The Persistence of Stigma and Other Challenges Experienced by Medical Cannabis Users: A Thematic Synthesis of Qualitative Studies.

Introduction

The therapeutic potential of medical cannabis (MC) has been recognized in a number of countries worldwide that have legalized its use, including Canada, the Netherlands, Israel, UK, Australia, Uruguay, Germany, Czechia, Switzerland, and 40 of the USA [ 1 – 3 ]. The vastly predominant reason for using MC around the globe is for managing chronic pain, where clinical and qualitative studies have demonstrated effectiveness, although with patients reporting variable access despite evidence of efficacy and purported convenience [ 4 – 7 ]. Substantial barriers persist regarding the provision and use of MC even in settings where it is legal [ 8 – 11 ]. Current studies report competing and confusing therapeutic and public health messaging, reservations among clinicians and policy-makers about the value and legitimacy of MC programs, access issues, challenges associated with stigma for providers and patients, and lengthy bureaucratic processes. Additionally, contextual complexities – in both policy and practical terms – such as the opioid crisis and the legalization of cannabis more generally, have added to uncertainties related to the use of and access to MC [ 12 – 15 ]. How patients experience and navigate these challenging contexts is not yet well described in the current literature.

Key features of policy design that influence the impact of “medicalizing” cannabis have been identified [ 16 , 17 ] and include its production, distribution and marketing, integration of treatment into medical practice [ 18 , 19 ], and anticipated public perception [ 16 , 20 , 21 ]. In some countries, these policy choices reside primarily with the national government [ 16 ], whereas in others, the control is primarily at subnational (state or provincial) levels [ 18 ]. Assessments of impact have focused on a handful of outcomes, such as the rates of adoption of cannabis-based therapies in medical settings, the impact of medicalization on other drug-related behaviors, including illicit drug use and treatment-seeking for drug disorder, the prevalence of cannabis use among the general public, and the harms and social costs [ 16 , 19 , 22 ]. There has been only limited assessment of the more social and experiential impacts for patients receiving cannabis-based treatments or for those whose conditions might warrant its use, but who fail to obtain treatments as a result of administrative barriers, clinician reluctance, or the stigma associated with intervention. In summary, patient experiences associated with MC use have been largely overlooked in policy analyses and therefore largely neglected in policy design.

In a review of regulatory regimes for MC, Schlag [ 11 ] states “most countries are still working in a trial-and-error situation,” noting the wide variation in regulation, access, prescribing habits, training, and support for healthcare professionals. The need for better engagement and communication with stakeholders, including patient groups and the need to address stigma, were noted among other lessons to improve regulation and access.

Study Aim

In this study, we aimed to further investigate the experiential evidence reported for the use of MC and the particular issue of stigma with a focus on policy context. The research questions guiding this review were as follows: How do people describe their lived experiences associated with using MC in different jurisdictions? How do they talk about their experiences of stigma? Given that regulations enabling access to MC have been in place for many years in most jurisdictions, we anticipated that patients would perceive a change in the nature of stigma in these contexts. To address the above questions, we conducted a scoping review involving a thematic synthesis of qualitative studies investigating patient experience associated with using MC.

Methods

We used the approach of Thomas and Harden [ 23 ] to conduct a thematic synthesis in 3 steps: (1) search the literature and select relevant primary studies; (2) extract the relevant data; and (3) identify descriptive and analytical themes that reflect the lived experiences associated with using MC.

Literature Search and Study Selection

Search strategies were developed with the assistance of a health sciences librarian to identify published literature on qualitative studies of the use of MC. The search strategy included articles published from 1995 (as the first MC programs were established in 2000) to August 2022 across Scopus, Web of Science, MEDLINE and CINAHL, and was run initially in 2019, with updates in December 2021 and August 2022. We considered papers that described the use of cannabis for chronic pain and other conditions, where there was potential medical benefit, as per self-reported therapeutic use or physician recommendation or approval, and/or via prescription. The search terms included “medical regulatory” or “medical” or “therapeutic” and “cannabis” or “marijuana” or equivalents as defined by the study authors, as well as “qualitative methods” and “experiences” and “interview.” The inclusion and exclusion criteria are shown in Table 1 .

