
==== Front
medRxiv
MEDRXIV
medRxiv
Cold Spring Harbor Laboratory

39228696
10.1101/2024.08.23.24312453
preprint
1
Article
Altered neurobehavioral reward response predicts psychotic-like experiences in youth exposed to cannabis prenatally
http://orcid.org/0000-0001-9078-8564
Amir Carolyn M. 12
Ghahremani Dara G. 13
Chang Sarah E. 12
Cooper Ziva D. 13
Bearden Carrie E. 14*
1 Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
2 Neuroscience Interdepartmental Program, University of California, Los Angeles, CA, USA
3 Center for Cannabis and Cannabinoids, University of California, Los Angeles
4 Department of Psychology, University of California, Los Angeles, CA, USA.
* Correspondence should be addressed to: Carrie E. Bearden, Ph.D. A7-460 Semel Institute, Los Angeles, CA 90095, cbearden@mednet.ucla.edu
23 8 2024
2024.08.23.24312453https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
nihpp-2024.08.23.24312453.pdf
Importance:

Rates of prenatal cannabis exposure (PCE) are rising with increasingly permissive legislation regarding cannabis use, which may be a risk factor for psychosis. Disrupted reward-related neural circuitry may underlie this relationship.

Objective:

To elucidate neural mechanisms involved in the association between PCE and youth-onset psychotic-like experiences by probing correlates of reward anticipation, a neurobehavioral marker of endocannabinoid-mediated dopaminergic function.

Design, setting, and participants:

This longitudinal, prospective study analyzed task-related functional neuroimaging data from baseline (n=11,368), 2-year follow-up (n=7,928), and 4-year follow-up (n=2,982) of the ongoing Adolescent Brain and Cognitive Development (ABCD) Study, which recruited children aged 9 to 10 years old at baseline from 22 sites across the United States.

Results:

PCE (n=652 exposed youth) is longitudinally associated with psychotic-like experiences. Blunted neural response to reward anticipation is associated with psychotic-like experiences, with stronger effects observed in PCE youth (all |β| > 0.5; false discovery rate [FDR]–corrected P < .05). This hypoactivation at baseline predicts psychosis symptomatology in middle adolescence (4-year follow-up visit; β=−.004; FDR-corrected P < .05). Dampened behavioral reward sensitivity is associated with psychotic-like experiences across baseline, 2-year follow-up visit, and 4-year follow-up visit (|β| = .21; FDR-corrected P < .001). Psychotic-like experiences are positively associated with trait-level measures of reward motivation and impulsivity, with stronger effects for PCE youth (all |β| > 0.1; all FDR-corrected P < .05).

Conclusions and Relevance:

Blunted activation in reward-related brain regions may serve as a biomarker for disrupted reward processing and increased psychosis risk during development. PCE may affect childhood behaviors and traits related to altered reward sensitivity.

National Institutes of HealthU01DA041048 U01DA050989 U01DA051016 U01DA041022 U01DA051018 U01DA051037 U01DA050987 U01DA041174 U01DA041106 U01DA041117 U01DA041028 U01DA041134 U01DA050988 U01DA051039 U01DA041156 U01DA041025 U01DA041120 U01DA051038 U01DA041148 U01DA041093 U01DA041089 U24DA041123 U24DA041147
==== Body
pmc1. Introduction

Past-month cannabis use among pregnant people increased by over 130% from 2003 to 2022 in the United States with increasingly permissive legislation.1,2 While there is growing evidence for associations between early cannabis use and elevated psychosis risk, less is known about the effects of cannabis exposure in utero.3–7 Recently, prenatal cannabis exposure (PCE) has been linked to psychotic-like experiences in early childhood.8,9 While the neurobiology underlying the link between cannabis and psychosis is not fully understood, the brain’s reward pathways including the dopaminergic mesocorticolimbic pathway are implicated in both cannabis use disorder (CUD) and psychosis.10,11 It is unclear whether these pathways mechanistically link early cannabis exposure and psychosis-proneness.

Cross-sectional evidence in a large sample of youth (n = 11,489) suggests that PCE increases risk for psychotic-like experiences—subthreshold psychotic symptoms that precede and may predict the onset of overt psychotic disorder12–14—even in pre-adolescence.8 Resting-state functional magnetic resonance imaging studies (rsFC) studies have found that rsFC in the salience network mediates the association between PCE and child psychopathology in pre-adolescence,15 and PCE is longitudinally associated with striatal rsFC in children ages 9–12.16 However, functional neural correlates of the relationship between PCE and psychotic-like experiences have not yet been fully elucidated, nor have these relationships been modeled longitudinally. Further, behavioral and trait-level factors contributing to psychosis and substance use vulnerability including reward motivation and impulsivity have not yet been examined. Studying the relationship between PCE, psychotic-like experiences, and their reward-related neural and behavioral correlates is of particular clinical significance in adolescence, representing a crucial risk period for the onset of overt psychotic disorder and substance use vulnerability.3,6,17

We examine the relationship between neurobehavioral markers of reward anticipation in task-based functional magnetic resonance imaging (fMRI) from the Adolescent Brain and Cognitive Development (ABCD) Study, a population-based, longitudinal cohort of 11,878 children ages 9 to 10 at baseline. We analyze the reward anticipation phase of the Monetary Incentive Delay (MID) task, a task designed to probe reward response, as dopamine neurons in reward-related brain regions fire more readily to reward-predictive cues rather than reward delivery.18 This preferential firing during reward anticipation is thought to represent the motivational processing of incentive attributed to reward mediated by larger systems encompassing mesolimbic dopaminergic transmission.19 Further, hypoactivation during the anticipation phase of the MID task has been demonstrated in both adults with schizophrenia19 and adults with CUD.20

