Evaluating the Role of Nicotine Stereoisomer on Nicotine Pouch Abuse Liability: A Randomized Crossover Trial

Abstract

Introduction

Many oral nicotine pouch (ONP) brands use synthetic nicotine, which typically contains a racemic (50:50) mixture of nicotine’s two stereoisomers: S-nicotine and R-nicotine. Because tobacco-derived nicotine contains more than 99% S-nicotine, the effects of R-nicotine in humans are not well known. We compared systemic nicotine exposure and product appeal of ONPs containing more than 99% S-nicotine versus racemic nicotine.

Aims and Methods

N = 18 adult smokers (M_age = 45 years, 66.7% male, 77.8% White) enrolled in a three-visit single-blind, randomized crossover study. During each visit, participants used one wintergreen-flavored, 3 mg nicotine ONP for 30 min following at least12 h nicotine abstinence. Study ONP #1 contained more than 99% S-nicotine and the other two study ONPs contained racemic nicotine (collapsed for analyses). Plasma nicotine assessments and measures of withdrawal relief occurred at t = 0, 5, 15, 30, 60, and 90 min; measures of product appeal were assessed following ONP use.

Results

Using the ONP with more than 99% S-nicotine resulted in greater plasma nicotine concentration from 15 to 90 min (p < .0001) and greater maximum plasma nicotine concentration than the ONPs with racemic nicotine (M = 9.9 ng/mL [SD = 2.5] vs. M = 5.7 ng/mL [SD = 2.8], respectively; p < .0001). Product liking and withdrawal relief were similar across ONPs, although participants reported more “bad effects” when using the ONP with more than 99% S-nicotine.

Conclusions

Participants reported few subjective differences in ONPs according to nicotine stereoisomer, but plasma nicotine concentration was greater for ONPs using more than 99% S-nicotine. ONPs with more than 99% S-nicotine (vs. racemic nicotine) might be better substitutes for cigarettes, but research into other ONP characteristics (eg flavors, freebase nicotine) is needed to inform regulation.

Implications

Little is known about the effects of racemic (vs. S-) nicotine in humans. In a sample of adults who smoke cigarettes, we identified that oral nicotine pouches containing racemic nicotine exposed participants to less nicotine than oral nicotine pouches containing only S-nicotine, but both types of oral nicotine pouches held similar, moderate appeal. Additional research evaluating the roles that flavorings, total nicotine concentration, and freebase nicotine play in the abuse liability of oral nicotine pouches would inform comprehensive product regulations to support public health.

Introduction

Oral nicotine pouches (ONPs) are small white pouches that contain nicotine but no tobacco leaf. After entering the United States (US) market in 2016,¹ ONP uptake has primarily occurred among adults and youth who already use other forms of tobacco.^2–4 Because ONPs carry a lower toxicant burden than other tobacco products,⁵ they hold the potential for harm reduction among current tobacco users (eg smokers and smokeless tobacco users). Identifying key characteristics of ONPs that might increase (or decrease) their harm reduction potential for smokers and smokeless tobacco users is necessary to inform ONP regulations that promote public health.⁶

The source of nicotine in ONPs is a product characteristic that likely influences their harm reduction potential by affecting their appeal and addiction potential. Some of the first ONP brands on the US market, and the most popular according to sales data, including Zyn and On!,⁷ use tobacco-derived nicotine. Newer brands, including Fre and Juice Head (formerly Niin), claim to use synthetic nicotine. Consumer perceptions of ONPs may be influenced by the source of nicotine: in one online survey study of young adults, ONPs described as using synthetic nicotine were perceived to carry lower health risks, be less addictive, and taste smoother and cleaner.⁸ The distinction of nicotine’s source in a tobacco product is also important because nicotine has two stereoisomers: S-nicotine and R-nicotine. Tobacco-derived nicotine contains more than 99% S-nicotine,⁹ and accordingly, S-nicotine’s pharmacokinetics and appeal in humans are well-documented. However, synthesis of nicotine in a laboratory (ie synthetic nicotine) typically results in a racemic, or 50:50, mixture of S- and R-nicotine, and has only recently become economically practical.¹⁰ Knowledge about R-nicotine’s pharmacokinetics is limited to animal models, which suggest that R-nicotine might be metabolized more quickly and be a less potent agonist of nicotinic receptors in the brain.^11–16

In March of 2022, the US Congress gave the Food and Drug Administration (FDA) authority to regulate consumer products containing synthetic nicotine as tobacco products.¹⁷ Given our very limited understanding of R-nicotine’s effects in humans, it is unclear how ONPs containing synthetic nicotine should be regulated to promote public health. The goal of this randomized crossover study was to compare product appeal and systemic nicotine exposure of ONPs with racemic nicotine to ONPs that have more than 99% S-nicotine. In a sample of adult cigarette smokers, we hypothesized that using ONPs containing more than 99% S-nicotine (vs. racemic nicotine) would be associated with greater maximum plasma nicotine concentration, reduction in withdrawal symptoms, and product liking.

