Systematic combinations of major cannabinoid and terpene contents in Cannabis flower and patient outcomes: a proof-of-concept assessment of the Vigil Index of Cannabis Chemovars | Journal of Cannabis Research

Study design

The study design was reviewed and deemed exempt from further oversight by the Institutional Review Board at the University of New Mexico due to the retrospective and anonymized nature of the data. The owner of the Releaf App, MoreBetter, Ltd., provided de-identified data to the investigators subject to a data use agreement. The freely available Releaf App educational mobile software was designed to enable users to document the labeled characteristics of their cannabis products, cannabis usage characteristics (e.g., dosing and route of administration), user health conditions, baseline and momentary symptom intensity levels, and experienced side effects during real-time, in vivo, self-administration sessions. State-legal cannabis product labels are required to include THC and CBD levels. Validation of these levels occurs through state-authorized cannabis testing laboratories with some of the labs also providing information on terpene concentrations. The potential terpenes available for entry in the ReleafApp™ software include alpha-pinene, beta-pinene, beta-caryophyllene, caryophyllene-oxide, alpha-humulene, linalool, limonene, myrcene, ocimene, terpinolene, terpineol, alpha-phellandrene, alpha-terpinene, fenchol, camphene, valencene, garaniol, guaiol, alphabisabolol, and farnasene. The Releaf App includes 52 health symptoms and 47 possible side-effects. The study sample includes treatment sessions with post-consumption symptom intensity levels reported at least once within the first hour after session initiation.

A description of data filtering procedures is shown in Fig. 1. The initial dataset consisted of 252,344 sessions recorded by 13,771 users between June 6, 2016 and March 11, 2021. Only the sessions using flower products (60.4% of total sessions) were included in the dataset, and 6.7% of the flower sessions included laboratory-provided information on the product’s terpene levels. Recorded potency levels for labeled THC, THCa, THCv, and THCva were aggregated (THC family), as were levels of CBD and CBDa (CBD family). To avoid confounding from user entry error, cutoff thresholds for cannabinoids and terpenes were selected based on the biological limitations of the Cannabis plant (Reimann-Philipp et al. 2020). The cutoff thresholds for reasonably labeled cannabinoid family levels were set at 35.0%/dry wt., and the cutoff for each of the 20 terpenes was set at 3.0%/dry wt. Sessions reporting levels that were higher than these cutoffs were excluded from the final analyses. Each product is unique at the user level, i.e., if two users were to purchase the same product, it would appear in the data as two separate products.

Fig. 1
figure 1

Diagram of flowchart of inclusionary criteria for data analyses

The final analyzed sample included 204 users who completed 6309 cannabis administration sessions using 633 distinct products with bona fide terpene and cannabinoid content labels between 09/10/2016 and 03/11/2021.

Chemovar indexing method

In order to accommodate measurement error in conventional laboratory testing results, to allow for natural variations in potency within a product batch, and to enable cannabis users the ability to better manage the nearly limitless possible number of chemovars across products, the absolute potency volumes provided on product labels were categorized on ordinal scales, separately for terpene and cannabinoid contents. To create the index system and the associated treatment variables, distinct plant chemovars were categorized according to a 4-character coding system that broadly describes the relative magnitudes of the primary and secondary terpenes detected and THC and CBD potency levels. The first two characters are the alphabetic symbols for the 20 recorded terpenes, with the highest concentrated terpene in the first place and the terpene with the 2nd highest concentration in the second place. Table 1 shows the number of sessions with information for each of the terpenes, the frequency that information was provided for each terpene, the average recorded concentration volume for each terpene, and the alphabetic index code for the terpenes.

Table 1
Cannabis plant terpene alphabetic codes and usage characteristics

Within the coding system itself, the relative magnitudes of the terpene concentrations are indicated with the presence of superscript(s) “+” following the alphabetic symbol indicating one of 4 possible concentration levels: (no superscript) = 0.01 to 0.49%/dry wt.; “+” = 0.50–0.99%/dry wt.; “++” = 1.00–1.99%/dry wt.; and “+++” = 2.00–3.00%/dry wt. In the main coding system, the “-” indicates the absence of a 2nd identified terpene and a “/” between terpenes in the 1st and 2nd places indicate exactly matched concentration levels.

