Introduction
Delta-8-tetrahydrocannabinol (delta-8-THC) is a chemical compound that is structurally similar to the primary psychotropic compound found in marijuana, delta-9-tetrahydrocannabinol (delta-9-THC), and produces comparable psychotropic effects.1,2 Delta-8-THC products are primarily made by converting cannabidiol (CBD) or delta-9-THC through a process known as isomerization.3 CBD is abundantly bioavailable in “hemp,” which, under the 2018 Farm Bill, is defined as Cannabis Sativa L. and its derivatives that contain ≤0.3% delta-9-THC on a dry weight basis; whereas Cannabis Sativa L. containing >0.3% delta-9-THC on a dry weight basis is defined as “marijuana”. Many US manufacturers have argued that products containing delta-8-THC produced from hemp-derived CBD are in compliance with the 2018 Farm Bill and can therefore be sold legally throughout most US states.4
Some steps have been taken to regulate psychotropic hemp-derived products, including delta-8-THC, at the federal level. The Drug Enforcement Agency (DEA) has promulgated that it considers delta-8-THC to be an analog of delta-9-THC, implying that it falls under similar regulatory restrictions as marijuana.5 However, to the authors’ knowledge, the DEA has not actively pursued enforcement actions against delta-8-THC manufacturers. A proposed revision to the 2024 Farm Bill, which awaits final rules at the time of writing, would impose a limit on “total THC” (including delta-8-THC) and restrict the manufacture, sale and distribution of product containing cannabinoids derived through isomerization.6 Separately, in May 2022, the FDA also determined that delta-8-THC products are not Generally Recognized as Safe (GRAS), and therefore food to which delta-8-THC is added are adulterated under the Food, Drug, and Cosmetic Act.7 In this determination, the Food and Drug Administration (FDA) also highlighted serious satisfy concerns following documented upticks in adverse event reports.8,9 Since this time, the FDA has responded sending a handful of warning letters to delta-8-THC manufactures that make products that resemble popular youth candies and snacks,10 but it is unclear whether it will take in broader actions.
Meanwhile, in the face of federal uncertainty, many US states have enacted their own laws concerning delta-8-THC and the types of regulation have varied considerably. Some states have chosen to prohibit all delta-8-THC products from being sold (e.g., Idaho). Others, allow sales with some restrictions, such a requiring delta-8-THC products to be sold to be at licensed dispensaries (e.g., Connecticut) or imposing limits on THC content (e.g., Louisiana). However, in most states, sales of delta-8-THC to adults remain unregulated either because the state has chosen not to enact regulations (e.g., Florida) or the state has not clarified its legal status (e.g., Pennsylvania).11–13
To date, there is limited research on how state marijuana and delta-8-THC policies effect use of delta-8-THC among US adults. Two previous studies using online search query analyses indicate growing public interest in delta-8-THC, particularly in states restricting marijuana use, suggesting its potential role as a legal substitute.14,15 Among adolescents, delta-8-THC use was higher in states without delta-8-THC regulations or recreational marijuana laws.16 A nationally representative sample of US adults found lower past-year delta-8-THC use among states with medical or recreational marijuana laws, but did not examine delta-8-THC regulations in addition to marijuana policies.17 Similarly, a convenience sample of US adults who use marijuana found higher rates of delta-8-THC use in states where marijuana use was prohibited and states without restrictions on delta-8-THC products;18 however, the study relied on self-reported state of residence. The present study utilized a nationally representative panel to measure delta-8-THC use by state marijuana use laws and delta-8-THC regulations.
Methods
Study Sample
The Characterizing the Epidemiology of Cannabidiol Use Survey (CBD-US) was conducted between October 25, 2023, and November 3, 2023, to collect data on behaviors related to CBD and other hemp-derived products among US adults. Respondents were recruited from Ipsos KnowledgePanel®, which is representative of 97% of the adult US general population, covers all 50 states and Washington DC, and has been widely used to provide representative statistics on drug use in the US.19–22 Additional details about the Ipsos KnowledgePanel® can be found in the Appendix.
