Infant Behaviors, Prenatal Cocaine Exposure, and Adult Intelligence.

Importance: Linking prenatal drug exposures to both infant behavior and adult cognitive outcomes may improve early interventions. Objective: To assess whether neonatal physical, neurobehavioral, and infant cognitive measures mediate the association between prenatal cocaine exposure (PCE) and adult perceptual reasoning IQ. Design, Setting, and Participants: This study used data from a longitudinal, prospective birth cohort study with follow-up from 1994 to 2018 until offspring were 21 years post partum. A total of 384 (196 PCE and 188 not exposed to cocaine [NCE]) infants and mothers were screened for cocaine or polydrug use. Structural equation modeling was performed from June to November 2023. Exposures: Prenatal exposures to cocaine, alcohol, marijuana, and tobacco assessed through urine and meconium analyses and maternal self-report. Main Outcomes and Measures: Head circumference, neurobehavioral assessment, Bayley Scales of Infant Development, Fagan Test of Infant Intelligence score, Wechsler Perceptual Reasoning IQ, Home Observation for Measurement of the Environment (HOME) score, and blood lead level. Results: Among the 384 mothers in the study, the mean (SD) age at delivery was 27.7 (5.3) years (range, 18-41 years), 375 of 383 received public assistance (97.9%) and 336 were unmarried (87.5%). Birth head circumference (standardized estimate for specific path association, -0.05, SE = 0.02; P = .02) and 1-year Bayley Mental Development Index (MDI) (standardized estimate for total of the specific path association, -0.05, SE = 0.02; P = .03) mediated the association of PCE with Wechsler Perceptual Reasoning IQ, controlling for HOME score and other substance exposures. Abnormal results on the neurobehavioral assessment were associated with birth head circumference (ß = -0.20, SE = 0.08; P = .01). Bayley Psychomotor Index (ß = 0.39, SE = 0.05; P < .001) and Fagan Test of Infant Intelligence score (ß = 0.16, SE = 0.06; P = .01) at 6.5 months correlated with MDI at 12 months. Conclusions and Relevance: In this cohort study, a negative association of PCE with adult perceptual reasoning IQ was mediated by early physical and behavioral differences, after controlling for other drug and environmental factors. Development of infant behavioral assessments to identify sequelae of prenatal teratogens early in life may improve long-term outcomes and public health awareness.

Prenatal and postnatal cocaine exposure enhances the anxiety- and depression-like behaviors in rats during cocaine withdrawal.

Prenatal drug exposure is a public health problem, which results in profound behavioral problems during childhood and adolescence, mainly represented by an increase in the risk of cocaine abuse at an early age. In rodents, prenatal and postnatal cocaine exposure enhanced locomotor activity and cocaine- or nicotine-induced locomotor sensitization. Various authors consider that the adverse emotional states (anxiety and depression) that occur during cocaine withdrawal are the main factors that precipitate, relapse, and increase chronic cocaine abuse, which could increase the risk of relapse of cocaine abuse. Therefore, the objective of this study was to characterize anxiety- and depression-like behaviors at different times (30, 60, 90, and 120 days) of cocaine withdrawal in rats born to females exposed prenatally and postnatally to cocaine. A group of pregnant female Wistar rats were administered daily from day GD0 to GD21 with cocaine (cocaine preexposure group), and another group of pregnant female rats was administered daily with saline (saline preexposure group). Of the litters resulting from the cocaine-pre-exposed and saline-pre-exposed pregnant female groups, only the male rats were used for the recording of the anxiety- and depression-like behaviors at different times (30, 60, 90, and 120 days) of cocaine withdrawal The study found that prenatal and postnatal cocaine exposure dose-dependent enhanced anxiety- and depression-like behaviors. This suggests that prenatal and postnatal cocaine exposure can result in enhanced vulnerability to cocaine abuse in young and adult humans.

Cocaine Gut: A Rare Case of Cocaine-Induced Esophageal, Gastric, and Small Bowel Necrosis.

Cocaine is an indirect-acting sympathomimetic drug that inhibits norepinephrine and dopamine reuptake in the adrenergic presynaptic cleft. Cocaine use has been associated with strokes, angina, arrhythmias, and agitation. Data on gastrointestinal complications such as mesenteric ischemia, bowel necrosis, ulceration, and perforation are scarce. Here, we present a rare case of cocaine-induced esophageal, gastric, and small bowel necrosis that contributes to the limited literature on this subject. Diagnosis of cocaine-induced gastrointestinal complications involves a combination of imaging studies, laboratory assessments, and histopathological examinations. Timely surgical resection, supported by intravenous fluids, antibiotics, and pain management, is the mainstay of treatment. The prognosis varies but is significantly influenced by the promptness and effectiveness of the intervention, underscoring the importance of vigilant clinical care in such cases.