First, we aim to test whether the association between psychotic-like experiences and PCE persists into later adolescence. Next, the main hypotheses tested using baseline data (n=11,368) are that: 1a) psychotic-like experiences are associated with blunted neural activation in reward-related brain regions (i.e., striatum and ventromedial prefrontal cortex) in response to reward expectancy; and 1b) within these models, relationships are stronger for PCE youth. We then examine the prospective relationship between brain activation to reward-predictive cues at baseline and psychotic-like experiences at 4-year follow-up (middle adolescence, n=2,982). We hypothesize that: 2) blunted activation in reward-related brain regions in PCE youth at baseline in response to reward-predictive cues is associated with more severe psychotic-like experiences in middle adolescence. Third, we examine associations between psychotic-like experiences by PCE status in behavioral and trait-level measures of reward motivation and impulsivity across time points, hypothesizing that: 3a) behavioral response time to reward-predictive cues is associated with psychotic-like experiences, and differs by PCE status; and 3b) psychotic-like experiences are associated with greater trait-level reward responsiveness, drive, and impulsivity, with stronger effects for PCE youth.

2. Methods and Materials

Data Source and Participants

Data came from children (n=11,368 at baseline; M±SD age = 9.83±0.6 years; 47.85% girls; 74.13% White), born between 2005 and 2009 in the ongoing longitudinal ABCD study (data release 5.1.0; https://abcdstudy.org/). All parents/caregivers and children provided written informed consent and verbal assent, respectively, to a research protocol approved by the institutional review board at each data collection site throughout the US (Supplementary Figure 1, Supplementary Methods, section 1, and https://abcdstudy.org/study-sites/). This included data from three study time points: baseline, 2-year study follow-up visit, and 4-year study follow-up visit.

Outcomes and Measures

Psychotic-like experiences

Psychotic-like experiences were assessed using a summary score for level of distress from the Prodromal Questionnaire - Brief Child Version (PQ-BC)21, a 21-item, developmentally-appropriate questionnaire that was validated in the ABCD study sample (for more information, see Supplementary Methods, section 2).

Prenatal Cannabis Exposure (PCE)

PCE is based on parent or caregiver (9,709 of 10,716 biological mothers [90.60%]) retrospective report. Three mutually exclusive groups were formed (at baseline): no exposure (n = 10,716), exposure prior to maternal knowledge of pregnancy only (n = 420), and exposure after maternal knowledge of pregnancy (this group includes exposure before and after knowledge of pregnancy; n = 232. Supplementary Methods, section 3).

fMRI Paradigm

ABCD imaging data collection, acquisition, and analysis have previously been described.22–24 The Monetary Incentive Delay (MID) Task is a well-validated probe designed to measure domains of reward processing, including anticipation and receipt of reward, and modulation of motivation.25,26 See Supplementary Methods, sections 1 and 4, and Supplementary Figure 2 for details on task design and data acquisition and analysis. We assessed neural activation in the striatum and ventromedial prefrontal cortex (vmPFC) during reward anticipation (Supplementary Methods, section 5).

Statistical analyses

All models included age, biological sex, parental education, and income as covariates, with research site and family unit (nested within site to account for twins and triplets in this study sample) as random effects. To determine if differences in psychotic-like experiences between groups could be attributed to differences in other prenatal or environmental exposures,27 we included variables measuring birth weight, prenatal exposure to tobacco or alcohol (before or after maternal knowledge of pregnancy), unplanned pregnancy, and prenatal vitamin use in models testing group differences in the association between PCE and psychotic-like experiences. Imaging analyses additionally included mean framewise displacement as a covariate.28 Models testing the association between baseline measures and psychotic-like experiences at 4-year follow-up included baseline psychotic-like experiences as an additional covariate. Participant ID was included as a random effects term in longitudinal models. All results reported were false discovery rate (FDR) corrected for multiple comparisons. A q-value <0.05 was considered statistically significant. Results are expressed as standardized coefficients with 95% confidence intervals. See Supplementary Figure 1 and Supplementary Methods, section 5 for further details.

To address the question of whether associations between PCE and psychotic-like experiences persist through middle adolescence, we conducted linear mixed models with psychotic-like experiences as the dependent variable and cannabis exposure group (unexposed versus exposed, with unexposed as the reference group) as the independent variable longitudinally (see Supplementary methods, section 6 for detailed statistical methods).

Cross-sectional relationships between activation in reward-related brain regions during reward anticipation and psychotic-like experiences at baseline tested hypotheses that psychotic-like experiences (DV) are associated with (a) blunted activation in response to reward anticipation in a priori reward-related regions of interest (ROIs), and that (b) effects would be stronger for PCE youth. Linear mixed models test the associations between activation in a priori ROIs and psychotic-like experiences, with group-by-region interactions tested on each ROI (striatum and vmPFC), during reward anticipation (Supplementary Methods, section 1). As a control analysis, we re-ran these models with amygdala and insula ROIs; though not primary elements of this pathway, both regions are involved in the mechanisms of addiction, substance use, and reward-related decision-making. (Supplementary Methods, section 7).29–32

To test the hypothesis that hypoactivation in reward-related brain regions at baseline is prospectively associated with greater psychotic-like experiences in adolescence, linear mixed models with psychotic-like experiences at 4-year follow-up as the DV, and baseline activation in reward-related ROIs as IVs, were tested across groups. We utilize baseline neuroimaging data to establish the predictive validity of an early biomarker of elevated risk for developing psychotic-like experiences, potentially present as early as childhood, as a potential predictor of outcome at the latest available time point.

