Assessment of cognitive and psychomotor impairment,subjective effects,and blood THC concentrations following acute administration of oral and vaporized cannabis

Participants

Research participants were recruited via media advertisements and word-of-mouth communication. Potential participants who appeared eligible based on an initial telephone screen completed an in-person screening visit. At this visit, health status was ascertained by medical history review, electrocardiogram (ECG), routine blood testing (chemistry, hematology, and serology), and a physical examination. Recent drug/alcohol use was assessed via the Timeline Follow-Back (Sobell and Sobell, 1992), and participants provided a urine specimen, which was tested (via a rapid enzyme immunoassay test kit) for cannabis, amphetamines, benzodiazepines, cocaine, MDMA, opioids, and phencyclidine and were given an alcohol breathalyzer. A serum pregnancy test was also conducted for female participants. All participants provided written informed consent prior to study participation and received monetary compensation for each completed visit. Experimental procedures were approved by the Institutional Review Board of Johns Hopkins University School of Medicine and were conducted in accordance with the Declaration of Helsinki.

In order to be eligible, participants were required to: (1) be between the ages of 18 and 45; (2) be in good health (determined using the screening visit procedures described above); (3) self-report no cannabis use for at least 1 month prior to their first experimental session; (4) report prior experience inhaling cannabis (either smoking or vaporizing); (5) provide a negative urine test for cannabis and other illicit drugs and a negative breath test for alcohol at the screening visit and before each session; (6) have a body mass index (BMI) between 19 and 36 kg/m²; (6) not be pregnant (assessed via serum at screening and via urine before study sessions) or breast feeding; (7) have no allergies to any of the ingredients used to prepare cannabis brownies (e.g. chocolate, eggs, etc.); and (8) have not donated blood for 30 days prior to screening.

Study design and procedure

This study utilized a placebo-controlled, within-subjects experimental design. All study participants (N = 20; 10 males and 10 females) completed six separate 10-h outpatient drug administration sessions during which they self-administered vaporized cannabis (containing 0, 5, and 20 mg THC) and cannabis brownies (containing 0, 10, and 25 mg THC). All study sessions were conducted at approximately the same time of day. Participants and research staff were blind to THC dose (but not route of administration) for all sessions. Sessions were conducted at the Johns Hopkins Behavioral Pharmacology Research Unit (BPRU) and were separated by at least 1 week to ensure adequate drug washout between doses. For each participant, sessions were clustered by route of administration, meaning they would complete the three oral cannabis sessions first and the three vaporized cannabis sessions second, or vice versa; session clusters were counterbalanced across participants. THC dose order within each session cluster was also counterbalanced across the first 18 participants, whereas dose order was randomly assigned for the final two participants (complete counterbalancing was not possible with a sample size of 20).

Prior to the start of each session, participants self-reported their use of cannabis, alcohol, tobacco, and other drugs since the previous study visit and provided urine and breath samples to test for drug use/pregnancy and alcohol use, respectively. Participants were provided a standardized low-fat breakfast of toast and jam, and an intravenous catheter was placed to allow for repeated blood sampling. Next, a baseline blood sample was collected, baseline vital signs were recorded, and participants completed baseline subjective drug effect questions, computerized performance tasks, and field sobriety tests (see below). Following baseline procedures, participants either consumed a cannabis-containing brownie or inhaled vaporized cannabis. For oral dosing, participants were asked to consume the entire brownie within 5 min and were permitted to drink water as needed. Participants inhaled vaporized cannabis using the Volcano Medic^® (Storz and Bickel, Tuttlingen, Germany). The Volcano heated cannabis at 204°C (400°F), and the resulting vapor was captured in a “balloon”; participants were asked to inhale three full balloons ad libitum within a 10-min period. New balloons were used in each session to avoid contamination from prior doses. Balloons were covered with an opaque bag to reduce the visibility of the vapor to participants and study staff. Following drug exposure, study outcomes were completed at regular intervals for 8 h (see section “Outcome measures” below). In-between study session time points, participants engaged in leisure activities of their choosing (e.g. watching television/movies, reading, playing board games, etc.).