Ipsos recruited a random sample of 4,505 KnowledgePanel® adults aged 18 years or older to complete the study survey in English or Spanish. Of these, 2,880 adults responded to the invitation (63.9% completion rate) and completed a screening questionnaire to determine eligibility. After a detailed description explaining what CBD was, the screening questionnaire queried about respondent’s lifetime use of CBD. A predetermined target sample of n=1000 people who have ever used CBD and n=500 people who have never used CBD was selected, with sample sizes determined to provide representative estimates of CBD use behaviors with <±3% margin of error. In total, n=1,523 of the 2,880 adults who completed the screening questionnaire qualified for the survey by screening into one of the two groups with set quotas (n=1008 people who used CBD and n=515 people who never used CBD), yielding a qualification rate of 53.0%. The survey was completed in a median of 10 minutes. The survey was considered exempt human subjects research by the Human Research Protections Program at the University of California San Diego.
Measures
Lifetime use of delta-8-THC was prefaced with a clarifying prompt that stated, “The next questions are about products that contain compounds found in the cannabis plant other than CBD or THC or are manufactured from parts of the cannabis plant.” Participants were then asked, ‘Have you ever, even once, used delta-8-THC?’ with response options (1 = Yes; 2 = No); those who responded “yes” to the previous question were categorized as having ever used delta-8-THC.
Using data on medical marijuana policies from the RAND-USC Schaeffer Opioid Policy Tools and Information Center23 and marijuana (i.e., cannabis) retail access from the Alcohol Policy Information System,24 each respondent’s state of residence was categorized into one of three marijuana policy groups: “prohibited”, “medical use-only”, or “recreational” based on state regulations before the administration of the survey (prior to October 2023) (Table 1).25,26 Prohibited use states included those where marijuana use was not permitted for medical or recreational purposes. Medical use-only states included those where marijuana use was medicinally legal but not legal for recreational use. Recreational use states included those allowing the use of marijuana for both medical and nonmedical use.
Table 1:
Categorization of state marijuana use and delta-8-THC sales policies
| State | Marijuana Use | Delta-8-THC Sales |
|---|---|---|
| Alabama | Medical only | Unregulated |
| Alaska | Recreational | Prohibited |
| Arizona | Recreational | Unregulated |
| Arkansas | Medical only | Unregulated |
| California | Recreational | Regulated |
| Colorado | Recreational | Prohibited |
| Connecticut | Recreational | Regulated |
| Delaware | Recreational | Prohibited |
| Florida | Medical only | Unregulated |
| Georgia | Prohibited | Unregulated |
| Hawaii | Medical only | Prohibited |
| Idaho | Prohibited | Prohibited |
| Illinois | Recreational | Unregulated |
| Indiana | Prohibited | Unregulated |
| Iowa | Prohibited | Regulated |
| Kansas | Prohibited | Regulated |
| Kentucky | Prohibited | Unregulated |
| Louisiana | Medical only | Regulated |
| Maine | Recreational | Unregulated |
| Maryland | Recreational | Unregulated |
| Massachusetts | Recreational | Prohibited |
| Michigan | Recreational | Regulated |
| Minnesota | Recreational | Regulated |
| Mississippi | Prohibited | Prohibited |
| Missouri | Recreational | Unregulated |
| Montana | Recreational | Prohibited |
| Nebraska | Prohibited | Unregulated |
| Nevada | Recreational | Prohibited |
| New Hampshire | Medical only | Prohibited |
| New Jersey | Recreational | Unregulated |
| New Mexico | Recreational | Unregulated |
| New York | Recreational | Prohibited |
| North Carolina | Prohibited | Unregulated |
| North Dakota | Medical only | Prohibited |
| Ohio | Medical only | Unregulated |
| Oklahoma | Medical only | Unregulated |
| Oregon | Recreational | Prohibited |
| Pennsylvania | Medical only | Unregulated |
| Rhode Island | Recreational | Prohibited |
| South Carolina | Prohibited | Unregulated |
| South Dakota | Prohibited | Unregulated |
| Tennessee | Prohibited | Unregulated |
| Texas | Prohibited | Unregulated |
| Utah | Medical only | Prohibited |
| Vermont | Recreational | Prohibited |
| Virginia | Medical onlya | Regulated |
| Washington | Recreational | Prohibited |
| West Virginia | Medical onlya | Unregulated |
| Wisconsin | Prohibited | Unregulated |
| Wyoming | Prohibited | Unregulated |
| Washington D.C. | Recreational | Prohibited |
The dataset used for medical only states was last updated on October 19, 2020. Therefore, the authors reviewed prohibited states to check for any updates and found that West Virginia passed a medical marijuana law by reviewing the most recent state law. Virginia was categorized as a medical only state even though it legalized marijuana use for recreational purposes because it had not taken the steps necessary to create a commercial adult-use retail market as of October 23, 2023.