We analyze behavioral performance on the MID task (reaction time to reward-predictive cues) using longitudinal linear mixed effects models across all time points, with psychotic-like experiences as the DV and RT as the IV. We then test group-by-behavior interactions to test the hypothesis that the relationship between behavioral performance and psychotic-like experiences differs as a function of exposure status.

We then investigated the relationship between psychotic-like experiences and trait-level factors related to reward motivation and impulsivity by PCE status to test the hypothesis that psychotic-like experiences would be associated with these trait-level factors, with stronger effects for PCE youth. Longitudinal linear mixed models tested the associations between trait measures and psychotic-like experiences, with group-by-trait interactions tested on each trait measure. See Supplementary Methods, section 8 for detailed information on trait measures.

3. Results

Participant Demographics

We analyzed task-based fMRI and behavioral data acquired during the Monetary Incentive Delay (MID) Task from participants in the Adolescent Brain and Cognitive Development Study (ABCD; https://abcdstudy.org) at baseline (n=11,368; Mage = 9.83±0.6, 47.85% girls), 2-year follow-up (n=7,479 unexposed youth; n=144 exposed after knowledge of pregnancy; n=305 exposed before knowledge of pregnancy), and 4-year follow-up (n=2,826 unexposed youth; n=61 exposed after knowledge of pregnancy; n=95 exposed before knowledge of pregnancy). Table 1 describes baseline demographics of our sample, stratified by PCE status. Supplementary Table 1 includes details on rates of participant substance use by study time point.

Psychotic-like Experiences by PCE Status

PCE was associated with more severe psychotic-like experiences longitudinally across three waves of data, relative to those who were unexposed (see Supplementary Table 2 for full results). Analyses assessing differences in youth exposed to cannabis before versus after parental knowledge of pregnancy revealed that cannabis exposure both before and after parental knowledge of pregnancy was associated with more severe psychotic-like experiences compared to the unexposed group, with no statistically significant differences between the two exposure groups (Supplementary Table 2).

Relationships between Neural Activity During Reward Anticipation and Psychotic-Like Experiences at Baseline

Figure 1 shows the results of models testing the relationships between PCE, activation in a priori ROIs, and psychotic-like experiences in youth. As hypothesized, striatal activation during reward anticipation was inversely associated with reported psychotic-like experiences and was blunted in PCE youth compared to unexposed youth (Supplementary Table 3). While there was no significant association between vmPFC activation and psychotic-like experiences, vmPFC activation was blunted in PCE youth compared to unexposed youth. Results of secondary analyses revealed that psychotic-like experiences were not associated with amygdala or insula activation during reward anticipation.

Association of Baseline ROI Activation with Psychotic-like Experiences at 4-Year Follow-up Visit

Figure 2 shows results of models using baseline fMRI data to predict psychotic-like experiences at 4-year follow-up. As hypothesized, activation in the striatum during reward anticipation at baseline was associated with greater psychotic-like experiences at 4-year follow-up across groups, despite controlling for baseline psychotic-like experiences. However, consistent with cross-sectional findings, baseline vmPFC activation was not significantly associated with psychotic-like experiences.

MID Task Behavioral Performance

Models testing the association between psychotic-like experiences and behavioral performance on the MID task revealed reaction time to reward-predictive cues was positively associated with psychotic-like experiences in both groups (Figure 3 and Supplementary Table 4).

Trait Measures

Psychotic-like experiences in PCE youth were associated with greater reward responsiveness, drive, excitement about reward receipt, negative urgency, and all four domains of impulsivity compared to unexposed youth, across time points (Supplementary Table 5 and Supplementary Figure 3). PCE youth scored higher across all trait-level measures. There were significant group-by-trait interactions for drive, negative urgency, lack of planning, and sensation seeking, such that relationships to psychotic-like experiences were stronger for PCE youth.

4. Discussion

This study is the first to examine longitudinal relationships between prenatal cannabis exposure (PCE), psychotic-like experiences, and behavioral and neural indices of reward anticipation over time in youth. We found, first, that previously observed associations between PCE and psychotic-like experiences in childhood persist through middle adolescence. Second, this study offers novel evidence implicating the brain’s reward pathways in the link between PCE and early signs of psychosis. Specifically: (1) Blunted neural response to reward anticipation is associated with psychotic-like experiences, with stronger effects observed in PCE youth; (2) Striatal hypoactivation at baseline predicts psychotic-like experiences in middle adolescence; (3) Dampened behavioral reward sensitivity is associated with psychotic-like experiences over time; and (4) Psychotic-like experiences are positively associated with trait-level measures of reward motivation and impulsivity across multiple timepoints, with stronger effects for PCE youth.

