Adipokines measured during pregnancy and at birth are associated with infant negative affect.

BACKGROUND: Increased adiposity during pregnancy may be related to offspring risk for mental health disorders, although the biological mechanisms are poorly understood. One promising hypothesis is that factors secreted from adipocytes such as leptin and adiponectin may explain this association. The current study examined whether pregnancy or umbilical cord blood concentrations of leptin and/or adiponectin a) predict elevated infant negative affect at 6 months (an early life marker of risk for psychopathology); and b) help explain the association between pregnancy adiposity and increased infant negative affect. METHODS: Data came from a prospective cohort (N = 305) of pregnant individuals and their offspring. Second trimester adiposity was assessed using air displacement plethysmography. Concentrations of leptin and adiponectin were measured in second trimester plasma and umbilical cord plasma. Infant negative affect was assessed by standardized observation at 6 months. Second trimester inflammation was assessed using a comprehensive panel of cytokines. RESULTS: Lower second trimester adiponectin was associated with elevated infant negative affect, and mediated the effect of pregnancy adiposity on infant negative affect. This association was independent of the effect of second trimester inflammation. Umbilical cord leptin also predicted higher infant negative affect and mediated the association between pregnancy adiposity and infant negative affect. CONCLUSIONS: This is the first study to link pregnancy adiponectin or cord blood leptin to infant markers of risk for psychopathology, and the first to demonstrate that these adipokines mediate the association between pregnancy adiposity and offspring behavioral outcomes, suggesting novel markers of risk and potential mechanisms of effect.

Role of platelet count in a murine stasis model of deep vein thrombosis.

Platelets are core components of thrombi but their effect on thrombus burden during deep vein thrombosis (DVT) has not been fully characterized. We examined the role of thrombopoietin-altered platelet count on thrombus burden in a murine stasis model of DVT. To modulate platelet count compared to baseline, CD1 mice were pretreated with thrombopoietin antisense oligonucleotide (THPO-ASO, 56% decrease), thrombopoietin mimetic (TPO-mimetic, 36% increase), or saline (within 1%). Thrombi and vein walls were examined on postoperative days (POD) 3 and 7. Thrombus weights on POD 3 were not different between treatment groups (p = .84). The mean thrombus weights on POD 7 were significantly increased in the TPO-mimetic cohort compared to the THPO-ASO (p = .005) and the saline (p = .012) cohorts. Histological grading at POD 3 revealed a significantly increased smooth muscle cell presence in the thrombi and CD31 positive channeling in the vein wall of the TPO-mimetic cohort compared to the saline and THPO-ASO cohorts (p < .05). No differences were observed in histology on POD 7. Thrombopoietin-induced increased platelet count increased thrombus weight on POD 7 indicating platelet count may regulate thrombus burden during early resolution of venous thrombi in this murine stasis model of DVT.

Deep vein thrombosis (DVT) is a pathology in which blood clots form in the deep veins of our body. Usually occurring in the legs, these clots can be dangerous if they dislodge and travel to the heart and are pumped into the lungs. Often these clots do not travel and heal where they formed. However, as the body heals the clot it may also cause damage to the vein wall and predispose the patient to future clots, i.e., the biggest risk factor for a second clot is the first clot. DVT can also cause symptoms of pain, swelling, and redness in the long-term, leading to post-thrombotic syndrome where the initial symptoms of the clot persist for a long time. All blood clots have common components of red blood cells, white blood cells, platelets, and fibrin in varying concentrations. Humans maintain a platelet count between 150 and 400 thousand platelets per microliter of our blood. However, diseases like cancer or medications like chemotherapy can cause a change in our body's platelet count. The effect of a changing platelet count on the size (clot burden) of DVT clot and how platelet count could affect DVT as the clot heals is not fully understood. Studying this might help us develop better targets and treat patients with a wide range of platelet counts who experience DVT. In this study, we intentionally decreased, left unchanged, and increased platelet counts in mice and then created a DVT to study what the effect of low, normal, and high platelet counts, respectively, would be on the clot burden. We observed that mice with higher platelet counts had a higher clot burden during the early part of the healing process of the clot. Within this study, we can conclude that higher platelet counts may lead to higher clot burden in DVT which furthers our understanding of how platelet count affects clot burden during DVT.

Yoga vs Cognitive Processing Therapy for Military Sexual Trauma-Related Posttraumatic Stress Disorder: A Randomized Clinical Trial.