Study drug

High THC and placebo cannabis were obtained for this study from the National Institute on Drug Abuse (NIDA) Drug Supply Program. High THC cannabis contained: 10.3% THC, 0.05% cannabidiol (CBD), and 0.85% cannabinol (CBN). The placebo cannabis contained: 0.001% THC, 0.003% CBD, and 0.005% CBN. For vaporized cannabis administration sessions, 194.2 mg of placebo cannabis, high THC cannabis, or a combination of the two were placed into the Volcano Medic^® vaporizer to achieve THC doses of 0, 5, or 20 mg. In a similar vein, placebo and active cannabis brownies were prepared by mixing 242.7 mg of placebo cannabis, high THC cannabis, or a combination of the two to achieve THC doses of 0, 10, or 25 mg. The low doses (i.e. 5 mg vaporized THC; 10 mg oral THC) were intended to produce discriminable drug effects without eliciting significant impairment of cognitive/psychomotor functioning, whereas the high doses (i.e. 20 mg vaporized THC; 25 mg oral THC) were intended to produce discriminable drug effects as well as marked cognitive/psychomotor impairment. Our prior controlled cannabis dosing studies (Schlienz et al., 2020; Spindle et al., 2018; Vandrey et al., 2017) informed dose selection for each respective route of administration.

Cannabis brownie preparation consisted of: (1) grinding individually weighed doses of cannabis into a fine powder with a food processor; (2) heating cannabis for 30 min at 250°F (130°C) to facilitate decarboxylation of Δ-9-tetrahydrocannabinolic acid (THC-A) to THC; and (3) mixing the decarboxylated cannabis with brownie batter, along with other required ingredients (e.g. eggs, flour, etc.). Each brownie was prepared separately in an individual baking tray to ensure exact dosing. In prior studies (Schlienz et al., 2020; Vandrey et al., 2017), we have confirmed that these methods result in full conversion from THC-A to THC and reliably yield targeted THC doses. Brownies were prepared 24–48 h prior to each experimental session. For vaporization, a precisely weighed amount of cannabis was placed on the stainless-steel dosing pad of the Volcano Medic^®, heated at 204°C (400°F), and the resulting cannabis vapor was self-administered by study participants who inhaled the contents of three fully inflated “balloons” in order to exhaust the entire dose (prestudy testing confirmed that these dosing parameters were sufficient to fully exhaust the highest vaporized dose, 20 mg THC). All cannabis was prepared and dispensed by the Johns Hopkins BPRU Pharmacy.

Outcome measures

All study outcomes described below were assessed at baseline, immediately following drug exposure (i.e. time “0”), and 1, 2, 3, 4, 5, 6, and 8 h after drug exposure. Because the assessment battery was extensive, additional data collection time points could not be included. The order of task administration was the same at all time points and for all participants throughout the experiment.

Subjective drug effects

A 21-item Drug Effect Questionnaire (DEQ) was administered, which included items to capture: positive (e.g. “like drug” and “pleasant drug effect”) and negative subjective drug effects (e.g. “unpleasant drug effect” and “anxious/nervous”), behavioral/mood states that are common following acute cannabis exposure (e.g. “paranoid” and “hungry/have munchies”), and participants’ perceived level of impairment (e.g. “trouble with memory” and “difficulty with routine tasks”); see Table 1 for list of all DEQ items. Each item was presented individually on a 100 mm visual analog scale (VAS) with a horizontal line anchored from 0 (“not at all”) on the left to 100 (“extremely”) on the right.

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Table 1.

Statistical analyses results for pharmacodynamic outcomes using change-from-baseline data.

