Search

BACKGROUND: Adverse childhood experiences (ACEs) show a graded association with the development of substance use disorders and engagement in risky substance use behaviors. Women are overrepresented among individuals with more severe childhood adversity (≥4 types of ACEs) and may be at particular risk for aberrant substance use. OBJECTIVES: To assess the prevalence of ACEs among men and women with cannabis, opioid, cocaine, and tobacco use disorders. METHODS: Non-treatment-seeking individuals participating in clinical addiction research at a single site completed the ACE questionnaire and provided a detailed substance use history. Data were analyzed using proportional odds models and logistic regression. RESULTS: Most participants (424/565; 75%) reported at least one ACE, and more than one-quarter (156/565; 27%) reported severe childhood adversity. Relative to men (n=283), women (n=282) reported more ACEs (OR=1.49; p=0.01) and more experiences of emotional/physical abuse (OR=1.52; p=0.02), sexual abuse (OR=4.08; p=0.04), and neglect (OR=2.30; p

Background: The endothelial cell–dependent PC (protein C) pathway is critically involved in the regulation of coagulation, anti-inflammatory, and cytoprotective signaling. Its reactivity shows high interindividual variability, and it contributes to prothrombotic disorders, such as the FVL (factor V Leiden) mutation. Methods: Endothelial colony–forming cells (ECFCs) were isolated from heparinized peripheral blood from healthy individuals and FVL carriers. Confluent monolayers of ECFCs were overlaid with plasma, and thrombin formation was initiated by addition of tissue factor (1 pmol/L). Subsequently, thrombin and APC (activated PC) formation rates were measured over time using oligonucleotide-based enzyme capture assays. To induce downregulation of TM (thrombomodulin) expression, ECFCs were stimulated with IL-1β (interleukin 1β). In vivo APC response rates were monitored in study participants after infusion of low-dose rFVIIa (recombinant activated factor VII). Results: The median peak APC concentration was 1.12 nmol/L in experiments with IL-1β stimulated ECFCs and 3.66 nmol/L without IL-1β. Although thrombin formation rates were comparable, APC formation rates were significantly higher in FVL carriers (n=6) compared to noncarriers (n=5) as evidenced by a higher ratio between the area under the curve of APC generation to the area under the curve of thrombin generation (median 0.090 versus 0.031, P =0.017). These ex vivo results were correlated with an increased APC response to rFVIIa-induced thrombin formation in FVL carriers in vivo. Conclusions: Patient-specific ex vivo modeling of the PC pathway was achieved using blood-derived ECFCs. The correlation between in and ex vivo APC response rates confirms that the autologous PC model accurately depicts the in vivo situation.

DNA sensor pathways can initiate inflammasome, cell death and type I interferon (IFN) signalling in immune-mediated inflammatory diseases (IMIDs); including type I interferonopathies. We investigated the involvement of these pathways in the pathogenesis of ulcerative colitis (UC); by analysing expression of DNA sensor, inflammasome, and type I IFN biomarker genes in colonic mucosal biopsy tissue from control (n=31), inactive UC (n=31), active UC (n=33) and a UC single cell RNA-Seq dataset. The effects of type I IFN (IFN-β), IFN-γ and TNF-α on gene expression, cytokine production and cell death were investigated in human colonic organoids. In organoids treated with cytokines alone, or in combination with NLRP3, caspase or JAK inhibitors, cell death was measured, and supernatants were assayed for IL-1β/IL-18/CXCL10. The expression of DNA sensor pathway genes - PYHIN family members (AIM2, IFI16, MNDA, PYHIN1), as well as ZBP1, cGAS and DDX41 were increased in active UC and expressed in a cell type restricted pattern. Inflammasome genes (CASP1, IL1B, IL18), type I IFN inducers (STING, TBK1, IRF3), IFNB1 and type I IFN biomarker genes (OAS2, IFIT2, MX2) were also increased in active UC. Co-treatment of organoids with IFN-β or IFN-γ and TNFα increased expression of IFI16, ZBP1, CASP1, cGAS and STING, induced cell death and IL-1β/IL-18 secretion. This inflammatory cell death was blocked by the JAK inhibitor tofacitinib but not by inflammasome or caspase inhibitors. Increased type I IFN activity may drive elevated expression of DNA sensor genes and JAK-dependent but inflammasome-independent inflammatory cell death of colonic epithelial cells in UC.

