Gender Differences in Cannabis as a Mediator Between Distress Factors and Non-Fatal Suicidal Behaviors

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Lin This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5843916/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Emerging evidence suggests gender-based heterogeneity in suicide risk associated with cannabis use, while the role of cannabis in gender-dependent suicide risk is elusive. The objective of the present study is to determine whether cannabis use contributes differently to the pathway from depression or pain conditions to non-fatal suicidal behaviors (e.g., suicidal ideation, plans, or attempts) in men versus women. We analyzed the data was extracted from the National Survey of Drug Use and Health (NSDUH) from 2020–2022 during the COVID-19 pandemic. Causal mediation analysis was conducted to assess the mediating role of cannabis in the association between depression, pain conditions, and suicide ideation/plan/attempt in two gender groups. A sample of 93,743 individuals aged 18–50 years who participated in the NSDUH survey. Mediation analysis revealed that cannabis use accounted for a greater proportion of the effect of depression on suicidal ideation or attempts in women (mediation fraction: 2.3% for ideation) compared to men (1.2% for ideation). Similarly, cannabis mediated 12.5% (95% CI: 0.081–0.272) of the effect of pain conditions on suicidal ideation in women, versus 5.9% (95% CI: 0.038–0.128) in men. These findings suggest that cannabis plays a more substantial role in non-fatal suicidal behaviors for women than men, particularly in the context of depression and pain conditions. Tailored interventions addressing cannabis use as a self-medication strategy, especially for women, are critical for suicide prevention. Psychiatry cannabis non-fatal suicidal behaviors gender mediation depression pain Introduction Lack of consideration of gender-dependent differences can lead to ineffective treatments for substance use disorders and their comorbid conditions such as suicidal behaviors (Lynch et al., 2020 ). Gender-dependent associations between cannabis on suicide risk have been reported by several previous studies. For example, Han et al. found the association between cannabis use and non-fatal suicidal behaviors to be stronger in females than males (Han et al., 2021 ). In addition, Foster et all reported that women seeking treatment for cannabis use disorder in late adolescence and middle adulthood might show a higher suicide risk compared to men (Foster et al., 2016 ). Conversely, other studies found that men who used cannabis could exhibit a higher risk of suicidal ideation that women who used cannabis (Naji et al., 2018 ; Shalit et al., 2016 ). A better understanding of the mechanisms underlying gender-dependent differences in the suicide risk linked to cannabis use could shed some light on causes for inconsistent findings across different populations. One possible role of cannabis use in suicidal behaviors is its potential mediating effect on the pathway from risk factors to suicide. Studying how cannabis use mediates the relationship between risk factors and suicide is crucial, as it may reveal actionable targets for intervention and prevention efforts. Emerging evidence suggests that cannabis use among depressed individuals leads to worse mental health outcomes and greater odds of suicidal ideation (Bahorik et al., 2018 ). Recent longitudinal studies confirm that cannabis exacerbates symptoms of depression and increases the likelihood of suicide attempts, particularly in young adults with pre-existing mental health conditions (Lev-Ran et al., 2014 ). This mediating role may be driven by the bidirectional relationship between depression and substance use, wherein individuals turn to cannabis to self-medicate depressive symptoms, inadvertently worsening their mental health. Marijuana's impact on cognitive processes, such as impairing emotional regulation and decision-making, could amplify the risk of transitioning from suicidal ideation to action, highlighting the importance of examining its role in this pathway (Cawkwell et al., 2021 ; Volkow et al., 2014 ). In addition, individuals with pain conditions may use cannabis for temporary symptomatic relief, which may worsen psychological distress leading to non-fatal suicidal behaviors (Dagher et al., 2024 ). Chronic pain is a well-documented risk factor for suicide, and cannabis use may mediate this relationship by exacerbating emotional dysregulation and impairing coping mechanisms, particularly among those already vulnerable to mental health challenges (Racine, 2018 ). Chronic pain conditions can lead to psychological distress and facilitate the development of key risk factors for suicide. One study proposes that chronic pain may contribute to the erosion of the natural fear of dying, potentially increasing an individual's capacity for suicide (Hooley et al., 2014 ). Individuals with chronic pain often turn to cannabis as a form of self-medication to alleviate their physical and emotional distress. The use of cannabis as a coping strategy may initially provide relief, but chronic use could potentially exacerbate emotional dysregulation and impair adaptive coping mechanisms, thereby increasing suicide risk (Hyman & Sinha, 2009 ). By understanding the role of cannabis use in mediating the relationship between pain and suicide, particularly in the context of gender differences, we can better identify at-risk individuals and develop targeted interventions to mitigate suicide risk in chronic pain patients. Taken together, these lines of evidence suggest that cannabis use may mediate the relationship between non-fatal suicidal behaviors and distress factors such as depression and pain, which represent the common psychological and physical conditions that co-occur with both cannabis and suicidal behaviors. We hypothesize that the magnitude of the mediating effect of cannabis use in the pathway from depression or pain conditions to non-fatal suicidal behaviors may vary by gender. Therefore, the key research questions are as follows: 1) Does cannabis contribute differently to the pathway from depression to non-fatal suicidal behaviors in women compared to men? 2) Does cannabis contribute differently to the pathway from