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Published in final edited form as: Psychopharmacology (Berl). 2021 Oct 27;239(2):385–397. doi: 10.1007/s00213-021-06007-2

A naturalistic study of orally administered vs. inhaled legal market cannabis: cannabinoids exposure, intoxication, and impairment

L Cinnamon Bidwell 1,2,3, Hollis C Karoly 1,4, Marco Ortiz Torres 1, Ashley Master 2, Angela D Bryan 2, Kent E Hutchison 5
PMCID: PMC12238766  NIHMSID: NIHMS2091309  PMID: 34708254

Abstract

Rationale

Published studies examining the effects of cannabis have largely utilized forms of cannabis that are not representative of the legal market products currently available.

Objectives

The present study aimed to characterize naturalistic use of legal market flower and edible products by examining associations among blood cannabinoids and amount of THC consumed as well as physiological, cognitive, and subjective effects in users of edible and flower forms.

Method

Eighty-four participants who used cannabis at least 1 × /week (55 flower cannabis using participants; 29 edible cannabis using participants mean age = 31.95 years, 44% female) participated. At the experimental appointment in our mobile laboratory, participants completed a blood draw to assess plasma cannabinoids, measures of heart rate, subjective drug effects, and cognition both before and after ad libitum use of legal market flower or edible cannabis.

Results

Average self-reported THC consumed was 15.97 mg (SD = 22.40) in edible users and 51.25 mg (SD = 45.23) in flower users. In the edible group, but not the flower group, strong correlations emerged between self-reported ad libitum THC consumed and plasma THC. Plasma THC was significantly higher after use of inhaled cannabis, but similar levels of plasma THC metabolites and similar levels of subjective intoxication and verbal memory impairment were observed in both flower and edible users.

Conclusions

Findings support strong correlations among ad libitum THC consumed and THC plasma levels after edible cannabis use and suggest few differences in intoxication and impairment between edible and flower cannabis users after ad libitum use. This novel study provides important preliminary data on the pharmacology and effects of legal market edible cannabis.

Keywords: Edibles, THC, CBD, Cannabinoids, Drug reward, Marijuana

Introduction

As of early 2021, 36 US states have legalized medical cannabis, and 15 states and the District of Columbia have legalized recreational cannabis (State Medical Marijuana Laws 2021). This rapidly growing legal market has increased demand for and availability of products that may pose new risks, but have not yet been tested in biobehavioral research due to federal restrictions on cannabis research. This gap is especially critical with respect to orally administered cannabis (“edibles”), which are increasing in popularity on the legal market. Point of sale data provided from Colorado recreational and medical dispensaries indicates edible sales doubled during the first 4 years of legalization (Light et al. 2014; Orens et al. 2018). Further, a report from Colorado’s Marijuana Enforcement Division (MED) showed that 14,313,361 edible units were sold commercially in 2019 (Córdova et al. 2020). This trend is reflected nationwide, as evidenced by a market research report showing gradual increase in edible market share across multiple states (now holding steady at 10–13% of overall market), with notable bumps occurring as additional states legalize recreational cannabis (Food for Thought 2019).

The rising popularity of edible cannabis can be attributed to a variety of factors. Anecdotal data attributes increased interest in edibles to several common perceptions: edibles (1) are more discreet and convenient than other routes of administration, (2) offer a more relaxing and enjoyable “high,” (3) have longer lasting effects, and (4) lack the significant health risks of smoking (Barrus et al. 2016; Poyatos et al. 2020). Potentially for these reasons, edibles are increasingly favored by medical users (Pacula et al. 2016; Weinkle et al. 2019) and older adults (Murphy et al. 2015). However, the putative effects of legal market edibles have not been scientifically evaluated, as few studies have compared commercially available edibles to other forms of consumption.

In addition, questions have arisen in regard to quality control for cannabinoid content and product labeling. Vandrey et al. (2015) found that only 17% of commercially available edibles were within 10% of their reported THC content, while 23% were under-labeled and 60% were overlabeled. Fortunately, recent years have seen considerable improvement, as evidenced by a 2019 report by Colorado’s Marijuana Enforcement Division (MED) showing that adult use (i.e., recreational) edibles passed tests of homogeneity (i.e., how evenly cannabinoids are distributed throughout the product) and potency (i.e., whether cannabinoid content listed on label is consistent with test results) at rates of 88.8% and 87.3%, respectively (Córdova et al. 2020). More research is needed to understand the standardization of edible products and dosages and how legal market dosing and labels link with pharmacokinetics and drug effects in users.