Outcome measures	Dose (D) F	p	Route (R) F	p	Time (T) F	p	D × R F	p	D × T F	p	R × T F	p	D × R × T F	p
Subjective measures
Drug Effect Questionnaire (DEQ)
Drug effect	30.79	<0.001	2.51	ns	38.89	<0.001	0.89	ns	10.54	<0.001	39.02	<0.001	10.86	<0.001
Unpleasant	14.25	<0.001	0.45	ns	3.25	0.007	1.28	ns	1.77	ns	4.29	<0.001	1.64	ns
Pleasant	27.22	<0.001	0.37	ns	24.22	<0.001	0.67	ns	4.93	<0.001	14.97	<0.001	3.69	<0.001
Like drug effect	17.24	<0.001	1.97	ns	21.15	<0.001	0.67	ns	3.62	<0.001	12.08	<0.001	2.76	0.004
Sick	8.18	0.003	0.51	ns	2.63	0.023	2.26	ns	1.39	ns	1.44	ns	2.15	ns
Heart racing	13.03	<0.001	0.77	ns	9.57	<0.001	0.82	ns	3.81	<0.001	9.02	<0.001	6.00	<0.001
Anxious/nervous	3.05	ns	5.89	ns	4.30	<0.001	0.75	ns	1.94	ns	2.89	0.032	2.54	0.012
Relaxed	2.31	ns	2.82	ns	2.48	0.023	0.12	ns	1.18	ns	1.74	ns	1.47	ns
Paranoid	5.89	0.023	0.93	ns	3.98	<0.001	0.35	ns	1.98	ns	5.30	<0.001	2.07	ns
Sleepy/tired	24.93	<0.001	0.25	ns	12.19	<0.001	0.10	ns	3.56	<0.001	0.58	ns	0.43	ns
Alert	1.04	ns	2.92	ns	5.39	<0.001	2.22	ns	0.85	ns	0.87	ns	0.67	ns
Irritable	4.64	ns	0.34	ns	1.33	ns	5.01	ns	0.96	ns	0.80	ns	1.56	ns
Vigorous/motivated	1.07	ns	2.03	ns	4.08	<0.001	1.59	ns	1.01	ns	0.61	ns	1.12	ns
Restless	11.78	<0.001	1.36	ns	2.93	0.013	0.08	ns	1.85	ns	3.97	0.001	1.79	ns
Munchies	13.02	<0.001	7.95	ns	13.84	<0.001	0.55	ns	2.39	0.020	5.51	<0.001	1.25	ns
Craving	1.55	ns	1.10	ns	4.04	<0.001	0.10	ns	1.04	ns	0.61	ns	0.39	ns
Dry mouth	26.99	<0.001	1.54	ns	8.25	<0.001	1.54	ns	3.24	<0.001	8.41	<0.001	4.00	<0.001
Dry/irritated eyes	19.89	<0.001	1.10	ns	5.01	<0.001	2.12	ns	2.94	0.001	4.46	<0.001	1.88	ns
Trouble with memory	11.25	<0.001	0.98	ns	3.12	0.009	2.20	ns	2.33	0.025	2.35	ns	1.85	ns
Throat irritated	8.73	0.002	22.79	<0.001	10.90	<0.001	7.44	0.015	4.20	<0.001	10.31	<0.001	5.14	<0.001
Diff. with routine tasks	9.64	0.001	0.36	ns	5.60	<0.001	2.24	ns	3.61	<0.001	5.42	<0.001	2.38	0.026
Cognitive measures
Digit Symbol Substitution Task (DSST)
Total attempted	2.54	ns	0.52	ns	3.08	0.002	1.37	ns	1.42	ns	1.69	ns	1.06	ns
Total correct	3.28	0.040	0.34	ns	3.36	0.001	2.77	ns	1.76	0.033	1.73	ns	1.20	ns
Divided Attention Task (DAT)
Mean distance from central target	6.93	0.001	0.13	ns	5.46	<0.001	1.01	ns	1.61	ns	2.34	0.017	0.71	ns
Total peripheral numbers correct	5.30	0.006	0.03	ns	3.27	0.001	0.58	ns	1.20	ns	0.55	ns	1.28	ns
Paced Auditory Serial Addition Task (PASAT)
Total correct	6.22	0.003	2.17	ns	5.25	<0.001	0.70	ns	1.24	ns	1.59	ns	0.68	ns
DRiving Under the Influence of Drugs (DRUID)
Global impairment score	13.24	<0.001	1.42	ns	4.95	<0.001	0.87	ns	2.89	<0.001	3.28	0.001	1.64	ns
Vital signs
Systolic BP	0.24	ns	0.35	ns	2.05	0.038	0.49	ns	0.69	ns	1.86	ns	1.31	ns
Diastolic BP	0.29	ns	0.50	ns	4.28	<0.001	1.79	ns	0.81	ns	0.42	ns	0.94	ns
Heart rate	10.74	<0.001	1.17	ns	19.90	<0.001	0.34	ns	3.58	<0.001	9.20	<0.001	5.06	<0.001

Analyses were repeated measures regressions (i.e. linear mixed models). All analyses used a first-order autoregressive (AR1) covariance structure.

ns: not significant.

Statistical significance was set at p < 0.05. For the DEQ items, Holm–Bonferroni alpha corrections were performed within each main effect and interaction (e.g. p-values for dose, p-values for dose × route, etc.); adjusted p-values are presented for all DEQ items.