Materials and Methods

Setting and Participants

Between May and September 2022, we recruited 20 cigarette smokers living in OH using targeted social media advertisements and word-of-mouth. Interested potential participants were directed to an online screening questionnaire, and those who screened eligible were contacted by telephone to confirm eligibility. Inclusion criteria were: (1) age ≥ 21-years-old; (2) willing and able to abstain from all tobacco, nicotine, and marijuana for ≥ 12 h prior to study visits; and (3) smoking ≥ 5 cigarettes per day for longer than the past 30 days. Exclusion criteria were: (1) use of other tobacco or nicotine products for more than 10 days of the past month; (2) currently trying to quit smoking or interested in quitting smoking in the next 3 months; (3) pregnant, trying to become pregnant, or breastfeeding; (4) uncontrolled mental health disorders or past-year hospitalization for a psychiatric condition; (5) cardiovascular health issues, including heart disease, chest pain or angina, irregular heartbeat or abnormal heart rhythm, uncontrolled diabetes or uncontrolled hypertension, and myocardial infarction or other cardiac event; (6) lung disease, including chronic obstructive pulmonary disorder, cystic fibrosis, or uncontrolled asthma; (7) a history of problematic or difficult blood draws; and (8) use of illicit drugs (except for marijuana) in the past 30 days. Clinical research assistants obtained informed consent from participants and all study procedures were approved by The Ohio State University’s Institutional Review Board.

Design and Procedures

Using a single-blind, randomized crossover design, participants completed three clinic visits, using a different study ONP at each visit: (1) 3 mg nicotine concentration Zyn (>99% S-nicotine), (2) 3 mg nicotine concentration Niin (racemic nicotine), and (3) 3 mg nicotine concentration Fre (racemic nicotine). All pouches were wintergreen flavor. We chose 3 mg nicotine concentration ONPs (vs. a higher nicotine concentration) because of the potential for participants with only a light smoking history to enroll in the study and the lack of independent data reporting on systemic nicotine exposure from ONP use at the time planning this study. Clinic visits were separated by at least 48 h. We biochemically confirmed at least 12 h combustible tobacco abstinence at the beginning of each visit using exhaled carbon monoxide (eCO) < 10ppm and participant self-report. We also administered urine pregnancy tests prior to ONP use at each visit for participants capable of pregnancy. Study visit order randomization was completed by the clinical research assistant using REDCap’s randomization function immediately following informed consent.

Participants completed baseline measures prior to initial ONP use at visit 1. At all visits, an intravenous line was placed prior to ONP use for repeat 3 mL blood draws at 0 min (immediately prior to ONP use), 5, 15, 30, 60, and 90 min. Participants were instructed to keep the ONP in place between their upper lip and gum for 30 min (manufacturers often recommend using an ONP for up to 30 min) and to remain seated and refrain from eating or drinking. Participants completed measures of withdrawal relief concurrent with each blood draw. Following the removal of the ONP, participants completed additional measures reporting product appeal. Participants were compensated $100 for each visit and received a $50 bonus for completing all-sessions within one month. After all study activities were completed, participants were offered a list of smoking cessation resources.

Materials

We selected one ONP that was described by its manufacturer as using tobacco-derived nicotine (Zyn) and two ONPs described by their manufacturers as using synthetic nicotine (Fre and Niin). ONPs were selected to have similar nicotine concentrations (3 mg/pouch) and characterizing flavor (wintergreen). The nicotine R:S stereoisomer ratio was confirmed using a validated Nuclear Magnetic Resonance (NMR) method.^18,19 Nicotine was extracted from ONPs using an acid/base liquid/liquid extraction, and aliquots were mixed with a chiral complexing agent [(R)-(−)-1,1ʹ-Binaphthyl-2,2ʹ-diyl hydrogenphosphate] and quantified using proton NMR (Bruker 400 MHz). Spectra showed clean isolation of the R- and S-nicotine isomers, ensuring accurate quantification of the isomer ratio. These analyses confirmed that Zyn pouches contained more than 99% S-nicotine and Fre and Niin pouches both contained 50% S-nicotine and 50% R-nicotine. Therefore, we combined Fre and Niin ONPs in all-statistical analyses.