pain conditions to non-fatal suicidal behaviors in women compared to men? Methods Participants The data were sourced from the National Survey on Drug Use and Health (NSDUH) during the COVID-19 pandemic spanning the years 2020–2022 (Center for Behavioral Health Statistics & Quality., 2017). This dataset provides a nationally representative sample of individuals in the United States, offering insights into patterns of substance use, mental health, and other related behaviors. To reduce potential confounding effects of age-related differences in the health consequences of substance use, we focused on individuals aged 18–50 years, a demographic that captures young to middle-aged adults with relatively stable developmental profiles. This yielded a final analytic sample of 93,743 participants for examining the mediating role of cannabis use in the link between risk factors and non-fatal suicidal behaviors. Measures The outcomes include three binary measures of non-fatal suicidal behaviors—suicidal ideation, suicide plan, and suicide attempt—reported within the 12 months preceding the survey. Other factors associated with both suicide and cannabis use including depression (i.e., depressive episode within past 12 months) and pain conditions (i.e., proxied by pain relievers use within past 12 months). Past-year cannabis use and uses of other substances including tobacco, opioid, cocaine, and heroin were queried. Sociodemographic factors such as age, gender, and family income were also based on self-reported data. Statistical Analysis To demonstrate the characteristics of the sample, the descriptive analysis was performed to show the mean rates, standard deviations, and sample sizes for suicidal ideation, plans, and attempts, stratified by gender and categorized based on cannabis use, depression status, and the presence of pain conditions. This analysis aimed to provide insights into the prevalence of suicidal outcomes across these risk factors. To compare the extents to which cannabis use mediated the association between depression and non-fatal suicidal behaviors in men and women, we stratified the sample by gender to perform causal mediation analysis, in which depression, cannabis use, and non-fatal suicidal behaviors, were treated as exposure, mediator, and outcome, respectively. Similarly, we evaluated the extents to which cannabis use mediated the association between pain conditions and non-fatal suicidal behaviors in men and women, separately. Pain conditions, cannabis use, and non-fatal suicidal behaviors, were treated as exposure, mediator, and outcome, respectively. Two-sided p-value of 0.05 was used as a significance cutoff. The Stata medeff package was used to perform the causal mediation analyses(Imai et al., 2010 ) using Stata, version 16.1 (StataCorp LLC, 2019 ). The report follows EQUATOR Reporting Guidelines. Since the current analysis used de-identified and publicly available data, it is not considered human subject research that requires research ethics approval. Results Table 1 shows the rates of suicidal ideation, plans, and attempts of the sample stratified by cannabis use, depression, and pain conditions over the past 12 months. Individuals with cannabis use exhibited higher mean rates of suicidal ideation, plans, and attempts compared to those without cannabis use, with women consistently showing slightly higher rates than men across all outcomes. Similarly, the presence of depression was strongly associated with elevated mean rates of suicidal outcomes in both genders, with women showing marginally higher rates of suicidal plans and attempts than men. In contrast, individuals without depression exhibited minimal rates of suicidal outcomes. The presence of pain conditions also corresponded to increased rates of suicidal ideation, plans, and attempts for both genders, though the rates were less pronounced compared to those associated with depression. Table 1 Rates of Suicidal ideation, plan and attempt stratified by gender, cannabis, depression and pain condition. Suicidal Ideation Suicidal Plan Suicidal Attempt Cannabis Use Men Women Men Women Men Women No Mean 0.05 0.06 0.02 0.02 0.01 0.01 SD 0.22 0.24 0.12 0.14 0.08 0.09 N 28461 37924 28461 37924 28461 37924 Yes Mean 0.12 0.17 0.04 0.06 0.02 0.03 SD 0.32 0.38 0.20 0.24 0.13 0.16 N 12966 14392 12966 14392 12966 14392 Depression Men Women Men Women Men Women No Mean 0.04 0.04 0.01 0.01 0.00 0.00 SD 0.19 0.20 0.10 0.10 0.07 0.07 N 37430 43855 37430 43855 37430 43855 Yes Mean 0.40 0.36 0.14 0.14 0.05 0.06 SD 0.49 0.48 0.35 0.34 0.23 0.23 N 3997 8461 3997 8461 3997 8461 Pain Conditions Men Women Men Women Men Women No Mean 0.06 0.08 0.02 0.02 0.01 0.01 SD 0.25 0.27 0.14 0.15 0.09 0.10 N 33600 39414 33600 39414 33600 39414 Yes Mean 0.11 0.12 0.04 0.05 0.02 0.02 SD 0.31 0.33 0.19 0.21 0.13 0.15 N 7827 12902 7827 12902 7827 12902 The results from the causal mediation analysis are summarized in Table 2 . For both men and women, cannabis use mediated the relationship between depression and non-fatal suicidal behaviors, but the mediation fractions appeared to be higher in women than men across all non-fatal suicidal behaviors linked to depression. Marijuana use mediated 1.2% (95% CI: 0.011–0.014) of the total effect of depression on suicidal ideation in men, while it mediated 2.3% (95% CI: 0.022–0.025) in women. For suicidal plans, cannabis use mediated 1.0% (95% CI: 0.008–0.011) of the total effect in men, compared to 1.6% (95% CI: 0.015–0.017) in women. In terms of suicidal attempts, the mediation fraction was 1.0% (95% CI: 0.008–0.014) in men, while it was 1.7% (95% CI: 0.015–0.020) in women. When examining the mediating role of cannabis in the relationship between pain conditions and non-fatal suicidal behaviors, its mediating fraction also differed between men and women. In men, cannabis use mediated 5.9% (95% CI: 0.038–0.128) of the effect of pain conditions on suicidal ideation, compared to a much larger 12.5% (95% CI: 0.081–0.272) in women. For suicidal plans, the mediation fraction attributable to cannabis use in men was 5.5% (− 0.526–0.787), which was not statistically significant, while in women it was 4.4% (95% CI: 0.030–0.078). Similarly, for suicidal attempts, the mediation fraction attributable to cannabis in men was lower, albeit not statistically significant, at 