Data presentation and analysis

Participant demographic characteristics and blood THC data are presented with descriptive statistics (i.e. means and SD). Change-from-baseline data for subjective drug effects, cognitive performance tasks, vital signs, and blood THC were analyzed using repeated-measures regressions (i.e. linear mixed models). Separate regressions were conducted for each outcome and the covariance structure used was a first-order autoregressive (AR1). Each model included three factors: time (9 time points), dose (placebo, low, and high), and route (oral and vaporized). Given the large amount of individual DEQ items, Holm–Bonferroni alpha corrections were performed within each main effect and interaction (e.g. p-values for dose, p-values for dose × route, etc.) to reduce the chances of Type 1 error; alpha corrections were not performed on the main effect and interaction terms for cognitive and psychomotor performance assessments or field sobriety tests given that these respective tests had far fewer unique endpoints (e.g. 1–2) and, as we describe above, each of these assessments taps into different aspects of functioning. Bonferroni-corrected planned comparisons (i.e. Fischer’s LSD tests) were conducted (using marginal means) to compare mean peak change-from-baseline scores across conditions of interest for these outcomes. Specifically, comparisons were made between: (1) placebo and the two active doses within each route of administration (e.g. 0 mg oral vs. 10 mg oral and 0 mg oral vs. 25 mg oral) and (2) both active doses within each route of administration (e.g. 5 mg vs. 20 mg vaporized); the threshold for statistical significance due to the Bonferroni correction was p < 0.016 for these planned comparisons. Peak scores were calculated for each respective route of administration within time frames previously shown to coincide with peak drug effects (i.e. 0–2 h for vaporized conditions and 2–5 h for oral conditions (Newmeyer et al., 2017a, 2017b; Spindle et al., 2018; Vandrey et al., 2017); time points falling outside of these ranges likely would have been impacted by nondrug-related factors (e.g. boredom and fatigue). For each individual participant, six total peak-change-from-baseline scores were determined (one for each drug condition), and scores from all 20 individual participants were averaged together to produce mean-peak-change-from-baseline scores for each of the six experimental conditions. Additional Bonferroni-corrected planned comparisons were conducted (using raw data only) to compare baseline scores to all other timepoints (i.e. 0, 1, 2, 3, 4, 5, 6, and 8 h post-dosing) within each experimental condition for three subjective items (“drug effect,” “trouble with memory,” and “difficulty with routine tasks”) and primary cognitive and vital sign outcomes; the threshold for statistical significance due to the Bonferroni correction was p < 0.00139 for these planned comparisons.

For field sobriety tests, nonparametric Friedman tests were employed to determine whether there were differences in peak clues observed (on individual tests and cumulatively across all three tests) between dosing conditions; separate Friedman tests were conducted for oral and vaporized dosing conditions. Planned comparisons (i.e. nonparametric Wilcoxon signed-rank tests; threshold for statistical significance: p < 0.016) were used to compare peak clues across individual dosing conditions (the same comparisons were made as with other pharmacodynamic outcomes). Calculation of peak clues was restricted to the same time frames as cognitive tasks for each respective route of administration.

For cognitive and field sobriety tasks, analyses were conducted twice: once using change-from-baseline data and once using raw data (the same Bonferroni corrections were applied in both sets of analyses). This was done to assess the utility of each outcome for measuring impairment both with and without consideration of baseline performance, which ultimately can inform the suitability of using these various tests in environments where a baseline level of performance can be ascertained (e.g. the workplace) versus those where baseline performance is unknown (e.g. roadside traffic stops).

Lastly, the percentage of participants who were “impaired” and “not impaired” based on field sobriety test results and performance on the DRUID^® application was compared across dosing conditions using nonparametric Cochran’s Q tests (these analyses were also conducted twice, accounting for and not accounting for baseline performance, and separate tests were conducted within oral and vaporized dosing conditions). Planned comparisons (i.e. nonparametric McNemar’s tests) were used to compare across the aforementioned conditions (e.g. placebo vs. active doses within each route of administration; threshold for statistical significance: p < 0.016). For raw data, participants who exhibited ⩾2 clues on a given field sobriety test following drug administration were classified as “impaired” on that test and those who exhibited a DRUID^® Global Impairment Score ⩾ 57 after drug administration were classified as “impaired.” In the set of analyses accounting for baseline performance, participants who exhibited a peak-change-from-baseline of ⩾2 clues on a given field sobriety test or ⩾13-point change (from baseline) on the DRUID^® Global Impairment Score were considered “impaired.” These particular thresholds for impairment for field sobriety tests and the DRUID^® were used because they were associated with a blood–alcohol concentration (BAC) of 0.08% (common per se limit to determine impairment from alcohol) in prior controlled studies (Richman and May, 2019; Stuster, 2006).