Measures

Dependent Variables

Dependent variables included plasma nicotine concentration, self-reported withdrawal and craving relief, and subjective measures of drug effects and product liking. Plasma nicotine assessments (primary outcome) occurred immediately prior to ONP use (0 min) and at 5, 15, 30, 60, and 90 min after ONP placement. Withdrawal and craving relief (secondary outcomes) were measured using the Minnesota Withdrawal Scale (MNWS)²⁰ concurrent with each blood draw. The MNWS was analyzed both in total and by the craving item. Subjective drug effects and liking (secondary outcomes) were measured using a visual analog scale (scale anchors: “not at all” to “extremely” or “very”) after product use and included pleasantness, desire and urge, need, and want to use the study product again; liking, enjoyment, pleasurableness, and satisfaction from using the study product; interest and willingness to use the study product again; and feeling any effects, good effects, or bad effects from the study product.^21,22

Independent Variables

The independent variable of interest was the nicotine stereoisomer ratio in the ONPs: more than 99% S-nicotine versus racemic nicotine. Other independent variables that were used to characterize the sample included age (years), sex, gender, race, ethnicity, the highest level of education, cigarettes smoked per day, and ever use of any oral tobacco product, including snuff, chewing tobacco, snus, and ONPs.

Statistical Analysis

We conducted a power analysis based on maximum plasma nicotine concentration. Using preliminary results from a separate study of plasma nicotine concentration associated with ONP use,²³ we estimated a mean maximum plasma nicotine concentration of 10 ng/mL for more than 99% S-nicotine ONP. For the racemic nicotine ONPs, we assumed that the mean maximum plasma nicotine concentration would be approximately half as high (5 ng/mL). Assuming a common SD of 5 ng/mL, a conservative within-subjects correlation of 0.2, and an alpha of 0.05, we estimated 81.2%–91.8% power to detect statistically significant differences with a target sample size of 15–20 participants.

We calculated descriptive statistics to characterize the sample and confirm that covariates were balanced by randomization. Next, we inspected distributions of dependent variables and log-transformed skewed distributions prior to analysis. We used linear mixed-effects models with fixed effects for ONP stereoisomer ratio and random subject intercepts for all analyses. Holm’s procedure was used to adjust for multiple comparisons for each of the longitudinal outcomes (eg MNWS, plasma nicotine), and t = 0 values for MNWS scores and plasma nicotine values were included in their respective models as fixed effects. Analyses were completed using SAS 9.4 (SAS Institute, Cary, NC).

Results

Participant Characteristics

N = 20 participants enrolled in the study and were randomized to a visit sequence (Figure 1). N = 2 participants failed intravenous line placement at visit 1 and were excluded from further participation and analyses. N = 17 participants completed all-three visits, and N = 1 participant completed two visits. This yielded a final analytic sample size of N = 18 participants. Participants were 45.3 years old (SD = 10.2) on average, two-thirds were men, 78% were White, 6% were Hispanic, and 22% had obtained a Bachelor’s degree (Table 1). Participants smoked an average of 12.6 (SD = 7.6) cigarettes per day, and 56% had ever used an oral tobacco product. All participant characteristics were balanced by randomization (results not shown).

Figure 1.

Study flow chart, OH, 2022. ^aIV line placement failed for two participants at visit 1. Participants were excluded from further participation and from study analyses. ^bOne participant withdrew from the study after visit 2 due to not liking ONPs. This participant’s data were retained in analyses.

Table 1.

Randomized Crossover Trial Participant Characteristics, OH, 2022^a

	N = 18
Age (mean, SD)	45.3 (10.2)
Sex assigned at birth (n, %)
Female	6 (33)
Male	12 (67)
Gender (n, %)
Woman	6 (33)
Man	12 (67)
Race (n, %)
White	14 (78)
Black or African American	4 (22)
Ethnicity (n, %)
Hispanic or Latino/a	1 (6)
Not Hispanic or Latino/a	17 (94)
Highest level of education (n, %)
< High school	1 (6)
Graduated high school	1 (6)
Currently attending college	1 (6)
Some college but no degree	11 (61)
Bachelor’s degree	4 (22)
Cigarettes smoked per day (mean, SD)	12.6 (7.6)
Ever use of oral tobacco products (n, %)
Yes	10 (56)
No	8 (44)
ONP assigned at visit 1 (n, %)
Niin (racemic nicotine)	5 (28)
Fre (racemic nicotine)	6 (33)
Zyn (>99% S-nicotine)	7 (39)

Abbreviation: ONP = oral nicotine pouch.