2.4% (95% CI: −0.083–0.173), compared to 3.7% (95% CI: 0.023–0.088) in women. [Insert Table 2 here] Discussion The mediation analysis reveals that cannabis use likely plays a more significant role in non-fatal suicidal behaviors among women, particularly in relation to pain conditions, despite the slightly higher rate of cannabis use in men. This indicates that the higher mediation fraction of the effect of depression or pain conditions on non-fatal suicidal behaviors in women cannot be attributed to differences in cannabis exposure. Instead, these findings may imply the presence of more complex mechanisms, such as potentially heightened sensitivity or vulnerability to the effects of cannabis on non-fatal suicidal behaviors in women. Tailored interventions that address cannabis use as a self-medication strategy could reduce non-fatal suicidal behaviors, particularly for women. Screening for cannabis use should be prioritized in patients with depression or chronic pain to highlight the health consequences associated with self-medication. A stronger mediating effect of cannabis use in the relationship between pain conditions and non-fatal suicidal behaviors compared to depression may suggest distinct mechanistic pathways demanding further exploration. These results point to gender-based differences in the risk of non-fatal suicidal behaviors linked to cannabis use, underscoring the need for gender-specific prevention and intervention strategies. Future research should focus on sex-specific analyses to better understand these differences and inform more effective, gender-tailored prevention efforts. These findings provide new insights into the role of cannabis in non-fatal suicidal behaviors, especially among women, and inform key opportunities for targeted interventions. Limitations Several limitations should be considered when interpreting the findings of this study. First, pain conditions were proxied by the use of analgesics, which may inadvertently include conditions with underlying pathophysiological issues that are not centered solely on pain (e.g., autoimmune disorders or inflammation-related conditions). This could introduce variability into the measurement of pain-related effects, potentially obscuring the true role of cannabis use as a mediator in the relationship between pain and non-fatal suicidal behaviors. Second, the cross-sectional nature of the National Survey on Drug Use and Health (NSDUH) data precludes causal inferences. While causal mediation analysis can help estimate indirect effects, the lack of longitudinal data limits the ability to establish temporal precedence between cannabis use, depression or pain, and non-fatal suicidal behaviors. The current study aims to evaluate a putative relationship, in which risk factors such as depression or pain could potentially influence the likelihood of using cannabis, which in turns affect the risk of suicidal ideation, plan, or attempt. Additionally, this strategy ignores possible bi-directional effects. Therefore, the results could not be used to directly infer causal effects. Future research should consider using longitudinal designs to better understand these pathways over time. Third, the current study treated cannabis use as a binary variable (use vs. non-use), which does not capture variations in frequency, intensity, or mode of use (e.g., recreational vs. medicinal). These factors could differentially impact suicidal behaviors and may vary by gender, introducing potential misclassification bias. Additionally, the outcomes were self-reported and retrospective, which could lead to recall or reporting bias, especially for sensitive topics like suicidal behaviors and substance use. Women, for instance, may be more likely to report emotional distress or cannabis use as a coping mechanism, which could partially explain the observed gender differences in the mediating effects. Another limitation is the lack of consideration for important contextual factors, such as access to healthcare, social support, and socioeconomic status, which may influence both substance use and suicidal behaviors. These unmeasured confounders could affect the observed associations and limit the generalizability of the findings. Furthermore, while the NSDUH dataset provides a robust sample, the focus on individuals aged 18–50 excludes older adults and adolescents, who may exhibit unique patterns of substance use and suicide risk. Future research should address these issues by incorporating more nuanced measures of cannabis use, exploring additional contextual variables, and including a broader age range to capture diverse experiences. Conclusion The current study underscores the critical need to better understand the gender-specific effects of cannabis use on non-fatal suicidal behaviors, particularly among women with depression or chronic pain. These findings have important public health and clinical implications, emphasizing the necessity for routine screening and monitoring of cannabis use in mental health and primary care settings. Integrating these assessments into standard care protocols, especially for women, can help identify individuals at heightened risk of suicidal behaviors and provide opportunities for early intervention. From a public health perspective, these results highlight the importance of developing gender-informed prevention strategies that address the unique vulnerabilities linked to cannabis use and its interaction with mental health and pain conditions. Tailored interventions should focus on reducing reliance on cannabis as a coping mechanism, enhancing access to alternative therapies, and addressing broader psychosocial and structural factors that contribute to gender disparities in suicide risk. Future research should explore the biological and psychosocial mechanisms driving these disparities and evaluate the effectiveness of targeted, gender-specific approaches in reducing the public health burden of non-fatal suicidal behaviors. Declarations Data Sharing Statement : The data used in this study are de-identified and publicly available from the National Survey on Drug Use and Health (NSDUH) database. Access to the data can be obtained through the Substance Abuse and Mental Health Data Archive (SAMHDA) website at https://www.datafiles.samhsa.gov/ . References Bahorik