Legal market edibles contain numerous phytocannabinoids, most notably delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC—the psychoactive compound primarily responsible for the intoxicating effects of cannabis—can confer potential negative effects, including addiction, cognitive impairment, and psychiatric comorbidities (Krebs et al. 2019). THC is also associated with increased risk of accident and injury (e.g., THC is linked to both fatal and nonfatal motor vehicle crashes (Hasin 2018)). CBD is thought to be mostly non-intoxicating, such that it is unlikely to cause impairment or strong interoceptive drug effects, although some recent work indicates these effects may appear at higher CBD doses (Spindle et al. 2020). In addition, there is conflicting evidence regarding the impact of CBD on the psychoactive effects of THC, with some studies suggesting that CBD may serve to modulate the psychoactive effects of THC and others suggesting that CBD does not impact the effects of THC (Vann et al. 2008; Englund et al. 2013; Bidwell et al. 2018; Freeman et al. 2019). Further, the limited existing data on this topic suggests that oral cannabis administration produces different pharmacokinetic effects compared to inhalation. Smoking/inhalation rapidly delivers cannabinoids from the lungs to the brain, resulting in almost instantaneous effects, whereas absorption is 30–90 min slower when cannabinoids are processed in the digestive system (Huestis 2007). As summarized in a recent review by Poyatos et al. (2020), several studies have directly compared blood cannabinoid concentration following smoking and oral consumption and reported that maximum blood concentration (Cmax) of orally consumed cannabinoids (predominantly studied in the form of synthetic THC) was significantly lower than Cmax after inhaling a similar dose (Ohlsson et al. 1980; Wachtel et al. 2002; Newmeyer et al. 2017). Additionally, cannabinoid absorption (measured by the correlation between dose and Cmax) was higher for a variety of oral formulations (ranging from r = 0.64 to 0.99) than is typical after use of inhaled forms.

Despite differences in pharmacokinetic patterns, objective and subjective intoxication effects of inhaled and oral cannabinoids appear similar on most dimensions (Ohlsson et al. 1980; Sholler et al. 2020; Wachtel et al. 2002). This appears to be the case both in comparisons between oral and inhaled synthetic cannabinoids—usually dronabinol (Lemberger et al. 1972; Chait and Zacny 1992b; Hart et al. 2002; Wachtel et al. 2002)—and in comparisons between oral and inhaled whole plant cannabis (Ohlsson et al. 1980; Newmeyer et al. 2017; Sholler et al. 2020; Spindle et al. 2021). Effects of cannabis on heart rate seem to vary by THC dose (Wachtel et al. 2002) but remain relatively consistent across oral and inhaled routes of administration (Chait and Zacny 1992a, b; Newmeyer et al. 2017). Conversely, a few early studies found greater increases in heart rate following smoked vs. oral THC (Lemberger et al. 1972; Ohlsson et al. 1980). Chait and Zacny (1992a, b) found that edible and smoked cannabis produced similar effects in terms of magnitude of subjective effects and mood changes. Similarly, Hart et al. (2002) compared the effects of oral and smoked cannabis in the same individuals and found no differences in measures of food intake, feelings of being “high” or “stoned,” and psychomotor performance. However, Ewusi Boisvert et al. (2020) found that compared to combustible forms, orally consumed cannabis was associated with lower ratings of positive subjective effects and higher ratings of negative subjective effects. Furthermore, the subjective effects of edible cannabis may be more susceptible to tolerance and therefore closely related to frequency of use (Hart et al. 2002). For example, Newmeyer et al. (2017) compared subjective effects of smoked, vaped, and ingested cannabis and found that oral consumption was associated with increased feeling of being “high “ in infrequent users, but not in frequent users. The effects of inhaled vs. oral administration have not been examined in the context of naturalistic use of amounts typically consumed via commercially available edible and flower cannabis.

Inconsistencies in the literature may be partially due to research methodologies that threaten external validity. Many studies have administered cannabis in a manner that is inconsistent with the way cannabis is used naturalistically. Most studies on the pharmacokinetics of orally administered cannabis focus on synthetic pharmaceutical forms, which are not commercially available nor representative of products sold to recreational and medical users on legal markets (Poyatos et al. 2020). In addition, research participants are typically not allowed to self-dose as they would in the real world. Given the size and scope of the legal market for edibles, research focusing on the effects of ad libitum dosing and real-world products is an important complement to this growing literature.

The present study uses novel observational research methods to address two objectives. The first study aim was to test associations between blood cannabinoid levels and self-reported THC and CBD amount consumed among participants using commercially available edible cannabis and compare that to the association between blood levels and self-reported THC consumed in flower users. Recent reviews examining the pharmacokinetics of oral formulations (Poyatos et al. (2020) suggest stronger correlations among dose and blood cannabinoid exposure after use of oral forms. Further, while some studies have suggested that doses are often mislabeled on edible packaging (Vandrey et al. 2015), more recent data from Colorado suggests that labels are reasonably accurate (Córdova et al. 2020). Thus, we hypothesized that even under naturalistic conditions, there would be significant and strong correlations between self-reported edible amount consumed and blood levels of cannabinoids and weaker correlations with blood levels and self-reported inhalation amount consumed. The second study aim was to examine subjective and objective measures of intoxication after ad libitum use of commercially available edible cannabis, as compared to ad libitum use of commercially available flower cannabis. Based on the studies cited above showing limited subjective and objective differences when comparing the effects of oral vs. inhaled forms, we hypothesized that the effects would be similar after naturalistic use across flower and edible forms.