We did not undertake a standardized quality assessment of included studies, although we did use the CASP (2018) Qualitative Checklist [ 24 ] to inform the inclusion/exclusion criteria. Search results were sent from the librarian to the research team. Given the large number of retrieved studies, the initial review of titles and abstracts for inclusion was divided between three members of the team (S.B. or S.L. or M.B.) with a single reviewer per paper, with any uncertainties resolved by discussion with a second reviewer. This was completed in 2020–2022 and 2023 following each search. Full-text review of included papers was conducted independently by 2 reviewers (M.B. and S.L.) with support from JN in 2022–2023 and again in 2023–2024 following the updated search. Discrepancies were resolved through discussion with fellow reviewers to reach a consensus on inclusion or exclusion. We used a screening and data extraction tool for conducting reviews (Covidence) to support this review. For inclusion, studies needed to be peer-reviewed and use qualitative methodology to explore patients’ or users’ lived experiences associated with using MC. Records were removed if titles referred to non-MC or cannabis use disorder, or if the focus of the study was on non-patient perspectives such as those of physicians, pharmacists, dispensary owners, or marijuana growers. Editorials, commentaries, quantitative studies, clinical trials, and ecologic retrospective studies were also excluded. Qualitative data within studies using mixed methodology were included.

Data Extraction

A data extraction form (see online suppl. Material; for all online suppl. material, see https://doi.org/10.1159/000 551584) was created to extract the following data from included articles: author details, country and year of publication, year of data collection (which helped identify MC policy status for that jurisdiction at the time of the study), study aim, study sample, data collection and analysis, types of users and medical conditions, findings, and findings specific to the theme of stigma.

Data Analysis

Three steps were followed for the thematic synthesis as per Thomas and Harden approach [ 23 ]: first, all included papers were read by at least two researchers (M.B., S.L., S.B., and J.N.). Next, S.L. and M.B. extracted relevant themes from the Results sections using the “One Sheet Of Paper” method [ 25 ] to provide a concise visual summary of key findings. The One Sheet Of Paper method enables the identification of different variants of experiences and core topics using an inductive approach. Final themes and subtopics were realized through iterative discussion of findings between the lead authors (S.L. and M.B.) in collaboration with J.N. and coauthors. In the last step, connections between the topics and higher abstraction themes were identified by the study team, capturing key concepts from the included studies.

Results

Search Results

A total of 1,983 articles were initially retrieved from the four databases; a total of 1,546 articles were identified as unique after duplicate removal. Here, 1,212 articles were excluded as per reasons listed in Table 1 . Of the 334 articles that were screened at the full-text stage, 288 were further excluded, leaving a total of 45 articles that were included for data extraction in this review [ 8 , 9 , 26 – 67 ]. See Figure 1 for PRISMA diagram; the PRISMA-ScR Checklist is available as online supplementary Material (for all online suppl. material, see https://doi.org/10.1159/000551584 ). See individual study characteristics presented in the data extraction table, Table 2 .

Policy Context

The policy context for each of the included studies was explored, and most studies ( n = 26) were conducted well after the legalization of MC in the respective jurisdiction, some after the legalization of recreational cannabis ( n = 13). In five studies, the legalization of recreational cannabis happened during the study collection period, and in one online study, the legal status was unknown ( Table 3 ). Only two studies were conducted in a jurisdiction where MC was not legal at the time of data collection (UK and Norway). The duration since MC legalization and/or recreational cannabis legalization and when data collection occurred varied. Only one study [ 64 ] was a longitudinal study.

Thematic Synthesis

Four main themes emerged from the analysis: (1) limited education or knowledge about medically appropriate use among both clinicians and the public; (2) persisting perception of stigma; (3) social consequences of stigma; and (4) continued challenges along pathways of access and use (including issues related to access and the blurred boundaries between recreational versus medical use). We developed a concept map to illustrate these themes and key issues raised by participants in the relevant studies (see Fig. 2 ). In this concept map, we make some plausible connections between the themes. The figure shows that the issues of perceived stigma and lack of education (for patients, doctors, and others) both contribute to social consequences of stigma but also influence the pathways of use. Similarly, in the other direction, when people start on a pathway of MC use, this can contribute to social consequences but can also expose gaps in education and knowledge as well as perceived stigma from all perspectives.