AL, Sterling SA, Campbell CI, Weisner C, Ramo D, Satre DD (2018) Medical and non-medical marijuana use in depression: Longitudinal associations with suicidal ideation, everyday functioning, and psychiatry service utilization. Journal of Affective Disorders , 241 . https://doi.org/10.1016/j.jad.2018.05.065 Cawkwell PB, Hong DS, Leikauf JE (2021) Neurodevelopmental Effects of Cannabis Use in Adolescents and Emerging Adults with ADHD: A Systematic Review. In Harvard Review of Psychiatry (Vol. 29, Issue 4). https://doi.org/10.1097/HRP.0000000000000303 Center for Behavioral Health Statistics, &, Quality (2017) National Survey on Drug Use and Health, 2017 (NSDUH-2017-DS0001) | SAMHDA. In National Survey on Drug Use and Health Public Use File Codebook. Substance Abuse and Mental Health Services Administration, Rockville, MD. Dagher M, Alayoubi M, Sigal GH, Cahill CM (2024) Unveiling the link between chronic pain and misuse of opioids and cannabis. J Neural Transm 131(5):563–580. https://doi.org/10.1007/s00702-024-02765-3 Foster KT, Li N, McClure EA, Sonne SC, Gray KM (2016) Gender Differences in Internalizing Symptoms and Suicide Risk Among Men and Women Seeking Treatment for Cannabis Use Disorder from Late Adolescence to Middle Adulthood. Journal of Substance Abuse Treatment , 66 . https://doi.org/10.1016/j.jsat.2016.01.012 Han B, Compton WM, Einstein EB, Volkow ND (2021) Associations of suicidality trends with cannabis use as a function of sex and depression status. JAMA Netw Open 4(6). https://doi.org/10.1001/jamanetworkopen.2021.13025 Hooley JM, Franklin JC, Nock MK (2014) Chronic pain and suicide: Understanding the association. In Current Pain and Headache Reports (Vol. 18, Issue 8). https://doi.org/10.1007/s11916-014-0435-2 Hyman SM, Sinha R (2009) Stress-related factors in cannabis use and misuse: Implications for prevention and treatment. J Subst Abuse Treat 36(4). https://doi.org/10.1016/j.jsat.2008.08.005 Imai K, Keele L, Tingley D (2010) A General Approach to Causal Mediation Analysis. Psychol Methods 15(4). https://doi.org/10.1037/a0020761 Lev-Ran S, Roerecke M, Le Foll B, George TP, McKenzie K, Rehm J (2014) The association between cannabis use and depression: A systematic review and meta-analysis of longitudinal studies. Psychol Med 44(4). https://doi.org/10.1017/S0033291713001438 Lynch FL, Peterson EL, Lu CY, Hu Y, Rossom RC, Waitzfelder BE, Owen-Smith AA, Hubley S, Prabhakar D, Williams K, Beck L, Simon A, G. E., Ahmedani BK (2020) Substance use disorders and risk of suicide in a general US population: A case control study. Addict Sci Clin Pract 15(1). https://doi.org/10.1186/s13722-020-0181-1 Naji L, Rosic T, Dennis B, Bhatt M, Sanger N, Hudson J, Mouravska N, Thabane L, Samaan Z (2018) The association between cannabis use and suicidal behavior in patients with psychiatric disorders: An analysis of sex differences. Biology Sex Differences 9(1). https://doi.org/10.1186/s13293-018-0182-x Racine M (2018) Chronic pain and suicide risk: A comprehensive review. In Progress in Neuro-Psychopharmacology and Biological Psychiatry (Vol. 87). https://doi.org/10.1016/j.pnpbp.2017.08.020 Shalit N, Shoval G, Shlosberg D, Feingold D, Lev-Ran S (2016) The association between cannabis use and suicidality among men and women: A population-based longitudinal study. Journal of Affective Disorders , 205 . https://doi.org/10.1016/j.jad.2016.07.010 StataCorp LLC (2019) Stata Statistical Software: Release 16. In StataCorp LLC Volkow ND, Baler RD, Compton WM, Weiss SRB (2014) Adverse Health Effects of Marijuana Use. N Engl J Med 370(23). https://doi.org/10.1056/nejmra1402309 Table 2 Table 2 is available in the Supplementary Files section. Additional Declarations The authors declare no competing interests. Supplementary Files Table2.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5843916","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":403158412,"identity":"dccd9163-d96f-42ec-a930-426bd84bd07d","order_by":0,"name":"Nawar Nayeem","email":"","orcid":"","institution":"Saint Louis University","correspondingAuthor":false,"prefix":"","firstName":"Nawar","middleName":"","lastName":"Nayeem","suffix":""},{"id":403158413,"identity":"3d0063f7-6ecd-4cd0-9c4e-4a485eee6469","order_by":1,"name":"Jennifer Bello-Kottenstette","email":"","orcid":"","institution":"Saint Louis University","correspondingAuthor":false,"prefix":"","firstName":"Jennifer","middleName":"","lastName":"Bello-Kottenstette","suffix":""},{"id":403158414,"identity":"30251379-3c37-4535-9e08-b6dfbb930901","order_by":2,"name":"Erick Messias","email":"","orcid":"","institution":"Saint Louis University","correspondingAuthor":false,"prefix":"","firstName":"Erick","middleName":"","lastName":"Messias","suffix":""},{"id":403158415,"identity":"6dbf8000-403f-4247-b427-168f77de2c1d","order_by":3,"name":"Ping-I D. Lin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCklEQVRIie3OMWvCQBTA8ReEdDni+kK0/QpPAtZC6GdRhExpcXQoxaldrHOEfgindr0Q0EVxdYyLU4ZM4iC272KHDr20Y4f7cxy5437kAZhM/zGp1gAaNtTmfOwAAVh8CdaokhAIG+yQj4h0vqwmoAiAaP+NOItVIgsmjjfeZ8UDPl7DRZYKCJoz+TNxl/fdJFaDNVbvrXiOeDMSxCT0dYRkxA8Uwbs3j3ckKYBJ2tOSdU7psSTRzjueFCkH+9CTDf8FzsT2rCdFQA0mtcTd5JSMCZmEbfdlgu6M50xeqe9PNcRZR35xGAaXV3F/h4d9UKfF8zbLh7fNiYZ8hd++a+XAlc9NJpPJ9EufMTZasPKvVDsAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-9739-7184","institution":"Saint Louis University","correspondingAuthor":true,"prefix":"","firstName":"Ping-I","middleName":"D.","lastName":"Lin","suffix":""}],"badges":[],"createdAt":"2025-01-16 17:39:22","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-5843916/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5843916/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":74218797,"identity":"bf97ada2-9d1b-43d5-9160-436fbca2aaf6","added_by":"auto","created_at":"2025-01-20 06:19:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":432767,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5843916/v1/b93ff515-1142-4461-9c0b-1c6146e9fab5.pdf"},{"id":74217411,"identity":"fb90cca6-46a7-4bd9-98fc-21f3dfbacff7","added_by":"auto","created_at":"2025-01-20 06:03:31","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":64513,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-5843916/v1/67364651fbab55da8dc2b313.