Importance: First-line treatment for posttraumatic stress disorder (PTSD) in the US Department of Veterans Affairs (VA), ie, trauma-focused therapy, while effective, is limited by low treatment initiation, high dropout, and high treatment refraction. Objective: To evaluate the effectiveness of Trauma Center Trauma-Sensitive Yoga (TCTSY) vs first-line cognitive processing therapy (CPT) in women veterans with PTSD related to military sexual trauma (MST) and the hypothesis that PTSD outcomes would differ between the interventions. Design, Setting, and Participants: This multisite randomized clinical trial was conducted from December 1, 2015, to April 30, 2022, within 2 VA health care systems located in the southeast and northwest. Women veterans aged 22 to 71 years with MST-related PTSD were enrolled and randomized to TCTSY or CPT. Interventions: The TCTSY intervention (Hatha-style yoga focusing on interoception and empowerment) consisted of 10 weekly, 60-minute group sessions, and the CPT intervention (cognitive-based therapy targeting modification of negative posttraumatic thoughts) consisted of 12 weekly, 90-minute group sessions. Main Outcome and Measures: Sociodemographic data were collected via self-report survey. The primary outcome, PTSD symptom severity, was assessed using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and PTSD Checklist for DSM-5 (PCL-5). Assessments were conducted at baseline, midintervention, 2 weeks post intervention, and 3 months post intervention. Results: Of 200 women veterans who consented to participate, the intent-to-treat sample comprised 131 participants (mean [SD] age, 48.2 [11.2] years), with 72 randomized to TCTSY and 59 randomized to CPT. Treatment was completed by 47 participants (65.3%) in the TCTSY group and 27 (45.8%) in the CPT group, a 42.6% higher treatment completion rate in the TCTSY group (P = .03). Both treatment groups improved over time on the CAPS-5 (mean [SD] scores at baseline: 36.73 [8.79] for TCTSY and 35.52 [7.49] for CPT; mean [SD] scores at 3 months: 24.03 [11.55] for TCTSY and 22.15 [13.56]) and the PCL-5 (mean [SD] scores at baseline: 49.62 [12.19] for TCTSY and 48.69 [13.62] for CPT; mean [SD] scores at 3 months: 36.97 [17.74] for TCTSY and 31.76 [12.47]) (P < .001 for time effects). None of the group effects or group-by-time effects were significant. Equivalence analyses of change scores were not significantly different between the TCTSY and CPT groups, and the two one-sided test intervals fell within the equivalence bounds of plus or minus 10 for CAPS-5 for all follow-up time points. Conclusions and Relevance: In this comparative effectiveness randomized clinical trial, TCTSY was equivalent to CPT in reducing PTSD symptom severity, with both groups improving significantly. The higher treatment completion rate for TCTSY indicates its higher acceptability as an effective and acceptable PTSD treatment for women veterans with PTSD related to MST that could address current VA PTSD treatment limitations. Trial Registration: ClinicalTrials.gov Identifier: NCT02640690.

Immunotherapeutic treatment of inflammation in mice exposed to methamphetamine.

Introduction: Currently, there are no FDA-approved medications to treat methamphetamine addiction, including the inflammatory, neurotoxic, and adverse neuropsychiatric effects. We have shown that partial (p)MHC class II constructs (i.e., Recombinant T-cell receptor Ligand - RTL1000), comprised of the extracellular α1 and ß1 domains of MHC class II molecules linked covalently to myelin oligodendrocyte glycoprotein (MOG)-35-55 peptide, can address the neuroimmune effects of methamphetamine addiction through its ability to bind to and down-regulate CD74 expression, block macrophage migration inhibitory factor (MIF) signaling, and reduce levels of pro-inflammatory chemokine ligand 2 (CCL2). The present study evaluated the effects of our third-generation pMHC II construct, DRmQ, on cognitive function and concentration of inflammatory cytokines in the frontal cortex, a region critical for cognitive functions such as memory, impulse control, and problem solving. Methods: Female and male C57BL/6J mice were exposed to methamphetamine (or saline) via subcutaneous (s.c.) injections administered four times per day every other day for 14 days. Following methamphetamine exposure, mice received immunotherapy (DRmQ or ibudilast) or vehicle s.c. injections daily for five days. Cognitive function was assessed using the novel object recognition test (NORT). To evaluate the effects of immunotherapy on inflammation in the frontal cortex, multiplex immunoassays were conducted. ANOVA was used to compare exploration times on the NORT and immune factor concentrations. Results: Post hoc analysis revealed increased novel object exploration time in MA-DRmQ treated mice, as compared to MA-VEH treated mice (non-significant trend). One-way ANOVA detected a significant difference across the groups in the concentration of macrophage inflammatory protein-2 (MIP-2) (p = 0.03). Post hoc tests indicated that mice treated with methamphetamine and DRmQ or ibudilast had significantly lower levels of MIP-2 in frontal cortex, as compared to mice treated with methamphetamine and vehicle (p > 0.05). Discussion: By specifically targeting CD74, our DRQ constructs can block the signaling of MIF, inhibiting the downstream signaling and pro-inflammatory effects that contribute to and perpetuate methamphetamine addiction.