Materials and methods

Participants

The research was approved by the University of Colorado Boulder Institutional Review Board. Participants were recruited using social media and mailed flyers advertising to cannabis flower or edible users. Trained research staff screened participants via telephone. Inclusion criteria were as follows: aged between 21 and 70; used any form of cannabis a minimum 4 times in the past month; there was no upper limit on cannabis use; for flower participants, self-reported prior use (at least once) of the highest potency of cannabis that could be assigned in the study (24% THC); for edible participants, self-reported prior dosage (at least once) of at least 2.5 mg of edible THC; no recreational/non-prescription drug use in the past 7 days, except for cannabis; confirmed with a urine toxicology screen; no daily tobacco use; drinking 3 times or fewer per week and < 5 drinks per occasion (for males) and < 4 drinks per occasion (for females); not pregnant (verified via pregnancy test) or trying to become pregnant; and no history of or current diagnosis of psychotic disorder, bipolar disorder, or schizophrenia and not receiving treatment for any of these disorders.

Baseline appointment

On the day of the baseline, participants were asked not to use any cannabis products prior to the study appointment. Abstinence was confirmed via self-report on the day of the baseline session, but abstinence from cannabis was not biologically verified. After participants provided written consent to participate in the study, a breathalyzer and urinalysis were administered to verify the absence of alcohol or recreational drug use. For females, the urinalysis included a pregnancy test. Participants underwent a blood draw and then completed questionnaires on demographics, medical history, and lifestyle, as well as self-report measures of substance use, subjective drug effects, and various measures of mood and cognition (details below).

Edible users were asked to continue using their typical cannabis products as usual until their experimental appointment, during which they self-administered an edible product at the amount of their choosing. Individuals in the flower comparison group were collected concurrently as part of a study comparing different flower and concentrate potencies (Bidwell et al. 2020). Flower participants were randomized to one of two THC potency conditions based on a random number generator. Participants were assigned to one of two strains of cannabis flower with varying amounts of THC: strain A (16% THC and < 1% CBD) and strain B (24% THC and < 1% CBD). Participants were instructed to purchase their assigned product at a local dispensary (The Farm; https://thefarmco.com/). Primary effects of the flower strains are reported previously (Bidwell et al. 2020) and did not support any potency differences between the two different flower strains in their objective or subjective effects. Therefore, the two flower products were grouped into a single flower group for the current analysis.

Experimental appointment

For the experimental session, researchers went to each participant’s place of residence to conduct the experimental session in a federally compliant, university-approved mobile laboratory. Both edible and flower participants were instructed to abstain from using cannabis that day before their session. Abstinence was confirmed via self-report. All participants were asked to submit a photograph of their product and its state required label, which contains detailed cannabinoid content in order to verify the product contents. At the first assessment in the mobile laboratory (pre-use), researchers administered a breathalyzer and conducted a blood draw, and participants completed primary outcome measures (described below). Participants then went inside their home.

Once inside their home, flower participants used their study cannabis flower product ad libitum via their preferred route of administration, weighing their product before and after using it in order to keep track of how much was consumed (see Table 1). After use of their flower product, participants were asked to immediately return to the mobile lab (mean time away from mobile lab = 13.38 min (SD = 5.39); range 8–29 min).

Table 1.

Participant characteristics

Overall sample n = 84 Flower sample n = 55 Edible sample n = 29
Demographics
 Age 31.95 (11.94) 28.76 (8.1)** 38 (15.42)**
 Gender (no. (%) female) 37 (44%) 23 (42%) 14 (48%)
 Education (no. (%) bachelors or higher) 48 (57%) 35 (64%) 13 (45%)
 Employment (no. (%) full-time employed) 39 (46%) 23 (42%) 16 (55%)
 Race (no. (%) White) 70 (83%) 43 (78%) 27 (93%)
Cannabis history and use measures
 Days of cannabis use (past 30 days) 20.16 (10.4) 23.63 (8.4)*** 13.69 (10.9)***
 Days of edible use (past 30 days) 4.88 (8.3) 3.12 (7.4)* 8.14 (9.1)*
 Days of flower use (past 30 days) 15.22 (12.1) 20.55 (10.0)*** 5.76 (10.1)***
 Dependence severity symptoms (MDS) 2.4 (2.8) 2.96 (2.7)* 1.45 (2.7)*
 Baseline plasma THC (ng/mL) 3.73 (7.21) 4.21 (6.6) 2.81 (8.3)
 Baseline plasma 11-OH-THC (ng/mL) 1.43 (3.1) 1.63 (2.8) 1.03 (3.5)
 Baseline plasma THC-COOH (ng/mL) 37.93 (62.4) 44.05 (64.5) 26.05 (57.3)
Cannabis use during ad libitum administration
 Milligrams of THC used during Exp Appta n/a 51.25 (45.23) 15.97 (22.40)
Mode of ad libitum administrationb
 Gummies (no. (%)) 10 (12%) n/a 10 (34%)
 Chocolate (no. (%)) 3 (4%) n/a 3 (10%)
 Cookies (no. (%)) 3 (4%) n/a 3 (10%)
 Tablet/mint (no. (%)) 3 (4%) n/a 3 (10%)
 Caramel (no. (%)) 1 (1%) n/a 1 (3%)
 Powder (no. (%)) 1 (1%) n/a 1 (3%)
 Tea (no. (%)) 1 (1%) n/a 1 (3%)
 Joint (no. (%)) 4 (5%) 4 (7%) n/a
 Bong (no. (%)) 17 (20%) 17 (31%) n/a
 Pipe (no. (%)) 28 (33%) 28 (51%) n/a
 Vaporizer (no. (%)) 6 (7%) 6 (11%) n/a
 Time away from mobile labc 46.31 (24.02) 13.38 (5.39)*** 62.77 (4.23)***
Other substance use and psychological factors
 AUDIT total 4.73 (3.09) 5.38 (3.13)** 3.52 (2.65)**
 Depression (BDI total) 4.47 (5.11) 4.26 (5.3) 4.86 (4.9)
 Anxiety (BAI total) 4.63 (4.92) 4.85 (4.9) 4.21 (4.95)
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Note. MDS Marijuana Dependence Scale, AUDIT Alcohol Use Disorders Identification Test, BDI Beck Depression Inventory-II, BAI Beck Anxiety Inventory; *’s indicate a significant difference emerged in the tests comparing the two user groups (edible vs. flower); ***p < 0.001, **p < 0.01, *p < 0.05. A difference of age (**p < 0.01), days of cannabis use (***p < 0.001), days of edible use (*p < 0.05), days of flower use (***p < 0.001), dependence severity symptoms (as measured by the MDS (*p < 0.05), time away from van (***p < 0.001), and AUDIT total (**p < 0.01) were found between edible and flower users using Welch two-sample t-test. No other significant differences were found.

