Examining acute psychopharmacological effects of nicotine vaping versus heated tobacco products in a randomised crossover study of product naïve adult smokers

Nicotine vaping products (NVPs) and heated tobacco products (HTPs) are designed to replicate the sensory and behavioural aspects of smoking cigarettes while avoiding combustion. The success of these products as harm reduction tools will partially depend on their ability to satisfy smokers and alleviate nicotine-related withdrawal symptoms. This study aims to compare short-term effects of NVPs (Juul and Aspire PockeX) versus HTPs (IQOS) on smoking-related withdrawal relief, product satisfaction, intention to switch to NVP/HTP, perceptions and attitudes in UK adult cigarette smokers naïve to these products. In a randomized cross-over study, 45 participants visited the lab twice, at each visit trying one of the two products (NVP/HTP) and completing a questionnaire. Responses were normalized on a 0–100% scale and mean differences (MD) between NVP and HTP scores computed, with positive and negative MD values indicating greater endorsement for NVP and HTP, respectively. Cigarette cravings were reduced similarly (~ 20.0%) by both products (MD = 4.5%, 95%Confidence Interval (CI) − 4.8, 13.8). Direct positive effects (MD = − 3.5%, 95%CI − 7.2, 0.2) and adverse side effects (MD = 1.8%, 95%CI − 0.3, 3.8) were comparable after each product use, though marginally favouring HTPs. HTPs were perceived as more satisfying overall (MD = − 13.2%, 95%CI − 20.3 − 6.1) than NVPs but both were perceived as similarly addictive (MD = 3.6%, 95%CI − 4.6, 11.8), relative to cigarettes. Intention to switch to either product was comparable (MD = 4.0%, 95%CI − 5.7, 13.8). Comparison of acute use of NVP versus HTP in a sample of UK smokers naïve to these products suggests that HTPs are perceived as more satisfying than NVPs, though still less satisfying than cigarettes. Registration: The analysis plan was pre-registered, and it is available at https://osf.io/6ymdu


Procedures
Participants visited the lab twice and were asked to refrain from smoking, eating food, drinking alcohol, or using the lavatory from one hour before each lab visit.After taking consent, participants completed a baseline questionnaire to assess socio-demographics, smoking-related characteristics and psychopharmacological outcomes.They then provided breath and urine samples for toxicological analysis.Following sample collection, participants were walked to an outside area and asked to use either a NVP or an HTP, provided by the study team, for 5 min.No specific instructions were given to participants about how to use the product in these 5 min, apart from how to switch it on and off.After product use, participants completed a follow-up questionnaire to assess psychopharmacological outcomes.At the second visit, participants again completed a baseline questionnaire on psychopharmacological outcomes, tried the other product, and completed a follow-up questionnaire to assess psychopharmacological outcomes after product use.The order of product use was randomised to account for sequence effects.Excel random number generator function was used to randomise the participants to which product they used first and which one second.

Materials
The NVP: The ' Aspire PockeX' or the 'Juul' were randomly assigned to each participant (20 participants have been randomised to Juul and 25 to Aspire PockeX; unequal numbers were due to a delay in obtaining Juul).The '' Aspire PockeX' is an all-in-one second-generation NVP kit with a 1500mAh internal battery and integrated 2 ml e-liquid tank.Participants could choose an e-liquid with 18 mg/ml concentration of nicotine, with tobacco, fruit or menthol flavour.The Juul is a slim NVP that has no buttons or switches and uses a regulated temperature control.It is charged through USB ports and has prefilled cartridges ('pods') of 18 mg/ml nicotine concentration in UK and participants could choose tobacco, mint, mango or menthol flavour.These NVPs were selected on the basis of nicotine delivery efficiency (Juul) and popularity (Aspire PockeX) in UK when the study begun 41,42 .NVPs were fully charged prior to the session.
The HTP: 'IQOS' is an HTP manufactured by Philip Morris, which heats specially designed tobacco sticks called HEETS.IQOS was the most popular HTP in the UK when the study begun.HTPs were fully charged prior to the session and participants could choose tobacco smooth, rich tobacco, or menthol HEETS of 18 mg/g nicotine to use.The amount of nicotine per gram of tobacco in a regular IQOS tobacco stick is ~ 15.4 mg/g and in a menthol tobacco stick is ~ 16.4 mg/g 27 .Evidence suggests that IQOS provide less efficient nicotine delivery than cigarettes and Juul, but more than Aspire PockeX 43 .While NVPs provide lower peak nicotine levels and lower overall nicotine levels to users than cigarette smoking 9 .
Smoking-related characteristics included length of smoking (in years), cigarette dependence (measured with five questions of Fagerstrom test of cigarette dependence 44 ; (i) number of cigarettes smoked per day (ii) How soon after you wake up do you smoke your first cigarette?(iii) Do you find it difficult to stop smoking in no-smoking areas?(iv) Which cigarette would you hate most to give up?(v) Do you smoke more frequently in the first hours after waking than during the rest of the day?(measured continuously).Motivation to stop (Motivation to stop scale (MTTS) 45 , continuous), and past 12 months quit attempts (yes/no).

