Cannabis and Tobacco Co-Use Predicts Psychosis in Clinical High Risk Cohorts

Cannabis and Tobacco Co-Use Predicts Psychosis in Clinical High Risk Cohorts | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Cannabis and Tobacco Co-Use Predicts Psychosis in Clinical High Risk Cohorts Daniel Bello , Sophia H. Blyth , Rachel A. Rabin , Jean Addington , Carrie E. Bearden , Kristin Cadenhead , Tyrone D. Cannon , Ricardo E Carrión , Barbara Cornblatt , Matcheri Keshavan , Daniel H. Mathalon , Diana O. Perkins , Larry Seidman , William S. Stone , Ming T. Tsuang , Elaine F. Walker , View ORCID Profile Scott Woods , Roscoe O. Brady Jr. , View ORCID Profile Heather Burrell Ward doi: https://doi.org/10.1101/2025.09.19.25336202 Daniel Bello 1 Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center BA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sophia H. Blyth 1 Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center BA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Rachel A. Rabin 2 Department of Psychiatry, McGill University, Montreal, Canada and The Douglas Mental Health University Institute , Verdun, Canada PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jean Addington 3 Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary , Alberta, Canada PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Carrie E. Bearden 4 Semel Institute for Neuroscience and Human Behavior, Departments of Psychiatry and Behavioral Sciences and Psychology, University of California, Los Angeles , Los Angeles, CA, USA PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kristin Cadenhead 5 Department of Psychiatry, University of California , San Diego, La Jolla, CA, USA MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Tyrone D. Cannon 6 Department of Psychology and Psychiatry, Yale University , New Haven, CT, USA PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ricardo E Carrión 7 Department of Psychiatry, Zucker Hillside Hospital and Donald and Barbara Zucker School of Medicine at Hofstra/Northwell , Glen Oaks, NY, USA PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Barbara Cornblatt 7 Department of Psychiatry, Zucker Hillside Hospital and Donald and Barbara Zucker School of Medicine at Hofstra/Northwell , Glen Oaks, NY, USA PhD, MBA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Matcheri Keshavan 8 Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School , Boston, MA MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Daniel H. Mathalon 9 Department of Psychiatry and Behavioral Sciences, University of California , San Francisco, San Francisco, CA, USA 10 Veterans Affairs San Francisco Health Care System , San Francisco, CA, USA PhD, MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Diana O. Perkins 11 Department of Psychiatry, University of North Carolina at Chapel Hill , Chapel Hill, NC, USA MD, MPH Find this author on Google Scholar Find this author on PubMed Search for this author on this site Larry Seidman 8 Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School , Boston, MA PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site William S. Stone 8 Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School , Boston, MA PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ming T. Tsuang 5 Department of Psychiatry, University of California , San Diego, La Jolla, CA, USA MD, PhD, DSc Find this author on Google Scholar Find this author on PubMed Search for this author on this site Elaine F. Walker 12 Department of Psychology, Emory University , Atlanta, GA, USA PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Scott Woods 13 Department of Psychiatry, Yale University , New Haven, CT, USA MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Scott Woods Roscoe O. Brady Jr. 8 Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School , Boston, MA MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Heather Burrell Ward 1 Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Heather Burrell Ward For correspondence: heather.b.ward{at}vumc.org Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Cannabis and tobacco use are highly prevalent among people with psychosis and are associated with medical comorbidities and poor prognosis. Concurrent use of cannabis and tobacco (“co-use”) is rising in the general population but has