a

Milligrams of THC used during the experimental appointment cannot be directly compared due to the product differences of cannabis flower and cannabis edibles. The milligrams of THC used for the flower group were estimated using both the THC concentrations of the two strains (16% THC and 24% THC) and the total weight of the product consumed (grams) at the experimental appointment. The milligrams of THC used for the edible group utilized the product labels which provide the total milligrams of THC and CBD and the self-reported number of edibles consumed at the experimental appointment.

b

Note that individuals provided the research team with photos of the flower and edible products they used. Six photos in the edible group were not of sufficient quality to determine what the edible product was. Thus, n = 22 for edible mode of administration data.

c

Note that some data were missing for the flower and edible groups (total group n = 37, flower n = 13, edible n = 26).

Upon returning to their home, edible participants consumed their desired amount of an edible cannabis product of their choosing, recorded the amount consumed based on label information, and waited inside for one hour for the edible to take effect. Because 60 min is the average time that CBD and THC levels begin to peak in the blood after oral administration of cannabis (Ohlsson et al. 1986; Nadulski et al. 2005), mobile laboratory assessments after ad libitum use of edible cannabis began at 1-h post-edible consumption (mean time away from mobile lab = 62.7 min (SD = 4.2); range 53–70 min). Participants in both groups completed the objective and subjective outcome measures (details below) while acutely intoxicated (post-use). A repeat measurement was taken 1-h later (2-h post-edible consumption). However, participant fatigue and refusal to complete the second assessment lead to a drop in N for the final time point (n = 22). Since not all participants received this final measurement, it was not included in the primary analyses presented here. However, the subsamples (n = 22) who had data from this final time point were included in a post-hoc sensitivity analysis reported at the end of the “Results” section.

Measures

Baseline demographics and psychological functioning

Demographic information was collected at baseline using a demographics questionnaire. Use measures for cannabis were collected by trained research staff using a 30-day Timeline Followback (TLFB) (Sobell et al. 1979). When measuring cannabis use, participants also reported details about cannabis form, amount, and mode of administration. The 11-item Marijuana Dependence Scale (MDS) (α = .841) (Stephens et al. 2000) provided a self-report assessment of dependence severity. Psychological functioning was measured at baseline using the Beck Depression Inventory-II (BDI-II) (α = .849) (Beck et al. 1988), which is a 21-item measure of depression symptom severity over the past two weeks. BDI-II scores range between 0 and 63, and the Beck Anxiety Inventory (BAI) (α = .84) (Beck and Steer 1990), which describes 21 common symptoms of anxiety. The items are summed to obtain a total score between 0 and 63. The Alcohol Use Disorders Identification Test (AUDIT) (items 10; α = .661) (Saunders et al. 1993) was used to measure severity of alcohol use in the population. Scores range from 0 to 40, and scores of 8 or above indicate possible hazardous alcohol consumption.

Blood cannabinoids

A certified phlebotomist collected 32 mL of blood at the baseline appointment and the experimental appointment via a sterile venipuncture using standard phlebotomy techniques. During the experimental appointment, the blood was stored on ice in the mobile laboratory for the remainder of the session. Upon return to the laboratory facility, plasma was separated from erythrocytes by centrifugation at 1000 × g for 10 min, transferred to a fresh microcentrifuge tube, and stored at − 80 °C. Plasma samples were sent to the iC42 Lab at the Anschutz Medical Campus. We quantified concentration of CBD, THC, THC-COOH, and 11-OH-THC using validated high-performance liquid chromatography/mass spectroscopy (HPLC–MS/MS) (API550034). Note that 11-OH-THC is the first pass active metabolite of THC and THC-COOH is a secondary more stable metabolite formed by oxidation of 11-OH-THC (Huestis et al. 1992).

Subjective drug effects were measured using the Addiction Research Center Inventory (McDonald et al. 2003), which measures subjective effects of cannabis in addition to drug-induced euphoria, stimulant-like effects, intellectual efficiency and energy, sedation, dysphoria, and other somatic effect. In addition, we used a modified Profile of Mood States (POMS; McNair et al. 1971) to assess subjective intoxication following cannabis use at the experimental session (Bidwell et al. 2020). Subscales of interest for this study were the POMS Elation (e.g., elated, cheerful) (4 items; α = .811) and Tension (e.g., anxious, shaky) (4 items; α = .767) subscales; the single item “Paranoia” was also evaluated; items were on a 5-point Likert-type scale, with responses ranging from “not at all” to “extremely.”