Outcomes
Supplementary Table 1 lists details of the outcomes, including response options.
(i) Withdrawal symptoms related to cigarettes were assessed before and after use of the NVP/HTP product.We used a question derived by the Mood and Physical Symptoms Scale (MPSS 46,47 ) which assesses momentarily (right now) cigarette craving strength.We also assessed six other general mood and physical symptoms related to withdrawal symptoms before and after use of the NVP/HTP product.The scale www.nature.com/scientificreports/examining mood and physical symptoms includes an item related to poor sleep, which was excluded from the present analysis since participants did not get a chance to sleep after using each product.(ii) Product satisfaction: (a) For assessing acute positive effects of NVP/HTP after their use, 14 items based on previous research 48 , such as 'hit' , 'satisfaction' , 'feels like smoking' were assessed.We calculated an overall positive effect score by summing all items, but we also reported responses to individual items.(b) To assess adverse side-effects of NVP/HTP immediately after their use, 21 items based on previous study 33 , such as 'confused' , 'dizzy' , 'headache' were assessed.An adverse side-effect score was calculated summing all items, but we also reported responses on the individual items.
(iii) Intention to switch to NVP/HTP Participants were asked to rank how likely they were to switch to NVP after NVP use, and how likely they were to switch to HTP after HTP use, on a 4-point Likert scale (0 = 'very unlikely' to 3 = 'very likely').(iv) Perceptions about NVPs/HTPs compared with cigarettes Participants were asked after product use compared with cigarettes (i) whether they think the NVP/ HTP is safe, (ii) whether the NVP/HTP is addictive, and (iii) how satisfying is NVP/HTP.People could respond "don't know" to the first two above questions.In the main analysis 'don't know' answers were excluded.Sensitivity analysis included individuals with 'don't know' responses and this option was placed in between the most popular response options of each product to have the least biasing impact on results.(v) Attitudes Participants were asked after product use (i) whether they found the product helpful in enabling them to refrain from smoking, (ii) how pleasant they found the product to use, (iii) how embarrassing they found the product to use in the company of others, (iv) whether they would recommend the product to a friend who wanted to stop smoking, (v) whether they would use the product outdoors, (vi) indoors at home, (vii) indoors at work/public spaces.(vi) Reasons that would motivate switching from cigarettes to NVPs/HPTs Participants were asked to indicate the importance of the following nine reasons in motivating them to switch from cigarettes to NVP/HTP after using the products.If the product (i) 'is satisfying' , (ii) 'is less smelly (than cigarettes)' , (iii) 'is being used by friend(s)' , (iv) 'helps to manage stress' , (v) 'is less harmful than cigarettes' , (vi) 'is less harmful to other people around' , (vii) 'can be used in smoke-free areas' , (viii) 'can help to stop smoking' , (ix) 'can help to cut down smoking' .
All responses were normalised on 0% to 100% scale, with higher values indicating higher endorsement of the items, and all measures have been used in previous research 49 .