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eGender Differences in Cannabis as a Mediator Between Distress Factors and Non-Fatal Suicidal Behaviors\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLack of consideration of gender-dependent differences can lead to ineffective treatments for substance use disorders and their comorbid conditions such as suicidal behaviors (Lynch et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Gender-dependent associations between cannabis on suicide risk have been reported by several previous studies. For example, Han et al. found the association between cannabis use and non-fatal suicidal behaviors to be stronger in females than males (Han et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). In addition, Foster et all reported that women seeking treatment for cannabis use disorder in late adolescence and middle adulthood might show a higher suicide risk compared to men (Foster et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Conversely, other studies found that men who used cannabis could exhibit a higher risk of suicidal ideation that women who used cannabis (Naji et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Shalit et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). A better understanding of the mechanisms underlying gender-dependent differences in the suicide risk linked to cannabis use could shed some light on causes for inconsistent findings across different populations. One possible role of cannabis use in suicidal behaviors is its potential mediating effect on the pathway from risk factors to suicide. Studying how cannabis use mediates the relationship between risk factors and suicide is crucial, as it may reveal actionable targets for intervention and prevention efforts.\u003c/p\u003e \u003cp\u003eEmerging evidence suggests that cannabis use among depressed individuals leads to worse mental health outcomes and greater odds of suicidal ideation (Bahorik et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Recent longitudinal studies confirm that cannabis exacerbates symptoms of depression and increases the likelihood of suicide attempts, particularly in young adults with pre-existing mental health conditions (Lev-Ran et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). This mediating role may be driven by the bidirectional relationship between depression and substance use, wherein individuals turn to cannabis to self-medicate depressive symptoms, inadvertently worsening their mental health. Marijuana's impact on cognitive processes, such as impairing emotional regulation and decision-making, could amplify the risk of transitioning from suicidal ideation to action, highlighting the importance of examining its role in this pathway (Cawkwell et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Volkow et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2014\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn addition, individuals with pain conditions may use cannabis for temporary symptomatic relief, which may worsen psychological distress leading to non-fatal suicidal behaviors (Dagher et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). Chronic pain is a well-documented risk factor for suicide, and cannabis use may mediate this relationship by exacerbating emotional dysregulation and impairing coping mechanisms, particularly among those already vulnerable to mental health challenges (Racine, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Chronic pain conditions can lead to psychological distress and facilitate the development of key risk factors for suicide. One study proposes that chronic pain may contribute to the erosion of the natural fear of dying, potentially increasing an individual's capacity for suicide (Hooley et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). Individuals with chronic pain often turn to cannabis as a form of self-medication to alleviate their physical and emotional distress. The use of cannabis as a coping strategy may initially provide relief, but chronic use could potentially exacerbate emotional dysregulation and impair adaptive coping mechanisms, thereby increasing suicide risk (Hyman \u0026amp; Sinha, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2009\u003c/span\u003e). By understanding the role of cannabis use in mediating the relationship between pain and suicide, particularly in the context of gender differences, we can better identify at-risk individuals and develop targeted interventions to mitigate suicide risk in chronic pain patients.\u003c/p\u003e \u003cp\u003eTaken together, these lines of evidence suggest that cannabis use may mediate the relationship between non-fatal suicidal behaviors and distress factors such as depression and pain, which represent the common psychological and physical conditions that co-occur with both cannabis and suicidal behaviors. We hypothesize that the magnitude of the mediating effect of cannabis use in the pathway from depression or pain conditions to non-fatal suicidal behaviors may vary by gender. Therefore, the key research questions are as follows:\u003c/p\u003e \u003cp\u003e1) Does cannabis contribute differently to the pathway from depression to non-fatal suicidal behaviors in women compared to men?\u003c/p\u003e \u003cp\u003e2) Does cannabis contribute differently to the pathway from pain conditions to non-fatal suicidal behaviors in women compared to men?\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003eThe data were sourced from the National Survey on Drug Use and Health (NSDUH) during the COVID-19 pandemic spanning the years 2020\u0026ndash;2022 (Center for Behavioral Health Statistics \u0026amp; Quality., 2017). This dataset provides a nationally representative sample of individuals in the United States, offering insights into patterns of substance use, mental health, and other related behaviors. To reduce potential confounding effects of age-related differences in the health consequences of substance use, we focused on individuals aged 18\u0026ndash;50 years, a demographic that captures young to middle-aged adults with relatively stable developmental profiles. This yielded a final analytic sample of 93,743 participants for examining the mediating role of cannabis use in the link between risk factors and non-fatal suicidal behaviors.