not been studied in psychosis. Given the devastating consequences of cannabis and tobacco use, it is critical to understand how their co-use affects psychiatric symptoms and the development of psychosis. We used the North American Prodrome Longitudinal Study 2, a multi-site prospective study of individuals at clinical high risk for psychosis (CHR) and healthy controls, to examine baseline differences in psychiatric symptoms and conversion to psychosis across substance groups: 1) CHR tobacco use, 2) CHR cannabis use, 3) CHR co-use, 4) CHR non-tobacco or cannabis substance use, 5) CHR without substance use, and 6) healthy controls. Among 1,014 participants (734 CHR, 280 controls), more frequent cannabis and tobacco use was linked to greater psychiatric symptom severity, including psychosis, anxiety, and depression. In survival analyses, co-use (HR = 2.53, 95% CI [1.44–4.45], p =.001), especially heavy co-use (HR = 3.63, 95% CI: 1.53–8.63, p = 0.003), was associated with increased risk of conversion to psychosis. Co-use of tobacco and cannabis was not associated with psychiatric symptom severity but did predict higher risk of conversion to psychosis. The combination of cannabis and tobacco use may exert a synergistic effect, amplifying conversion risk more than either substance alone, or may be a marker of an elevated underlying psychosis risk. These results highlight the need for early intervention strategies that address co-use in CHR populations to mitigate potential long-term psychiatric consequences. Introduction Cannabis and tobacco use are highly prevalent among people with psychosis. 1 Up to 60% of people with schizophrenia use tobacco – a prevalence three times that of the general population. Cannabis use is also common, especially among individuals with first episode psychosis. 2 The current and lifetime rates of cannabis use disorders among people with psychosis are estimated to be 16% and 27.1%, respectively. 3 In schizophrenia, 43% have a cannabis use disorder, compared to 15% in the population. 4 Tobacco and cannabis use are associated with significant medical and psychiatric comorbidities in people with psychosis. Tobacco use is the leading preventable cause of early mortality in schizophrenia, leading to a 20-year decreased life expectancy compared to the general population. 5 , 6 Individuals with psychosis smoke more heavily, are more nicotine dependent, and are less likely to quit smoking than people without a psychotic disorder. 6 – 8 Cannabis use is associated with psychotic symptom exacerbation, psychotic relapse, treatment nonadherence, and poorer overall functioning. 4 , 9 – 11 Lifetime cannabis use is associated with a 1.4-fold increase in the risk of developing psychotic illness, with cannabis dependence conferring a 3.4-fold increase. 10 Cannabis use is involved in roughly half of psychotic disorder cases, and regular use is a predictor of heightened schizophrenia risk. 12 – 15 Cannabis use is known to cause positive symptoms of psychosis, including paranoia, hallucinations, 16 as well as anhedonia and amotivation, 17 , 18 which are commonly associated with negative symptoms. Substance use generally begins in adolescence, prior to the onset of psychosis. Approximately 77% of individuals report using tobacco before the onset of psychotic symptoms. 6 Similarly, individuals who use cannabis have onset of schizophrenia 2-3 years earlier than those who do not use cannabis, which is predictive of poorer long-term clinical outcomes. 10 Existing literature has studied the effects of single substances (i.e., tobacco or cannabis use) on psychiatric symptoms and treatment outcomes in psychosis. However, the real world is not a controlled trial of tobacco or cannabis use alone, as many individuals use both substances. Concurrent use of tobacco and cannabis, defined as “co-use,” has become increasingly prevalent in the general population. Co-use can include using the substances at the same time, on the same occasion, or within a defined timeframe where their effects may overlap. Co-use of tobacco and cannabis can occur simultaneously , such as spliffs, which are joints that include cannabis and loose-leaf tobacco, or asynchronously , where the individual uses both substances at different times (e.g., using tobacco in the morning and cannabis at night). 