A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) is a metalloprotease that regulates the size of circulating von Willebrand factor (vWF) multimers. Severe lack of ADAMTS-13 activity [10% of normal (0.1 IU/mL)] leads to thrombotic thrombocytopenic purpura (TTP), a specific type of thrombotic microangiopathy (TMA). Timely determination of plasma ADAMTS-13 activity is essential to discriminate TTP from other types of TMA with respect to adequate treatment. Identification of the minimal substrate motif for ADAMTS-13 within the A2 domain of vWF (vWF73) as well as the generation of monoclonal antibodies (mAbs) that specifically recognize the ADAMTS-13 cleavage site enabled the development of a variety of methods for determination of plasma ADAMTS-13 activity. In order to further extend the range of analytical platforms applicable for quantitative determination of plasma ADAMTS-13 activity, a specific, vWF/mAb-based assay with flow cytometric readout was developed and validated. Basic assay characteristics include a total assay time of 80 to 90 min, a near linear dynamic range from 0.005 (lower limit of quantification) to 0.2 IU/mL, and intra- and interassay coefficients of variation below 5 and 30% at input plasma ADAMTS-13 activities of 0.015 and ≤0.050 IU/mL, respectively. When compared to the results obtained with a commercially available quantitative ADAMTS-13 activity ELISA, analysis of 18 plasma samples obtained from patients with suspected TTP revealed full agreement of results with respect to the clinical 0.1 IU/mL TTP threshold. Based on these data, it is assumed that the described assay principle can be successfully transferred to virtually all laboratories that have a flow cytometer available.

OBJECTIVE Abstinence is rarely achieved in clinical trials for cannabis use disorder (CUD). Cannabis reduction is associated with functional improvement, but reduction endpoints have not been established, indicating a need to identify and validate clinically meaningful reduction endpoints for assessing treatment efficacy. METHOD Data from a 12-week double-blind randomized placebo-controlled medication trial for cannabis cessation (NCT01675661) were analyzed. Participants (N = 225) were treatment-seeking adults, M = 30.6 (8.9) years old, 70.2% male, and 42.2% Non-White, with CUD who completed 12 weeks of treatment. Frequency (days of use per week) and quantity (grams per using day) were used to define high-, medium-, and low-risk levels. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale and cannabis-related problems were assessed using the Marijuana Problems Scale. General linear models for repeated measures tested associations between the magnitude of risk reduction and functional outcomes from baseline (BL) to end-of-treatment (EOT). RESULTS Cannabis risk levels were sensitive to reductions in use from BL to EOT for frequency- (χ² = 19.35, p = .004) and quantity-based (χ² = 52.06, p < .001) metrics. Magnitude reduction in frequency-based risk level was associated with magnitude decrease in depression (F = 2.76, p = .043, ηp² = .04), anxiety (F = 3.70, p = .013, ηp² = .05), and cannabis-related problems (F = 8.95, p < .001, ηp² = .12). Magnitude reduction in quantity-based risk level was associated with magnitude decrease in anxiety (F = 3.02, p = .031, ηp² = .04) and cannabis-related problems (F = 3.24, p = .023, ηp² = .05). CONCLUSIONS Cannabis use risk levels, as operationalized in this study, captured reductions in use during a clinical trial. Risk level reduction was associated with functional improvement suggesting that identifying risk levels and measuring the change in levels over time may be a viable and clinically meaningful endpoint for determining treatment efficacy. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background Sleep disturbance in individuals prescribed medications for opioid use disorder (MOUD) is common, though the nature and progression of such concerns are difficult to discern due to differing terminology and assessment type between studies. Accurately identifying and treating sleep problems in this growing population has the potential to improve comorbidity and other MOUD outcomes. Objective The aim of the present review is to provide an overview of sleep in individuals stabilized on MOUD. Specifically, the following aspects of sleep were reviewed: 1) prevalence of clinically significant sleep disturbance; 2) sleep disturbance compared to findings in those not prescribed MOUD; 3) correlates of sleep disturbance; 4) self-reported sleep compared to objective measures. Method Studies were identified using 6 large databases and included if they contained at least one measure of sleep during MOUD treatment as usual. Studies were excluded if they were case studies, not available in English, or participants were in withdrawal or detoxification. Results Forty-two studies were included and categorized by type of sleep assessment: validated self-report questionnaire; provider-assessed; polysomnography; multi-method. Correlates were included if they were statistically significant (generally p Conclusions This review indicates there is a high prevalence of chronic self-reported sleep disturbance (eg, insomnia symptoms) in this population and suggests quantitative sleep parameters (eg, total sleep time) and respiratory problems during sleep are worse than in the general population. These sleep problems are correlated with psychiatric comorbidity and other substance use. Other correlates (eg, sociodemographic factors) require further study to draw definitive conclusions.