Cognitive outcomes were collected by having participants complete a set of four cognitive tasks in domains that have been linked to cannabis use (Bidwell et al., 2018), including a 30-min delayed verbal recall memory assessed by the ISLT (Thompson et al. 2011) and List Sorting Working Memory, Picture Sequence Memory, and Flanker Inhibitory Control and Attention assessed by three tasks from the NIH toolbox (Weintraub et al. 2013).

Statistical analysis

To test associations between blood cannabinoid levels and amount of THC consumed in edible and flower users, we ran Pearson correlations between plasma THC and self-reported THC ingested (based on weighed amounts in the flower group and product labels in the edible group). To test the effects of time (pre- and post-cannabis use) and cannabis form on plasma cannabinoids and behavioral outcomes of interest, repeated measures ANOVA models were conducted separately for cannabinoid blood levels (THC, THC-COOH, 11-OH-THC, and CBD), subjective intoxication (ARCI and POMS), and cognitive outcomes across two time points (before and after participants consumed their cannabis products in their homes). In order to control for individual and group differences at baseline (see Table 1), age and typical cannabis use (number of self-reported days of cannabis use in the prior month at baseline via the TLFB) were controlled for in all analyses. Interactions tested whether change over time varied by form of cannabis used (flower vs. edible user groups). All models included time point (pre- and post-cannabis use), cannabis user group (flower vs. edible), and the interaction of cannabis user group by time, with baseline days of cannabis use at baseline as a covariate. Effect sizes for group differences are represented using the generalized eta squared (η2G) statistic. Small, medium, and large effect size can be identified by having a η2G greater than a threshold of .03, .13, and .26, respectively. For example, an η2G of .13 for cannabis use group indicates that 13% of the variance on the outcome is accounted for via differences between user groups and would generally represent the minimal threshold for a medium-sized group effect. All analyses were conducted in R (Team 2013). R Studio (Version 1.2.5042) ggplot2 library (Version 3.3.3) was used to generate all figures.

Results

Descriptive information

A total of 31 participants in the edible user group completed the baseline and experimental measures. One edible participant was excluded from analyses due incomplete and inconsistent self-report about their chosen cannabis product and THC levels of 0 ng/mL at the post use assessment, suggesting they had not followed study instructions to use their cannabis in their home before returning to the mobile lab. One edible participant was removed for having THC plasma levels three standard deviations above the mean for edible users at the pre-use assessment (273.2 ng/mL vs. edible users, M = 12.6 ng/mL, SD = 56.8 ng/mL). The flower user group (as reported previously (Bidwell et al. 2020) included 55 participants with data at both baseline and experimental sessions. Therefore, a total of 84 participants were analyzed (flower = 55, edible = 29). Table 1 provides descriptive information about the study participants and user groups.

Characterizing naturalistic use: product amount consumed and compliance

Correlations among ad libitum use and cannabinoid blood levels in the edible group

Edible users

The average amount consumed of THC in the edible group was 15.59 mg (SD = 22.09, range = 1–120) with an average CBD amount of 4.04 mg (SD = 7.08, range = 0–20). The majority of the participants used a THC product, but 11 participants selected a product with CBD included as well (THC + CBD). In the edible user group, strong correlations emerged between self-reported THC consumed (based on product label information) and THC plasma levels [r(29) = .834, p < .001], plasma THC-COOH levels [r(29) = .917, p < .001], and plasma 11-OH-THC [r(29) = .767, p <.001] at post-use. In addition, strong correlations emerged between self-reported CBD consumed and plasma CBD at post-use [r(29) = .769, p < .001]. These findings suggest high correlations among self-reported amount used and post-use cannabinoid levels in plasma in the edible group.

Flower users

The average estimated amount used of THC in the flower group was 51.25 mg (SD = 45.23, range = 7.2–216). In the flower user group, small, nonsignificant correlations emerged between estimated THC amount and plasma THC [r(55) = .154, p = .261] and plasma CBD [r(55) = .177, p = .196] at post-use. However, correlations between estimated THC amount and plasma THC-COOH [r(55) = .352, p = .008] and plasma 11-OH-THC [r(55) = .289, p = .032] were moderate at post-use. Figure 1 includes scatter plots of ad libitum THC dose and THC plasma levels at 1-h post-use in edible users (Fig. 1a) and ad libitum THC dose and THC plasma levels at 1-h post-use in flower users (Fig. 1b).

Fig. 1.