Sex differences were explored for the DRUID^® and field sobriety tests within each of the six experimental conditions. We focused on these two outcomes only because, in another recent paper (Sholler et al., 2020), we pooled pharmacokinetic and pharmacodynamic data from the present study with data from three other acute cannabis dosing studies to conduct a comprehensive and well-powered set of comparisons between males/females on subjective drug effects (i.e. DEQ), cognitive/psychomotor performance (i.e. DSST, DAT, and PASAT), and THC pharmacokinetics following administration of oral and vaporized cannabis.

All statistical analyses were conducted using the IBM SPSS software (version 25; IBM SPSS, Armonk, NY, USA), and figures were made using the GraphPad Prism (version 8; GraphPad, La Jolla, CA, USA). The choice of statistical tests was based on the respective scales of the data collected. Linear mixed models and Fischer’s LSD tests (SPSS, 2005) were utilized for outcomes with continuous data (i.e. subjective drug effects, cognitive performance tasks, and vital signs), Friedman’s tests and Wilcoxon signed-rank tests (Sheldon et al., 1996; Woolson, 2007) were utilized for outcomes on an ordinal scale (i.e. number of field sobriety clues observed), and Cochran’s Q-tests and McNemar’s tests (McCrum-Gardner, 2008) were used for data on a dichotomous scale (i.e. “impaired” vs. “not impaired” field sobriety and DRUID data).

Participants

Thirty-six individuals provided informed consent and were screened for the study. Of these individuals, 23 (13 males and 10 females) were determined to be eligible and were randomized. Of those randomized, 20 (10 males and 10 females) completed the study. Two participants were lost to follow-up during the study participation, and one was discharged from the study due to extremely poor performance on cognitive tasks at baseline. The racial/ethnic breakdown of study completers was: 45% Caucasian, 35% African American, 15% Hispanic, and 5% Asian. Participants were all nontobacco users, and, on average, had not used cannabis for 270 days (SD = 370; range = 30–1278) prior to their first session. Their mean (SD) BMI was 25.1 kg/m² (4.0), their mean weight was 164.9 lbs (37.5), and their mean age was 28.5 years old (6.2). No participants experienced unanticipated or serious adverse events during the study.

Computerized cognitive and psychomotor measures

Divided attention test

Linear mixed models detected a main effect of dose for mean distance from central target and total peripheral numbers correct. Planned comparisons between dosing conditions revealed that peak-change-from-baseline scores for mean distance from central target differed between the 25 mg oral THC and oral placebo conditions. Planned comparisons (between baseline and post-dosing time points) revealed that, relative to baseline, DAT performance (mean distance from central target) was significantly impaired at hours 4 and 5 in the 25 mg oral THC condition and at hour 2 in the 20 mg vaped THC condition (see Figure 1). Linear mixed model results were largely consistent when the raw data were used, except the main effect of dose for peripheral integers correct did not remain significant. When the raw data were used, planned comparisons no longer detected significant differences across dosing conditions within either route of administration.

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Figure 1.

Mean (+SEM) performance on cognitive/psychomotor tasks (change-from-baseline scores) over time in each experimental condition. BL = baseline time point; mg = milligrams THC. Filled symbols indicate significant difference from baseline within that experimental condition. Higher scores on the DAT and DRUID^® indicate worse performance (i.e. greater impairment), whereas lower scores on the DSST and PASAT indicate worse performance. Note this exact figure is presented in Supplemental material, but using raw data. Oral and vaporized cannabis dosing was completed immediately prior to “time 0.”

DRUID^® application

Figure 2 illustrates performance on the DRUID^® (i.e. Global Impairment Scores) for each individual participant at baseline and post-cannabis administration (i.e. raw peak scores). For the DRUID^® Global Impairment Score, linear mixed models detected a main effect of dose, a dose × time interaction, and a route × time interaction. Planned comparisons between dosing conditions detected significant differences between the two high doses (i.e. 25 mg oral THC and 20 mg vaped THC) and their respective placebo conditions. In addition, the mean peak score in the 25 mg oral THC condition was significantly greater than that observed in the 10 mg oral THC condition. Planned comparisons between baseline and post-dosing time points revealed that, within the 25 mg oral THC condition, DRUID^® performance was significantly impaired relative to baseline at hours 2–5; within the 20 mg vaped THC condition, DRUID^® performance was significantly impaired at hours 0–1 (see Figure 1). Linear mixed model results were consistent between change-from-baseline and raw data. Planned comparisons for raw data again revealed significant differences between peak scores in the high dose conditions and each corresponding placebo condition, but there was no longer a significant difference between the two active oral doses. However, when raw data was used, a significant difference emerged between the 20 mg vaped THC and 5 mg vaped THC conditions (see Supplemental material). In the 20 mg vaped THC condition, females exhibited greater peak scores on the DRUID^® compared with males (females: mean = 63.2; SD = 13.8; males: mean = 52.5; SD = 6.5; Fischer’s LSD p < 0.05), and sex differences were also observed in this condition when peak-change-from-baseline data were used (females: mean = 16.6; SD = 16.5; males: mean = 4.4; SD = 11.5; Fischer’s LSD p < 0.05); peak DRUID^® scores did not differ between males and females in any other condition (using raw and peak-change data).