Cognitive impairment in long-COVID and its association with persistent dysregulation in inflammatory markers.

Objective: To analyze the potential impact of sociodemographic, clinical and biological factors on the long-term cognitive outcome of patients who survived moderate and severe forms of COVID-19. Methods: We assessed 710 adult participants (Mean age = 55 ± 14; 48.3% were female) 6 to 11 months after hospital discharge with a complete cognitive battery, as well as a psychiatric, clinical and laboratory evaluation. A large set of inferential statistical methods was used to predict potential variables associated with any long-term cognitive impairment, with a focus on a panel of 28 cytokines and other blood inflammatory and disease severity markers. Results: Concerning the subjective assessment of cognitive performance, 36.1% reported a slightly poorer overall cognitive performance, and 14.6% reported being severely impacted, compared to their pre-COVID-19 status. Multivariate analysis found sex, age, ethnicity, education, comorbidity, frailty and physical activity associated with general cognition. A bivariate analysis found that G-CSF, IFN-alfa2, IL13, IL15, IL1.RA, EL1.alfa, IL45, IL5, IL6, IL7, TNF-Beta, VEGF, Follow-up C-Reactive Protein, and Follow-up D-Dimer were significantly (p<.05) associated with general cognition. However, a LASSO regression that included all follow-up variables, inflammatory markers and cytokines did not support these findings. Conclusion: Though we identified several sociodemographic characteristics that might protect against cognitive impairment following SARS-CoV-2 infection, our data do not support a prominent role for clinical status (both during acute and long-stage of COVID-19) or inflammatory background (also during acute and long-stage of COVID-19) to explain the cognitive deficits that can follow COVID-19 infection.

Inflammatory and mental health sequelae of COVID-19.

The COVID-19 pandemic has caused significant negative consequences to mental health. Increased inflammatory factors and neuropsychiatric symptoms, such as cognitive impairment ("brain fog"), depression, and anxiety are associated with long COVID [post-acute sequelae of SARS-CoV-2 infection (PASC), termed neuro-PASC]. The present study sought to examine the role of inflammatory factors as predictors of neuropsychiatric symptom severity in the context of COVID-19. Adults (n = 52) who tested negative or positive for COVID-19 were asked to complete self-report questionnaires and to provide blood samples for multiplex immunoassays. Participants who tested negative for COVID-19 were assessed at baseline and at a follow-up study visit (∼4 weeks later). Individuals without COVID-19 reported significantly lower PHQ-4 scores at the follow-up visit, as compared to baseline (p = 0.03; 95% CI-1.67 to -0.084). Individuals who tested positive for COVID-19 and experienced neuro-PASC had PHQ-4 scores in the moderate range. The majority of people with neuro-PASC reported experiencing brain fog (70% vs. 30%). Those with more severe COVID-19 had significantly higher PHQ-4 scores, as compared to those with mild disease (p = 0.008; 95% CI 1.32 to 7.97). Changes in neuropsychiatric symptom severity were accompanied by alterations in immune factors, particularly monokine induced by gamma interferon (IFN-γ) (MIG, a. k.a. CXCL9). These findings add to the growing evidence supporting the usefulness of circulating MIG levels as a biomarker reflecting IFN-γ production, which is important because individuals with neuro-PASC have elevated IFN-γ responses to internal SARS-CoV-2 proteins.

Differences in rates of impairment in adults who use methamphetamine using two sets of demographically corrected norms.