12 Of individuals aged 18-25 in the United States, 20% of individuals who smoke cigarettes also use cannabis daily. In 2014, the prevalence of daily cannabis use among cigarette smokers doubled from 4.9% in 2002 to 9%. 12 Importantly, co-use of tobacco and cannabis is associated with higher rates of psychiatric conditions, worse substance use outcomes, and poorer physical health. 12 Both cannabis and tobacco may sensitize dopamine neurotransmission, cortical maturation, and genetic risk, 13 thereby amplifying psychosis risk. 14 , 19 Nicotine use may predispose to cannabis use or potentiate its effects by increasing tetrahydrocannabinol (THC) absorption. 20 Given the devastating medical and psychiatric consequences of use of these substances, it is critical to understand the effects of co-use on psychiatric symptoms and risk of developing a psychotic disorder. Because substance use often begins prior to the onset of psychosis, we investigated patterns of tobacco and cannabis co-use during the clinical high risk (CHR) period, a time prior to the onset of psychosis when individuals experience attenuated psychotic symptoms, alterations in mood and anxiety, and changes in social functioning. 21 , 22 We compared baseline symptom severity among CHR with current co-use, tobacco use only or cannabis use only, other substance use, and no substance use from the North American Prodrome Longitudinal Study (NAPLS2), a multisite prospective study of individuals at risk for psychosis who underwent neuroimaging and clinical characterization then were followed for 2 years for development of a psychotic disorder (i.e., conversion to psychosis). We also assessed if baseline tobacco and cannabis co-use was associated with conversion to psychosis. We hypothesized that CHR with co-use would have 1) more severe psychiatric symptoms and 2) a higher rate of conversion to psychosis than CHR using only tobacco or cannabis. Materials & Methods Participants NAPLS2 is a longitudinal case-control study studying individuals at CHR for psychosis across 8 sites in North America. Individuals meeting CHR criteria (N=734) and healthy controls (N=280) were enrolled. See supplement for inclusion/exclusion criteria. Participants underwent assessment at baseline and every 6 months for two years and upon conversion to psychosis (if applicable) from January 2009 to April 2013. Only baseline assessments were used for this analysis. Prior to participation, all participants provided written informed consent (or, if under age 18, informed assent with parental consent) in accordance with institutional review boards. See supplement for details. Measures Diagnosis : CHR individuals met Criteria for the Psychosis Risk Syndrome 23 based on the Structured Interview for Psychosis-Risk Syndrome (SIPS). 23 Conversion to psychosis was determined from follow-up SIPS interview, defined as meeting the Presence of Psychosis Syndrome criteria. Substance Use : Current substance use at baseline was measured using the Alcohol Use Scale/Drug Use Scale (AUS/DUS), which assesses substance use frequency over the past 30 days on an ordinal scale. 24 Tobacco use was rated in cigarettes per day (0 = no use, 1 = occasionally, 2 = 25 per day). Cannabis frequency was reported as (0 = no use, 1 = once or twice per month, 2 = 3-4 times per month, 3 = 1-2 times per week, 4 = 3-4 times per week, 5 = almost daily). See supplement for details. We categorized CHR individuals into groups based on their reported substance use in the past 30 days: 1) Tobacco only; 2) Cannabis only; 3) Tobacco and Cannabis Co-Use; 4) Neither Tobacco nor Cannabis (Non-TC use); or 5) No substance use. Healthy controls had minimal substance use and so were treated as one group. Because these co-use categories did not consider intensity of use, tobacco and cannabis use were also treated as ordinal variables to test for dose-response relationships. Psychiatric Symptoms : Severity of psychosis symptoms at baseline was rated using the Scale of Psychosis-Risk Symptoms (SOPS). 23 Anxiety and depressive symptoms were measured with the Self-Rating Anxiety Scale (SAS), 25 Social Interaction Anxiety Scale (SIAS), 26 and Calgary Depression Scale for Schizophrenia (CDSS). 