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eMeasures\u003c/h3\u003e\n\u003cp\u003eThe outcomes include three binary measures of non-fatal suicidal behaviors\u0026mdash;suicidal ideation, suicide plan, and suicide attempt\u0026mdash;reported within the 12 months preceding the survey. Other factors associated with both suicide and cannabis use including depression (i.e., depressive episode within past 12 months) and pain conditions (i.e., proxied by pain relievers use within past 12 months). Past-year cannabis use and uses of other substances including tobacco, opioid, cocaine, and heroin were queried. Sociodemographic factors such as age, gender, and family income were also based on self-reported data.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eTo demonstrate the characteristics of the sample, the descriptive analysis was performed to show the mean rates, standard deviations, and sample sizes for suicidal ideation, plans, and attempts, stratified by gender and categorized based on cannabis use, depression status, and the presence of pain conditions. This analysis aimed to provide insights into the prevalence of suicidal outcomes across these risk factors.\u003c/p\u003e \u003cp\u003eTo compare the extents to which cannabis use mediated the association between depression and non-fatal suicidal behaviors in men and women, we stratified the sample by gender to perform causal mediation analysis, in which depression, cannabis use, and non-fatal suicidal behaviors, were treated as exposure, mediator, and outcome, respectively. Similarly, we evaluated the extents to which cannabis use mediated the association between pain conditions and non-fatal suicidal behaviors in men and women, separately. Pain conditions, cannabis use, and non-fatal suicidal behaviors, were treated as exposure, mediator, and outcome, respectively. Two-sided p-value of 0.05 was used as a significance cutoff. The Stata \u003cem\u003emedeff\u003c/em\u003e package was used to perform the causal mediation analyses(Imai et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2010\u003c/span\u003e) using Stata, version 16.1 (StataCorp LLC, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). The report follows EQUATOR Reporting Guidelines. Since the current analysis used de-identified and publicly available data, it is not considered human subject research that requires research ethics approval.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eTable \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e shows the rates of suicidal ideation, plans, and attempts of the sample stratified by cannabis use, depression, and pain conditions over the past 12 months. Individuals with cannabis use exhibited higher mean rates of suicidal ideation, plans, and attempts compared to those without cannabis use, with women consistently showing slightly higher rates than men across all outcomes. Similarly, the presence of depression was strongly associated with elevated mean rates of suicidal outcomes in both genders, with women showing marginally higher rates of suicidal plans and attempts than men. In contrast, individuals without depression exhibited minimal rates of suicidal outcomes. The presence of pain conditions also corresponded to increased rates of suicidal ideation, plans, and attempts for both genders, though the rates were less pronounced compared to those associated with depression.\u003c/p\u003e\n\u003cp\u003e\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eRates of Suicidal ideation, plan and attempt stratified by gender, cannabis, depression and pain condition.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eSuicidal Ideation\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eSuicidal Plan\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eSuicidal Attempt\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCannabis Use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWomen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWomen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWomen\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28461\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37924\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28461\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37924\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28461\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37924\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12966\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14392\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12966\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14392\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12966\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14392\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDepression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWomen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWomen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWomen\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37430\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43855\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37430\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43855\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37430\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43855\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3997\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8461\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3997\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8461\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3997\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8461\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePain Conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWomen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWomen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWomen\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33600\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39414\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33600\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39414\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33600\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39414\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7827\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12902\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7827\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12902\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7827\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12902\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eThe