Design and participants

A randomised, double-blind, placebo-controlled four-way crossover trial was used to investigate the acute effects of cannabis and tobacco, both alone and combined. Participants attended four sessions, separated by at least 1 week (>3 times the half-life of THC (Hindocha et al. 2015a)) in a randomised order determined by a Latin square. Previous data from this study has been published elsewhere focussing on memory and psychotomimetic effects (Hindocha et al. 2017a) and validation of self-reported dose per joint (Hindocha et al. 2017b). The estimated sample size of 24 was based on a previous four-way crossover study examining the interactive effects of THC and CBD (Hindocha et al. 2015a). This would achieve an effect size of d = 0.5 with 80% power at an alpha of 0.05 (G*power version 3.1.9.2) (Faul et al. 2007). Participants from the community were recruited through posters around London universities and on online notice boards. All participants provided written, informed consent. Ethical approval was given by the UCL Ethics Committee.

Inclusion criteria were (i) age 18–60 years; (ii) regular use (>once per month and <3 times a week) of cannabis mixed with tobacco in joints for the previous 6 months (Lawn et al. 2016); (iii) normal or corrected to normal vision; (iv) fluent English; (v) self-reported abstinence from tobacco, cannabis, alcohol and other drugs for at least 12 h prior to each test day; (vi) alveolar carbon monoxide (CO) ≤6 ppm to confirm no recent smoking on each test day (Cooper and Haney 2009); and (vii) self-reported ability to smoke one whole ‘standard’ joint which is considered a relatively high bar as common practise is to share joints in recreational users (Lawn et al. 2016).

Exclusion criteria were (i) scoring ≥3 on the Cannabis Severity of Dependence Scale (SDS; Gossop et al. 1995); (ii) seeking treatment for cannabis or tobacco use or currently using nicotine replacement therapy or other cessation pharmacotherapy; (iii) smoking ≥10 cigarettes a day or scoring ≥4 on the Fagerstrom Test of Nicotine Dependence (FTND (Heatherton et al. 1991)); (iv) first cigarette smoked within the first 3 h after waking (to ensure results were not simply due to reversal of withdrawal from tobacco (Jarvik et al. 2000)); (v) significant respiratory or physical disorder or a clinically diagnosed learning impairments; (vi) clinically diagnosed schizophrenia or psychosis (or a first-degree family member with either) or substance use disorder and (vii) use of illicit substance use other than cannabis more than once per week.

Drug administration (Fig. 1/Table 1)

We compared the effects of (a) active cannabis + active tobacco (CAN-TOB), (b) active cannabis + placebo tobacco (CAN), (c) placebo cannabis + active tobacco (TOB) and (d) placebo cannabis + placebo tobacco (no active drug) (PLACEBO). The dose of cannabis and tobacco specified in Table 1 was based on previous experimental studies reporting robust subjective, cardiovascular, psychotomimetic and memory-impairing effects (Lawn et al. 2016; Mokrysz et al. 2016) for cannabis and a reliable increase in peak plasma nicotine levels of >20 ng/ml for tobacco (Mendelson et al. 2005; Mendelson et al. 2003). This is also similar to a standard cannabis + tobacco joint (Hunault et al. 2009; van der Pol et al. 2014). Placebo cannabis is produced from active cannabis and contains less than 0.1% THC (but with the same terpene content, so it retains the look and smells of cannabis). Placebo tobacco was the same dose of very low nicotine (VLN; typically referred to as denicotinised) tobacco (Magic 0 (XXII Century Group Ltd)). The smoking procedure was standardised to control for dose titration and maximise absorption of THC (Ramaekers et al. 2006). The smoking procedure was paced. Participants were asked to inhale for 4 s, hold their breath for 8 s and then exhale and break for 30 s. This sequence was repeated until the joint was smoked up to a designated line (Fig. 1). Drug administered took place in a sheltered outdoor area. This protocol was timed and enforced by the experimenter.

Fig. 1 Drug administration was conducted using ‘joints’, the most common method of administering cannabis in the Europe and Australasia (Hindocha et al. 2016). ‘Study drug’ region contained a mixture of 66.67-mg cannabis (active or placebo) and 311-mg tobacco (active or placebo) dependent on condition (see Table 1). The ‘placebo tobacco filler’ region contained 311 mg of placebo tobacco at the bottom of the joint (nearest to the mouth) which was not smoked. This filler was added to improve compliance with the fixed inhalation procedure, as puff volume typically decreases towards the end of the joint, probably due to rising heat (van der Pol et al. 2014). The stop line is the point at which participants stopped smoking the joint, separating the two regions. It was marked 1 cm after the ‘study drug’ to ensure complete inhalation Full size image

Table 1 Cannabis and tobacco doses in the study drug and their matched placebos for the four drug conditions Full size table

Assessments

The pleasantness rating task (PRT) tapped explicit liking and response time to cannabis-, tobacco-, food- and neutral-related cues. In this computer-based task, participants were presented with a fixation cross (500 ms) followed by four types of pictorial stimuli in a randomised order for 3 s. Participants were asked to rate the pleasantness of each image on a scale of −3 (very unpleasant) to +3 (very pleasant). Stimuli were matched on brightness and complexity and included 36 critical trials. Pictorial stimuli for cigarettes involved smoking-related scenes and were used previously by Mogg et al. (2005). Neutral stimuli were taken from the International Affective Picture System (IAPS) (Lang et al. 1999). Cannabis and food pictorial stimuli were expanded from a previous stimulus set (Morgan et al. 2010). The task design was modified from Metrik et al. (2015). Four versions were used and counterbalanced across drug design. The experiment was built and conducted using Psychopy (Peirce 2007; Peirce 2009).