Our study extends recent work demonstrating an association between PCE and psychotic-like experiences in 9 and 10-year-olds exposed to cannabis after parental knowledge of pregnancy, which remains robust through middle adolescence after rigorously controlling for covariates.8 Not only did the association persist through middle adolescence, but the longitudinal association held regardless of whether a child was exposed before or after parental knowledge of pregnancy, indicating that even early exposure contributes to psychotic-like symptomatology later in childhood. The CB1 receptor is not expressed in the fetus until 5–6 weeks’ gestation, which corresponds approximately with knowledge of pregnancy;33–35 our findings support hypotheses suggesting there may still be indirect associations through endocannabinoid receptor expression in the placenta.36

In addition, we provide the first evidence that hypoactivation in the striatum during anticipation of reward at ages 9 to 10 is associated with psychotic-like experiences, with stronger effects for PCE youth; this baseline hypoactivation also predicts psychotic-like experiences in middle adolescence. Youth exposed to cannabis prenatally additionally showed more blunted activation in the vmPFC during reward anticipation compared to unexposed youth. Preclinical research shows adolescent and adult animals prenatally exposed to THC and other CB1 receptor agonists exhibit alterations in reward-related neural circuitry.7 Our results align with previous work demonstrating hypoactivation of the striatum during reward anticipation in adult patients with psychosis,38 extending this work to a youth sample with varying degrees of subthreshold psychotic symptoms. Additionally, we extend a previous study reporting blunted activation of the striatum to monetary reward anticipation in adult cannabis users,20 which may imply diminished orientation to a diminished future reward. The prefrontal cortex and value-based decision-making functions are not yet fully developed in this age group, which may explain the specificity of the association between psychotic-like experiences and blunted striatal activation, versus no association with vmPFC activation.39–43 That there were no associations between psychotic-like experiences and amygdala or insular activation implies specificity of these effects to the mesocorticolimbic pathway.44 These findings also extend recent work showing PCE is longitudinally associated with greater striatal resting state functional connectivity in children ages 9–12,16 in line with evidence of altered connectivity between the cortex and striatum during acute cannabinoid administration.37 Future work should elucidate whether the changing strength of frontostriatal connectivity during neurodevelopment is associated with youth psychopathology.

The endocannabinoid system, specifically the cannabinoid type 1 receptor (CB1), is the site of action of delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis. CB1 receptors are preferentially expressed in key reward-related brain areas and regulate dopaminergic signaling.45–47 While a causal mechanism linking PCE to later onset of psychotic-like experiences has not yet been established, early alterations to the endocannabinoid-mediated dopaminergic system may contribute to vulnerability to psychosis in PCE youth.48–53 Our finding of prospective associations between baseline activation in reward-related brain regions and increased psychotic-like experiences in adolescence supports one potential mechanism through which PCE may lead to enhanced vulnerability to psychosis and produce long-term alterations in neural circuits involved in reward processing implicated in both acute psychotic-like symptoms and increased risk for the development of overt psychotic disorder. Moreover, blunted striatal activation may represent a biomarker of disrupted reward processing associated with subsequent psychotic-like experiences, observable as early as ages 9 and 10. While rates of substance use are low at the early ABCD study time points, future studies may wish to investigate whether this blunted striatal activation in childhood is also associated with later risk for substance use in adolescence.

The observed association between slower reaction times to reward-predictive cues and psychotic-like experiences in the present study may suggest dampened sensitivity to reward-related cues. Compared to typically developing youth, youth at clinical high risk for psychosis (CHR) display impaired behavioral performance during reward and cognitive tasks, associated with altered activation in reward-related brain regions and greater psychosis symptom severity, regardless of cannabis use history.54–56 Early THC exposure in both rodents and humans results in behavioral changes relevant to reward processing during adulthood such as increased risky decision-making and impulsivity, and an enhancement of the rewarding properties of drugs of abuse in rodents as measured by drug self-administration.57–61 Traits including increased reward responsiveness and impulsivity have previously been linked to adult cannabis use, although no causal mechanism has been established.62 In a rat model, high-dose THC exposure in adolescence results in risky decision-making and impulsivity in adulthood, as well as changes in reward learning, similar to findings seen in people who use cannabis.63

Strengths and Limitations

This study leverages the largest prospective neuroimaging and behavioral study of adolescence to date to examine a key environmental risk variable associated with increased risk for psychosis. As the ABCD Study is an ongoing 10-year study, follow-up waves can be used to investigate whether childhood and adolescent psychotic-like experiences and reward processing deficits predict the persistence of psychopathology into later adolescence and young adulthood. Task-based functional imaging may offer a valuable biomarker for understanding mechanisms by which early cannabis exposure may contribute to later mental health outcomes.

This study also has certain limitations that should be noted. Cannabis use during pregnancy occurred roughly a decade earlier than these retrospective reports, and self-reported cannabis use was reliant on recall. Further, there is a lack of detailed information on cannabis potency, frequency of use, gestational age of exposure, and quantity of cannabis exposure during pregnancy in the ABCD study. While we rigorously controlled for multiple demographic and other covariates, unmeasured confounders may have a role. Direct studies of dose, frequency, and age-of-exposure are crucial for a better understanding of cannabis’ impact on the developing brain.

5. Conclusions

The results of this study demonstrate the significance of neurobehavioral markers of reward anticipation in the association between PCE and youth psychotic-like experiences. Ultimately, we provide important new evidence for lasting effects of early cannabis exposure on reward-related neural circuitry that may be a pathway impacting early psychosis risk.

Supplementary Material

Supplement 1

Funding:

The ABCD Study is supported by the National Institutes of Health and additional federal partners via the following awards: U01DA041048, U01DA050989, U01DA051016, U01DA041022, U01DA051018, U01DA051037, U01DA050987, U01DA041174, U01DA041106, U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039, U01DA041156, U01DA041025, U01DA041120, U01DA051038, U01DA041148, U01DA041093, U01DA041089, U24DA041123 and U24DA041147. A full list of federal supporters is available at https://abcdstudy.org/federal-partners.html. Participating study sites and site principal investigators can be found at https://abcdstudy.org/consortium_members/. This work is also supported by the National Institute on Drug Abuse Grant F31DA060068 (to CMA).