Substance use continues to contribute to significant morbidity and mortality in the United States, for both women and men, more so than any other preventable health condition. To reduce the public health burden attributable to substances, the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism have identified that medication development for substance use disorder is a high priority research area. Furthermore, both Institutes have stated that research on sex and gender differences in substance use medication development is a critical area. The purpose of the current narrative review is to highlight how sex and gender have been considered (or not) in medication trials for substance use disorders to clarify and summarize what is known regarding sex and gender differences in efficacy and to provide direction to the field to advance medication development that is consistent with current NIH ‘sex as a biological variable’ (SABV) policy. To that end, we reviewed major classes of abused substances (nicotine, alcohol, cocaine, cannabis, opioids) demonstrating that, sex and gender have not been well-considered in addiction medication development research. However, when adequate data on sex and gender differences have been evaluated (i.e., in tobacco cessation), clinically significant differences in response have been identified between women and men. Across the other drugs of abuse reviewed, data also suggest sex and gender may be predictive of outcome for some agents, although the relatively low representation of women in clinical research samples limits making definitive conclusions. We recommend the incorporation of sex and gender into clinical care guidelines and improved access to publicly available sex-stratified data from medication development investigations.

BACKGROUND In recent years, there has been renewed interest in whole blood (WB) transfusion, particularly in damage control resuscitation, in part due to the ability to provide the adequate ratio of blood components in a single transfusion. However, there is insufficient evidence to suggest that WB units maintain their haemostatic function during storage, which could compromise their quality and efficacy if transfused. Here, we evaluate the in vitro haemostatic function of stored WB units over a 28-day refrigeration period. METHODS Standard WB units were collected from healthy volunteers and stored at 4°C for 28 days. Samples were collected from each unit on several days throughout the storage period and tested for complete blood count (CBC), WB aggregation, clot kinetics as measured by thromboelastography (TEG), closure time and plasma-free haemoglobin. RESULTS Throughout the storage period, there were gradual, significant decreases in platelet count and function, including WB aggregation in response to collagen (P

Ischemia–reperfusion injury (IRI) is a complex inflammatory process that detrimentally affects the function of transplanted organs. Neutrophils are important contributors to the pathogenesis of renal IRI. Signaling by G-CSF, a regulator of neutrophil development, trafficking, and function, plays a key role in several neutrophil-associated inflammatory disease models. In this study, we investigated whether targeting neutrophils with a neutralizing mAb to G-CSFR would reduce inflammation and protect against injury in a mouse model of warm renal IRI. Mice were treated with anti–G-CSFR 24 h prior to 22-min unilateral renal ischemia. Renal function and histology, complement activation, and expression of kidney injury markers, and inflammatory mediators were assessed 24 h after reperfusion. Treatment with anti–G-CSFR protected against renal IRI in a dose-dependent manner, significantly reducing serum creatinine and urea, tubular injury, neutrophil and macrophage infiltration, and complement activation (plasma C5a) and deposition (tissue C9). Renal expression of several proinflammatory genes (CXCL1/KC, CXCL2/MIP-2, MCP-1/CCL2, CXCR2, IL-6, ICAM-1, P-selectin, and C5aR) was suppressed by anti–G-CSFR, as was the level of circulating P-selectin and ICAM-1. Neutrophils in anti–G-CSFR–treated mice displayed lower levels of the chemokine receptor CXCR2, consistent with a reduced ability to traffic to inflammatory sites. Furthermore, whole transcriptome analysis using RNA sequencing showed that gene expression changes in IRI kidneys after anti–G-CSFR treatment were indistinguishable from sham-operated kidneys without IRI. Hence, anti–G-CSFR treatment prevented the development of IRI in the kidneys. Our results suggest G-CSFR blockade as a promising therapeutic approach to attenuate renal IRI.