27 Statistical Approach T-tests were used to compare continuous outcomes based on dichotomous variables. ANOVAs were used to compare continuous outcomes (e.g., symptom scores) based on three or more groups. Kruskal-Wallis tests were used to compare differences in ordinal variables (e.g., substance use frequency) across substance use groups. Spearman correlations were used to determine relationships with ordinal variables. Linear regression models were used to predict 1) symptom severity and 2) substance use frequency based on age, sex, site, diagnosis, and diagnosis*substance use interactions. All analyses were conducted in RStudio (Version 2023.03.1+446) using alpha<.05, except as indicated in results to correct for multiple comparisons. Survival Analyses Cox proportional hazards regression models were used to examine the association between tobacco and cannabis use and conversion to psychosis. Time was measured as days from initial assessment to last follow up assessment or post-conversion assessment. We fitted five Cox proportional hazards models controlling for age and sex: Cannabis use (ordinal) Tobacco use (ordinal) Categorical Co-Use (No use, Tobacco use only, Cannabis use only, Co-Use) Categorical Intensity of Co-Use (No use, Light use, Heavy use for Tobacco and Cannabis) Cannabis and Tobacco simultaneously (both ordinal) The reference category for the categorical models was no use of either substance. Hazard ratios with 95% confidence intervals were calculated for each predictor. All analyses were conducted using R version 4.5.1 (2025-06-13) and the following packages: survival and survminer . Results There were 1,014 participants with data for analysis (Supplemental Table 1). In the CHR group (n=734), 83 converted to psychosis (i.e. developed a psychotic disorder, CHR-C) during the 2-year study duration. Healthy Controls (n=280) were older than CHR individuals (19.73 vs. 18.50 years, t(1042) =-4.04, p < 0.001). There were no other differences in age, sex, or race. There were no differences in age, sex, race, or socioeconomic status between the CHR substance use groups ( Table 1 , Supplemental Figure 1). View this table: View inline View popup Download powerpoint Table 1. Demographics by Substance Use Group Individuals with Co-Use and Single Substance Use Have Comparable Frequency of Use There were no differences in cannabis use frequency between the Cannabis Use and Co-Use groups (Supplemental Figure 2A, p>.05) nor in tobacco use frequency between the Tobacco Use and Co-Use groups (Supplemental Figure 2B, p>.05). See supplement. Psychosis, Depression, and Anxiety Symptoms Do Not Differ Among CHR Substance Use Groups We investigated if symptom severity differed by substance use group. Symptom severity was assessed across 7 domains: SOPS Positive, Negative, General, and Disorganization; CDSS, SAS, and SIAS. Healthy controls had lower symptoms than all CHR substance use groups (all p.05, Supplement), anxiety, social anxiety, or depression (Supplemental Figure 6) among the CHR substance use groups. Download figure Open in new tab Figure 1. Psychosis Symptoms Do Not Differ Among CHR Substance Use Groups. Shown here are SOPS Positive (1A), Negative (1B), Disorganization (1C), and General (1D) Score across different substance use groups, including Cannabis Use, Co-Use, Non-Substance Use, Non-TC Use, Tobacco Use, and Healthy Controls. Healthy Controls had significantly lower SOPS scores than all other groups (Non-Substance Use, Non-TC Use, Tobacco Use, Cannabis Use, and Co-Use, Bonferroni-corrected p=.05/7 symptom domains=.007, p<.001), but their significance bars have been omitted for simplicity. Greater Tobacco and Cannabis Use are Associated with Greater Psychiatric Symptom Severity In the combined study population (i.e., CHR and healthy controls), more frequent cannabis and tobacco use was associated with greater psychiatric symptom severity on all domains (Bonferroni-corrected p=.05/7 symptom domains=0.007, all p<.001, Figure 2 ). See supplement for details and analyses in CHR group alone (Supplemental Figure 7). In linear regression models, diagnosis and sex were significant predictors of psychiatric symptom severity (Supplemental Results). Download figure Open in new tab Figure 2. Cannabis and Tobacco Use Frequency Are Associated with Higher Psychiatric Symptom Severity. Across the combined sample (CHR and Healthy Controls), more frequent cannabis use