Figure 1: a. Baseline (cross-sectional) associations between psychotic-like experiences and activation in A) the striatum and B) the ventromedial prefrontal cortex during reward anticipation in the Monetary Incentive Delay Task by group status (exposed to cannabis prenatally versus unexposed). Striatal activation was inversely associated with reported psychotic-like experiences (A). There was no significant association between vmPFC activation and psychotic-like experiences regardless of PCE status (B). There were significant main effects of group; specifically, blunted activation in the striatum and vmPFC in youth exposed to cannabis prenatally during reward anticipation compared to unexposed youth. There were no significant group-by-region interactions. Shading around the best-fit lines indicates standard error. Covariates: age, biological sex, parental education, income, and mean framewise displacement as fixed effects, with research and family unit (nested within site to account for twins and triplets in this study sample) as random effects. Abbreviations: PQ-BC=Prodromal Questionnaire - Brief Child Version; vmPFC=ventromedial prefrontal cortex. Significance: *p<.05, FDR corrected.

Figure 2: Results of models testing prospective associations between baseline activation during reward anticipation in A) the striatum and B) the ventromedial prefrontal cortex on the Monetary Incentive Delay Task across groups and psychotic-like experiences at year 4. Striatal activation was inversely associated with psychotic-like experiences at year 4 (A), whereas there was no significant association between vmPFC activation to reward anticipation at baseline and psychotic-like experiences at year 4 (B). Shading around the best-fit lines indicates standard error. Covariates: age, biological sex, parental education, income, mean framewise displacement, and baseline psychotic-like experiences as fixed effects with research and family unit (nested within site to account for twins and triplets in this study sample) as random effects. Abbreviations: PQ-BC=Prodromal Questionnaire - Brief Child Version; vmPFC=ventromedial prefrontal cortex. Significance: *p<.05, FDR corrected.

Figure 3: Associations between psychotic-like experiences and behavioral differences in reaction time during reward anticipation in the Monetary Incentive Delay Task by group status (exposed to cannabis prenatally versus unexposed) to high-magnitude reward-predictive cues. Reaction time was positively associated with psychotic-like experiences in both groups. Covariates: age, biological sex, parental education, and income as fixed effects, with research site and family unit (nested within site to account for twins and triplets in this study sample) as random effects. Participant ID was also included as a random effect to account for within-subject effects in longitudinal models. Beta values correspond to the relationship between psychotic-like experiences and behavioral measures (across groups), with stars indicating the strength of the relationship. Shading around the best-fit lines indicates standard error. Abbreviations: PQ-BC=Prodromal Questionnaire - Brief Child Version. Significance: ***p<.001, FDR corrected.

Table 1: Baseline Adolescent Brain and Cognitive Development (ABCD) Study Sample Characteristics.

Variable	Prenatal Cannabis Exposure Post Knowledge of Pregnancy (N=232)	Prenatal Cannabis Exposure Before Knowledge of Pregnancy (N=420)	No Prenatal Exposure (N=10,716)	
Child Variables	
Age in months at baseline, mean (SD)	117.90 (7.44)	119.05 (7.70)	119.05 (7.49)	
Sex, female, N (%)	126 (54.3)	199(47.4)	5123 (47.8)	
Birth weight in kgs.,mean (SD)	6.36 (1.53)	6.63 (1.39)	6.63 (1.39)	
Race/Ethnicity, N (%)	
White1	144 (59.50)	242 (58.60)	8203 (75.72)	
Black	105 (43.39)	170 (41.16)	2089 (19.28)	
Asian	3 (1.24)	3 (0.73)	193 (1.78)	
Pacific Islander	0 (0.00)	4 (.97)	34 (0.31)	
Native American	14 (5.79)	24 (5.81)	351 (3.24)	
Hispanic	33 (14.2)	90 (21.5)	2191 (20.5)	
Other	9 (3.72)	33 (7.99)	733 (6.77)	
Pregnancy and Family Variables	
Unplanned Pregnancy, N (%)2	164 (70.69)	304 (72.38)	3837 (35.81)	
Prenatal Vitamin Use, N (%)3	171 (73.7)	379 (90.2)	9872 (92.2)	
Household Income, N (%)1	
$0–49,999k	181 (78.02)	307 (73.10)	6267 (58.48)	
$50k–74,999k	16 (6.90)	50 (11.90)	1577 (14.72)	
$75–$99,999k	11 (4.74)	23 (5.48)	859 (8.02)	
$100k–$199,999k	4 (1.72)	12 (2.86)	836 (7.80)	
$200k or more	8 (3.45)	3 (.71%)	186 (1.74)	
1 No Prenatal Exposure>Prenatal Exposure both Before and Post-parental knowledge of pregnancy

2 No Prenatal Exposure<Prenatal Exposure both Before and Post parental knowledge of pregnancy

3 Prenatal Exposure Post parental knowledge of pregnancy <both No Prenatal Exposure and Prenatal Exposure Before parental knowledge of pregnancy.