Background Platelet transfusion is associated with logistical problems with the national storage guidelines of platelets. This results in decreased function in vivo as a result of the platelet storage lesion, and complications such as allergic or hemolytic reactions and thrombosis. We evaluated a new, freshly prepared platelet modified lysate (PML) product designed to be more procoagulant than fresh and stored platelets. Methods Fresh platelets were concentrated, sonicated, and centrifuged to produce PML. Samples of both washed and unwashed PML were evaluated for particle size, concentration, and activity, and then tested for clot kinetics and thrombin generation. PML samples were also stored at various temperatures for durations up to 6 months and evaluated for clot kinetics and thrombin generation throughout. Results PML showed significantly higher concentration of platelet microparticles, increased procoagulant properties, and increased thrombin generation as compared to fresh and stored platelets. In addition, PML maintained its clot kinetics over a 6-month storage period with variable storage conditions. Conclusions The newly proposed PML product is more procoagulant, stable, and has additional potential applications than currently available platelet products. Further studies will be performed to assess its functions in vivo and to assess thrombotic potential.

RATIONALE: Cocaine use disorder (CUD) is associated with dysregulation of the hypothalamic-pituitary-adrenal axis, which plays a critical role in the human stress response. Men and women with CUD differ in reactivity to social stressors. The hypothalamic neuropeptide oxytocin is involved in anxiolytic and natural reward processes, and has shown therapeutic potential for addictive disorders and stress reduction. OBJECTIVES: To examine the impact of oxytocin (oxytocin (OXY) vs. placebo (PBO)) and gender (female (F) vs. male (M)) on response to a social stress task in individuals with CUD. To explore whether ovarian hormones moderate this stress response. METHODS: One hundred twelve adults with CUD were randomized to receive 40 IU intranasal oxytocin (n = 56) or matching placebo (n = 56). Forty minutes after drug administration, participants were exposed to a social stressor. Generalized linear mixed models were used to examine neuroendocrine (cortisol) and subjective (craving, stress) response at pre-stressor, stressor + 0, + 10, + 30, + 60 min. RESULTS: Gender moderated the effect of oxytocin on neuroendocrine response (p = 0.048); women receiving oxytocin (F + OXY) showed blunted cortisol response compared to the other three groups (F + PBO; M + OXY; M + PBO). There was a main effect of gender on subjective stress response; women reported greater stress following the stressor compared to men (p = 0.016). Oxytocin had no significant effect on craving or stress, and gender did not moderate the effect of oxytocin on either measure. Higher endogenous progesterone was associated with lower craving response in women (p = 0.033). CONCLUSIONS: Oxytocin may have differential effects in men and women with CUD. Women may be at greater risk for relapse in response to social stressors, but ovarian hormones may attenuate this effect.