Limited Education: Knowledge Gaps for Patients, Providers, and Public

Patients in the included studies consistently reported that they lacked information, knowledge, and educational materials about MC [ 33 , 34 , 49 , 56 ]. They described this as a major barrier for them but also in their encounters with physicians and other providers [ 31 , 43 ]. Patients also found that many physicians were unwilling to engage, and/or appeared to be lacking knowledge about potential benefits and the practical aspects of using MC [ 29 , 33 ]. As noted by Athey et al. [ 28 ], sources of information were rarely from the medical community or healthcare practitioners; patients relied on their personal social circles, dispensary staff, prior experience, and their own research when seeking information about MC.

“I think they should be a lot more open to learning about it and discussing it with their patients. Because at this point, I have told my primary care [provider] I was using it on my shoulder. And that was the end of the conversation. He didn’t want to know why, he didn’t want to know about effects, didn’t want to know about side effects, didn’t want to know anything” ([ 30 ], p. 660).

“Hopefully marijuana will be taught in med school at some point. Hopefully we will have some CMEs [continuing medical education courses] that are well put together and covering an array of issues” ([ 31 ], p. 428).

Studies also reported the need for more education for the general public [ 29 ] which could contribute to general awareness raising and reduction of stigma.

Perceptions of Stigma

Two topics describing experiences of stigma evolved from the thematic analysis: perceptions of stigma and social consequences of stigma. Perceptions of stigma included patients’ perceptions of themselves using MC, the perceived stigma from doctors and healthcare providers, and perceived stigma from others including friends and family, as well as coworkers (see Fig. 2 ) [ 30 – 33 , 36 , 38 , 40 – 44 , 46 – 48 , 52 , 54 – 56 , 58 – 65 , 67 , 68 ]. With regard to patients indicating that they had a stigmatizing view of themselves when using MC, they described themselves as being influenced by lifelong views of cannabis as harmful, associated with drug abuse, and feeling bad about others who use recreational cannabis and are criminalized [ 31 , 42 , 47 ].

“When I used medical cannabis for the first time I thought, ‘Now I’ve lost it; I’ve abandoned my faith. I can never say that I haven’t used drugs anymore’” ([ 40 ], p. 247).

However, some older patients in Canada reported a change in their own attitude after legalization of cannabis, as they now felt more unrestricted in their use of MC [ 67 ]. Further, patients described their doctors and health professionals as having negative attitudes against MC [ 30 , 48 ], indicating that their doctors were likely worried about their own professional reputation as it relates to prescribing MC [ 48 ].

In a study by Mercurio, a participant shared that their doctor said

“… his colleagues were against the program…he thought it would be good for me but professionally he doesn’t think it would be good for him to do it” ([ 44 ], p. 7).

This attitude may be related to the lack of education as described above. Lastly, patients described perceived stigma from others. In their interactions with other people (e.g., neighbors, friends, family), patients expressed feeling negatively judged by others, including being looked down on, being seen as a drug addict [ 30 , 31 , 42 ], and feeling frowned upon at work or in the community.

“That’s personal, and people are, some people are still offended by marijuana. They really are — and I think it’s hard to get that information out, because of stigma, anonymity, ‘you’re a little pot head!’ Nobody wants that label” ([ 30 ], p. 662).

In some studies, generational differences emerged related to MC accessibility and social stigma; for instance, older people were described as relying on information and attitudes from the sixties, whereas younger people were more open to new developments such as legal use of MC [ 62 , 63 , 67 ]. To gain deeper insight into the effects of this contextual framing of patient experiences, we compared perceptions of stigma if/as reported based on the legalization status at the time of study data collection (see Table 3 ). We considered two groups of study results related to the topics of perception of stigma and social consequences: the studies in which data were collected after legalization of MC (see Table 3 for studies published in Denmark, before 2018 in Canada, some US states – e.g., Rhode Island, Florida, MI, Vermont, and DC); and studies in which data were collected after legalization of recreational cannabis (studies in Netherlands, Canadian studies after 2018, the Netherlands, some US states – e.g., Washington, Colorado, Illinois, and MA). We considered whether there was a change in the reported data in the patterns of stigma (see Table 2 ) – in particular whether there was any evidence that stigma was becoming less of an issue if more legal options for cannabis use were available. The comparison, although preliminary, showed that there has sometimes been a perceived positive change in stigma and yet, sometimes stigma persisted despite a change in legalization. Some studies included data collection that covered a time of legislative change from MC only to legalization of both medical and recreational uses [ 42 , 49 , 68 ]; however, comparisons of change with respect to qualitative evidence about stigma were not captured in these studies. No comparative studies were found reporting lived experiences and/or stigma pre- versus post-regulatory changes (whether for medical or recreational cannabis use); two studies (Baumbusch et al. [ 67 ]; Kharuna et al. [ 64 ]) included direct consideration of individuals’ changing perceptions of stigma associated with cannabis use (medicinal or recreational) following legalization of recreational cannabis. While these studies found some de-stigmatization among older and younger adults with regulatory changes, some stigma for medicinal and recreational use persisted [ 64 , 67 ].