Fig. 1

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Scatter plot of ad Libitum THC dose and THC plasma concentrations after naturalistic edible vs. flower use. a Correlations among ad libitum THC dose (mg) and THC plasma levels (ng/mL) 1-h post-use in edible users. b Correlations among ad libitum THC dose (mg) and THC plasma levels immediately post-use (ng/mL) in flower users. Results show a strong linear relationship among ad libitum THC dose and THC plasma levels in the edible group (r = 0.83) and no linear relationship among ad libitum THC dose and THC plasma in flower users (r = 0.15)

Intoxication outcomes after naturalistic use of edibles and flower

Cannabinoids

RM-ANOVAs revealed significant effects of time (p’s < .001) on plasma THC, 11-OH-THC, and CBD with all levels increasing between pre-use and 1-h post-use. In addition, we observed a small significant group effect in the THC model (F(1,157) = 20.181, p < .001, η2G = .114), such that the flower group had higher levels of plasma THC on average (Fig. 2a). A small significant group by time interaction also emerged in this model (F(1,157) = 20.351, p < .001, η2G = .115), such that the flower group showed a greater change post-use than the edible group, resulting in higher levels of plasma THC post-use (t(54) = 6.24, p < .001; flower M = 144.27, SD = 156.71; edible M = 10.32, SD = 13.42). No group or group by time effects emerged in the model predicting plasma THC-11-OH (p’s > .05) (Fig. 2b). No time, group, or group by time effects emerged in the model predicting THC-COOH (p’s > .05) (Fig. 2c). Small group effects (F(1,157) = 11.653, p < .001, η2G = .069) and a small group by time interaction (F(1,157) = 11.098, p < .01, η2G = .066) emerged in the model predicting plasma CBD, such that the edible group showed a larger change post-use than the flower group, resulting in higher levels of plasma CBD at post-use (t(28) = − 2.53, p < .05; flower M = 0.51, SD = 0.84; edible M = 2.89, SD = 4.96) (see Fig. 2d).

Fig. 2.

Fig. 2

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Cannabinoid plasma concentrations before and after naturalistic edible vs. flower use. a Changes in blood THC (nanograms per milliliter (ng/mL)) before cannabis use (pre-use) and immediately after cannabis use (post-use) (pre-use median = 0.88, range = 0–52.51; post-use median = 44.81, range = 0–993). b Changes in blood THC metabolite COOH-THC (ng/mL) before cannabis use and immediately after cannabis use (pre-use median = 12.98, range = 0–574.549; post-use median = 24.74, range = 0–392.04). c Changes in blood THC metabolite 11-OH-THC (ng/mL) before cannabis use and immediately after cannabis use (pre-use median = 0, range = 0–21.075; post-use median = 2.68, range = 0–24.242). d Changes in blood CBD (ng/mL) before cannabis use (pre-use) and immediately after cannabis use (post-use) (pre-use median = 0, range = 0–2.061; post-use median = 0.42, range = 0–22.97). Orange lines indicate the edible group and blue lines indicate the flower group. Across both forms of cannabis, THC, 11-OH-THC, and CBD were elevated after cannabis administration. The flower group had higher levels and a stronger linear effect of THC after cannabis administration (i.e., a higher peak at the post use assessment). The edible group had higher levels of CBD across both assessments, as well as a stronger linear effect after cannabis administration (i.e., a higher peak at the post use assessment)

Physiological effects

When observing heart rate, RM-ANOVAs revealed a significant large effect of time (F(1,157) = 56.318, p < .001, η2G = .264) and a small significant group by time interaction (F(1,157) = 5.26, p = .02, η2G = .032). The flower group started with lower heart rates than the edible group at pre-use but had higher average heart rates at post-use (t(52) = 1.797, p = .078; flower M = 91.38, SD = 16.93; edible M = 84.31, SD = 16.18) (Fig. 3). There was no main effect of group (p > .05, η2G < .03).

Fig. 3.

Fig. 3

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Heart rate before and after naturalistic edible vs. flower use. Changes in heart rate before cannabis use (pre-use), immediately after cannabis use (post-use) (pre-use median = 72, range = 52–108; post-use median = 87, range = 54–128). Orange lines indicate the edible group, and blue lines indicate the flower group. Across both forms of cannabis, heart rate was elevated after cannabis administration. There was a significant group × time interaction, such that flower group had a higher heart rate after cannabis administration (i.e., a higher peak at the post-use assessment)

Subjective drug effects

The predominant pattern for subjective drug effects across both flower and edible users was an increase in subjective drug effects between pre-use and post-use (Fig. 4). RM-ANOVAs revealed small significant effects of time on the POMS Elation subscale (F(1,149) = 11.315, p < .001, η2G = .071) (Fig. 4a), POMS Tension subscale (F(1,155) = 4.849, p = .03, η2G = .03) (Fig. 4b), single item POMS paranoid (F(1,157) = 15.871, p < .001, η2G = .0918) (Fig. 4c), and a large significant effect of time on the ARCI-M. (F(1,153) = 138.311, p < .001, η2G = .475) (Fig. 4d). In the POMS Elation subscale, there was a small significant group effect, with flower users showing higher positive mood overall (F(1,149) = 8.802, p < .01, η2G = .056); however, no group by time interaction (p > .05, η2G < .03) was found. In all other subjective drug effect models, no significant effects of group (p’s > .05, η2G’s < .03) or group by time interactions (p’s < .05, η2G’s < .03) were demonstrated.

Fig. 4.