Statistical analysis
Descriptive statistics were calculated to characterise the sample.For all analyses below, we report the mean difference (MD) in scores for NVPs versus HTPs alongside 95% confidence intervals (CI), with positive MD values indicating greater endorsement for NVPs and negative values greater endorsement for HTPs.
Linear regressions were conducted to examine the differences in (i) cigarette-related withdrawal symptoms after using NVP and HTP, adjusted for urges or mood and physical symptoms (respectively) before using each product.Similarly, to examine differences between NVP and HTP in (ii) product satisfaction, (iii) intention to switch to NVP/HTP, (iv) perception, (v) attitudes, (vi) reasons for switching to NVP/HTP, linear regressions were conducted.The intercept/constant of these regressions were the estimate, and 95% CIs were calculated by multiplying the standard error appropriate critical value from the t-distribution.All the regressions were adjusted for period.
Statistical analysis was conducted on complete cases in SPSS Statistics version 27.The protocol and analysis plan were pre-registered on Open Science Framework (https:// osf.io/ 6ymdu).
An exploratory analysis examined potential differences between the two NVPs used (Juul and Aspire PockeX) in product satisfaction and throat irritation.We examined this because prior studies suggest that the aerosol from NVPs that use nicotine salts e-liquid, such as Juul, is less harsh to inhale than aerosol from products using freebase nicotine, like the Aspire PockeX 50  and slightly more favourable after HTPs than after NVPs use, though differences were non-significant (Fig. 2).Overall adverse side-effects score was very low after product use, but slightly less favourable after NVPs than HTPs use, though again this was not significant (Fig. 3).Examining the individual acute positive effect scores following use, participants reported that the HTPs reduced their craving for nicotine more than the NVPs, that it was more satisfying, and that it felt more like their usual brand.In addition, participants reported a greater burning sensation and throat hit from the NVPs than HTPs (Fig. 2).(b) Similarly, when looking at individual adverse side-effect scores, participants reported more throat irritation from the NVPs than the HTPs (Fig. 3).These differences in throat hit, burning sensation, and throat irritation were driven by the participants who used the Aspire PockeX NVP device; mean rating to these items were much higher for participants who used the Aspire PockeX than for Juul (burning cessation: Aspire PockeX mean (M) = 63.6%,Standard deviation (SD) = 35.2,Juul M = 13.3%,SD = 21.(iii) Intention to switch to NVPs/HTPs The mean intention to switch was similar for both NVPs (M = 39.3%,SD = 27.8) and HTPs (M = 34.8%,SD = 27.5)after trying each product (MD = 4.0%, 95% CI − 5.7, 13.8).(iv) Perceptions about NVPs/HTPs compared with cigarettes Figure 4 shows participants' perceptions about NVPs and HTPs compared with cigarettes.When reporting on the perceived addictiveness of each product compared with cigarettes, two participants chose 'don't know' for NVPs and five for HTPs.When excluding these participants, both products were perceived as having similar addictiveness (48.3% vs 44.4%, MD = 3.2%, 95% CI = − 5.9, 12.3).Participants reported that the HTP was more satisfying than the NVP (17.8% vs 30.6%;MD = -13.2%,95% CI − 20.3, − 6.1), though their scores indicated that both products were less satisfying compared with cigarettes.When reporting on the perceived safety of these products relative to cigarettes, seven chose 'don't know' for NVPs compared with ten for HTPs.After excluding these participants, both products were generally judged to be safer than cigarettes, with little difference between HTPs and NVPs (33.6% vs 35.0%,MD = -0.8%,95% CI − 8.9, 7.4).Results remained unchanged in sensitivity analyses where participants who responded "don't know" were included in the middle of the scales (see Supplementary Fig. 1

(vi) Reasons that would motivate switching from cigarettes to NVPs/HTPs
There was little difference between products in reasons motivating participants to switch.Generally, all but one reason were endorsed, with the most highly rated focusing on the product being 'less harmful than tobacco cigarettes' , 'satisfying' , 'less harmful to other people around' , and helpful to 'stop smoking' and 'to cut down smoking' (Fig. 5).

