported lifetime use of a CEVP, and other state-level surveys report 3.4% usage among middle-schoolers, (32) 5.4–11.4% for high-schoolers, (32,33) and 10.7% for college students. (34) Sparse data exists on prevalence of dabbing, though it appears to be common among regular cannabis users. Twenty percent of daily/nearly daily cannabis users in the Washington state reported dabbing in the past week, (35) and 36.5% of respondents from a Reddit survey of a similar cohort endorsed regular use of dabbing as well. (36) An internet survey of Twitter posts found that dabbing-related posts are more prevalent in states with medical marijuana laws, (37) suggesting that dabbing may grow in popularity as legalization of cannabis expands access to alternative cannabis products.

The thermal behavior of cannabinoids has been studied in the context of the conversion of CBD to THC or other potentially psychoactive compounds in smoked marijuana, smoked tobacco with CBD, (38−41) and pyrolysis of CBD alone. (42,43) While searching for potentially psychoactive CBD pyrolysis products, many olivetol derivatives with intact pentyl chains ( Figure 2 , compds 1–5) (44,45) and other products were found to stem from rearrangement of CBD’s terpene moiety ( Figure 2 , compds 6 and 7), (46) indicating that this may be particularly labile. Exhaustive in its efforts to identify potential pharmacologically active products, work at the University of Utrecht did not prioritize identifying volatile organic compounds (VOCs). Harmful and potentially harmful constituents (HPHCs) of cannabis smoke have been previously studied, (47,48) but no information is available concerning pyrolysis or oxidation products of cannabinoids relevant to dabbing or vaping conditions. Moreover, it is not clear if the HPHCs arise from the cannabinoids, terpenes, or any other plant constituents. A recent study described BHO diluted in glycerol and propylene glycol added to a CV-type device, which does not embody the manner in which cannabis concentrates are vaporized. (49) Evidence-based data is needed to better understand toxicology and routes of administration of these emerging products. We currently do not know, for instance, the aerosol doses of cannabinoids, terpenes, and potentially toxic degradation products being delivered to vulnerable cohorts such as teens and pre-teens or to medical marijuana patients with compromised immune systems.

Figure 2 Figure 2. Cannabidiol degradation products.

3 concentration of a given chemical. T ) and HI, respectively, which may be used to guide policy decisions regarding environmental cleanup projects and consumer products. Quantitative risk assessment (QRA) is an analytically driven risk calculation that pools biological and chemical data to approximate the probability of the incidence of a defined outcome or symptom upon exposure to a given HPHC. QRA has been previously performed for tobacco products, (50,52) for example, for comparison of “reduced exposure” cigarettes to regular cigarettes. (51) Cancer risk may be approximated using the excess lifetime cancer risk (ELCR) and noncancer risks using the hazard index (HI). ELCR, the incremental probability of contracting cancer upon specified conditions of exposure to a carcinogen, (52) is derived from the inhalation unit risk (IUR), an estimate of the increased risk (i.e., above baseline) of developing cancer due to exposure to a 1 μg/mconcentration of a given chemical. (53) The reference exposure level (REL) is an estimate of an air concentration that is not likely to create an appreciable risk in humans after continuous inhalation and is calculated in reference to a given symptom that occurs after chronic exposure. (53) Both the IUR and REL may have uncertainties spanning an order of magnitude. A given exposure concentration divided by the REL yields a hazard quotient (HQ) wherein HQ > 1 indicates that the threshold of toxic effects on the target system is surpassed. ELCR and HQ values for individual chemicals are summed to yield total ELCR (ELCR) and HI, respectively, which may be used to guide policy decisions regarding environmental cleanup projects and consumer products. (52)