Social Consequences of Stigma

In many papers, the perceived stigma described above was linked to particular social consequences of stigma as described by participants. These ranged from considerations about the disclosure of the use of MC (i.e., whom do I tell about it?) [ 31 , 61 , 62 , 67 ], to fears about the consequences of their MC use (e.g., fears about losing one’s job, fears regarding the unclear legal situation of driving under the “influence” of MC, and concerns related to travel [ 47 , 65 ]).

“My family knows, but I don’t want my friends and other people to know. I don’t tell a lot of people because many people still see cannabis as criminal or a taboo recreational and gateway drug. We also have this issue at the state and the federal level and that cannabis is still a level-1 controlled substance. I have a government job and I don’t want to be fired” ([ 43 ], p. 38).

Patients described how they adapted their use of MC to avoid social consequences, e.g., by using oils, topical creams, pills or vaping devices instead of smoking, taking other prescription medicine instead of MC, avoiding travel, or moving to another state (in the USA) where MC is legalized [ 27 , 58 , 61 , 65 , 67 ]. The perceived stigma and the social consequences are related to patients’ descriptions of experiences where they have made efforts to distinguish themselves (as MC users) from people who use cannabis for recreational purposes [ 31 , 61 , 67 ]. We have illustrated our results for this theme in Figure 3 .

Pathways of Use: Complex Pathways Create Challenges for Access

The above issues influence the way patients access and use MC – in particular, the lack of education and the experiences of perceived stigma and its consequences have shaped the pathways of use for patients. Patients described four different challenges with using MC: access to MC via doctors or dispensaries; administrative issues of using MC; financial barriers; and the challenges around defining the use of cannabis as either “recreational” or “medical.”

The most frequently cited access issue was related to patients’ frustration with doctors or care teams who were not available, unable or unwilling to approve, and/or not knowledgeable about MC as a potential solution for their situation (see topic 1 “lack of education”). Some patients turned to an alternate physician or recreational cannabis dispensary, although Bobitt et al. [ 31 ] noted that patients typically preferred to remain with their existing local provider who is familiar with their health condition and treatment history. Patients’ experiences with using MC dispensaries appeared to be mixed, although sometimes this was due to differing regulations in different states or countries. Grella et al. [ 40 ] reported that MC users in their California study unanimously preferred legal dispensaries versus “on the street” dealers. Patient participants in other US studies [ 30 , 44 , 48 ] found that dispensaries offered helpful advice and information, and good labeling of the products, when unable to receive this information from healthcare professionals; however, the dispensary often had limited privacy for such conversations. In the study by Baumbusch et al. [ 29 ] about older people using MC in Canada, participants felt confused about the difference between licensed and non-licensed MC and dispensaries; most received their cannabis from non-licensed stores.

Whereas some studies [ 35 , 36 ] found that patients had access to a wide range of modes and types of products, some modes of administration were associated with more stigma, where, for instance, patients were uncomfortable smoking MC in certain settings [ 27 ]. Others described patients’ uncertainty in terms of how to determine appropriate doses across different modes and strains of MC [ 33 ]. The problem of dosing is likely related to the issues raised above regarding the lack of healthcare professional and patient education and/or perceived stigma that may prevent information-seeking by patients or professionals.

“… it is really hard to tell because I don’t know how much [ sic ] grams there are in a lot of my capsules and in my honey and all that stuff,” “with the snake oil I have no idea how much weed’s in there,” and “I don’t know, I’m not able to translate what’s in the oil to grams” ([ 33 ], p. 217–218).