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Figure 2.

Performance on the DRUID^® (i.e. global impairment scores) for each individual participant at baseline and post-cannabis administration (i.e. raw peak scores) in each experimental condition. Higher scores indicate worse performance (i.e. greater impairment). The dotted line (i.e. score of 57) signifies the threshold used to classify participants as “impaired”; this threshold was associated with a blood–alcohol concentration of 0.08% in a prior controlled alcohol dosing study (Richman and May, 2019). Peak scores were calculated for each respective route of administration within time frames previously shown to coincide with peak drug effects (i.e. 0–2 h for vaporized conditions and 2–5 h for oral conditions).

Field sobriety tests

Figure 3 depicts performance (i.e. peak-change-from-baseline clues for each participant) on the three individual field sobriety tests within each condition; the same figure is presented using raw data (i.e. peak clues observed post-dosing) in Supplemental material.

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Figure 3.

Performance on individual field sobriety tasks (i.e. peak change-from-baseline clues) in each experimental condition. The y-axes indicate the number of participants (out of 20) who displayed a given number of clues, whereas the x-axes display the number of clues observed. More clues indicate worse performance (i.e. greater impairment). Two or more clues on a given test is indicative of impairment. The McNemar’s tests did not detect significant differences across dosing conditions in the number of individuals judged as “impaired” (based on the ⩾2 clue criteria) for any of the tests (see Table 3). Note this exact figure is presented in Supplemental material, but using raw data.

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Table 3.

Percentage of participants (n = 20) classified as “impaired” based on performance on the DRUID^® application and field sobriety tests.

Number (%)	0 mg oral	10 mg oral	25 mg oral	0 mg vaped	5 mg vaped	20 mg vaped
Impaired based on raw data scores
Walk and turn a	3 (15%)	6 (30%)	8 (40%)	5 (25%)	10 (50%)	9 (45%)
One leg stand a	3 (15%)	7 (35%)	6 (30%)	3 (15%)	3 (15%)	8 (40%)
Modified Romberg balance a	4 (20%)	6 (30%)	7 (35%)	6 (30%)	7 (35%)	11 (55%)
DRUID b	1 (5%)	4 (20%)	10 (50%)*	2 (10%)	3 (15%)	9 (45%)
Impaired based on change-from-baseline scores
Walk and turn a	2 (10%)	2 (10%)	6 (30%)	3 (15%)	7 (35%)	6 (30%)
One leg stand a	1 (5%)	4 (20%)	5 (25%)	1 (5%)	1 (5%)	4 (20%)
Modified Romberg balance a	2 (10%)	3 (15%)	4 (20%)	1 (5%)	2 (10%)	7 (35%)
DRUID c	0 (0%)	2 (10%)	9 (45%)*	0 (0%)	2 (10%)	7 (35%)*

*

Significant difference from placebo within that route of administration (Bonferroni-corrected, p < 0.016); Δ = significant difference between low and high dose within that route of administration (Bonferroni-corrected, p < 0.016). McNemar’s tests were used for planned comparisons.

Impairment criteria:

a

⩾2 peak (or peak change-from-baseline) clues observed = “impaired”; <2 peak (or peak change-from-baseline) clues = “not impaired.”

b

⩾57 DRUID^® global impairment score = “impaired”; <57 score = “not impaired.”

c

⩾13-point change (from baseline) on DRUID^® global impairment score = “impaired”; <13-point change (from baseline) = “not impaired.”

Percentage of impaired and nonimpaired participants

Using the respective criteria for impairment (i.e. ⩾2 clues on a given field sobriety test; DRUID^® Global Impairment Score ⩾57) the frequency at which participants were considered “impaired” at baseline on these measures was as follows: WT (16/120 sessions, 13%), OLS (10/120 sessions, 8%), MRB (8/120 sessions, 7%), and DRUID (5/120 sessions, 4%).