To the authors’ knowledge, no single authoritative source of information on delta-8-THC policies exists. As such, consistent with previous policy review,4 the study authors searched for laws relevant to delta-8-THC that were referenced on manufacturers websites (i.e., 3CHI), in industry blogs (i.e., CBD Oracle), and in a policy brief on hemp products’ legal status by Rice University’s Baker Institute for Public Policy.27,28 The authors then independently reviewed the indexed laws to make their own determination about the legal status (Appendix Table 1) using the categories as follows:
Prohibited: states that have disallowed all sales of delta-8-THC products (n=18 including Washington DC).
Regulated: states that allowed legal sales of delta-8-THC to adults (18+ years) with some restriction including by requiring sales to be restricted to marijuana dispensaries or by requiring products to have a potency limit (n=8).
Unregulated: states that permitted all sales of delta-8-THC products to adults (18+ years) or that have not clarified the legal status of delta-8-THC sales (n=25).
Standard sociodemographic characteristics were provided by Ipsos for all KnowledgePanel® members. Age was provided as a continuous variable ranging from 18 to 93. Sex was provided as a dichotomous variable: 1) male or 2) female. Race/ethnicity was provided as a categorical, five-level variable: 1) Non-Hispanic (NH) White, 2) NH Black, 3) NH Other including 2+ races, and 4) Hispanic. Education level was provided as a categorical, four-level variable: 1) no high school diploma or General Educational Development (GED), 2) high school graduate (high school diploma or the equivalent GED), 3) some college or Associate’s degree, and 4) Bachelor’s degree or higher.
Marijuana use was assessed using the question “In your entire lifetime, have you ever used cannabis (i.e., marijuana) that contained THC?” (yes/no).
Other drug use was assessed using the question “In your entire lifetime, have you ever used any of the following substances?” with response options 1) Cocaine or crack, 2) Non-prescription stimulants like methamphetamine or speed, 3) Psychedelics like LSD or psilocybin-containing mushrooms, 4) Empathogens like, MDMA also known as ecstasy or molly, 5) Dissociative substances like ketamine, 6) Any other drugs like heroin, inhalants, or solvents, and 7) None of the categories apply. Use of any of the substances was coded “yes” and none was coded “no”.
Modeled after the Population Assessment of Tobacco and Health study,29 the survey asked each participant to self-report their general physical health, mental health, and quality of life on a 5-point Likert scale ranging from “1) Poor” to “5) Excellent”.
Statistical Analysis
To produce population-based estimates, this study used study-specific poststratification weights constructed by Ipsos that accounted for the oversampling of people who used CBD in the study design, demographic characteristics of the qualified sample and survey non-response (Appendix). Weighted frequencies and the corresponding 95% confidence intervals (CIs) of lifetime delta-8-THC use were calculated and differences in the distributions for lifetime delta-8-THC use were examined across state marijuana and delta-8-THC policy categories. Complete case analyses were conducted as ≤3.6% of observations were missing from any variable (Appendix Table 2).