Discussion
In this cross-over randomized study of UK adult cigarette smokers naïve to NVPs and HTPs, we directly compared NVP and HTP short-term use in terms of cigarette-related withdrawal relief, acute positive effects and adverse side-effects, intention to switch and reasons for motivating smokers switching, as well as attitudes towards them and perceptions about them compared to cigarettes, and we observed little differences.Both products reduced cigarette cravings and withdrawal symptoms effectively and to a similar degree.Acute positive effects and adverse side-effects were comparable, if marginally favouring HTPs.Relative to cigarettes HTPs were perceived as more satisfying than NVPs but both products were seen as addictive as each other compared with cigarettes.Lastly, intention to switch to either product did not differ.
Consistent with previous findings demonstrating reliable nicotine delivery after acute administration using NVP and HTP (e.g., 31,32,34 ), our results indicated that urge to smoke and nicotine-related withdrawal symptoms were reduced after each product use.Since HTPs perform similarly to NVPs in cigarette-related withdrawal relief and available evidence indicates that NVPs are effective for cigarette smoking reduction and cessation (i.e., 13,17,20 ), this suggest that HTPs may prove similarly effective in smoking cessation as NVPs.
Levels of acute positive effects were close to the middle values of the scales, and slightly higher after HTP use compared to after NVP use.Participants felt that the HTP had reduced their craving for nicotine, it was satisfying, and it felt like their usual cigarette brand.Unlike NVPs, HTPs contain tobacco leaf, and their flavour may more closely resemble cigarette smoke 51 , which is also reflected in our findings.Similar to previous research (e.g. 32,36) adverse side-effects after each product use were minimal, though slightly higher after NVP use.However, this may be a function of the specific NVP used as items related to throat irritation and burning cessation were particularly associated with Aspire PocketX device and not Juul use.Juul is among the first NVP devices to use e-liquids that contain nicotine salts rather than freebase nicotine.Nicotine salt formulations have a pH that is more similar to the extravascular fluid in the lung than non-protonated nicotine.This allows users to vape  www.nature.com/scientificreports/much higher concentrations of nicotine without experiencing irritation to the throat 50,52 , which may explain the different experience between the two NVP products.The minimal adverse side-effects, the middling acute positive effects and the favourable attitudes reported after NVP and HTP use may indicate these products are viable cigarette substitutes that could promote switching.However, when participants were asked directly their intention to switch to these products, 46.7% and 42.2% replied that this was somewhat unlikely for NVP and HTP, respectively.One reason for this is that even the HTP, which was considered more satisfying than the NVP, was still perceived as less satisfying compared with cigarettes.It could also be attributed to the fact that motivation to quit smoking assessed before product use was moderate, and this acute experience of NVP/HTP use was not enough to change participants' intention to substitute smoking with another nicotine delivery device.Additionally, our sample included adult cigarette smokers naïve to NVPs and HTPs, which may further suggest that these people purposively stayed away from trying to use these products and thus might be harder to persuade to switch.Interestingly, a few participants who reported no intention to quit smoking in the next 3 months (based on the MTSS scale), reported that they were somewhat likely/very likely switching to NVPs and HTPs (22.2% and 20.0% respectively), which may indicate that these products could substitute cigarette smoking in smokers unmotivated to quit and contribute to harm reduction.Similar to previous research among cigarette smokers, we found that the most important reasons for switching to NVPs/HTPs were satisfaction, to reduce harm to themselves and others, to reduce smoking, and to help them stop smoking 53,54 .Current prevalence of adult NVP and HTP use in England is 9.3% and 0.2% respectively, though our sample showed similar levels of intention to switch to either product after trying them.This might be due to the fact that only NVPs are promoted as an effective way of quitting cigarette smoking in UK and that NVPs have been more widely available for a longer period of time than HTPs.Additionally, poor marketing may have also contributed to the poor diffusion of HTPs in England.
Finally, views on the safety of these novel products were somewhat out of step with the evidence.NVPs generally expose users to much lower levels of carcinogens and toxicants than cigarettes 13,14 , and have been promoted as less harmful alternatives to cigarette smoking for smokers struggling to quit in UK 9 .By contrast, there is insufficient independent evidence to draw strong conclusions about the safety of HTP 9 , although newer studies are consistent with reduced harm 55,56 , and recently in the US, the FDA has authorized the legal commercialization of HTPs, affirming "that marketing of these products is appropriate for the protection of public health" based on the FDA's scientific evaluation of reduced consumers' exposure to harmful chemicals when completely switching away from conventional cigarettes 57 .Yet, when both products were compared to cigarettes, most respondents perceived them to be equally as harmful as each other, and a fair number considered them to be as harmful as, or more harmful than, cigarettes.Similar findings regarding NVPs safety were observed in a cohort study in Canada 58 , and it has been suggested that after the US outbreak of vaping-associated lung injury 59 , views on NVPs among smokers deteriorated and many smokers perceiving NVPs at least as harmful to health as cigarettes 60,61 .Likewise, studies examining perceptions of harmfulness of HTPs compared to cigarettes suggest that a fair number of smokers considered them to be equally as harmful as cigarettes or they do not know 53,62 .
All results obtained should be seen in the light of the following limitations.First, the results and their interpretations are based on a small convenience sample of London-based adults.Though considering the cross-over design of the study, the sample is equivalent to having at least double the sample of a parallel-group randomised trial.Nonetheless, the sample is unlikely to be representative for the average regular smoker.Yet, many of our findings are comparable to other studies (i.e. 32,34,54,58) suggesting some, albeit limited, generalisability to other contexts.Additionally, both NVPs and HTPs are available in UK, while most of the available data on HTPs come from Japan where NVPs are not available.Second, participants only received a brief explanation on how to use the two products, which were new for them, and they got no more than five minutes to use each product, while it is well established that people may need to experiment for a couple of days with these products to learn to use them effectively 25 .Though first impressions (i.e., craving reduction, satisfaction) also count and may contribute to continue use of a product (or not), so it is important to capture information on effects of acute use in terms of likely uptake/continued use.Third, for the NVP, we used only two different devices and for the HTP just one specific type.Whereas the offer of the different HTP is rather limited, a plethora of NVPs and of flavours of e-liquids with various nicotine concentrations are available, which may well differ with respect to the effect of the outcomes studied here.Fourth, we used validated measures for some of the outcomes (i.e., 46,47 ), while for others we used measures based on previous research (i.e., 33,48 ).Fifth, in this study we used two NVP devices (Juul and Aspire PockeX,) and one HTP device (IQOS).Thus, these results may not generalise to other types of NVP or HTP.Sixth, the results need to be treated as preliminary and that studies with longer user and follow-up are needed to confirm our findings.
To conclude, comparison of acute use of NVP versus HTP in a sample of UK smokers naïve to these products suggests that HTPs are perceived as more satisfying than NVPs, though still less satisfying than cigarettes.Few differences were observed between the two products for other outcomes.Both products reduced cigarettes cravings and were seen as similarly addictive to each other when compared to cigarettes.The perceived adverse side-effects after using each product were minimal, apart from throat irritation after Aspire PockeX NVP use.Acute positive effects were modest and attitudes towards both products were favourable, though intention to switch to either product was relatively low.Nonetheless, given the comparable psychopharmacological profile and perceived acceptability of both products, taken together with the now established effectiveness of NVP for smoking cessation, this would suggest that HTP may play a useful role in combustible tobacco harm reduction.