The third and fourth places in the coding system are reserved for the plant’s absolute THC and CBD potency levels, respectively. The units consist of digits across two separate scales (1–8 for THC, and 0–8 for CBD) representing the distribution of the most common cannabinoid levels listed on product labels. The possible THC codes (the 3rd place in the index code) are as follows: 1 = 0.01–0.9%; 2 = 1–4.9%; 3 = 5–9.9%; 4 = 10–14.9%; 5 = 15–19.9%; 6 = 20–24.9%; 7 = 25–29.9%; 8 = 30–35%. (Given the scarcity of Cannabis flower strains with no [0.0%] detectable THC, the value “0” is not used for this scale.) The possible CBD codes (the 4th place in the index code) are as follows: 0 = 0.0%; 1 = 0.01–0.9%; 2 = 1–4.9%; 3 = 5–9.9%; 4 = 10–14.9%; 5 = 15–19.9%; 6 = 20–24.9%; 7 = 25–29.9%; 8 = 30–35%.

As shown in Supplemental Table S1, a total of 478 unique chemovar codes were identified in the current sample. The five most frequent chemovar index codes are described in Table 2. As shown in Table 2, four of the five most frequently represented chemovars contained mercene as the primary or secondary terpene, all the chemovars had THC levels that ranged between 15 and 25%, and all but one had less than 1% CBD. Although the exemplar chemovars were comprised of products with differing strain names, the product labels showed strong trends indicating either a Cannabis sativa or Cannabis indica dominance, or hybridization of the two.

Table 2 Descriptions of frequently consumed Cannabis flower chemovar index codes

Study outcomes

The study objectives are to identify common examples of unique chemovars and evaluate whether differences exist in their effectiveness at reducing the severity of patients’ symptoms, and their associations with experienced side effects. Symptom relief is measured by subtracting the (post-dosing) lowest recorded symptom intensity level from the baseline (pre-dosing) intensity level, resulting in potential symptom changes ranging between − 10 (maximum symptom relief) and 9 (minimum symptom relief/maximum increase in symptom severity) points. (Only sessions with starting symptom intensity levels of one or more are included, so as to include only sessions attempting to treat a measurable health symptom.) The 47 possible side effects are categorized into 17 negative side effects, 19 positive side effects, and 11 context-specific side effects. We convert these categories of side effects into continuous variables measuring the absolute number of total side effects in each category that the user selected. The full list of possible side effects, the frequency in which they were reported, and their categorical distinctions are shown in Supplemental Table S2. The most commonly reported negative side effects in the current sample are dry mouth (40.6% of sessions) and red eye (26.8%), the most common positive side effects are feeling chill (63.1%) and relaxed (56.2%), and the most common context-specific side effects are feeling high (56.3%) and tingly (33.0%).

Statistical analysis

Analyses of covariances (ANCOVAs) were used to measure the relationships between the exemplified chemovars and symptom relief within the first hour following consumption and between the chemovars and experienced side effects reported during that first hour. Baseline symptom intensity level was included as a covariate given the relationship between the starting symptom level and the magnitude of potential symptom relief (Stith et al. 2018; Stith et al. 2019). We also included the product’s total terpene contents as a covariate to control for the volume of additional terpenes not represented in the primary or secondary indexing position, and we included the total number of side effects recorded as a covariate for examining each side effect category. The analyses focused on the full sample, as well as two patient subgroups: (a) consumption sessions used to treat pain (n = 2372, 37.6% of total sample) and (b) consumption sessions for treating either anxiety symptoms or depression (n = 1,062, 16.8%). We group these conditions together because they often occur concomitantly and to maintain a large enough sample for analysis. In order to ensure that the results are not driven by users with disproportionate numbers of session entries, robustness checks were conducted limiting the analyses to products that were tested within the first ten sessions recorded by a user. Analyses were conducted using IBM SPSS Statistics 23 (IBM 2015).

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