Participants

Volunteers, 18–50 years of age, were recruited through newspaper advertisements and word of mouth. Those who met inclusion/exclusion criteria after an initial phone screen were invited to the laboratory for further screening. Before enrolling, candidates provided a detailed drug and medical history, received medical and psychiatric evaluations, and signed consent forms detailing all aspects of the research. Participants were accepted into the study if they were healthy, as determined by physical examination, psychiatric screening, electrocardiogram, blood pressure and heart rate, and urine and blood chemistries, were not regular users of drugs other than cannabis (aside from nicotine and caffeine), and were not seeking treatment for their cannabis use. Eligible participants smoked at least half a cannabis cigarette four or more times per week for the 4 weeks before screening, as determined by urine toxicology and self-report. Those who met the Diagnostic and Statistical Manual (of Mental Disorders), fourth edition, revised criteria for Axis 1 conditions that would benefit from medical intervention were also excluded. Females were excluded if they were pregnant or nursing or failing to practice an effective form of birth control. Current use of over-the-counter or prescription medication was also exclusionary.

Participants were told that the study objective was to determine how CBD, an experimental compound not approved by the FDA, influences the effects of cannabis in cannabis smokers. All procedures were approved by the Institutional Review Boards of the New York State Psychiatric Institute, University of Kentucky and Medical University of South Carolina and were in accordance with the Declaration of Helsinki.

Study Design and Procedures

This within-subject study included eight outpatient sessions over a minimum of eight weeks. Participants completed only one session per week to avoid potential carryover effects resulting from CBD’s long terminal half-life (21–33 h; Aguerell et al, 1986; Consroe et al, 1991). Prior to the first laboratory session, participants completed one or two practice sessions during which they were familiarized with the study tasks and procedures (no cannabis or capsules were administered). For experimental sessions, capsules containing placebo or CBD (200, 400, 800 mg) were administered, and half of an inactive or active cannabis cigarette was smoked 90 min later. The order of cannabis strength and CBD dose was randomized.

Experimental Sessions

Table 1 portrays the schedule for experimental sessions, which started at 0900 h and lasted ~8 h. At the beginning of each session, we conducted a timeline followback questionnaire querying cannabis, alcohol, and other drug use as well as any side-effects or medication use since the last visit. Participants were instructed to refrain from using illicit drugs (other than cannabis, for which no instructions were given) for the duration of the study. They were instructed not to eat, drink alcohol, or smoke cannabis or tobacco cigarettes beginning at midnight prior to each session. A urine drug screen, pregnancy test, breath alcohol test, and carbon monoxide test (⩽9 ppm) were conducted at the beginning of each session to confirm compliance. If there was evidence of illicit drug, alcohol or cannabis use on the morning of the session the session was rescheduled.

Table 1 Time-course of Sessions Full size table

Participants were given a light breakfast (bagel or cereal, juice, coffee). Following breakfast, baseline cardiovascular measures, subjective effects questionnaires, and performance tasks were completed. CBD or placebo capsules were given 30 min after completion of breakfast. In order to minimize nicotine withdrawal symptoms, tobacco cigarette smokers were given up to two smoking breaks per session scheduled at the same time for all eight sessions. The participant and study staff were blind to capsule content. Ninety minutes after capsule administration, half of a cannabis cigarette was smoked (see below). Cardiovascular and subjective effects measures and a cognitive task battery were completed at baseline and at 15–120 min intervals following capsule and cannabis administration. Participants were allowed to select from a variety of lunch options, including an entree, beverage, and snack 60 min following cannabis administration. To measure the reinforcing effects of cannabis, participants were offered the opportunity to purchase up to three additional 5-s puffs of the cannabis sampled that morning 150 min after cannabis administration. Each puff cost $0.50 of their study earnings. At the end of each session, participants were free to leave after passing field sobriety and balancing tasks.

Study Drugs

Placebo or CBD (0, 200, 400, 800 mg, STI Pharmaceuticals) capsules in size 00 opaque capsules, prepared by the EMINENT Services Corporation, were administered under double-blind conditions under observation of research staff 90 min prior to cannabis administration. The broad and upper range of CBD doses were chosen to ensure pharmacological activity given its known poor oral bioavailability of <20% (Mechoulam et al, 2002). Timing of cannabis administration was designed to coincide with time-to-peak (T max ) plasma CBD concentrations estimated at 1–2 h (Agurell et al, 1981; Bhattacharyya et al, 2010; Winton-Brown et al, 2011; Englund et al, 2013).