Neuropsychologists can expect to meet with increasing rates of patients who use methamphetamine (MA), as MA use is on the rise, often comorbid with other substance use disorders, and frequently accompanied by changes in cognitive functioning. To detect impairment, neuropsychologists must apply the appropriate normative data according to important demographic factors such as age, sex, and education. This study involved 241 adults with and without MA dependence who were administered the Neuropsychological Assessment Battery. Given the high rates of polysubstance use among adults who use MA, we included adults with mono-dependence and poly-dependence on MA and at least one other substance. We compared the rates of adults with and without previous MA dependence classified as impaired on neurocognitive testing when using norms corrected for age, education, and sex versus norms corrected only for age. Norms corrected for age, education, and sex resulted in less frequent identification of impairment compared to norms corrected only for age, but both sets of norms appeared sufficient and similar enough to warrant their use with this population. It may be appropriate to explore the possible implications of discrepancies between education-corrected and non-education corrected sets of scores when assessing impairment in individuals who use MA.

The association between heightened ADHD symptoms and cytokine and fatty acid concentrations during pregnancy.

Objective: Previous research conducted with samples of children suggest that individuals with attention-deficit/hyperactivity disorder (ADHD) have altered fatty acid concentrations and may have increased systemic inflammation. Whether these differences are also apparent in other populations of individuals with heightened ADHD symptoms (e.g., pregnant adults) is unknown. The goal of the current study was to examine whether there are ADHD-associated differences in polyunsaturated fatty acid concentrations or pro-inflammatory cytokine concentrations during pregnancy, a developmental period when fatty acid concentrations and systemic inflammation have implications for the health of both the pregnant person and the developing child. We hypothesized that plasma levels of the ratio of omega-6s to omega-3s (n-6:n-3) and plasma inflammatory cytokine levels would be higher in individuals with heightened ADHD symptoms, consistent with previous findings in children with ADHD. Methods: Data (N = 68) came from a prospective study of pregnant community volunteers who were oversampled for ADHD symptoms. During the 3rd trimester, plasma concentrations of fatty acids and the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were assessed. Dietary intake was examined in the 3rd trimester using three 24-h recalls conducted by trained dietitians and by examining plasma levels of conjugated linoleic acid (n-6) and α-linolenic acid (n-3), essential fatty acids that must come from dietary intake. Results: The group with heightened ADHD symptoms had higher n-6:n-3s (ß = 0.30, p < 0.01) and higher TNF-α concentrations (ß = 0.35, p < 0.001) relative to controls. There were no group differences in dietary variables, as assessed by self-report and via plasma concentrations of essential fatty acids. IL-6 was not reliably associated with ADHD status in this sample. Conclusion: Pregnant individuals with ADHD, on average, had higher plasma n-6:n-3s and higher TNF-α concentrations relative to controls. A difference was not detected in their dietary intake of fatty acids or other relevant nutrients. Though these null findings are inconclusive, they are consistent with the hypothesis that ADHD-associated differences in plasma fatty acid concentrations are the result of ADHD-associated differences in fatty acid metabolism, rather than simply differences in dietary intake.

Synchronous Telehealth Yoga and Cognitive Processing Group Therapies for Women Veterans with Posttraumatic Stress Disorder: A Multisite Randomized Controlled Trial Adapted for COVID-19.

Background: Providing care over telehealth grew slowly until the COVID-19 pandemic. Since the onset of the COVID-19 pandemic, providing mental health care was readily adapted to virtual means; however, clinical trial research is nascent in adapting methods and procedures to the virtual world. Methods: We present protocol modifications to pivot a multisite randomized controlled trial study, conducted at Southeastern and Pacific Northwestern Veterans Affairs Health Care Systems, from being conducted in-person to virtually, following the onset of the COVID-19 pandemic. We measured outcomes of posttraumatic stress disorder (PTSD) symptoms and psychophysiological markers of stress among female Veterans with PTSD secondary to military sexual trauma. We collected qualitative data about provider and participant experiences with telehealth. Results: Across sites, 200 participants were consented (48 virtually), 132 were randomized (28 to virtual groups), and 117 completed data collection and treatment (69 completed all or some data collection or treatment virtually). Conclusions: The pivots made for this study were in response to the COVID-19 pandemic and offer innovative procedures leveraging technology and contributing to the broader landscape of conducting research virtually. Clinical Trials Number: NCT02640690.