was associated with worsened psychiatric symptoms of psychosis across all SOPS domains (positive, 2A; negative, 2B; disorganization, 2C; general, 2D), anxiety (2E), social anxiety (2F), and depression (2G), Bonferroni-corrected p=.05/7 symptom domains=.007. Similarly, more frequent tobacco use was also associated with worsened psychiatric symptom of psychosis (positive, 2H; negative, 2I; disorganization, 2J; general, 2K) and anxiety (2L), social anxiety (2M), and depression (2N), Bonferroni-corrected p=.05/7 symptom domains=.007. These results suggest a consistent association between more frequent substance use and greater psychiatric symptom burden in this population. Relationships between cannabis and tobacco frequency in the CHR group alone are reported in the Supplement. Diagnosis and Tobacco Use Predict Cannabis Use Linear regression models were used to predict cannabis use frequency based on age, sex, site, diagnosis, tobacco frequency, and diagnosis*tobacco use frequency (F(12,996)=13.23, p<.001). Male sex (Estimate=-0.189, SE=0.070, t=-2.695, p=.0072), CHR diagnosis (Estimate=0.191, SE=0.0836, t=2.287, p=.022), and the Georgia site (Estimate=0.397, SE=0.1434, t=2.768, p=.0057) were significant predictors of cannabis use. The diagnosis*tobacco use interaction (Estimate=0.371. SE=0.146, t=2.537, p=.011) predicted more frequent cannabis use such that CHR participants who used tobacco more frequently also used cannabis more frequently (Supplemental Figure 8). Diagnosis and Cannabis Use Predict Tobacco Use Linear regression models were used to predict tobacco use frequency based on age, sex, site, diagnosis, cannabis use frequency, and diagnosis*cannabis use frequency (F(12,996)=15.97, p<.001). Older age (Estimate=0.0262, SE=0.0058, t=-4.51, p<.001), CHR diagnosis (Estimate=0.224, SE=0.058, t=3.866, p<.001), male sex (Estimate=-0.109, SE=0.0489, t=-2.225, p=.026), and the diagnosis*cannabis use frequency interaction (Estimate=0.157, SE=0.0654, t=2.404, p=.016) were predictors of tobacco use such that CHR participants with more frequent cannabis use also had more frequent tobacco use (Supplemental Figure 8). The Atlanta, New York, North Carolina, and Calgary sites predicted greater tobacco use (see Supplement). Survival Analyses A total of 838 participants (CHR and healthy controls) provided data for survival analyses. Sample details in Supplement. In separate analyses, higher baseline cannabis use ( HR = 1.27, 95% CI [1.10–1.45], p <.001, Supplemental Figure 9) and higher baseline tobacco use ( HR = 1.29, 95% CI [1.03–1.60], p =.02, Supplemental Figure 10) were associated with higher risk of conversion to psychosis. Details in Supplement. Tobacco and Cannabis Co-Use is Associated with Higher Risk of Conversion to Psychosis When we defined tobacco and cannabis use categorically (no use, tobacco use only, cannabis use only, co-use), co-use of cannabis and tobacco was associated with higher risk of conversion compared to no use of either substance ( HR = 2.53, 95% CI [1.44–4.45], p =.001, Figure 3 ). Cannabis use only ( HR = 1.54, 95% CI [0.77–3.07], p =.22) and tobacco use only ( HR = 1.69, 95% CI [0.79–3.64], p =.18) did not significantly predict conversion compared to no use of either substance. Age had a trending reduced risk of conversion ( HR = 0.95, 95% CI [0.90– 1.00], p =.06), but sex was not associated with conversion. Download figure Open in new tab Figure 3. Tobacco and Cannabis Co-Use is Associated with Higher Risk of Conversion to Psychosis. When we defined tobacco and cannabis use categorically (no use, tobacco use only, cannabis use only, co-use), co-use of cannabis and tobacco was associated with higher risk of conversion compared to no use of either substance ( HR = 2.53, 95% CI [1.44–4.45], p =.001). Cannabis use only ( HR = 1.54, 95% CI [0.77–3.07], p =.22) and tobacco use only ( HR = 1.69, 95% CI [0.79–3.64], p =.18) did not significantly predict conversion compared to no use of either substance. Age had a trending reduced risk of conversion ( HR = 0.95, 95% CI [0.90– 1.00], p =.06), but sex was not associated with conversion. Kaplan-Meier survival curves for time to conversion to psychosis by categorial co-use of cannabis and tobacco (None, Cannabis Only, Tobacco Only, Both). The curve is plotted for the purpose of descriptive survival