Endurance training enhances the capacity for fat oxidation during exercise due to increased utilization of intramuscular lipid (IMCL). This study quantitatively investigated the impact of exercise training status on muscle fiber type-specific abundance of regulatory proteins involved in IMCL utilization. Endurance-trained [ n = 7 subjects, peak oxygen consumption (V̇o2peak) 62.6 ± 4.1 (SD) mL·min−1·kg−1] and non-endurance-trained ( n = 8 subjects, V̇o2peak 44.9 ± 5.3 mL·min−1·kg−1) young men completed an incremental exercise test to determine maximal fat oxidation (MFO) and maximal oxygen uptake. Fiber type-specific IMCL content and protein abundance were assessed with immunofluorescence microscopy and immunoblot analysis of pooled single muscle fibers and whole muscle. Endurance-trained individuals displayed a higher MFO rate (0.45 ± 0.15 vs. 0.19 ± 0.07 g/min, P < 0.05), a greater proportion of type I muscle fibers, and higher IMCL content compared with untrained individuals ( P < 0.05). Adipose triglyceride lipase, hormone-sensitive lipase, perilipin 2, perilipin 5, and hydroxyacyl-coenzyme A dehydrogenase abundances were ~2–3-fold higher in type I muscle fibers compared with type IIa fibers ( P < 0.05). Correspondingly, these lipid proteins and oxidative enzymes were higher in endurance-trained individuals when assessed in whole muscle. MFO rate was strongly related to the proportion of type I fibers ( R = 0.81, P < 0.01). The abundance of proteins involved in the regulation of IMCL storage and oxidation is highly muscle fiber type specific. The increased capacity for fat oxidation in endurance-trained individuals corresponded with increased IMCL content and elevated abundance of lipolytic and oxidative enzymes in combination with a greater proportion of type I muscle fibers. NEW & NOTEWORTHY We have utilized contemporary techniques to compare the fiber type-specific characteristics of skeletal muscle from endurance-trained athletes and untrained individuals. We show that type I muscle fibers have a coordinated upregulation of proteins controlling intramuscular lipid storage, mobilization, and oxidation. Furthermore, the enhanced capacity for intramuscular lipid storage and utilization in endurance-trained individuals is related to the increased expression of lipid regulatory proteins combined with a greater proportion of type I muscle fibers.

RATIONALE. Depression is common among individuals with cannabis use disorder (CUD), particularly individuals who present to CUD treatment. Treatments that consider this comorbidity are essential. OBJECTIVES. The goal of this secondary analysis was to examine whether N-Acetylcysteine (NAC) reduced depressive symptoms among adults (age 18–50) with CUD (N=302) and whether the effect of NAC on cannabis cessation varied as a result of baseline levels of depression. Bidirectional associations between cannabis use amount and depression were also examined. METHODS. Data for this secondary analysis were from a National Drug Abuse Treatment Clinical Trials Network (NIDA CTN) multi-site clinical trial for CUD. Adults with CUD (N=302) were randomized to receive 2400 mg of NAC daily or matched placebo for 12 weeks. All participants received abstinence-based contingency management. Cannabis quantity was measured by self-report, and weekly urinary cannabinoid levels (11-nor-9-carboxy-Δ9-tetrahydrocannabinol) confirmed abstinence. Depressive symptoms were measured by the Hospital Anxiety and Depression Scale. RESULTS. Depressive symptoms did not differ between the NAC and placebo groups during treatment. There was no significant interaction between treatment and baseline depression predicting cannabis abstinence during treatment. Higher baseline depression was associated with decreased abstinence throughout treatment and a significant gender interaction suggested that this may be particularly true for females. Cross-lagged panel models suggested that depressive symptoms preceded increased cannabis use amounts (in grams) during the subsequent month. The reverse pathway was not significant (i.e, greater cannabis use preceding depressive symptoms). CONCLUSIONS. Results from this study suggest that depression may be a risk factor for poor CUD treatment outcome and therefore should be addressed in the context of treatment. However, results do not support the use of NAC to concurrently treat co-occurring depressive symptoms and CUD in adults.

Inflammatory bowel disease (IBD) is characterized by a dysregulated intestinal epithelial barrier leading to breach of barrier immunity. Here we identified similar protein expression changes between IBD and Citrobacter rodentium-infected FVB mice with respect to dysregulation of solute transporters as well as components critical for intestinal barrier integrity. We attribute the disease associated changes in the model to the emergence of undifferentiated intermediate intestinal epithelial cells. Prophylactic treatment with IL-22.Fc in C. rodentium-infected FVB mice reduced disease severity and rescued the mice from lethality. Multi-omics and solute analyses revealed that IL-22.Fc treatment prevented disease-associated changes including disruption of the solute transporter machinery and restored proper physiological functions of the intestine, respectively. Taken together, we established the disease relevance of the C. rodentium-induced colitis model to IBD, demonstrated the protective role of IL-22 in amelioration of epithelial dysfunction and elucidated the molecular mechanisms with IL-22's effect on intestinal epithelial cells.