Percentages might not sum to 100 due to rounding.

^aHealthy adults who smoke cigarettes were recruited from the community to complete a three-visit, single-blind, and randomized crossover experiment, in which they sampled oral nicotine pouches containing either more than 99% S-nicotine or racemic nicotine.

Plasma Nicotine Concentration

Mean plasma nicotine concentrations were higher when using the ONP with more than 99% S-nicotine from 15 min through 90 min (Table 2; Figure 2). Maximum plasma nicotine concentrations occurred at 30 min for ONPs with more than 99% S-nicotine (M = 9.9 [SD = 2.5] ng/mL) and racemic nicotine (M = 5.7 [SD = 2.8] ng/mL).

Table 2.

Plasma Nicotine Concentration, Withdrawal Relief, and Subjective Drug Effects and Liking for Oral Nicotine Pouches Containing More Than 99% S-Nicotine Versus Racemic Nicotine in a Sample of Healthy Adults Who Smoke Cigarettes, OH, 2022^a

	Racemic nicotine	>99% S-nicotine
	Mean (SD)	Mean (SD)	p-valueb
Plasma nicotine (ng/mL)
5 min	3.3 (2.2)	4.0 (2.1)	.17
15 min	4.8 (2.7)	7.8 (3.1)	<.001
30 min	5.7 (2.8)	9.9 (2.5)	<.001
60 min	4.2 (2.5)	6.7 (2.8)	<.001
90 min	3.3 (2.5)	5.6 (2.6)	<.001
Withdrawal symptomsc,d
5 min	3.3 (4.0)	3.6 (3.7)	.26
15 min	2.6 (3.4)	2.5 (3.0)	.68
30 min	2.6 (3.3)	2.5 (3.2)	.81
60 min	3.4 (3.5)	2.8 (3.2)	.73
90 min	3.7 (3.9)	3.3 (3.4)	.86
Cravingc
5 min	1.9 (1.4)	1.7 (1.5)	.62
15 min	1.5 (1.2)	1.3 (1.3)	.95
30 min	1.7 (1.2)	1.4 (1.3)	.78
60 min	1.8 (1.2)	1.7 (1.2)	.90
90 min	2.1 (1.2)	1.6 (1.5)	.26
Pleasant to use again right nowe	45.3 (32.9)	46.1 (28.9)	.99
Desire or urge to use right nowe	29.2 (26.1)	28.2 (24.7)	.80
Need to use for reliefe	35.2 (34.0)	29.7 (21.5)	.37
Want to usee	29.6 (27.8)	29.6 (27.8)	.95
Extent of likinge	41.6 (31.1)	43.4 (29.3)	.92
Extent of enjoymente	40.8 (30.2)	41.5 (29.0)	.94
Extent of pleasurablenesse	43.1 (33.4)	45.4 (29.7)	.85
Extent of satisfactione	44.7 (29.9)	45.0 (28.3)	.98
Interest in using again in futuref	3.8 (3.2)	4.0 (3.3)	.85
Willing to use againf	4.6 (3.3)	5.2 (2.9)	.48
Felt any effectsg	33.1 (26.0)	31.1 (27.0)	.66
Felt good effectsg	35.8 (27.8)	35.7 (25.9)	.92
Felt bad effects g , d	12.9 (15.9)	22.1 (25.2)	.03

^a N = 18 participants were recruited from the community to complete a three-visit, single-blind, and randomized crossover experiment. Fre and Niin 3 mg wintergreen ONPs were used for the racemic nicotine conditions, and responses for these two ONPs were collapsed for analyses. Zyn 3 mg wintergreen ONPs were used for the more than 99% S-nicotine condition.

^bStatistical significance is denoted using bold.

^cWithdrawal and craving were measured via the Minnesota Withdrawal Scale.

^dVariable was log-transformed for analyses. Untransformed means and SDs are reported in this table.

^eResponse options ranged from 0: “Not at all” to 100 “Very.”

^fResponse options ranged from 0: “Not at all” to 10 “Very.”

^gResponse options ranged from 0: “Not at all” to 100 “Extremely.”

Figure 2.