Fig. 4

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Subjective drug effects before and after naturalistic edible vs. flower use. a Changes in self-reported positive mood (POMS Elation subscale) before cannabis use (pre-use) and immediately after cannabis use (post-use) (pre-use median = 5, range = 0–16; post-use median = 7, range = 0–16). b Changes in self-reported tension (Profile of Mood States (POMS) Tension subscale) before cannabis use (pre-use) and immediately after cannabis use (post-use) (preuse median = 1, range = 0–11; post-use median = 1, range = 0–13). c Changes in self-reported paranoid (single measure POMS Paranoid) before cannabis use (pre-use) and immediately after cannabis use (post-use) (pre-use median = 0, range = 0–1; post-use median = 0, range = 0–4). d Changes in the ARCI-marijuana scale before cannabis use and immediately after cannabis use (post-use) (pre-use median = 2, range = 0–8; post-use median = 6, range = 2–12). Orange lines indicate the edible group, and blue lines indicate the flower group. POMS Elation, POMS Tension, POMS Paranoid, and ARCI were elevated after cannabis administration. The flower group reported a greater positive mood (POMS Elation) overall, but across all other measures, there were no difference between edible and flower groups. Further, no group × time interactions were present suggesting no differential effects of product type on subjective drug or mood effects after use of flower vs. edible products

Delayed verbal recall memory

RM-ANOVAs showed significant medium effects of time on ISLT response errors (F(1,115) = 19.024, p < .001, η2G = .142), with errors increased at post-use. No group (p’s > .05, η2G’s < .03) or group by time interactions (p’s > .05, η2G’s < .03) were found.

NIH Cognitive Toolbox

Consistent with our prior report in flower users, RM-ANOVAs showed no significant time effects after use of flower or edible cannabis across List Sorting Working Memory, Picture Sequence Memory, or Flanker Inhibitory Control and Attention measures (p > .05, η2G’s < .02). Further, no effects group (p > .05, η2G’s < .02) or group by time interactions (p > .05, η2G’s < .02) emerged in any of the NIH toolbox cognition task models.

Sensitivity analyses

Analyses were repeated using all three time points (pre-use, 1-h post-use, and 2-h post-use) in the smaller subset of individuals who completed the assessment at the final time point (n = 22), and the pattern of results did not change for all of the analysis described in the “Results” section. All significant findings remained significant, and no new significant group or group × time effects emerged in this secondary analyses.

In addition, in order to determine if the effects reported above were driven by the subset of edible individuals who consumed edibles containing both CBD and THC, we ran a sensitivity analysis with these participants dropped from the edible group (n = 10 CBD + THC). This analysis revealed that the majority of the group and time effects reported above remained significant when these participants are excluded. In one exception, the time effect for the POMS tension subscale was reduced to trend level (p = .081, η2G = .023).

Discussion

The present analysis sought to examine use and effects of commercially available edible cannabis. First, we examined associations between blood cannabinoid levels and self-reported cannabinoid consumption, which showed strong correlations in edible users among ad libitum THC and CBD consumed, and post-use THC and CBD levels in plasma. When we examined objective and subjective effects of naturalistic use of commercially available edible cannabis, as compared to naturalistic use of commercially available flower cannabis, we found broadly that the effects of use across these commonly used forms was similar. It was particularly notable that comparable drug effects were observed after naturalistic use of different doses of THC administered by two different routes, and even after controlling for baseline levels of cannabis use, suggesting that the regular cannabis users in the study tended to achieve similar levels of intoxication and drug effects from using these products, even across different tolerances, doses, and routes of administration.

In the edible user group, robust correlations emerged between ad libitum THC consumed and plasma THC, THC-COOH, and 11-OH-THC post-use. In addition, strong correlations emerged between ad libitum CBD consumed and plasma CBD post-use. Ad libitum THC consumed in the flower group was not correlated with THC blood levels and only modestly correlated with THC metabolites. These correlations across flower and edible forms are in line with those reported in Poyatos et al. (2020), who reviewed correlations with cannabinoid blood levels and doses across controlled cannabis administration studies with known doses and precise administration procedures and found similarly strong correlations with oral forms and weaker correlations with inhaled forms of cannabis. Importantly, some of these differences between oral vs. inhaled forms can be accounted for by pharmacokinetic and individual user topography variations with use of inhaled cannabis. This variation in flower pharmacokinetics is further exacerbated by our naturalistic design where self-administration, dosing, and timing were more varied. However, strong correlations reported here among self-reported edible dosing and blood levels are consistent with data from controlled oral administration studies and suggest that participants may be able to accurately report THC and CBD consumed using labels from edible products purchased from a subset of Colorado state dispensaries. Second, given that participants based their self-reported dose on the product label, findings preliminarily support consistency between the amount of actual THC and CBD exposure and the labeled dose on their edible products, supporting the need for more data on the accuracy of product labels across different state markets and forms of cannabis (Córdova et al. 2020).