Epigenetic inheritance of phenotypes associated with parental exposure to cocaine.

Parental exposure to drugs of abuse induces changes in the germline that can be transmitted across subsequent generations, resulting in enduring effects on gene expression and behavior. This transgenerational inheritance involves a dynamic interplay of environmental, genetic, and epigenetic factors that impact an individual's vulnerability to neuropsychiatric disorders. This chapter aims to summarize recent research into the mechanisms underlying the inheritance of gene expression and phenotypic patterns associated with exposure to drugs of abuse, with an emphasis on cocaine. We will first define the epigenetic modifications such as DNA methylation, histone post-translational modifications, and expression of non-coding RNAs that are impacted by parental cocaine use. We will then explore how parental cocaine use induces heritable epigenetic changes that are linked to alterations in neural circuitry and synaptic plasticity within reward-related circuits, ultimately giving rise to potential behavioral vulnerabilities. This discussion will consider phenotypic differences associated with gestational as well as both maternal and paternal preconception drug exposure and will emphasize differences based on offspring sex. In this context, we explore the complex interactions between genetics, epigenetics, environment, and biological sex. Overall, this chapter consolidates the latest developments in the multigenerational effects and long-term consequences of parental substance abuse.

Cocaine-related ischemic priapism. Systematic review and presentation of a single center series.

INTRODUCTION: Ischemic priapism is a medical emergency that, if not treated, could lead to permanent erectile dysfunction. The association between cocaine and priapism is well-known; however, data on patient characteristics, treatment, and outcomes is missing. This work aimed to answer the research question: What are the characteristics, management strategies, and erectile prognosis of patients consuming cocaine and presenting with priapism? METHODS: We conducted a systematic review according to PRISMA guidelines and described our case series. RESULTS: Eight studies were selected for qualitative synthesis, presenting information on ten patients. In our case series, we showed information regarding four patients. From the systematic review, the mean presentation time was 42.6 h, and the mean number of procedures to solve priapism was 2,4; in our case series was 42.75 h and 2, respectively. CONCLUSION: Cocaine-related priapism might present with a delayed diagnosis, need more procedures to be managed, and have a worse prognosis. More extensive and prospective studies are required.

ANCA-associated vasculitis presenting with isolated neurological manifestations in a patient with cocaine abuse: a case report and literature review.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of rare conditions predominantly affecting small vessels of skin, musculoskeletal, pulmonary, renal, and rarely central and peripheral nervous systems. Isolated neurological manifestations of AAV are uncommon and challenging to diagnose. Cocaine has been reported as a potential trigger for the development of AAV. There are only a few case reports of isolated neurological involvement in cocaine-induced AAV with poorly characterized histopathological features. We present a unique case of AAV with isolated neurological manifestations presenting with multiple cranial neuropathies, leptomeningeal enhancement on imaging and histopathologic evidence of small-vessel vasculitis in the leptomeninges and brain and extensive dural fibrosis in a patient with cocaine abuse. The patient's progressive neurological deficits were controlled after starting immunosuppression with rituximab and prednisone. We also reviewed the literature to provide the diagnostic overview of AAV and evaluate intervention options. To our knowledge, this is the first case of AAV with isolated neurological manifestations and histopathologic evidence of small-vessel vasculitis in a patient with cocaine abuse. Patients with multiple cranial neuropathies and meningeal involvement should be screened for AAV, especially if they have a history of cocaine abuse.

Transcriptomic effects of paternal cocaine-seeking on the reward circuitry of male offspring.