The marijuana purchase task (MPT) (Aston et al. 2015; Collins et al. 2014) and cigarette purchase task (CPT) (MacKillop et al. 2008) assess cigarette/cannabis demand, i.e. the relationship between cigarette/cannabis consumption and cost (Aston et al. 2015; MacKillop et al. 2008). It is an analogue of a progressive ratio operant task as consumption is investigated under progressively increasing financial cost. It is an established and well-validated task (Aston et al. 2015; Chase et al. 2013; MacKillop et al. 2008; Secades-Villa et al. 2016). In this version, participants were asked how many cigarettes/cannabis puffs they would hypothetically buy in the next 3 h at increasing prices (Hitsman et al. 2008; Lawn et al. 2017). Specifically, they were asked, ‘How many cigarettes would you smoke if they were _____ each’ or ‘How many puffs of cannabis would you smoke if they were _____ each’. Prices included £0 (free), 1p, 2p, 5p, 10p, 15p, 20p, 30p, 40p, 50p, 75p, £1, £1.50 £2, £2.50, £3, £3.50, £4, £5, £7.50, £10, £15 and £20 and were presented in that order for both the CPT and MPT. Five indices of cigarette/cannabis demand were generated: breakpoint (cost suppressing consumption to zero), intensity (amount of drug consumed at zero cost), O max (peak expenditure), P max (price at maximum expenditure) and elasticity (the slope of the demand curve). Importantly, adjustments were made for UK participants for the MPT, including replacing ‘marijuana’ with ‘cannabis’ and ‘hits’ with ‘puffs’. Full instructions for the CPT and the MPT are in Online Resource 1.

Craving

This was assessed ‘right now’ at all five time points with three single-item visual analogue scales (VAS) for cannabis, tobacco and food. Each item began with ‘I am craving…’ with anchors ‘not at all’ and ‘extremely’.

Subjective effects

This was assessed ‘right now’ at all five time points with two single-item VAS for euphoric and stimulated. Anchors were ‘not at all’ and ‘extremely’.

Procedure

Participants attended a baseline session followed by four experimental sessions over a 4–6-week period. Eligibility was assessed by telephone screening and during the baseline session. Each experimental session began with pre-drug VAS for craving and subjective effects. After drug administration, participants completed further VAS for craving and subjective effects at four time points over the next hour as well as the CPT, MPT and PRT (see Schedule of Assessments in Online Resource 1). Other tasks that are not reported here took place in the intervening time (see Hindocha et al. 2017a). They were reimbursed £60 for their time on the last test day and debriefed fully.

Statistical analysis

All data were analysed using IBM Statistical Package for Social Sciences (IBM SPSS version 23) and GraphPad Prism 7 for Windows (GraphPad Software, La Jolla California USA, www.graphpad.com). For the PRT, outliers >2.5 SD from the sample mean were replaced with a score falling within 2.5 SD of the mean following Das et al. (2015). Normality was explored using visual inspection of diagnostic plots. When sphericity was violated, the Greenhouse-Geisser correction was used and corrected degrees of freedom are reported. For the PRT, we conducted a 2 (cannabis, placebo) × 2 (tobacco, placebo) × 4 (picture type) repeated measures ANOVA on both valence and response time measures.

Data from the purchase tasks was examined for outliers using standard scores (Z), with a criterion of Z = 3.29 to retain maximum data (Tabachnick and Fidell 2000). Of the data, 0.02% were outliers (Tabachnick and Fidell 2000). The outliers were determined to be legitimate high-magnitude values and were re-coded as one unit higher than the next lowest non-outlying value as per Aston et al. (2015) (Tabachnick and Fidell 2000). Zero data (i.e. when participants responded that they would not buy purchase any cannabis or cigarettes for 0p, i.e. free) was calculated as 41% (39/96 data points) for the CPT and 7% (7/96 data points) for the MPT, and this was due to floor effects post-drug administration. Annual income was considered as a potential covariate, but as it did not correlate with demand indices under any drug (p > 0.09), it was not included (MacKillop et al. 2012). Each demand characteristic was analysed using mixed-effects models, which accounts for missing data whilst behaving like a repeated measures ANOVA. Cannabis (active, placebo) and tobacco (active, placebo) were entered as fixed effects, and the intercept was allowed to vary randomly. Breakpoint, intensity, O max and P max were directly observed from the data. Price elasticity was generated using a modification of the non-linear exponential demand curve model (Koffarnus et al. 2015): Q = Q 0 × 10k( e −αP−1), where Q = quantity consumed, Q 0 = derived intensity, k = a constant across individuals that denotes the range of the dependent variable (cannabis puffs or cigarettes) in logarithmic units, P = price and α = elasticity or the rate constant determining the rate of decline in log consumption based on increases in price (i.e. essential value). k was fixed to log(80) = 1.9 for the MPT and log(9) = 0.9 for the CPT. Q 0 was fitted as consumption at 0 pence (free), i.e. intensity. This is a modification of the Hursh and Silberberg (2008) exponential demand equation and avoids poor model fit because of exclusion of zeros in the equation (Yu et al. 2014).

VAS scores had an additional task-specific factor of time, which was investigated using Helmert contrasts for time (1 (pre-drug) vs 2, 3, 4, 5 (post-drug)).