Our study reported significant differences in THC levels after ad libitum use of smoked cannabis as compared to edible cannabis. Although blood levels reported here are much higher than many prior reports, these findings are generally consistent with three prior studies that compared the oral administration of THC with that of smoking/inhalation in more controlled studies. In Ohlsson et al. (1980) subjects smoked 19.0 mg of THC (ad libitum, with a mean of 13.0 mg of THC) and took an oral dose of 20 mg of THC via a chocolate cookie. Despite being administered in a similar dose, the peak THC plasma levels obtained after smoking was significantly higher than the oral administration. Importantly, although the 20 mg of THC is within the average range of the ad libitum THC consumed reported in the current study, the THC plasma levels after oral administration in the Ohlsson study ranged between 4.4 and 11 ng/mL, much lower than the current report. Similar findings were shown by Wachtel et al. (2002) and Newmeyer et al. (2017) who both reported peak plasma THC after oral administration was significantly lower than that of inhaled routes. Notably, although data are limited, prior work has found few differences in 11-OH-THC and THC-COOH when comparing oral vs. inhaled forms of administration in regular users, likely due to the relatively high baseline concentrations of these metabolites in frequent or regular users (e.g., Ohlsson et al. 1980).

Our findings that subjective and cognitive drug effects of edible and flower cannabis (even at different THC doses) are consistent with some prior laboratory work (Hart et al., 2002). Regarding physiological effects of the edibles and inhaled products, we observed a group by time effect on heart rate, such that the flower group had a higher heart rate post-use than the edible group. These differential effects on heart rate are consistent with Sholler et al. (2020) but contrast to findings described by Newmeyer et al. (2017) in which the subjective effects of oral cannabis were significantly lower than those of inhaled cannabis; however, the physiological effects on heart rate did not differ between the inhaled and oral cannabis administration conditions. Two major differences between the present study and the Newmeyer study are the products used (a range of legal market vs. NIDA supplied cannabis cigarettes converted to edibles) and the administration methods (naturalistic vs. controlled dosing). The observed differences in results suggest that naturalistic studies, in which participants are free to use ad libitum (as they would when using cannabis in daily life), may provide different results compared to controlled dose laboratory studies.

Limitations

This study has a number of important limitations. This was a naturalistic study that made use, at least in part, of self-report measures and is thus subject to the potential bias inherent in observational designs. Participants engaged in self-administration of cannabis ad libitum with their typical mode of administration rather than consuming controlled doses with a specified administration protocol, which limits experimental control over the amount of cannabis consumed and the timing of assessments during the study session. In addition, full pharmacokinetic curves for both oral and inhaled cannabis were not assessed in this naturalistic study, and thus group differences may have been missed across full range of drug effects. Further, the flower group reported more frequent cannabis use than the edible group at baseline. While group differences were controlled statistically in all analyses here, future work should directly test whether any differences in cannabis use history or tolerance have impacted these results. We also lacked precision in timing for the flower and edible self-administration in relation to the subsequent blood draw and post-use time point. Specifically, the time that flower participants spent inside their homes was relatively brief (12 min on average) and was likely spent administering cannabis flower and then immediately returning to the lab, whereas the edible participants spent that time consuming their edible and then waiting 60 min. Further, during the 60-min waiting period, researchers did not have control over their activities or ask them to do anything in particular. It is possible that variation in participant activities could have influenced subjective responses at the post-use time point. Although this is a meaningful limitation to consider when interpreting the present results, it should also be noted that large differences did not emerge between the edible and flower groups at the post-use time point, suggesting that the 60-min delay for the edible group likely did not have a major impact on outcomes at the post-use time point.

Another limitation is the fact that there was no biological confirmation of cannabis abstinence on the days of the baseline or experimental laboratory sessions. Further, there was no placebo control condition, and ethical limitations precluded assignment of participants to flower versus edible conditions, which limits causal interpretations of our findings. Additionally, Poyatos et al. (2020) found that cannabinoid absorption may depend on type of edible, as evidenced by stronger correlations for capsules, tablets, and decoctions (tea), compared to oils and baked goods such as cookies and brownies. In the present study, gummies, chocolates, and cookies were the edible products used by the most participants, while teas, powders, caramels, and mints were reported by the fewest participants. However, we were not powered to examine the differences across these different product forms.

Despite these limitations, the study benefited from a naturalistic design, which increases external validity. This type of approach complements more controlled studies by allowing for conditions self-dosing and self-titration that more realistically mirror everyday use. Further, this was the first study to our knowledge to work within federal restrictions to study the effects of legal market edible cannabis in order to provide novel data that may have public health implications. Specifically, these data report on typical use dosing ranges across flower and edible forms, which can inform dosing regimens of laboratory studies and improve their external validity. In addition, commercially available cannabis products are typically derived from the whole plant and therefore include myriad phytocannabinoids and terpenes that may impact both objective and subjective drug effects. As previously noted, most studies on cannabis—particularly rigorously controlled clinical trials—employ synthetic cannabinoids, which are chemically homogeneous and thus less representative of legal market products. As this research aims to promote public health by informing harm reduction strategies, it is crucial to mimic conditions in which individuals use cannabis in real life.

Conclusions

Using naturalistic methods, we found differing cannabinoid plasma levels, but few differences in intoxication, physiological effects, and impairment, after ad libitum use of legal market edibles as compared to flower forms. In addition, robust correlations were demonstrated among self-reported cannabinoids consumed, and cannabinoid plasma concentrates after use of legal market edible forms of cannabis. These findings are among the first to report on the relationship among ad libitum amounts of cannabinoids consumed and objective concentrations in plasma, as well as objective and subjective intoxication measures after legal market edible use.

Funding

Funding for this study was provided by a grant from the National Institutes of Health (DA039707 to KEH).

Footnotes

Conflict of interest The authors declare no competing interests.

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