The authors have nothing to disclose.
==== Refs
References

1. 2022 NSDUH Detailed Tables | CBHSQ Data. Accessed June 14, 2024. https://www.samhsa.gov/data/report/2022-nsduh-detailed-tables
2. Results from the 2021 National Survey on Drug Use and Health (NSDUH): Key Substance Use and Mental Health Indicators in the United States | SAMHSA Publications and Digital Products. Accessed June 14, 2024. https://store.samhsa.gov/product/results-2021-national-survey-drug-use-and-health-nsduh-key-substance-use-and-mental-health
3. Arseneault L , Cannon M , Poulton R , Murray R , Caspi A , Moffitt TE . Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. BMJ. 2002;325 (7374 ):1212–1213. doi:10.1136/bmj.325.7374.1212 12446537
4. Hasan A , von Keller R , Friemel CM , Cannabis use and psychosis: a review of reviews. Eur Arch Psychiatry Clin Neurosci. 2020;270 (4 ):403–412. doi:10.1007/s00406-019-01068-z 31563981
5. Foti DJ , Kotov R , Guey LT , Bromet EJ . Cannabis Use and the Course of Schizophrenia: 10-Year Follow-Up After First Hospitalization. AJP. 2010;167 (8 ):987–993. doi:10.1176/appi.ajp.2010.09020189
6. Levine A , Clemenza K , Rynn M , Lieberman J . Evidence for the Risks and Consequences of Adolescent Cannabis Exposure. Journal of the American Academy of Child & Adolescent Psychiatry. 2017;56 (3 ):214–225. doi:10.1016/j.jaac.2016.12.014 28219487
7. Bara A , Ferland JMN , Rompala G , Szutorisz H , Hurd YL . Cannabis and synaptic reprogramming of the developing brain. Nat Rev Neurosci. 2021;22 (7 ):423–438. doi:10.1038/s41583-021-00465-5 34021274
8. Paul SE , Hatoum AS , Fine JD , Associations Between Prenatal Cannabis Exposure and Childhood Outcomes: Results From the ABCD Study. JAMA Psychiatry. 2021;78 (1 ):64–76. doi:10.1001/jamapsychiatry.2020.2902 32965490
9. Fine JD , Moreau AL , Karcher NR , Association of Prenatal Cannabis Exposure With Psychosis Proneness Among Children in the Adolescent Brain Cognitive Development (ABCD) Study. JAMA Psychiatry. 2019;76 (7 ):762–764. doi:10.1001/jamapsychiatry.2019.0076 30916716
10. Gunasekera B , Diederen K , Bhattacharyya S . Cannabinoids, reward processing, and psychosis. Psychopharmacology. 2022;239 (5 ):1157–1177. doi:10.1007/s00213-021-05801-2 33644820
11. Volkow ND . Substance Use Disorders in Schizophrenia—Clinical Implications of Comorbidity. Schizophrenia Bulletin. 2009;35 (3 ):469–472. doi:10.1093/schbul/sbp016 19325163
12. Karcher NR , Paul SE , Johnson EC , Psychotic-like Experiences and Polygenic Liability in the Adolescent Brain Cognitive Development Study. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. 2022;7 (1 ):45–55. doi:10.1016/j.bpsc.2021.06.012 34271214
13. Dominguez MDG , Wichers M , Lieb R , Wittchen HU , van Os J . Evidence That Onset of Clinical Psychosis Is an Outcome of Progressively More Persistent Subclinical Psychotic Experiences: An 8-Year Cohort Study. Schizophr Bull. 2011;37 (1 ):84–93. doi:10.1093/schbul/sbp022 19460881
14. Downs JM , Cullen AE , Barragan M , Laurens KR . Persisting psychotic-like experiences are associated with both externalising and internalising psychopathology in a longitudinal general population child cohort. Schizophrenia Research. 2013;144 (1–3 ):99–104. doi:10.1016/j.schres.2012.12.009 23321428
15. Faraj MM , Evanski J , Zundel CG , Impact of prenatal cannabis exposure on functional connectivity of the salience network in children. Journal of Neuroscience Research. n/a(n/a). doi:10.1002/jnr.25136
16. Baranger DAA , Miller AP , Gorelik AJ , Prenatal cannabis exposure, the brain, and psychopathology during early adolescence. Nat Mental Health. 2024;2 (8 ):975–986. doi:10.1038/s44220-024-00281-7
17. Johnston L. Monitoring the Future: National Survey Results on Drug Use, 1975–2006. National Institute on Drug Abuse, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health; 2007.
18. Schultz W , Tremblay L , Hollerman JR . Reward prediction in primate basal ganglia and frontal cortex. Neuropharmacology. 1998;37 (4 ):421–429. doi:10.1016/S0028-3908(98)00071-9 9704983
19. Zeng J , Yan J , Cao H , Neural substrates of reward anticipation and outcome in schizophrenia: a meta-analysis of fMRI findings in the monetary incentive delay task. Transl Psychiatry. 2022;12 (1 ):1–14. doi:10.1038/s41398-022-02201-8 35013113
20. Martz ME , Trucco EM , Cope LM , Association of Marijuana Use With Blunted Nucleus Accumbens Response to Reward Anticipation. JAMA Psychiatry. 2016;73 (8 ):838–844. doi:10.1001/jamapsychiatry.2016.1161 27384542
21. Loewy RL , Bearden CE , Johnson JK , Raine A , Cannon TD . The prodromal questionnaire (PQ): Preliminary validation of a self-report screening measure for prodromal and psychotic syndromes. Schizophrenia Research. 2005;79 (1 ):117–125. doi:10.1016/j.schres.2005.03.007 16276559