Table 3 displays the percentage of participants who were classified as “impaired” on the DRUID^® and each individual field sobriety test using both change-from-baseline and raw data. On the WT, using the raw data, there were no differences in the percentage of individuals classified as impaired across vaporized (Cochran’s Q (2) = 3.8, p: ns) or oral cannabis conditions (Cochran’s Q (2) = 4.2, p: ns); the same pattern was observed when using change-from-baseline data: oral (Cochran’s Q (2) = 3.2, p: ns); vaporized (Cochran’s Q (2) = 2.2, p: ns). For the OLS, using raw data, the percentage of individuals classified as impaired differed significantly across vaporized (Cochran’s Q (2) = 10.0, p < 0.01) but not oral conditions (Cochran’s Q (2) = 3.7, p: ns); this significant finding did not remain when change-from-baseline data was used: oral (Cochran’s Q (2) = 3.3, p: ns) and vaporized (Cochran’s Q (2) = 6.0, p: ns). On the MRB, there were no differences in the percentage of impaired participants across oral (Cochran’s Q (2) = 1.8, p: ns) or vaporized cannabis conditions (Cochran’s Q (2) = 4.2, p: ns). However, when change-from-baseline data were used, significant differences were detected across vaporized (Cochran’s Q (2) = 7.8, p = 0.02), but not oral (Cochran’s Q (2) = 0.9, p: ns) conditions for the MRB. Despite these significant omnibus Cochran’s Q-tests, planned comparisons between dosing conditions did not detect differences in the percentage of individuals classified as “impaired” on the WT, OLS, or MRB within either oral or vaporized conditions, and these results were the same for both raw and change-from-baseline data. The percentage of participants classified as impaired on the three field sobriety tests did not differ based on sex in any experimental condition (results were consistent using raw and peak-change-from-baseline data).

For the DRUID^®, significant differences were detected within both oral and vaporized conditions using both raw (oral (Cochran’s Q (2) = 14.0, p < 0.001) and vaporized (Cochran’s Q (2) = 7.8, p = 0.02)) and change-from-baseline data (oral (Cochran’s Q (2) = 13.4, p < 0.001) and vaporized (Cochran’s Q (2) = 9.3, p = 0.01)). Planned comparisons between dosing conditions revealed that a greater percentage of participants were classified as impaired based on DRUID^® performance in both high dose conditions (i.e. 25 mg oral THC; 20 mg vaped THC) compared with the respective placebo conditions, and results were mostly consistent when raw and change-from-baseline data were used (the lone exception was that, when raw data was used, there was not a significant difference between the high vaporized and placebo vaporized conditions). When using raw data, the percentage of participants classified as impaired on the DRUID^® differed by sex in the 20 mg vaped THC condition (7 women were classified as impaired in this condition vs. 2 men; Chi-square test, p < 0.05), though this finding did not remain significant when using change-from-baseline data. Sex differences in the percentage of impaired participants were not observed in the other experimental conditions using raw or change-from-baseline data.

Subjective drug effects

Three items (“drug effect,” “trouble with memory,” and “difficulty with routine tasks”) were considered subjective indices of impairment because these questions inquired about overall perceived drug effects or participants’ perceived ability to perform a cognitive or behavioral function (Figure 4 displays mean ratings for each of these items over time for each study condition). Main effects of dose and dose × time interactions (on linear mixed models) were observed for each of these three items, and dose × route × time interactions were also observed for “drug effect” and “difficulty with routine tasks.” For oral cannabis conditions, planned comparisons between dosing conditions revealed significantly higher ratings in the 25 mg oral THC condition compared to placebo for all three items; ratings for “drug effect” also differed between 10 mg oral THC and placebo and between 25 mg oral THC and 10 mg oral THC. For vaporized cannabis conditions, ratings for all three items in the 20 mg vaped THC condition were significantly greater than placebo; ratings for “drug effect” also differed between 5 mg vaped THC and placebo. In addition, ratings for each item differed significantly between the 20 mg vaped THC and 5 mg vaped THC conditions. Planned comparison results between baseline and all subsequent time points within each condition for these three items are illustrated in Figure 4. In the 10 mg oral THC condition, “drug effect” ratings significantly increased at hours 1–4; in the 25 mg oral THC condition, ratings increased significantly at hours 1–6. Ratings for “drug effect” were significantly increased at hours 0–3 in the 5 mg vaped THC condition and at hours 0–5 in 20 mg vaped THC condition. For “trouble with memory,” ratings increased significantly at hours 2–3 in the 25 mg oral THC condition and at hours 0–4 in 20 mg vaped THC condition. For “difficulty with routine tasks,” ratings increased significantly at hours 2–3 in the 25 mg oral THC condition and at hours 0–3 in the 20 mg vaped THC condition.