This study used inverse probability of treatment weighting (IPTW) to ensure that estimates of the impact of state regulations on marijuana use and delta-8-THC sales were appropriately adjusted for individual factors related to a person’s state of residence and also related to self-selected use of delta-8-THC (e.g., age).18,30,31 To calculate propensity scores, separate logistic regression models were fit to predict four state policy comparisons: 1) prohibited marijuana use vs medical marijuana use only, 2) prohibited marijuana use vs recreational marijuana use, 3) unregulated delta-8-THC sales vs regulated delta-8-THC sales, and 4) unregulated delta-8-THC sales vs prohibited delta-8-THC sales. Predictors in these models included all measured potential confounders and, as recommended,32 the Ipsos-constructed survey weights. Stabilized inverse propensity score weights were computed with the resulting propensity scores.33 Diagnostics of the resulting distributions of stabilized weights suggested no evidence of non-positivity or of misspecification of the propensity score model as all means were near 1.0 and there were no extreme observations (Appendix Table 3).34 The resulting stabilized weights were multiplied by the Ipsos-constructed survey weights to form a final weight for subsequent balance assessments and effect estimation.32
To assess balance between the state policy groups, weighted standardized mean differences (SMD) of each potential confounder were computed between the exposed and unexposed groups before and after including the stabilized inverse propensity scores with the composite weights.35 The authors chose a conventional threshold of the SMD < |0.1|, as an indicator of good balance.36 The impact of state policies on delta-8-THC use were estimated through adjusted risk ratios (aRR) and 95% CIs obtained from log-binomial models37 using the IPTW-adjusted weights and with lifetime use of delta-8-THC as the outcome and state policy category as the exposure. All analyses were performed using R, version 4.1 (R Project for Statistical Computing), and weighted analyses were conducted using the R package ‘survey’.38
Results
Among 1,523 US adults in this sample, 7.7% (95% CI: 6.5–9.1) reported using delta-8-THC in their lifetime, corresponding to approximately 19.3 million individuals (Table 2); demographics by delta-8-THC use are available in Appendix Table 4. The prevalence of lifetime delta-8-THC use was highest among adults who resided in states that prohibited marijuana use (10.9% (95% CI: 8.6–13.8), followed by medical only-use states (8.5%; 95% CI: 5.8–12.2), and states that permitted recreational marijuana use (5.5%; 95% CI: 4.1–7.4). Overall, the prevalence of delta-8-THC use was over twice as high in states without delta-8-THC regulations (10.5%; 95% CI: 8.7–12.7), compared to states with delta-8-THC regulations (3.9%; 95% CI: 2.5– 6.5) and states that prohibited the sale of delta-8-THC products (4.5%; 95% CI: 2.8– 7.2). Small sample sizes for combinations of marijuana and delta-8-THC policies resulted in unstable estimates, so analyses were restricted to separately examine associations between marijuana and delta-8-THC laws and delta-8-THC use.
Table 2:
Lifetime delta-8-THC use by state marijuana and delta-8-THC policies among US adults (n=1523)
| State Policies | Overall Sample | Delta-8-THC Ever Use |
|---|---|---|
| n | Prevalence % (95% CI) | |
| Overall | 1523 | 7.7 (6.5 – 9.1) |
| Marijuana use | ||
| Prohibited | 434 | 10.9 (8.6 – 13.8) |
| Medical only | 369 | 8.5 (5.8 – 12.2) |
| Recreational | 720 | 5.5 (4.1 – 7.4) |
| Delta-8-THC | ||
| Unregulated | 885 | 10.5 (8.7 – 12.7) |
| Regulated | 335 | 3.9 (2.4 – 6.5) |
| Prohibited | 304 | 4.5 (2.8 – 7.2) |
All estimates were weighted using Ipsos-provided population weights.
In an unadjusted dataset, a comparison of the SMDs identified imbalance across the marijuana use policies on the constructed propensity score (SMD = 0.37) as well as for age (SMD = 0.16) and self-reported health (SMD = 0.16) between prohibited states and medical only states (Table 3). Similarly, there was imbalance across delta-8-THC policy categories on the constructed propensity score (SMD = 0.45) and age (SMD = −0.16) and bachelor’s degree or higher level of education (SMD = 0.13) between prohibited and unregulated states. However, the use of IPTW improved the comparability of policy groups for every variable assessed, including the propensity scores, resulting in SMDs that were closer to 0. The final IPTW comparisons were well balanced, as SMDs for all variables and the propensity scores were <|0.1|, the conventional threshold, for all comparisons.