results from the causal mediation analysis are summarized in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. For both men and women, cannabis use mediated the relationship between depression and non-fatal suicidal behaviors, but the mediation fractions appeared to be higher in women than men across all non-fatal suicidal behaviors linked to depression. Marijuana use mediated 1.2% (95% CI: 0.011\u0026ndash;0.014) of the total effect of depression on suicidal ideation in men, while it mediated 2.3% (95% CI: 0.022\u0026ndash;0.025) in women. For suicidal plans, cannabis use mediated 1.0% (95% CI: 0.008\u0026ndash;0.011) of the total effect in men, compared to 1.6% (95% CI: 0.015\u0026ndash;0.017) in women. In terms of suicidal attempts, the mediation fraction was 1.0% (95% CI: 0.008\u0026ndash;0.014) in men, while it was 1.7% (95% CI: 0.015\u0026ndash;0.020) in women.\u003c/p\u003e\n\u003cp\u003eWhen examining the mediating role of cannabis in the relationship between pain conditions and non-fatal suicidal behaviors, its mediating fraction also differed between men and women. In men, cannabis use mediated 5.9% (95% CI: 0.038\u0026ndash;0.128) of the effect of pain conditions on suicidal ideation, compared to a much larger 12.5% (95% CI: 0.081\u0026ndash;0.272) in women. For suicidal plans, the mediation fraction attributable to cannabis use in men was 5.5% (\u0026minus;\u0026thinsp;0.526\u0026ndash;0.787), which was not statistically significant, while in women it was 4.4% (95% CI: 0.030\u0026ndash;0.078). Similarly, for suicidal attempts, the mediation fraction attributable to cannabis in men was lower, albeit not statistically significant, at 2.4% (95% CI: \u0026minus;0.083\u0026ndash;0.173), compared to 3.7% (95% CI: 0.023\u0026ndash;0.088) in women.\u003c/p\u003e\n\u003cp\u003e[Insert Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e here]\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe mediation analysis reveals that cannabis use likely plays a more significant role in non-fatal suicidal behaviors among women, particularly in relation to pain conditions, despite the slightly higher rate of cannabis use in men. This indicates that the higher mediation fraction of the effect of depression or pain conditions on non-fatal suicidal behaviors in women cannot be attributed to differences in cannabis exposure. Instead, these findings may imply the presence of more complex mechanisms, such as potentially heightened sensitivity or vulnerability to the effects of cannabis on non-fatal suicidal behaviors in women. Tailored interventions that address cannabis use as a self-medication strategy could reduce non-fatal suicidal behaviors, particularly for women. Screening for cannabis use should be prioritized in patients with depression or chronic pain to highlight the health consequences associated with self-medication.\u003c/p\u003e \u003cp\u003eA stronger mediating effect of cannabis use in the relationship between pain conditions and non-fatal suicidal behaviors compared to depression may suggest distinct mechanistic pathways demanding further exploration. These results point to gender-based differences in the risk of non-fatal suicidal behaviors linked to cannabis use, underscoring the need for gender-specific prevention and intervention strategies. Future research should focus on sex-specific analyses to better understand these differences and inform more effective, gender-tailored prevention efforts. These findings provide new insights into the role of cannabis in non-fatal suicidal behaviors, especially among women, and inform key opportunities for targeted interventions.\u003c/p\u003e "},{"header":"Limitations","content":"\u003cp\u003eSeveral limitations should be considered when interpreting the findings of this study. First, pain conditions were proxied by the use of analgesics, which may inadvertently include conditions with underlying pathophysiological issues that are not centered solely on pain (e.g., autoimmune disorders or inflammation-related conditions). This could introduce variability into the measurement of pain-related effects, potentially obscuring the true role of cannabis use as a mediator in the relationship between pain and non-fatal suicidal behaviors.\u003c/p\u003e\u003cp\u003eSecond, the cross-sectional nature of the National Survey on Drug Use and Health (NSDUH) data precludes causal inferences. While causal mediation analysis can help estimate indirect effects, the lack of longitudinal data limits the ability to establish temporal precedence between cannabis use, depression or pain, and non-fatal suicidal behaviors. The current study aims to evaluate a putative relationship, in which risk factors such as depression or pain could potentially influence the likelihood of using cannabis, which in turns affect the risk of suicidal ideation, plan, or attempt. Additionally, this strategy ignores possible bi-directional effects. Therefore, the results could not be used to directly infer causal effects. Future research should consider using longitudinal designs to better understand these pathways over time.\u003c/p\u003e\u003cp\u003eThird, the current study treated cannabis use as a binary variable (use vs. non-use), which does not capture variations in frequency, intensity, or mode of use (e.g., recreational vs. medicinal). These factors could differentially impact suicidal behaviors and may vary by gender, introducing potential misclassification bias. Additionally, the outcomes were self-reported and retrospective, which could lead to recall or reporting bias, especially for sensitive topics like suicidal behaviors and substance use. Women, for instance, may be more likely to report emotional distress or cannabis use as a coping mechanism, which could partially explain the observed gender differences in the mediating effects.