22. Casey BJ , Cannonier T , Conley MI , The Adolescent Brain Cognitive Development (ABCD) study: Imaging acquisition across 21 sites. Developmental Cognitive Neuroscience. 2018;32 :43–54. doi:10.1016/j.dcn.2018.03.001 29567376
23. Hagler DJ , Hatton Sean N , Cornejo MD , Image processing and analysis methods for the Adolescent Brain Cognitive Development Study. NeuroImage. 2019;202 :116091. doi:10.1016/j.neuroimage.2019.116091 31415884
24. Garavan H , Bartsch H , Conway K , Recruiting the ABCD sample: Design considerations and procedures. Developmental Cognitive Neuroscience. 2018;32 :16–22. doi:10.1016/j.dcn.2018.04.004 29703560
25. Knutson B , Westdorp A , Kaiser E , Hommer D . FMRI Visualization of Brain Activity during a Monetary Incentive Delay Task. NeuroImage. 2000;12 (1 ):20–27. doi:10.1006/nimg.2000.0593 10875899
26. Yau WYW , Zubieta JK , Weiland BJ , Samudra PG , Zucker RA , Heitzeg MM . Nucleus Accumbens Response to Incentive Stimuli Anticipation in Children of Alcoholics: Relationships with Precursive Behavioral Risk and Lifetime Alcohol Use. J Neurosci. 2012;32 (7 ):2544–2551. doi:10.1523/JNEUROSCI.1390-11.2012 22396427
27. Paul SE , Hatoum A , Fine JD , Prenatal cannabis exposure and childhood outcomes: Results from the ABCD study. Published online December 19, 2019:2019.12.18.19015164. doi:10.1101/2019.12.18.19015164
28. Power JD , Barnes KA , Snyder AZ , Schlaggar BL , Petersen SE . Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion. Neuroimage. 2012;59 (3 ):2142–2154. doi:10.1016/j.neuroimage.2011.10.018 22019881
29. Droutman V , Read SJ , Bechara A . Revisiting the role of the insula in addiction. Trends in Cognitive Sciences. 2015;19 (7 ):414–420. doi:10.1016/j.tics.2015.05.005 26066588
30. Naqvi NH , Bechara A . The Insula. In: The Wiley Handbook on the Cognitive Neuroscience of Addiction. John Wiley & Sons, Ltd; 2015:128–150. doi:10.1002/9781118472415.ch6
31. Wilcox CE , Pommy JM , Adinoff B . Neural Circuitry of Impaired Emotion Regulation in Substance Use Disorders. AJP. 2016;173 (4 ):344–361. doi:10.1176/appi.ajp.2015.15060710
32. Haaranen M , Scuppa G , Tambalo S , Anterior insula stimulation suppresses appetitive behavior while inducing forebrain activation in alcohol-preferring rats. Transl Psychiatry. 2020;10 (1 ):1–11. doi:10.1038/s41398-020-0833-7 32066695
33. Wu CS , Jew CP , Lu HC . Lasting impacts of prenatal cannabis exposure and the role of endogenous cannabinoids in the developing brain. Future Neurol. 2011;6 (4 ):459–480.22229018
34. Buckley NE , Hansson S , Harta G , Mezey E . Expression of the CB1 and CB2 receptor messenger RNAs during embryonic development in the rat. Neuroscience. 1998;82 (4 ):1131–1149. doi:10.1016/s0306-4522(97)00348-5 9466436
35. Zurolo E , Iyer AM , Spliet WGM , CB1 and CB2 cannabinoid receptor expression during development and in epileptogenic developmental pathologies. Neuroscience. 2010;170 (1 ):28–41. doi:10.1016/j.neuroscience.2010.07.004 20621164
36. Fügedi G , Molnár M , Rigó J , Schönléber J , Kovalszky I , Molvarec A . Increased placental expression of cannabinoid receptor 1 in preeclampsia: an observational study. BMC Pregnancy Childbirth. 2014;14 (1 ):395. doi:10.1186/s12884-014-0395-x 25444073
37. Lorenzetti V , Gaillard A , Thomson D , Englund A , Freeman TP . Effects of cannabinoids on resting state functional brain connectivity: A systematic review. Neuroscience & Biobehavioral Reviews. 2023;145 :105014. doi:10.1016/j.neubiorev.2022.105014
38. Radua J , Schmidt A , Borgwardt S , Ventral Striatal Activation During Reward Processing in Psychosis: A Neurofunctional Meta-Analysis. JAMA Psychiatry. 2015;72 (12 ):1243–1251. doi:10.1001/jamapsychiatry.2015.2196 26558708
39. Casey BJ . Beyond Simple Models of Self-Control to Circuit-Based Accounts of Adolescent Behavior. Annual Review of Psychology. 2015;66 (Volume 66, 2015 ):295–319. doi:10.1146/annurev-psych-010814-015156
40. Casey BJ , Jones RM . Neurobiology of the Adolescent Brain and Behavior: Implications for Substance Use Disorders. Journal of the American Academy of Child & Adolescent Psychiatry. 2010;49 (12 ):1189–1201. doi:10.1016/j.jaac.2010.08.017 21093769
41. Somerville LH , Jones RM , Casey BJ . A time of change: Behavioral and neural correlates of adolescent sensitivity to appetitive and aversive environmental cues. Brain and Cognition. 2010;72 (1 ):124–133. doi:10.1016/j.bandc.2009.07.003 19695759
42. Barkley-Levenson E , Galván A . Neural representation of expected value in the adolescent brain. Proceedings of the National Academy of Sciences. 2014;111 (4 ):1646–1651. doi:10.1073/pnas.1319762111