Table 3:
Standardized mean differences showing balance improvement through weighting the propensity scores for state policy comparisons
| Marijuana use: Prohibited vs recreational | Marijuana use: Prohibited vs medical only states | Delta-8-THC: Prohibited vs unregulated | Delta-8-THC: Regulated vs unregulated | |||||
|---|---|---|---|---|---|---|---|---|
| Covariate | Composite | IPTW | Composite | IPTW | Composite | IPTW | Composite | IPTW |
| Propensity score | 0.61 | 0.00 | 0.37 | 0.01 | 0.45 | −0.01 | 0.58 | −0.01 |
| Female sex | −0.04 | −0.01 | 0.03 | 0.01 | −0.04 | 0.01 | −0.07 | 0.01 |
| Age (continuous) | 0.05 | 0.01 | 0.16 | 0.00 | −0.16 | 0.03 | 0.06 | 0.01 |
| Race/ Ethnicity | ||||||||
| White | −0.04 | 0.00 | 0.06 | 0.00 | −0.06 | 0.00 | −0.16 | −0.01 |
| Black | −0.08 | 0.00 | −0.03 | 0.00 | −0.02 | 0.00 | 0.00 | 0.01 |
| Other/2+ more | 0.07 | 0.00 | 0.02 | 0.00 | 0.07 | 0.00 | 0.09 | 0.00 |
| Hispanic | 0.05 | 0.00 | −0.05 | 0.00 | 0.01 | 0.00 | 0.07 | −0.01 |
| Education | ||||||||
| No high school diploma or GED | −0.01 | 0.00 | −0.04 | −0.01 | −0.01 | 0.00 | 0.03 | −0.01 |
| High school graduate | −0.08 | 0.00 | −0.01 | 0.00 | −0.07 | 0.00 | −0.08 | 0.01 |
| Some college/ Associate’s degree | 0.01 | 0.00 | 0.01 | 0.00 | −0.04 | 0.01 | 0.01 | 0.00 |
| Bachelor’s degree or higher | 0.09 | 0.00 | 0.05 | 0.00 | 0.13 | 0.00 | 0.04 | 0.00 |
| Lifetime marijuana use | 0.08 | 0.00 | 0.05 | 0.00 | −0.05 | 0.01 | 0.01 | 0.00 |
| Lifetime other drug use | 0.04 | 0.01 | 0.04 | 0.00 | −0.03 | −0.01 | 0.05 | 0.00 |
| Self-reported physical health a | 0.11 | −0.01 | 0.16 | 0.01 | 0.04 | 0.00 | 0.07 | −0.03 |
| Self-reported mental health a | 0.11 | 0.00 | 0.12 | 0.01 | 0.00 | −0.01 | 0.12 | −0.01 |
| Self-reported quality of life a | 0.08 | 0.00 | 0.11 | 0.01 | 0.00 | −0.01 | 0.10 | −0.01 |
| Living in a non-metropolitan area | −0.14 | 0.00 | −0.05 | 0.00 | −0.05 | 0.00 | −0.09 | 0.01 |
IPTW= inverse probability of treatment weighting; GED = General Educational Development
Self-reported measures ranged from a score of 1 (excellent) to 5 (poor).
Table 4 presents the IPTW-adjusted associations between delta-8-THC use and state marijuana use and delta-8-THC sales policies. Compared to prohibited states, adults in medical only states had a 27% lower probability of using delta-8-THC (aRR=0.73; 95% CI 0.46–1.14), although these results were not statistically significant. Compared to prohibited states, those in states permitting recreational marijuana use had a 52% lower probability of using delta-8-THC (aRR=0.48; 95% CI 0.33–0.70). Residing in a state with delta-8-THC regulations was associated with a 67% (aRR=0.33; 95% CI 0.20–0.55) lower probability of delta-8-THC use, compared to residing in states where delta-8-THC sales were unregulated. Similarly, residing in a state that prohibited delta-8-THC sales was associated with a 53% (aRR=0.47; 95% CI 0.28–0.78) lower probability of delta-8-THC use compared to states where delta-8-THC sales were unregulated. The IPTW-adjusted risk ratios were similar to those obtained from multivariable logistic regression models (Appendix Table 5).
Table 4:
Propensity score-weighted associations between state policy categories and probability of lifetime delta-8-THC use
| State Policies | Delta-8-THC Ever Use |
|---|---|
| IPTW aRR (95% CI) | |
| Marijuana use | |
| Prohibited | Ref |
| Medical only | 0.73 (0.46 – 1.14) |
| Recreational | 0.48 (0.33 – 0.70) |
| Delta-8-THC | |
| Unregulated | Ref |
| Regulated | 0.33 (0.20 – 0.55) |
| Prohibited | 0.47 (0.28 – 0.78) |
IPTW= inverse probability of treatment weighting; RR= Risk ratio; CI= confidence interval
Discussion
A substantial proportion of US adults in this nationally representative sample have used delta-8-THC (7.7%), translating to about 19.3 million individuals at the national level. The prevalence of lifetime delta-8-THC use varied considerably by the regulatory status of marijuana and hemp-derived products, including delta-8-THC, across US states. Regulations and prohibitions for delta-8-THC products were associated with lower rates of use. The prevalence of delta-8-THC use was highest among adults who resided in states like Florida, where marijuana use is prohibited for both medical and recreational reasons, but hemp-derived delta-8-THC products are not regulated.