Plasma nicotine concentration associated with using oral nicotine pouches containing more than 99% S-nicotine versus racemic nicotine among adult smokers, OH, 2022.a

*Denotes statistical significance following Holm’s procedure (all p < .001).

aOne ONP was placed between the upper lip and gum and held in place for 30 min. Blood was drawn immediately before ONP placement (t = 0) and at t = 5, 15, 30, 60, and 90 min. Error bars represent 95% CI.

Withdrawal and Craving Relief

We identified no significant differences in withdrawal or craving relief according to the nicotine stereoisomer (Table 2). In general, withdrawal and craving symptoms decreased over the first 15–30 min of ONP use. After the ONP was removed at 30 min, withdrawal and craving symptoms gradually increased over the remaining 60 min of follow-up.

Subjective Drug Effects and Liking

Participants reported moderate liking of study ONPs, and there were no significant differences in product liking (eg pleasantness, liking, and satisfaction) according to nicotine stereoisomer ratio (Table 2). Participants reported greater “bad effects” of using the ONP with more than 99% S-nicotine than the ONPs with racemic nicotine (M = 22.1 [SD = 25.2] vs. M = 12.9 [SD = 15.9], respectively; p = .03).

Discussion

We compared systemic nicotine exposure, withdrawal relief, and product appeal of ONPs with racemic nicotine versus an ONP that had more than 99% S-nicotine. As hypothesized, we identified differences in plasma nicotine concentration according to ONPs’ nicotine stereoisomer ratio. Using the ONP with more than 99% S-nicotine resulted in greater maximum plasma nicotine concentration starting 15 min after product placement in the mouth and continuing through 90 min of follow-up. Beyond increased perceived “bad effects” of using the ONP with more than 99% S-nicotine, we identified no differences in product appeal or withdrawal relief associated with nicotine stereoisomer in ONPs. As the US FDA only recently gained the authority to regulate synthetic nicotine, our results provide some of the first information that can be used to inform future scientific investigations to determine the most appropriate regulations for ONPs.

The most notable differences we identified between ONPs according to nicotine stereoisomer were in plasma nicotine pharmacokinetics, with systemic nicotine exposure being greater for the ONP with more than 99% S-nicotine than the racemic nicotine ONPs. The plasma nicotine pharmacokinetics associated with using the more than 99% S-nicotine ONP were comparable to other studies of ONP pharmacokinetics^23–25 and followed the same temporal pattern—although maximum plasma nicotine concentrations were lower in magnitude—as moist snuff.^26,27 Plasma nicotine pharmacokinetics differed from what is typical for cigarette smoking both in maximum plasma nicotine concentration (which was lower for ONPs) and time of maximum plasma nicotine concentration (which was much later for ONPs).^25,27 Altogether, these results suggest that ONPs that contain more than 99% S-nicotine may serve as closer substitutes for other tobacco products, particularly moist snuff, as opposed to ONPs containing racemic nicotine, and that higher nicotine concentrations in ONPs might additionally improve their potential for complete substitution in smokers. As manufacturers frequently cross-promote cigarettes and ONPs,²⁸ understanding how product characteristics and marketing strategies affect ONP use patterns among smokers would be useful to understand the role ONPs might play in this population.

We hypothesized that participants would report greater product liking and reductions in withdrawal symptoms when using the ONP with more than 99% S-nicotine. However, the only difference we identified in product appeal was that participants reported greater “bad effects” from using the ONP with more than 99% S-nicotine. One possible reason for minimal differences in these subjective effects is that the smokers in our sample were not regular users of oral tobacco products (per our eligibility criteria) and thus may not be able to differentiate subtle differences in ONPs. The sensory effects and systemic nicotine exposure from an oral product are so distinct from that of cigarette smoking that differences between pouches may be minor in comparison. Given that smokeless tobacco use is associated with ONP use,⁴ the use topographies for these oral tobacco products are likely much more similar, and ONPs appear to have a much lower toxicant burden than other forms of smokeless tobacco,⁵ revisiting this research question in a sample of smokeless tobacco users could inform our understanding of whether ONPs have potential to function as a reduced risk product in this population.

A second reason for the lack of differences in subjective effects may be related to the nicotine concentration of ONPs used in the study. Consistent with animal models,^11–16 our plasma nicotine concentration results suggest that administering racemic nicotine results in a lower maximum plasma nicotine concentration than administering more than 99% S-nicotine. Using a lower concentration of total nicotine could have suppressed the magnitude of these differences, making them more difficult to subjectively discern by participants. Conducting this research using ONPs with higher nicotine concentrations may lead to larger differences in plasma nicotine concentration and associated subjective effects.