patterns and was not adjusted for age or sex. Heavy Co-Use is Associated with the Highest Risk of Conversion to Psychosis To investigate dose-response relationships of tobacco and cannabis use on conversion to psychosis, we categorized the intensity of cannabis and tobacco use (no use, light use, heavy use for each substance, see Supplemental Methods). Light tobacco use only (HR = 3.08, 95% CI: 1.21–7.85, p = 0.018), light cannabis use and heavy tobacco use (HR = 2.86, 95% CI: 1.29– 6.35, p = 0.010), and heavy cannabis use and heavy tobacco use (HR = 3.63, 95% CI: 1.53– 8.63, p = 0.003, Figure 4 ) were associated with higher risk of conversion than no use of either substance. Age had a trending reduced risk of conversion (HR = 0.94, 95% CI: 0.89–1.00, p = 0.052), but sex was not associated with conversion. Download figure Open in new tab Figure 4. Heavy Co-Use is Associated with the Highest Risk of Conversion to Psychosis. To investigate dose-response relationships of tobacco and cannabis use on conversion to psychosis, we categorized the intensity of cannabis and tobacco use (no use, light use, heavy use for each substance). Light tobacco use only (HR = 3.08, 95% CI: 1.21–7.85, p = 0.018), light cannabis use and heavy tobacco use (HR = 2.86, 95% CI: 1.29–6.35, p = 0.010), and heavy cannabis use and heavy tobacco use (HR = 3.63, 95% CI: 1.53–8.63, p = 0.003) were associated with higher risk of conversion than no use of either substance. Age had a trending reduced risk of conversion (HR = 0.94, 95% CI: 0.89–1.00, p = 0.052), but sex was not associated with conversion. Kaplan-Meier survival curves for time to conversion to psychosis by categorial cannabis x tobacco interaction groups (None/Low/High combinations). The curve is plotted for the purpose of descriptive survival patterns and was not adjusted for age or sex. Cannabis Use Frequency is Associated with Higher Risk of Conversion when Controlling for Tobacco Use To isolate the contributions of cannabis and tobacco use individually on conversion to psychosis, we performed analyses using cannabis or tobacco use frequency as a predictor while controlling for use of the other substance. Higher frequency of cannabis use was associated with higher risk of conversion to psychosis ( HR = 1.22, 95% CI [1.05–1.43], p =.009 ) when controlling for tobacco use. However, tobacco use was no longer significant ( HR = 1.15, 95% CI [0.90– 1.46], p =.26) when controlling for cannabis use. Age had a trending reduced risk of conversion ( HR = 0.95, 95% CI [0.90–1.01], p =.08), but sex was not associated with conversion. Discussion This is the first investigation of tobacco and cannabis co-use in individuals at CHR for psychosis. We observed associations between baseline tobacco and cannabis co-use and psychiatric symptom severity and increased risk of conversion to psychosis. More frequent tobacco and cannabis use was associated with greater symptoms of psychosis, anxiety, and depression. However, psychiatric symptom severity did not differ between substance use groups (i.e., CHR individuals with Co-Use did not have more severe symptoms than with isolated tobacco or cannabis use). These results were contrary to our hypothesis and suggest that tobacco and cannabis use do not have additive effects on clinical symptomatology. However, we also did not observe any beneficial effects of tobacco or cannabis use on symptoms. Our findings dovetail with mixed reports in the literature. Nicotine transiently improves cognitive deficits and negative symptoms in schizophrenia, likely via agonism of nicotinic acetylcholine receptors to increase dopamine and glutamate transmission in the brain. 7 , 28 , 29 However, heavy nicotine use has been associated with worse outcomes in chronic psychosis, as individuals who smoke more heavily have more severe positive and negative symptoms, more frequent hospitalizations, and higher relapse rates. 7 Cannabis use exhibits a similarly paradoxical profile: acutely, some individuals report anxiolytic or mood-elevating effects from cannabis, yet sustained use is associated with worsened symptom severity, poorer treatment adherence, and poorer functional outcomes. 11 Yet, prior research observed that CHR individuals who used cannabis had lower social anhedonia and higher social engagement compared to those who did not use cannabis. 