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Figure 4.

Mean (+ SEM) subjective ratings for visual analog scale (VAS) items “drug effect,” “trouble with memory,” and “difficulty with routine tasks” from the Drug Effect Questionnaire (DEQ) in each experimental condition over time. BL = baseline time point; mg = milligrams THC. Filled symbols indicate significant difference from baseline within that experimental condition. Oral and vaporized cannabis dosing was completed immediately prior to “time 0.”

For other subjective items, main effects of dose and two- or three-way interactions with dose and route/time were often observed on linear mixed models (see Table 1). Planned comparisons between dosing conditions for oral cannabis conditions revealed that mean peak ratings were significantly higher for both active doses (i.e. 10 mg oral THC and 25 mg oral THC) compared with placebo for “pleasant drug effect,” “like drug effect” “sleepy/tired,” “dry mouth,” and “dry/red eyes.” Moreover, ratings in the 25 mg oral THC condition were significantly higher for “unpleasant drug effect,” “heart racing,” “restless,” and “hungry/have munchies” compared with placebo. Peak ratings for “heart racing” and “dry mouth” were also higher for 25 mg oral THC compared to 10 mg oral THC. For vaporized conditions, mean peak ratings were significantly higher for both active doses (i.e. 5 mg vaped THC and 20 mg vaped THC) compared with placebo for “pleasant drug effect,” “like drug effect,” “hungry/have munchies,” and “dry mouth.” Relative to placebo, ratings were also higher in the 20 mg vaped THC condition for “unpleasant drug effect,” “sick,” “heart racing,” “anxious/nervous,” “paranoid,” “sleepy/tired,” “irritable,” “restless,” “dry/red eyes,” and “throat irritated.” Lastly, peak ratings for “unpleasant drug effect,” “sick,” “heart racing,” “anxious/nervous,” “paranoid,” “restless,” “dry mouth,” “dry/red eyes,” and “throat irritated” were also higher in the 20 mg vaped THC compared to 5 mg vaped THC condition (see Table 2).

Physiological outcomes

For HR, a main effect of dose was observed, along with dose × time, route × time, and dose × route × time interactions on the linear mixed model analysis. Planned comparisons between dosing conditions revealed that mean peak beats per minute following administration of both high doses (i.e. 25 mg oral THC and 20 mg vaped THC) was significantly higher compared with the respective placebo conditions. Planned comparisons (between baseline and post-dosing time points) revealed that, within the 25 mg oral THC condition, HR increased significantly at hour 2 relative to baseline (see Figure 5); within the 5 and 20 mg vaped THC conditions, HR was significantly elevated at hours 0–1 relative to baseline.

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Figure 5.

Mean (+SEM) heart rate (beats per minute; raw data) in each experimental condition over time. BL = baseline time point; mg = milligrams THC. Filled symbols indicate significant difference from baseline within that experimental condition. Oral and vaporized cannabis dosing was completed immediately prior to “time 0.”

Whole blood THC concentrations

On average, whole blood THC concentrations peaked 2 h after oral cannabis administration (see Figure 6). The mean (SD) whole blood THC concentration (in ng/ml) observed at hour 2 for each oral cannabis condition was: 10 mg: 1.78 (1.93) and 25 mg: 3.06 (2.41). On average, whole blood THC concentrations peaked immediately after inhalation of vaporized cannabis (i.e. at hour “0”; see Figure 6). The mean (SD) whole blood THC concentration (in ng/ml) observed at hour 0 for each vaporized cannabis condition was: 5 mg: 9.19 (10.43) and 20 mg: 37.24 (22.36).

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Figure 6.

Mean (+SEM) blood THC concentrations (ng/ml) over time in each experimental condition. Note that blood specimens were not collected at hour 0 and hour 5 in oral dosing sessions and vaporized dosing sessions, respectively. Data are displayed for the 17 participants who had whole blood specimens collected. Oral and vaporized cannabis dosing was completed immediately prior to “time 0.”

The linear mixed model analysis detected main effects of dose (F = 81.51, p < 0.001) and time (F = 96.17, p < 0.001), along with a dose × time interaction (F = 51.06, p < 0.001) for blood THC data. Planned comparisons between dosing conditions revealed that mean peak blood THC concentrations were significantly higher following administration of the 5 and 20 mg vaped THC doses compared with vaped placebo. In addition, mean peak blood THC concentrations were significantly higher following administration of the 20 mg THC dose compared with the 5 mg vaped THC dose. Planned comparisons did not detect significant differences in peak blood THC concentrations across the three oral dosing conditions.