It has been previously established that paternal development of a strong incentive motivation for cocaine can predispose offspring to develop high cocaine-seeking behavior, as opposed to sole exposure to the drug that results in drug resistance in offspring. However, the adaptive changes of the reward circuitry have not been fully elucidated. To infer the key nuclei and possible hub genes that determine susceptibility to addiction in offspring, rats were randomly assigned to three groups, cocaine self-administration (CSA), yoked administration (Yoke), and saline self-administration (SSA), and used to generate F1. We conducted a comprehensive transcriptomic analysis of the male F1 offspring across seven relevant brain regions, both under drug-naïve conditions and after cocaine self-administration. Pairwise differentially expressed gene analysis revealed that the orbitofrontal cortex (OFC) exhibited more pronounced transcriptomic changes in response to cocaine exposure, while the dorsal hippocampus (dHip), dorsal striatum (dStr), and ventral tegmental area (VTA) exhibited changes that were more closely associated with the paternal voluntary cocaine-seeking behavior. Consistently, these nuclei showed decreased dopamine levels, elevated neuronal activation, and elevated between-nuclei correlations, indicating dopamine-centered rewiring of the midbrain circuit in the CSA offspring. To determine if possible regulatory cascades exist that drive the expression changes, we constructed co-expression networks induced by paternal drug addiction and identified three key clusters, primarily driven by transcriptional factors such as MYT1L, POU3F4, and NEUROD6, leading to changes of genes regulating axonogenesis, synapse organization, and membrane potential, respectively. Collectively, our data highlight vulnerable neurocircuitry and novel regulatory candidates with therapeutic potential for disrupting the transgenerational inheritance of vulnerability to cocaine addiction.

Paternal cocaine-seeking motivation defines offspring's vulnerability to addiction by down-regulating GABAergic GABRG3 in the ventral tegmental area.

Epidemiological investigations indicate that parental drug abuse experiences significantly influenced the addiction vulnerability of offspring. Studies using animal models have shown that paternal cocaine use and highly motivated drug-seeking behavior are important determinants of offspring addiction susceptibility. However, the key molecules contributing to offspring addiction susceptibility are currently unclear. The motivation for cocaine-seeking behavior in offspring of male rats was compared between those whose fathers self-administered cocaine (SA) and those who were yoked with them and received non-contingent cocaine administrations (Yoke). We found that paternal experience with cocaine-seeking behavior, but not direct cocaine exposure, could lead to increased lever-pressing behavior in male F1 offspring. This effect was observed without significant changes to the dose-response relationship. The transcriptomes of ventral tegmental area (VTA) in offspring were analyzed under both naive state and after self-administration training. Specific transcriptomic changes in response to paternal cocaine-seeking experiences were found, which mainly affected biological processes such as synaptic connections and receptor signaling pathways. Through joint analysis of these candidate genes and parental drug-seeking motivation scores, we found that gamma-aminobutyric acid receptor subunit gamma-3 (Gabrg3) was in the hub position of the drug-seeking motivation-related module network and highly correlated with parental drug-seeking motivation scores. The downregulation of Gabrg3 expression, caused by paternal motivational cocaine-seeking, mainly occurred in GABAergic neurons in the VTA. Furthermore, down-regulating GABAergic Gabrg3 in VTA resulted in an increase in cocaine-seeking behavior in the Yoke F1 group. This down-regulation also reduced transcriptome differences between the Yoke and SA groups, affecting processes related to synaptic formation and neurotransmitter transmission. Taken together, we propose that paternal cocaine-seeking behavior, rather than direct drug exposure, significantly influences offspring addiction susceptibility through the downregulation of Gabrg3 in GABAergic neurons of the VTA, highlighting the importance of understanding specific molecular pathways in the intergenerational inheritance of addiction vulnerability.

Pathways from prenatal cocaine exposure to adult substance use and behavior.

This is a report from the most recent adult follow-up of the longest running cohort study of prenatal cocaine exposure (PCE), in which women were enrolled prenatally and offspring were assessed in infancy, childhood, adolescence, and young adulthood. In previous studies, PCE was linked to offspring behavior problems such as early substance use and externalizing behavior problems. The current analyses examine pathways from PCE to behavioral outcomes in offspring at the 25-year assessment. Prenatal cocaine exposure was moderate in this cohort; most women decreased or discontinued use after the first trimester. During the first and third trimesters, 38% and 11% used cocaine, respectively. This represents the most common pattern of PCE in non-treatment samples. At this phase, the adult offspring were, on average, 27.3 years old (range = 25-30), had 13.4 years of education, 83% were employed, 55% were Black, and 55% were female. Offspring who were exposed to cocaine during the first trimester were significantly more likely to use marijuana in the past year, report more arrests, and have poorer scores on a decision-making task, controlling for other prenatal substance exposure, demographic, and socioeconomic factors. In mediation analyses, there were indirect pathways from PCE to current marijuana use through early initiation of marijuana use and 21-year marijuana use, and through 15-year status offenses and 21-year marijuana use. There was also an indirect pathway from PCE to lifetime arrests through early initiation of marijuana use and 21-year Conduct Disorder, although the direct pathway from PCE to arrests also remained significant. These findings are consistent with those from previous phases and are an indication that there are detrimental associations with PCE that persist across developmental stages and into adulthood.