30 Another critical aspect is why individuals at risk for psychosis are also at greater risk for substance use. Epidemiologically, those who develop schizophrenia are 4–5 times more likely to have had substance use disorders in their youth than the general population. 30 Similarly, in CHR cohorts, problematic substance use is extremely common (affecting 22% to >50% of CHR individuals) and significantly higher than in age-matched healthy peers. One proposed mechanism is the self-medication hypothesis: adolescents in the prodromal phase often experience subthreshold symptoms of psychosis and may turn to substances to cope with these distressing experiences. 11 Another important factor is shared neurobiological and genetic vulnerability. There is evidence that neural reward pathways (especially dopaminergic circuits) affect both psychosis and addiction risk. 30 Individuals with heightened dopaminergic reactivity might be more prone to psychotic experiences and more sensitive to the reinforcing effects of substances, making them more likely to use substances. Genetic studies have identified common gene variants that increase the risk for both schizophrenia and substance use disorders (including nicotine dependence), suggesting pleiotropic genetic factors influencing both conditions. 30 Thus, the high co-occurrence of psychosis-risk status and substance use likely arises from a confluence of factors: attempts to quell emerging symptoms, overlapping biological susceptibilities, and lifestyle or social factors that provide access to substances. Critically, co-use of tobacco and cannabis was associated with a markedly increased risk of conversion to psychosis. Survival analysis revealed that individuals with co-use had more than double the risk of developing a psychotic disorder relative to CHR with no substance use. In a more granular model differentiating light versus heavy use, individuals with heavy co-use had the highest conversion risk – over a 3-fold increase. Our findings indicate that co-use of tobacco and cannabis is a more potent risk factor for psychosis conversion than use of either substance alone. However, the directionality of this relationship cannot be known. One possible interpretation is a synergistic effect, where tobacco might enhance the impact of cannabis use on the brain’s dopaminergic or endocannabinoid systems, thereby amplifying the biological processes underlying psychosis onset. Both substances increase dopamine in mesolimbic brain regions. 31 , 32 Rather than being directly causal, it is also possible that tobacco and cannabis co-use reflects an even higher underlying risk for psychosis among individuals already at CHR for psychosis. However, cannabis use appears to be the primary culprit, as cannabis use predicted conversion to psychosis even after controlling for tobacco use, which was not true of tobacco when we controlled for cannabis use. These results extend prior research on cannabis use in CHR populations. Cannabis use is linked to increased psychosis risk across multiple epidemiological studies. Prior longitudinal research has shown that heavy cannabis use in adolescence substantially raises the likelihood of later developing schizophrenia-spectrum disorders. 33 Individuals reporting very frequent cannabis use (50+ times by late teens) have up to a six-fold higher odds of a schizophrenia diagnosis in adulthood compared to individuals without substance use. 33 Likewise, meta-analyses have concluded that, while cannabis is neither a necessary nor sufficient cause of psychosis, it likely contributes to psychosis risk in predisposed individuals. 33 Strengths and Limitations Our study has several notable strengths. This is the first investigation examining tobacco and cannabis co-use in a CHR cohort. Prior work in psychosis risk largely focused on single substances, whereas our approach captures the real-world scenario where many young people use tobacco and cannabis together. While many cross-sectional studies assess current or lifetime substance use disorders, few studies characterize current substance use below the level of a disorder. Our sample is large (734 CHR individuals, from an initial pool of 1,014 participants including controls) and drawn from eight sites across North America, enhancing generalizability. While our study sheds new light on tobacco and cannabis co-use in the CHR period, it has several limitations. Our measures of substance use were limited in detail, relying on self-reported current substance use without data on quantity or use history. Further, substance use data lacked granularity to differentiate effects of simultaneous versus asynchronous use of tobacco and cannabis, which may have differing neurobiological effects. Use of non-tobacco forms of nicotine (i.e., patch, lozenge, vaping, pouches) are not assessed in the AUS/DUS. However, as data were collected 2009–2013, vaping is likely uncommon. 