43. Galván A , McGlennen KM . Enhanced Striatal Sensitivity to Aversive Reinforcement in Adolescents versus Adults. Journal of Cognitive Neuroscience. 2013;25 (2 ):284–296. doi:10.1162/jocn_a_00326 23163417
44. Volman SF , Lammel S , Margolis EB , New Insights into the Specificity and Plasticity of Reward and Aversion Encoding in the Mesolimbic System. J Neurosci. 2013;33 (45 ):17569–17576. doi:10.1523/JNEUROSCI.3250-13.2013 24198347
45. Fields HL . Understanding How Opioids Contribute to Reward and Analgesia. Reg Anesth Pain Med. 2007;32 (3 ):242–246. doi:10.1016/j.rapm.2007.01.001 17543821
46. Wise RA . Roles for nigrostriatal—not just mesocorticolimbic—dopamine in reward and addiction. Trends in Neurosciences. 2009;32 (10 ):517–524. doi:10.1016/j.tins.2009.06.004 19758714
47. Wise RA , Rompre PP . Brain Dopamine and Reward. Annual Review of Psychology. 1989;40 (Volume 40, 1989 ):191–225. doi:10.1146/annurev.ps.40.020189.001203
48. Volkow ND , Fowler JS , Wang GJ , Swanson JM . Dopamine in drug abuse and addiction: results from imaging studies and treatment implications. Mol Psychiatry. 2004;9 (6 ):557–569. doi:10.1038/sj.mp.4001507 15098002
49. Sarikahya MH , Cousineau S , Felice MD , Prenatal THC Exposure Induces Sex-Dependent Neuropsychiatric Endophenotypes in Offspring and Long-Term Disruptions in Fatty-Acid Signaling Pathways Directly in the Mesolimbic Circuitry. eNeuro. 2022;9 (5 ). doi:10.1523/ENEURO.0253-22.2022
50. Gessa G , Melis M , Muntoni A , Diana M . Cannabinoids activate mesolimbic dopamine neurons by an action on cannabinoid CB1 receptors. European Journal of Pharmacology. 1998;341 (1 ):39–44. doi:10.1016/S0014-2999(97)01442-8 9489854
51. Ellis RJ , Bara A , Vargas CA , Prenatal Δ9-Tetrahydrocannabinol Exposure in Males Leads to Motivational Disturbances Related to Striatal Epigenetic Dysregulation. Biological Psychiatry. 2022;92 (2 ):127–138. doi:10.1016/j.biopsych.2021.09.017 34895699
52. DiNieri JA , Wang X , Szutorisz H , Maternal Cannabis Use Alters Ventral Striatal Dopamine D2 Gene Regulation in the Offspring. Biological Psychiatry. 2011;70 (8 ):763–769. doi:10.1016/j.biopsych.2011.06.027 21820648
53. Aguilar DD , Giuffrida A , Lodge DJ . Adolescent Synthetic Cannabinoid Exposure Produces Enduring Changes in Dopamine Neuron Activity in a Rodent Model of Schizophrenia Susceptibility. International Journal of Neuropsychopharmacology. 2018;21 (4 ):393–403. doi:10.1093/ijnp/pyy003 29329382
54. Kesby JP , Murray GK , Knolle F . Neural Circuitry of Salience and Reward Processing in Psychosis. Biol Psychiatry Glob Open Sci. 2023;3 (1 ):33–46. doi:10.1016/j.bpsgos.2021.12.003 36712572
55. Karcher NR , Martin EA , Kerns JG . Examining Associations between Psychosis Risk, Social Anhedonia, and Performance of Striatum-Related Behavioral Tasks. J Abnorm Psychol. 2015;124 (3 ):507–518. doi:10.1037/abn0000067 26075968
56. Waltz J , Demro C , Schiffman J , Reinforcement learning performance and risk for psychosis in youth. J Nerv Ment Dis. 2015;203 (12 ):919–926. doi:10.1097/NMD.0000000000000420 26588080
57. Fernández-Ruiz J , Berrendero F , Hernández ML , Ramos JA . The endogenous cannabinoid system and brain development. Trends in Neurosciences. 2000;23 (1 ):14–20. doi:10.1016/S0166-2236(99)01491-5 10631784
58. Thornton SR , Compton DR , Smith FL . Ontogeny of mu opioid agonist anti-nociception in postnatal rats. Brain Res Dev Brain Res. 1998;105 (2 ):269–276. doi:10.1016/s0165-3806(97)00185-5 9541744
59. Lamarque S , Taghzouti K , Simon H . Chronic treatment with Delta(9)-tetrahydrocannabinol enhances the locomotor response to amphetamine and heroin. Implications for vulnerability to drug addiction. Neuropharmacology. 2001;41 (1 ):118–129. doi:10.1016/s0028-3908(01)00039-9 11445192
60. Vela G , Martín S , García-Gil L , Maternal exposure to Δ9-tetrahydrocannabinol facilitates morphine self-administration behavior and changes regional binding to central μ opioid receptors in adult offspring female rats. Brain Research. 1998;807 (1 ):101–109. doi:10.1016/S0006-8993(98)00766-5 9757010
61. Szutorisz H , DiNieri JA , Sweet E , Parental THC Exposure Leads to Compulsive Heroin-Seeking and Altered Striatal Synaptic Plasticity in the Subsequent Generation. Neuropsychopharmacol. 2014;39 (6 ):1315–1323. doi:10.1038/npp.2013.352
62. Wrege J , Schmidt A , Walter A , Effects of Cannabis on Impulsivity: A Systematic Review of Neuroimaging Findings. Current Pharmaceutical Design. 2014;20 (13 ):2126–2137.23829358
63. Ferland JMN , Ellis RJ , Betts G , Long-Term Outcomes of Adolescent THC Exposure on Translational Cognitive Measures in Adulthood in an Animal Model and Computational Assessment of Human Data. JAMA Psychiatry. 2023;80 (1 ):66–76. doi:10.1001/jamapsychiatry.2022.3915 36416863