Cannabis (0.01, 5.30–5.80% THC; 0.01% CBD, ca. 800 mg), provided by the National Institute on Drug Abuse, was administered under single-blind conditions using a cued-smoking procedure (Foltin et al, 1987). In the morning administration, participants were instructed to ‘light the cigarette’ (30 s), ‘prepare’ (5 s), ‘inhale’ (5 s), ‘hold smoke in lungs’ (10 s), and ‘exhale’. They smoked one puff every minute with a 40-s interval between each puff, until they had smoked 50% of the cannabis cigarette. In the afternoon, participants were similarly guided through smoking up to three puffs of self-administered cannabis, depending on their choice. Because the color of cannabis leaves varies as a function of THC content (Chait and Pierri 1989), the cannabis was smoked through a cigarette holder and rolled at the end so the cannabis was not visible. Cannabis cigarettes were stored frozen in an airtight container and humidified at room temperature for 24 h prior to use. The order of cannabis strength and CBD dose were completely randomized.

Assessments

Subjective Mood and Drug Effects

All subjective effects were measured using visual analog scales, a series of 100-mm long lines labeled ‘not at all’ at one end (0 mm) and ‘extremely’ at the other end (100 mm). Participants were instructed to rate their subjective experiences according to how they felt at that moment. Measurements were taken at baseline and at scheduled intervals after CBD and cannabis administration (Table 1).

Mood scale

Participants completed a 44-item scale assessing a range of affective and physical symptoms capturing effects, eg, friendly, mellow, sedated, anxious (eg, Haney et al, 2004).

Marijuana rating form

Subjective cannabis-related effects were assessed using a five-item visual analog scale asking participants to rate the strength of the cannabis effect, good effect, bad effect, drug liking, and willingness to smoke the cannabis again. Participants also indicated whether they thought the cannabis was active or inactive.

Capsule rating form

Participants completed a five-item visual analog scale, rating the strength of the drug effect, good effect, bad effect, willingness to take drug again, and drug liking. In addition, participants were asked to indicate whether they thought the capsule was placebo or active.

Performance task battery

Cognitive function was assessed with a computerized battery including a Digit Symbol Substitution Task (DSST; 3 min) and a Continuous Performance Task (CPT: 5 min). This battery, designed for repeated assessments, measures psychomotor speed and sustained and selective attention.

Cardiovascular function

Heart rate and blood pressure were measured at baseline, 30, 60, and 85 min after capsule administration and 15–150 min after cannabis administration.

Plasma CBD

A subset of participants (n=8) at the Columbia University site who completed the eight-week study completed one additional session to assess plasma CBD concentrations following CBD (800 mg) administration. These sessions occurred a minimum of 5 days following the last session day. Sessions began with a breathalyzer, urinalysis, carbon monoxide measure, breakfast, and baseline balance, and then a 20-gauge indwelling catheter (Quik-Cath; Treavenol Laboratories, Deerfield, IL, USA) was placed into a peripheral vein in the arm for blood withdrawal. Baseline blood (6 ml) was drawn and the CBD capsule (800 mg) was administered. Additional samples (6 ml) were collected at 60, 120, 180, 240, 300, and 360 min after CBD administration. Participants were allowed to leave the facility once they passed the field sobriety test. Samples were analyzed by a validated method that uses liquid/liquid extraction, derivitization, and gas chromatography-tandem mass spectrometry (David Moody, PhD unpublished data). The objective of this measurement was to confirm the bioavailability of the oral CBD doses administered relative to other published studies.

Data Analysis

Subjective measures, performance tasks, and cardiovascular measures collected before and after experimenter-administered cannabis were analyzed as (1) time course data using a three-factor repeated measures model (CBD condition, cannabis condition, and time) with an AR (1) covariance structure and (2) peak effect, which was calculated for individual subjects and dose conditions, and analyzed in a two-factor model (CBD condition and MJ condition) using Proc Mixed in SAS 9.3 (Cary, NC). Although subjective effects and cardiovascular data were also collected after the option to self-administer cannabis, these data were not analyzed because the amount of cannabis self-administered varied across participants. Number of cannabis puffs purchased was analyzed using a two-factor model (CBD condition and MJ condition); the percentage of participants choosing to self-administer cannabis as a function of cannabis strength and CBD dose was analyzed with a McNemar’s Test. Tukey’s post hoc tests were performed to explore the time course effects and to clarify the effects of individual CBD doses compared with placebo.