34 , 35 We could not determine specifics such as cannabis potency (e.g. THC levels or use of high-potency products), which is important as THC potency has increased since 2013. 36 , 37 Finally, the observational design precludes conclusions about causality, and we did not include longitudinal assessments in this analysis. Although co-use predicted conversion to psychosis, we cannot be certain that substance use is driving this outcome. It is possible that a shared third factor (e.g. genetic vulnerability, childhood trauma) leads some CHR individuals to both use substances and develop psychosis. Future Directions Given the scarcity of literature on tobacco and cannabis co-use in psychosis risk, our findings expand several avenues for future research. Replication and extension in independent samples will be important to confirm the heightened conversion risk among individuals who co-use tobacco and cannabis. Future studies should investigate longitudinal relationships between patterns of tobacco and cannabis use and psychiatric symptoms in CHR and psychosis spectrum samples. Ongoing prospective studies of CHR individuals should investigate if relationships between co-use and psychiatric symptoms and conversion persist in more recent samples in the context of shifting trends in cannabis legalization and vaping. Future work should include more nuanced measurement of substance use and interrogation of underlying biological mechanisms related to substance use and psychosis risk. From a clinical perspective, our findings suggest that interventions to reduce substance use in CHR populations are warranted. If co-use indeed contributes to conversion risk, then reducing substance use might delay or prevent psychosis onset in some individuals. In conclusion, our study underscores that tobacco and cannabis co-use is an important, yet understudied, factor in the psychosis prodrome. Data Availability Statement Data available upon reasonable request. Data Availability Data available upon reasonable request. Author Contributions DB: data curation, formal analysis, investigation, visualization, writing – original draft. SB: formal analysis, investigation, visualization, writing – original draft. RR: conceptualization, investigation, writing – reviewing & editing. JA, CB, KC, TC, RC, MK, DM, DO, WS, MT, EW, SW: funding acquisition, investigation, writing – reviewing & editing. BC, LS: funding acquisition, investigation. RO: data curation, investigation, supervision, writing – reviewing & editing. HBW: conceptualization, data curation, formal analysis, funding acquisition, investigation, methodology, project administration, resources, software, supervision, validation, visualization, writing – original draft, and writing – reviewing & editing. Funding This work was supported by a National Institutes of Health (NIH) grants U01 MH066134 to Dr. Addington, P50 MH066286 to Dr. Bearden, U01 MH081944 to Dr. Cadenhead, U01 MH081902 to Dr. Cannon, U01 MH081857 to Dr. Cornblatt, R01 MH076989 to Dr. Mathalon, U01 MH066069 to Dr. Perkins, U01 MH081928 to Dr. Stone, and U01 MH081988 to Dr. Walker, U01 MH82022 to Dr. Woods, R01 MH116170 to Dr. Brady, and K23DA059690 to Dr. Ward. Stipend support for Ms. Blyth was provided by the National Institute on Alcohol Abuse and Alcoholism of the NIH under Award Number T32AA013525. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Competing Interests The authors have no competing interests to disclose. Acknowledgments Barbara Cornblatt and Larry Seidman passed away tragically before submission of this manuscript. Their colleagues wish to honor their contributions to the work posthumously. 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