Some studies mentioned financial barriers , e.g., higher out-of-pocket costs to patients for MC in comparison with prescription drugs, such as opiates that were covered by insurance, the high cost of vaping equipment [ 27 ] or the higher cost of MC in comparison with the cost of recreational cannabis [ 30 , 31 , 48 , 54 , 56 ].

“Financially, it’s extremely expensive … particularly the doses that I had to have or was recommended to have. It was becoming financially prohibitive” ([ 28 ], p. 198).

Reed et al. [ 54 ] noted the culture of “friendship and reciprocity” as part of the MC culture, where people buy from friends or family with MC cards to reduce costs. Due to costs or access barriers, patients report that they sometimes rely on the illicit market [ 37 ], or supplement their supply through the illicit market [ 54 ]. Wilson et al. [ 56 ] found that patients were less likely to disclose to medical staff whether they are using cannabis to help manage their conditions if they had purchased the cannabis from illicit sources.

Another topic that determines the pathways of MC use is related to the distinction between medical and recreational cannabis . Although some authors defined categories of use related to the intended purpose, such as Bruce et al. [ 36 ] who made a distinction between medical, therapeutical, and recreational use of cannabis, others, including Athey et al. [ 28 ], argued that the boundaries between such categories are more blurred in reality and questioned the relevance of rigid distinctions. Some studies found evidence of changing patterns and intent of use over time. For instance, those who may have used recreational cannabis regularly in their youth reported a change in their reason for using cannabis as they aged for health reasons [ 31 ]. Given the reported issues around access, modes of administration, financial barriers, and the fuzzy boundaries between medical versus recreational cannabis, the resultant pathway of use for MC for individuals is typically complex involving different purposes over time, variable knowledge and access, and strategies to manage a range of barriers, including stigma.

Discussion

Contributions to the Literature

In this review, we identified four themes in the analysis as reported above: limited education and knowledge among patients, providers, and others; perception of stigma; social consequences of stigma; and complexities and challenges associated with different pathways of use. These issues have been reported to some extent in other studies and reviews of MC use [ 69 – 72 ]. The issue of the blurred and overlapping boundary between recreational and medical use has also been noted elsewhere [ 45 , 50 ] and presents challenges for current initiatives (such as the Canadian Cannabis Act review [ 73 ]) to develop MC-related policy and implement change. During the analysis and identification of the four themes we acknowledged, there were different situations represented in the studies regarding the legal status of MC at the time and location of data collection. For some studies and settings, MC was only legally available with prescription in some pilot trials, whereas in others it was legalized for specific conditions (and different in different countries), and in other countries, recreational cannabis was also legalized. In addition to differing legalization status, the time since the change in legalization and study data collection also appeared to matter (e.g., if there was a recent change in legalization or if it was many years ago). As such, patient lived experiences associated with using MC were reported under many different socio-legal conditions and regulatory contexts.

Our analysis of persistent perceived stigma over time and legislative boundaries is, we believe, a new contribution to this field of research: the challenges for people using MC have proven to be resilient over time, place, and as contributed by this study, types of regulatory regimes. We had expected to find reductions in reported experiences with stigma in countries with more liberal legalization policies but, in fact, we found relatively consistent descriptions of stigma throughout the literature irrespective of the legalization status of cannabis in the country/state. While some perceptions of stigma appear to have changed in some cases with evolving legalization status [ 23 , 52 ], there was also frequent reporting of perceptions of stigma that persisted over time [ 30 – 33 , 36 , 38 , 40 – 44 , 46 – 48 , 52 , 54 – 56 , 58 – 65 , 67 , 68 ]. To better understand these processes of change and resilience, it would be helpful to have more longitudinal studies regarding perceptions of stigma with respect to changing legislation. Only one study [ 64 ] in our search results collected data over a longer period of time with regard to changing legalization status in the country/state. In this longitudinal study, qualitative data were collected in four waves from 2014 to 2021 in CA, USA. The authors describe transitions of participants with prescriptions for MC to users of recreational cannabis after recreational cannabis was legalized.

There is a gap in research considering the processes of social change with respect to stigma perception and associated experiences as well as the impact of policy change. Patients often described a lack of education on the part of medical professionals, patients, and society – but it is unknown to what extent education and stigma are intertwined for individual patients and/or professionals and may hinder access and/or the delivery of care.