The one subjective effect that differed according to nicotine stereoisomer was increased “bad effects” of using the ONP with more than 99% S-nicotine. Anecdotally, participants reported more intense oral sensations associated with using the more than 99% S-nicotine ONP (Zyn), including tingling and burning sensations on their lips or gums. While this could be due to the higher fraction of S-nicotine, it is also possible that potential variations in flavorings or the fraction of unprotonated versus protonated (ie freebase vs. salt) nicotine²⁹ could have contributed to these sensory differences. Evaluating whether this effect is also found in a sample of smokeless tobacco users who are familiar with holding a nicotine product in their mouth for at least 30 min, and determining whether this effect is unique to Zyn or is consistent across ONPs with more than 99% S-nicotine, would be useful to interpret these results.

This study is subject to the following limitations, which can be addressed in future research. By using commercially available ONPs, we cannot conclude that the differences we identified are solely due to nicotine stereoisomer, because they could be due to other variations in ONPs not divulged by the manufacturers’ packaging, such as mislabeled total nicotine concentration, the fraction of freebase nicotine, flavorings, and other additives that may affect buccal absorption. Relatedly, as described, using ONPs with low nicotine concentration could have suppressed differences in subjective effects. Next, because we did not use a double-blind design, it is possible that research staff could have acted in a manner that biased participants’ assessment of ONPs, although rigorous training and supervision should have minimized such effects. Finally, because we conducted this research using a small convenience sample, our results might not generalize to all cigarette smokers.

In conclusion, we identified differences in systemic nicotine exposure according to nicotine stereoisomer ratios present in ONPs but identified very few differences in subjective effects. ONPs carry a lower toxicant burden than other forms of tobacco,⁵ indicating that they hold potential for harm reduction among adults who use other forms of tobacco. The extent of their harm reduction potential, however, depends in part on how successfully adult tobacco users can completely switch to ONPs.^6,30 Our finding that the use of ONPs containing more than 99% S-nicotine results in greater systemic nicotine exposure than ONPs containing racemic nicotine suggests that regulations to restrict the fraction of R-nicotine in ONPs could support greater nicotine exposure and thus greater switching from cigarettes (or smokeless tobacco) to ONPs. Additional research that controls flavorings and the fraction of freebase nicotine across ONPs is needed to better isolate the effects of nicotine stereoisomer on product appeal and systemic nicotine exposure. Finally, understanding the role that nicotine stereoisomer might play in ONPs’ appeal and addictiveness among people who do not use other forms of tobacco is needed to inform comprehensive ONP regulations that best position ONPs as a public health benefit.

Clinical Trial Registration: NCT05236894

Funding

This study was funded by The Ohio State University Comprehensive Cancer Center—The James. This research was also partially supported by grant number P30CA016058 from the National Cancer Institute of the National Institutes of Health. BKH reports additional support from grant number K01DA055696 from the National Institute on Drug Abuse. BKH, AH, MCB, AE-H, TLW, and DM report support from grant number U54CA287392 from the National Cancer Institute. The sponsors had no role in the study design; in the collection, analysis, or interpretation of the data; in the writing of the report; or in the decision to submit the manuscript for publication.

Declaration of Interests

The authors have no conflicts of interest to disclose.

Author contributions

Brittney Keller-Hamilton (Conceptualization [lead], Funding acquisition [lead], Methodology [lead], Project administration [lead], Supervision [lead], Writing—original draft [lead], Writing—review & editing [equal]), Leanne Atkinson (Investigation [equal], Writing—review & editing [equal]), Hayley Curran (Investigation [equal], Project administration [equal], Supervision [equal], Writing—review & editing [equal]), Mahmood Alalwan (Investigation [equal], Writing—review & editing [equal]), Alice Hinton (Data curation [lead], Formal analysis [lead], Writing—review & editing [Equal]), Marielle Brinkman (Methodology [equal], Writing—review & editing [equal]), Ahmad El-Hellani (Methodology [equal], Writing—review & editing [equal]), Theodore Wagener (Conceptualization [equal], Methodology [equal], Writing—review & editing [equal]), Kirsten Chrzan (Investigation [equal], Writing—review & editing [equal]), Sriya Suraapaneni (Investigation [equal], Writing—review & editing [equal]), and Darren Mays (Conceptualization [equal], Methodology [equal], Writing—review & editing [equal]).

Data availability

The data underlying this article will be shared upon reasonable request to the corresponding author.