\u003c/p\u003e\u003cp\u003eAnother limitation is the lack of consideration for important contextual factors, such as access to healthcare, social support, and socioeconomic status, which may influence both substance use and suicidal behaviors. These unmeasured confounders could affect the observed associations and limit the generalizability of the findings. Furthermore, while the NSDUH dataset provides a robust sample, the focus on individuals aged 18–50 excludes older adults and adolescents, who may exhibit unique patterns of substance use and suicide risk. Future research should address these issues by incorporating more nuanced measures of cannabis use, exploring additional contextual variables, and including a broader age range to capture diverse experiences.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe current study underscores the critical need to better understand the gender-specific effects of cannabis use on non-fatal suicidal behaviors, particularly among women with depression or chronic pain. These findings have important public health and clinical implications, emphasizing the necessity for routine screening and monitoring of cannabis use in mental health and primary care settings. Integrating these assessments into standard care protocols, especially for women, can help identify individuals at heightened risk of suicidal behaviors and provide opportunities for early intervention.\u003c/p\u003e \u003cp\u003eFrom a public health perspective, these results highlight the importance of developing gender-informed prevention strategies that address the unique vulnerabilities linked to cannabis use and its interaction with mental health and pain conditions. Tailored interventions should focus on reducing reliance on cannabis as a coping mechanism, enhancing access to alternative therapies, and addressing broader psychosocial and structural factors that contribute to gender disparities in suicide risk. Future research should explore the biological and psychosocial mechanisms driving these disparities and evaluate the effectiveness of targeted, gender-specific approaches in reducing the public health burden of non-fatal suicidal behaviors.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e \u003cb\u003eData Sharing Statement\u003c/b\u003e: The data used in this study are de-identified and publicly available from the National Survey on Drug Use and Health (NSDUH) database. Access to the data can be obtained through the Substance Abuse and Mental Health Data Archive (SAMHDA) website at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.datafiles.samhsa.gov/\u003c/span\u003e\u003cspan address=\"https://www.datafiles.samhsa.gov/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBahorik AL, Sterling SA, Campbell CI, Weisner C, Ramo D, Satre DD (2018) Medical and non-medical marijuana use in depression: Longitudinal associations with suicidal ideation, everyday functioning, and psychiatry service utilization. \u003cem\u003eJournal of Affective Disorders\u003c/em\u003e, \u003cem\u003e241\u003c/em\u003e. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jad.2018.05.065\u003c/span\u003e\u003cspan address=\"10.1016/j.jad.2018.05.065\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCawkwell PB, Hong DS, Leikauf JE (2021) Neurodevelopmental Effects of Cannabis Use in Adolescents and Emerging Adults with ADHD: A Systematic Review. 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In \u003cem\u003eStataCorp LLC\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVolkow ND, Baler RD, Compton WM, Weiss SRB (2014) Adverse Health Effects of Marijuana Use. N Engl J Med 370(23). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1056/nejmra1402309\u003c/span\u003e\u003cspan address=\"10.1056/nejmra1402309\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Table 2","content":"\u003cp\u003eTable 2 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Saint Louis University","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"cannabis, non-fatal suicidal behaviors, gender, mediation, depression, pain","lastPublishedDoi":"10.21203/rs.3.rs-5843916/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5843916/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eEmerging evidence suggests gender-based heterogeneity in suicide risk associated with cannabis use, while the role of cannabis in gender-dependent suicide risk is elusive. The objective of the present study is to determine whether cannabis use contributes differently to the pathway from depression or pain conditions to non-fatal suicidal behaviors (e.g., suicidal ideation, plans, or attempts) in men versus women. We analyzed the data was extracted from the National Survey of Drug Use and Health (NSDUH) from 2020\u0026ndash;2022 during the COVID-19 pandemic. Causal mediation analysis was conducted to assess the mediating role of cannabis in the association between depression, pain conditions, and suicide ideation/plan/attempt in two gender groups. A sample of 93,743 individuals aged 18\u0026ndash;50 years who participated in the NSDUH survey. Mediation analysis revealed that cannabis use accounted for a greater proportion of the effect of depression on suicidal ideation or attempts in women (mediation fraction: 2.3% for ideation) compared to men (1.2% for ideation). Similarly, cannabis mediated 12.5% (95% CI: 0.081\u0026ndash;0.272) of the effect of pain conditions on suicidal ideation in women, versus 5.9% (95% CI: 0.038\u0026ndash;0.128) in men. These findings suggest that cannabis plays a more substantial role in non-fatal suicidal behaviors for women than men, particularly in the context of depression and pain conditions. Tailored interventions addressing cannabis use as a self-medication strategy, especially for women, are critical for suicide prevention.\u003c/p\u003e","manuscriptTitle":"Gender Differences in Cannabis as a Mediator Between Distress Factors and Non-Fatal Suicidal Behaviors","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-20 06:03:27","doi":"10.21203/rs.3.rs-5843916/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7b7316ab-6dcb-4908-9b91-b289d053022d","owner":[],"postedDate":"January 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":42984012,"name":"Psychiatry"}],"tags":[],"updatedAt":"2025-01-20T06:03:27+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-20 06:03:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5843916","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5843916","identity":"rs-5843916","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}