Cocaine-associated Eustachian tube stenosis causing chronic 'glue ear': a rare cocaine-induced destructive lesion.

BACKGROUND: Cocaine is one of the most used recreational drugs. Whilst medical uses exist, chronic recreational nasal use of cocaine is associated with progressive destruction of the osseocartilaginous structures of the nose, sinuses and palate - termed cocaine-induced midline destructive lesions. CASE REPORT: A 43-year-old male with a history of chronic cocaine use, presented with conductive hearing loss and unilateral middle-ear effusion. Examination under anaesthesia revealed a completely stenosed left Eustachian tube orifice with intra-nasal adhesions. The adhesions were divided and the hearing loss was treated conservatively with hearing aids. Whilst intra-nasal cocaine-induced midline destructive lesions are a well-described condition, this is the first known report of Eustachian tube stenosis associated with cocaine use. CONCLUSION: This unique report highlights the importance of thorough history-taking, rhinological and otological examination, and audiometric testing when assessing patients with a history of chronic cocaine use. This paper demonstrates the complexity of managing hearing loss in such cases, with multiple conservative and surgical options available.

Prenatal incidence of cleft lip/palate and cocaine abuse in parents: a systematic review and meta-analysis.

BACKGROUND: The study aimed to investigate the association between maternal cocaine abuse during pregnancy and the prevalence of cleft lip/palate (CL/P) in offspring, synthesizing existing evidence through a systematic review and meta-analysis. CL/P is a congenital craniofacial anomaly with complex etiology, and prior research has suggested potential links between maternal cocaine use and CL/P. However, these associations remain inconclusive. METHODS: A comprehensive literature search was conducted to identify relevant studies published up to the study's cutoff date in September 2021. Several databases were systematically searched using predefined search terms. Inclusion criteria were set to encompass studies reporting on the prevalence of CL/P in infants born to mothers with a history of cocaine use during pregnancy, with a comparison group of non-cocaine-using mothers. Data were extracted, and a meta-analysis was performed using a random-effects model to calculate pooled odds ratios (OR) and relative risks (RR) with their respective 95% confidence intervals (CI). RESULTS: The review included data from 4 studies that met the inclusion criteria. The combined OR from two studies was 0.05 (95% CI: 0.00, 4.41), which does not suggest a statistically significant association between prenatal cocaine exposure and the incidence of CL/P due to the confidence interval crossing the null value. Additionally, the combined RR was 0.17 (95% CI: 0.04, 0.66), indicating a statistically significant decrease in the risk of CL/P associated with prenatal cocaine exposure. These results, with an OR that is not statistically significant and an RR suggesting decreased risk, should be interpreted with caution due to considerable heterogeneity and variability among the included studies' findings. Further research is needed to clarify these associations. CONCLUSION: The findings from this systematic review and meta-analysis suggest that maternal cocaine use during pregnancy is not a statistically significant independent risk factor for the development of CL/P in offspring. These results underscore the multifactorial nature of CL/P etiology and emphasize the importance of considering other genetic, environmental, and nutritional factors in understanding the condition's origins. While the study provides important insights, limitations such as data heterogeneity and potential confounders should be acknowledged. Future research should adopt rigorous study designs and explore a broader range of potential risk factors to comprehensively elucidate CL/P development.

Mucocutaneous Manifestations of Recreational Drug Use.

Recreational drug use is increasingly common in the dermatology patient population and is often associated with both general and specific mucocutaneous manifestations. Signs of substance use disorder may include changes to general appearance, skin, and mucosal findings associated with particular routes of drug administration (injection, insufflation, or inhalation) or findings specific to a particular drug. In this review article, we provide an overview of the mucocutaneous manifestations of illicit drug use including cocaine, methamphetamine, heroin, hallucinogens, marijuana, and common adulterants to facilitate the identification and improved care of these patients with the goal being to connect this patient population with appropriate resources for treatment.

Retrospective Case Series of Cocaine-Associated Plasma Cell Orificial Mucositis.