Areas of future research building from this work could include the pursuit of a deeper understanding of stigma in the context of social change from the perspectives of patients and healthcare professionals. This could also include an exploration of the different forms of stigma (e.g., social stigma, self-stigma, healthcare practitioner stigma, and perceived stigma) and the associated significance, for instance: is persistent stigma connected in some way to other characteristics that are stigmatized in some jurisdictions, as, for example, subsets of people being stigmatized as less productive or marginalized by societies? Do such biases and prejudices account for some of the persistent stigma? Furthermore, it would be interesting to know if there are specific personal and/or professional relationships relevant to using MC in which stigma persists and others where stigma dissolves, for example, private vs. professional relationships, close vs. distant relationships. Another topic for future research should be the effectiveness of educational strategies for patients and providers with respect to enhancing knowledge about the existing evidence relating to MC. This could provide insights regarding barriers and motivations for providers to learn about MC, changes in practice or attitudes, and the impact on stigma for patients and providers.

Finally, it would be interesting to know if the magnitude of the opioid crisis in any given jurisdiction reduces or exacerbates the stigma associated with MC use. This could be best answered in an international or cross-jurisdictional comparison. The authors wish to note that the positioning and opportunity provided by our existing international collaboration of qualitative patient experience researchers across 14 countries, known as Health Experiences International (see: https://healthexperiencesinternational.org/ ), could enable rapid access to such cross-jurisdictional multidisciplinary and comparative research efforts.

Strengths and Limitations

There are a few important limitations to note for this study. First, we only considered papers published in English, limiting inclusion of potential research evidence from non-English journals, research teams, or jurisdictions. This may explain the majority of US and North American studies included in this review. It would be helpful if future research could be inclusive of studies conducted and published in other languages. Second, we found very few longitudinal studies so could not derive results about actual changes of experiences over time within jurisdictions, but rather we have highlighted the inconsistencies and persistence of stigma across studies conducted in different time periods. Third, the process of summarizing the results and assessing implications was challenging given rapidly changing legislative and social contexts across jurisdictions and studies. Nevertheless, important strengths of this study include the breadth of research in this field captured in this study and consideration of the regulatory contexts, enabling a broader perspective on findings and themes relevant to future research in this area.

Conclusions

In this review, we found that although reports of patients’ lived experiences associated with using MC have focused on similar topics over time, i.e., pathways of use, stigma and related social consequences, and the (lack of) education and information, there is a lack of overall progress on perceived challenges over time despite legislative changes within jurisdictions. The topics around stigma seem to be of great importance for patients, sometimes with the experience that stigma has changed over time, sometimes with the experience of persistence of stigma. Stigma is often described as a barrier for patients with chronic pain and other conditions in seeking or receiving professional guidance for the use of MC, leaving the patients to use MC by way of trial and error. In a world where regulations and attitudes regarding MC are rapidly changing, it would be useful in improving patient-centered care to focus future research on the necessary conditions or strategies to reduce stigma in ways meaningful for patients and providers. Such efforts are likely to contribute benefits in terms of improved care processes, experiences, and outcomes for those living with chronic pain and other conditions where MC could contribute to better symptom management.

Acknowledgments

We would like to acknowledge the contribution of the medical cannabis working group within an international network on qualitative research and patient experience, known as Health Experiences International (HEXI); working group members involved researchers from Australia, Canada, Germany, Israel, Netherlands, USA, and the UK. We would also like to acknowledge the support of the health sciences librarian, Antonia Giannarakos, at Trillium Health Partners in Mississauga, Canada.

Statement of Ethics

A statement of ethics is not applicable because this study is based exclusively on published literature.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

Development of this manuscript was supported by a grant from the Canadian Institutes of Health Research (CIHR), grant #PCS-152615. The funder had no role in the design, data collection, data analysis, and reporting of this study.

Author Contributions

M.B. and S.L. conceptualized the study, conducted the formal analysis, developed the original draft of the manuscript and methodology, and managed feedback from coauthors. J.N. conducted the formal analysis, provided project management, and contributed to revisions and editing. M.S., M.L.-A., and L.S. provided support in rewriting and feedback. S.B. conducted the initial literature research on data extraction. All authors read and approved the final manuscript.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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