Figure 1 .
Figure 1.Cigarette smoking related withdrawal relief after NVP and HTP use.NVP = nicotine vaping product, HTP = heated tobacco product, SD = standard deviation, MD* = mean within-person difference in the outcome variable after NVP use minus HTP use with adjustment for both period and the mean difference in variable before product use, CI = Confidence Interval.Cigarette cravings were measured on a 6-point Likert scale from 1 = 'no urges' to 6 = 'extremely strong' .All the others were measured on a 5-point Likert scale, 1 = 'not at all' to 5 = 'extremely' .All scales were normalised on 0% to 100%.

Figure 2 .
Figure 2. Acute positive effects after NVP and HTP use.NVP = nicotine vaping product, HTP = heated tobacco product, SD = standard deviation, MD* = mean within-person difference in outcome after NVP use minus HTP use with adjustment for period, CI = Confidence Intervals.Answer option a 10-point Likert scale, 1 = 'not at all' to 10 = 'extremely' , normalised on 0% to 100% scale.

Figure 5 .
Figure 5. Reasons that would motivate switching from cigarettes to NVPs/HTPs.NVP = nicotine vaping product, HTP = heated tobacco product, SD = standard deviation, MD* = mean within-person difference in outcome after NVP use minus HTP use with adjustment for period, CI = Confidence Intervals.Normalised on 0% to 100% scale.Answer options on a 5-point Likert scale, 1 = 'not at all' to 5 = 'extremely' , normalised on 0% to 100% scale.

Table 1 .
Socio-demographic and smoking-related characteristics.SD = standard deviation.Cigarette dependence was measured with the Fagerstrom test of cigarette dependence, scores 1-9 with higher scores presenting higher cigarette dependence.Motivation to stop was measured with the motivation to stop scale, scores 1-7 with higher score presenting higher motivation to quit cigarette smoking.