Importance: Plasma cell orificial mucositis (PCOM) associated with cocaine use is an emerging, rare condition that has become a concern in Spain in recent years. Limited knowledge exists regarding this novel condition. Objectives: To delineate the clinicopathologic characteristics of this emerging entity and establish a novel approach in the differential diagnosis of cocaine-associated lesions. Design, Setting, and Participants: A descriptive, retrospective, multicenter case series of 10 patients diagnosed with cocaine-associated PCOM was conducted in Spain from April 2020 to March 2023. Main Outcomes and Measures: Patient demographic, clinical, histopathologic, and treatment data were collected. Results: A total of 10 patients (6 [60%] male; median [range] age, 45.5 [36-66] years) presenting with exudative ulcerated plaques were identified for this study. The lesions had raised and erythematous edges over the nostril and a median (range) evolution time of 9 (2-24) months. Septal or palate perforations were observed in 4 (40%) of the patients. Biopsies revealed a dense inflammatory infiltrate of plasma cells in the dermis without atypia and with eosinophils. All patients reported recent cocaine use. Three urine tests detected cocaine but found no presence of amphetamines or opiates. Six patients improved with corticosteroid therapy. Up to 60% of patients were lost to follow-up. Conclusions and Relevance: This case series describes the clinicopathologic characteristics of PCOM, an emerging entity associated with cocaine use in Spain, and demonstrates a novel approach in the differential diagnosis of cocaine-associated lesions. To date, cocaine-associated skin lesions have been reported as neutrophilic dermatoses and vasculitis. The appearance of a plasma cell infiltrate changes what has been described in the medical literature so far. PCOM is a benign condition of unknown cause characterized by a proliferative polyclonal plasma cell infiltrate. A comprehensive differential diagnosis workup is required to reach this exclusionary diagnosis. Several irritants have been documented in cases of PCOM, and a hypersensitivity mechanism has been proposed. Since the initial report of cocaine-associated PCOM in Spain, its incidence has experienced a surge in the country. The cause of this phenomenon may be attributed to newly unidentified adulterants. The administration of corticosteroids and discontinuation of cocaine use are the sole treatments that have demonstrated efficacy. Clinicians should be vigilant regarding this emerging condition and conduct inquiries into cocaine use. Additional research is required to clarify the pathophysiology of this emerging condition.

Mesocorticolimbic function in cocaine polydrug users: A multimodal study of drug cue reactivity and cognitive regulation.

Addictions are thought to be fostered by the emergence of poorly regulated mesocorticolimbic responses to drug-related cues. The development and persistence of these responses might be promoted by altered glutamate transmission, including changes to type 5 metabotropic glutamate receptors (mGluR5s). Unknown, however, is when these changes arise and whether the mGluR5 and mesocorticolimbic alterations are related. To investigate, non-dependent cocaine polydrug users and cocaine-naïve healthy controls underwent a positron emission tomography scan (15 cocaine users and 14 healthy controls) with [11 C]ABP688, and a functional magnetic resonance imaging scan (15/group) while watching videos depicting activities with and without cocaine use. For some drug videos, participants were instructed to use a cognitive strategy to lower craving. Both groups exhibited drug cue-induced mesocorticolimbic activations and these were larger in the cocaine polydrug users than healthy controls during the session's second half. During the cognitive regulation trials, the cocaine users' corticostriatal responses were reduced. [11 C]ABP688 binding was unaltered in cocaine users, relative to healthy controls, but post hoc analyses found reductions in those with 75 or more lifetime cocaine use sessions. Finally, among cocaine users (n = 12), individual differences in prefrontal [11 C]ABP688 binding were associated with midbrain and limbic region activations during the regulation trials. Together, these preliminary findings raise the possibility that (i) recreational polydrug cocaine users show biased brain processes towards cocaine-related cues and (ii) repeated cocaine use can lower cortical mGluR5 levels, diminishing the ability to regulate drug cue responses. These alterations might promote susceptibility to addiction and identify early intervention targets.

Cocaine-use disorder and childhood maltreatment are associated with the activation of neutrophils and increased inflammation.