The results are consistent with previous research on delta-8-THC use and public interest across different state policies. Confirming results of public interest,14,15 the present data suggest that delta-8-THC use was highest among states prohibiting marijuana use. Similar to an online survey of people who used delta-8-THC in the past month,18 this study found that adults who resided in states with regulations and bans on delta-8-THC sales were less likely to use delta-8-THC. The lower rates of delta-8-THC use among states that prohibit marijuana use, such as Florida, further supports the possibility that delta-8-THC might be fulfilling the demand for marijuana in areas where marijuana use is prohibited. This relationship may be driven by several factors, such as greater accessibility, as delta-8-THC products are often sold online and are not subject to the same regulations as state-licensed marijuana products.39
Study findings also suggest that states with regulations and prohibitions on delta-8-THC products have lower prevalence of delta-8-THC use. While the legality of hemp-derived cannabinoid products is under question at the federal level, due to pending revisions to the 2024 Farm Bill, these results suggest that state delta-8-THC restrictions could be a way to reduce delta-8-THC use.8,9 State regulations on delta-8-THC products often include serving size, sales, and marketing restrictions,4,40 which may limit their availability and access and therefore result in lower rates of delta-8-THC use. If the revision to the 2024 Farm Bill includes restrictions on delta-8-THC at the federal level, these findings suggest they may result in a lower rate of delta-8-THC.
Limitations
The current study relied on self-reported measures of substance use, which may be subject to recall bias or social desirability bias—particularly in states where delta-8-THC or marijuana is more strictly regulated. Furthermore, due to the cross-sectional nature of the survey, the results should not be interpreted as causal. Moreover, although the Ipsos KnowledgePanel® used address-based sampling methods to obtain a nationally representative sample, the participant characteristics within each US state might not be representative of the residents for that given state. There is no gold standard resource available for delta-8-THC policies and some laws are contested and interpreted differently between sources. The authors of the current study conducted their own comprehensive review and categorization of delta-8-THC policies and provided references for all of their determinations, but there is a chance that their classification of delta-8-THC policies may be interpreted differently by other legal experts and the authors invite replication of their analysis. Finally, actual enforcement practices may differ from state to state which could result in heterogeneity in policy effects across states that could not be accounted for in their estimates.
Conclusions
The results of this study suggest that delta-8-THC use is highest in environments that restrict marijuana use and are lower in states that restrict delta-8-THC sales. Future research should use qualitative methods to explore motivations for delta-8-THC use, perceptions of legality, and experiences with state-level policy implementation as well as larger sample that can test the effects of individual components of regulations on delta-8-THC on use. As regulations governing hemp-derived cannabinoids like delta-8-THC continue to change, understanding how state marijuana and hemp restrictions influence use will inform public health and policy response.
Supplementary Material
Financial Disclosure:
The work is supported in part by grant K01DA054303 from the U.S. National Institute on Drug Abuse. Dr. Satybaldiyeva acknowledges salary support from grant 5T32HL161270 from the National Heart, Lung, and Blood Institute of the National Institutes of Health. Dr. Kepner also acknowledges salary support from grant T32DA035165 from the National Institutes On Drug Abuse of the National Institutes of Health.
Footnotes
Conflict of Interest: Dr. Leas reports receiving consulting fees from The National Association of Attorneys General and consulting fees and an equity position in the AI company Medeloop, all for work performed outside the context of this manuscript. All other authors report no conflicts of interests.
CRediT authorship contribution statement:
Nora Satybaldiyeva: Conceptualization, Methodology, Data curation, Formal analysis, Writing – original draft, Writing – review & editing. Kevin H. Yang: Data curation, Writing – original draft, Writing – review & editing. Wayne Kepner: Data curation, Writing – review & editing. Eric C. Leas: Conceptualization, Funding acquisition, Project administration, Investigation, Methodology, Writing – original draft, Writing – review & editing.
Data Sharing Statement:
The data underlying this article will be shared on reasonable request to the corresponding author.
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The data underlying this article will be shared on reasonable request to the corresponding author.