Social relationship quality, depression and inflammation: A cross-cultural longitudinal study in the United States and Tokyo, Japan.

BACKGROUND: Depression is an illness with biological, psychological, and social underpinnings, which may include the interplay of inflammation, psychological traits, stress, social relationships, and cultural background. AIMS: This work examines the prospective associations between social relationship quality and depressive symptoms, and between social relationship quality and inflammatory outcomes in two distinct cultures. METHODS: Data were obtained from two longitudinal, prospective cohort studies: Midlife in the United States (MIDUS), and Midlife Development in Japan (MIDJA) between 2004 and 2010. One thousand three hundred and twenty-seven community-based adults were included in analyses, 1,054 from the United States and 273 from Tokyo, Japan. Depressive symptoms (measured by the CES-D Depression Scale) and inflammation (measured by blood sample concentrations of the inflammatory biomarkers interleukin-6 and C-reactive protein) were the outcomes. Social relationship quality was the predictor. Culture, trait independence and interdependence, and psychosocial stressors were examined as moderators of the link between social relationship quality and depressive symptoms. RESULTS: Higher social relationship quality was associated with lower depressive symptoms in the United States (ß = -6.15, p < .001), but not in Japan (ß = -1.25, p = .390). Social relationship quality had no association with inflammation. Psychosocial stressors moderated the link between social relationship quality and depressive symptoms in both the United States (ß = -0.39, p = .001) and Tokyo (ß = -0.55, p = .001), such that social relationship quality acted as a buffer against depressive symptoms as psychosocial stress increased. CONCLUSION: Improving the perceived quality of social relationships appears to be a stronger target for depression interventions in the United States than in Tokyo, Japan.

Cognition during active methamphetamine use versus remission.

OBJECTIVE: To evaluate whether cognitive performance in adults with active methamphetamine use (MA-ACT) differs from cognitive performance in adults in remission from MA use disorder (MA-REM) and adults without a history of substance use disorder (CTLs). METHOD: MA-ACT (n = 36), MA-REM (n = 48), and CTLs (n = 62) completed the Neuropsychological Assessment Battery (NAB). RESULTS: The MA-ACT group did not perform significantly worse than CTLs on any NAB Index. The MA-REM group performed significantly (p < 0.050) worse than CTLs on the NAB Memory Index. The MA-ACT group performed significantly better than CTLs and the MA-REM group on the Executive Functions Index. CONCLUSIONS: Some cognitive deficits are apparent during remission from MA use, but not during active use; this may result in clinical challenges for adults attempting to maintain recovery and continue with treatment.

Yoga for veterans with PTSD: Cognitive functioning, mental health, and salivary cortisol.

Objective: Research indicates that cognitive functioning is negatively impacted by exposure to chronic stress due to overactivation of the stress response. Yoga has demonstrated benefits when practiced by individuals diagnosed with posttraumatic stress disorder (PTSD). This quasi-experimental pilot study examined the impact of a yoga intervention on cognitive functioning, symptoms of PTSD, and the biological stress response in Veterans diagnosed with PTSD. Method: Cognitive functioning, self-report measures of mental health symptoms, and salivary cortisol were measured within two weeks prior to beginning and following completion of a 10-week yoga protocol. Veterans with PTSD participated in gender-specific groups of the yoga intervention. Paired t tests and correlational analyses were used to analyze quantitative data. Results: Statistically significant improvements were observed between baseline and postintervention scores on measures of response inhibition, PTSD, depression, sleep, quality of life, and subjective neurocognitive complaints. Positive correlations were found between baseline and postintervention changes in sleep and depression, and between change in cortisol output and a measure of life satisfaction. Statistically significant differences (baseline to postintervention) for other objective measures of cognitive performance and cortisol were not detected. Conclusions: Results provide preliminary support for the practice of yoga to improve cognitive functioning (response inhibition) related to symptoms of PTSD while also improving mental health symptoms, sleep, and quality of life. Positive correlations affirm the role of sleep in mood symptoms and indicate the need for further examination of the role of cortisol in life satisfaction. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Evaluation of maternal inflammation as a marker of future offspring ADHD symptoms: A prospective investigation.