BACKGROUND: Cocaine-use disorder (CUD) has been associated with early life adversity and activated cellular immune responses. Women are most vulnerable to complications from chronic substance disorders, generally presenting an intense feeling of abstinence and consuming significant drug amounts. Here, we investigated neutrophil functional activities in CUD, including the formation of neutrophil extracellular traps (NETs) and related intracellular signalling. We also investigated the role of early life stress in inflammatory profiles. METHODS: Blood samples, clinical data, and history of childhood abuse or neglect were collected at the onset of detoxification treatment of 41 female individuals with CUD and 31 healthy controls (HCs). Plasma cytokines, neutrophil phagocytosis, NETs, intracellular reactive oxygen species (ROS) generation, and phosphorylated protein kinase B (Akt) and mitogen-activated protein kinases (MAPK)s were assessed by flow cytometry. RESULTS: CUD subjects had higher scores of childhood trauma than controls. Increased plasma cytokines (TNF-α, IL-1ß, IL-6, IL-8, IL-12, and IL-10), neutrophil phagocytosis, and production of NETs were reported in CUD subjects as compared to HC. Neutrophils of CUD subjects also produced high levels of intracellular ROS and had more activated Akt and MAPKs (p38/ERK), which are essential signalling pathways involved in cell survival and NETs production. Childhood trauma scores were significantly associated with neutrophil activation and peripheral inflammation. CONCLUSION: Our study reinforces that smoked cocaine and early life stress activate neutrophils in an inflammatory environment.

The Modulatory Effects of Atomoxetine on Aberrant Connectivity During Attentional Processing in Cocaine Use Disorder.

BACKGROUND: Cocaine use disorder is associated with cognitive deficits that reflect dysfunctional processing across neural systems. Because there are currently no approved medications, treatment centers provide behavioral interventions that have only short-term efficacy. This suggests that behavioral interventions are not sufficient by themselves to lead to the maintenance of abstinence in patients with cocaine use disorder. Self-control, which includes the regulation of attention, is critical for dealing with many daily challenges that would benefit from medication interventions that can ameliorate cognitive neural disturbances. METHODS: To address this important clinical gap, we conducted a randomized, double-blind, placebo-controlled, crossover design study in patients with cocaine use disorder (n = 23) and healthy control participants (n = 28). We assessed the modulatory effects of acute atomoxetine (40 mg) on attention and conflict monitoring and their associated neural activation and connectivity correlates during performance on the Eriksen flanker task. The Eriksen flanker task examines basic attentional processing using congruent stimuli and the effects of conflict monitoring and response inhibition using incongruent stimuli, the latter of which necessitates the executive control of attention. RESULTS: We found that atomoxetine improved task accuracy only in the cocaine group but modulated connectivity within distinct brain networks in both groups during congruent trials. During incongruent trials, the cocaine group showed increased task-related activation in the right inferior frontal and anterior cingulate gyri, as well as greater network connectivity than the control group across treatments. CONCLUSIONS: The findings of the current study support a modulatory effect of acute atomoxetine on attention and associated connectivity in cocaine use disorder.

Prenatal cocaine exposure and self-reported behavioral adjustments from ages 12 to 21: environmental pathways.

BACKGROUND: In a birth-cohort study, we followed offspring with prenatal cocaine exposure (PCE) to investigate longitudinal associations of PCE with self-reported behavioral adjustment from early adolescence to emerging adulthood (EA). Environmental pathways (family functioning, non-kinship care, maltreatment) were specified as potential mediators of PCE. METHODS: Participants were 372 (190 PCE; 47% male), primarily Black, low socioeconomic status, enrolled at birth. Internalizing and externalizing behaviors were assessed using Youth Self-Report at ages 12 and 15 and Adult Self-Report at age 21. Extended random-intercept cross-lagged panel modeling was used to account for potential bidirectional relationships between internalizing and externalizing behaviors over time, examining potential mediators. RESULTS: Adjusting for covariates, significant indirect effects were found for each mediator at different ages. For family functioning, these were both internalizing (ß = 0.83, p = 0.04) and externalizing behaviors (ß = 1.58, p = 0.02) at age 12 and externalizing behaviors at age 15 (ß = 0.51, p = 0.03); for non-kinship care, externalizing behaviors at ages 12 (ß = 0.63, p = 0.02) and 15 (ß = 0.20, p = 0.03); and for maltreatment, both internalizing and externalizing behaviors at ages 15 (ß = 0.64, p = 0.02 for internalizing; ß = 0.50, p = 0.03 for externalizing) and 21 (ß = 1.39, p = 0.01 for internalizing; ß = 1.11, p = 0.01 for externalizing). Direct associations of PCE with internalizing and externalizing behaviors were not observed, nor cross-lagged relationships between internalizing and externalizing behaviors. CONCLUSIONS: Negative associations of PCE with behavioral adjustment persist into EA via environmental pathways, specifying intervention points to disrupt adverse pathways toward healthy development.