Early life predictors of attention-deficit/hyperactivity disorder (ADHD) are critically needed; they could inform etiological theory and may help identify new prevention targets. The current study examined prospectively whether maternal cytokine levels during pregnancy predict offspring ADHD symptoms at age 4-6 years. Secondarily, we evaluated maternal cytokine levels as a possible common pathway through which prenatal risks exert influence on child ADHD. Data came from a sample of women recruited during the 2nd trimester of pregnancy (N = 62) and followed postnatally until children were 4-6 years old. Maternal inflammation was assessed using 3rd trimester plasma concentrations of three indicators of nuclear factor kappa B signaling: interleukin-6, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 which were combined into a latent variable. Mothers and teachers reported on child ADHD symptoms, negative affect, and externalizing behaviors at 48-72 months of age. Maternal inflammation in the 3rd trimester predicted ADHD symptoms when children were 4-6 years old (ß = 0.53, 95% CI = 0.154, 0.905, p = 0.006). Further, maternal inflammation mediated the effect of prenatal distress on child ADHD (ß = 0.21, 95% CI = 0.007, 0.419, p = 0.04). The inflammation effect on ADHD was not explained by concurrent child negative affect, externalizing behavior, or familial ADHD status. This is the first human study to prospectively link maternal pregnancy cytokine levels and offspring ADHD symptoms, suggesting that cytokine levels are a possible marker of ADHD risk. Results also provide new evidence that maternal prenatal inflammation may be one common pathway by which prenatal risk factors influence offspring mental health outcomes.

Partial MHC/neuroantigen peptide constructs attenuate methamphetamine-seeking and brain chemokine (C-C motif) ligand 2 levels in rats.

There are no medications that target the neurotoxic effects or reduce the use of methamphetamine. Recombinant T-cell receptor ligand (RTL) 1000 [a partial major histocompatibility complex (pMHC) class II construct with a tethered myelin peptide], addresses the neuroimmune effects of methamphetamine addiction by competitively inhibiting the disease-promoting activity of macrophage migration inhibitory factor to CD74, a key pathway involved in several chronic inflammatory conditions, including substance use disorders. We previously reported that RTL constructs improve learning and memory impairments and central nervous system (CNS) inflammation induced by methamphetamine in mouse models. The present study in Lewis rats evaluated the effects of RTL1000 on maintenance of self-administration and cue-induced reinstatement using operant behavioral methods. Post-mortem brain and serum samples were evaluated for the levels of inflammatory factors. Rats treated with RTL1000 displayed significantly fewer presses on the active lever as compared to rats treated with vehicle during the initial extinction session, indicating more rapid extinction in the presence of RTL1000. Immunoblotting of rat brain sections revealed reduced levels of the pro-inflammatory chemokine (C-C motif) ligand 2 (CCL2) in the frontal cortex of rats treated with RTL1000, as compared to vehicle. Post hoc analysis identified a positive association between the levels of CCL2 detected in the frontal cortex and the number of lever presses during the first extinction session. Taken together, results suggest that RTL1000 may block downstream inflammatory effects of methamphetamine exposure and facilitate reduced drug seeking-potentially offering a new strategy for the treatment of methamphetamine-induced CNS injury and neuropsychiatric impairments.

Methamphetamine use alters human plasma extracellular vesicles and their microRNA cargo: An exploratory study.

Methamphetamine (MA) is the largest drug threat across the globe, with health effects including neurotoxicity and cardiovascular disease. Recent studies have begun to link microRNAs (miRNAs) to the processes related to MA use and addiction. Our studies are the first to analyse plasma EVs and their miRNA cargo in humans actively using MA (MA-ACT) and control participants (CTL). In this cohort we also assessed the effects of tobacco use on plasma EVs. We used vesicle flow cytometry to show that the MA-ACT group had an increased abundance of EV tetraspanin markers (CD9, CD63, CD81), but not pro-coagulant, platelet-, and red blood cell-derived EVs. We also found that of the 169 plasma EV miRNAs, eight were of interest in MA-ACT based on multiple statistical criteria. In smokers, we identified 15 miRNAs of interest, two that overlapped with the eight MA-ACT miRNAs. Three of the MA-ACT miRNAs significantly correlated with clinical features of MA use and target prediction with these miRNAs identified pathways implicated in MA use, including cardiovascular disease and neuroinflammation. Together our findings indicate that MA use regulates EVs and their miRNA cargo, and support that further studies are warranted to investigate their mechanistic role in addiction, recovery, and recidivism.