Poor sleep health is common among individuals in early treatment for substance use disorders (SUDs) and may serve an important role in predicting SUD outcomes. However, sleep parameters have been inconsistently linked with risk of relapse, perhaps because previous research has focused on mean values of sleep parameters (e.g., total sleep time [TST], sleep efficiency [SE], and sleep midpoint [SM]) across multiple nights rather than night-to-night fluctuations (i.e., intraindividual variability [IIV]). The current study assessed sleep across the first week of SUD treatment, with the aim of prospectively examining the relationship between mean and IIV of TST, SE, and SM and treatment completion and relapse within one-month post-treatment.Treatment-seeking adults (N = 23, MGreater IIV in TST was associated with higher odds of relapse (OR = 3.55, p =.028). Greater IIV in SM was associated with lower odds of treatment completion, but only when removing mean SM from the model (OR = 0.75, p =.046).Night-to-night variability in actigraphy-measured TST is more strongly associated with SUD treatment outcomes than average sleep patterns across the week. Integrating circadian regulation into treatment efforts to improve SUD treatment outcomes may be warranted. Given the small sample size utilized in the present study, replication of these analyses with a larger sample is warranted.

The complement system is a potent mediator of ischemia–reperfusion injury (IRI), which detrimentally affects the function and survival of transplanted kidneys. Human complement receptor 1 (HuCR1) is an integral membrane protein that inhibits complement activation by blocking the convertases that activate C3 and C5. We have previously reported that CSL040, a truncated form of recombinant soluble HuCR1 (sHuCR1), has enhanced complement inhibitory activity and improved pharmacokinetic properties compared to the parent molecule. Here, we compared the capacity of CSL040 and full-length sHuCR1 to suppress complement-mediated organ damage in a mouse model of warm renal IRI. Mice were treated with two doses of CSL040 or sHuCR1, given 1 h prior to 22 min unilateral renal ischemia and again 3 h later. 24 h after reperfusion, mice treated with CSL040 were protected against warm renal IRI in a dose-dependent manner, with the highest dose of 60 mg/kg significantly reducing renal dysfunction, tubular injury, complement activation, endothelial damage, and leukocyte infiltration. In contrast, treatment with sHuCR1 at a molar equivalent dose to 60 mg/kg CSL040 did not confer significant protection. Our results identify CSL040 as a promising therapeutic candidate to attenuate renal IRI and demonstrate its superior efficacy over full-length sHuCR1 in vivo.

Solvent/detergent-treated, pooled plasma (SDP) is approved for use in orthotopic liver transplantation (OLT) and thrombotic thrombocytopenic purpura (TTP) patients; however, studies evaluating safety and effectiveness of SDP in these populations are limited.This prospective study included two cohorts: OLT patients (n = 40) who received either SDP (n = 20) or FFP (control group) (n = 20), and TTP patients (n = 20) who received either SDP (n = 10) or FFP (control group) (n = 10) throughout hospitalization. Medical, laboratory, and blood bank records were retroactively assessed for both cohorts for differences in clinical outcomes, laboratory values, and transfusion data from admission to discharge.In the OLT cohort, significant changes in AST and ALP were observed in the control group as compared to SDP (p .05 each), and creatinine levels improved significantly in the SDP group as compared to the control group (p .05) from admission to discharge. In the TTP cohort, platelet counts were significantly improved within the control and SDP groups from admission to discharge, but there were no significant differences between groups (p = .31). LDH levels improved between admission and discharge for both groups (70% decrease in the control group, p .001, and 80% decrease in the SDP group, p = .001). There were no significant differences detected in clinical outcomes in either cohort.As evidenced by the lack of adverse events in either cohort and similar clinical outcomes, we conclude that SDP is comparable in safety and effectiveness to FFP in OLT and TTP patients. Further studies are needed to evaluate the potential for improved safety with SDP.

Purpose To image colon-expressed alternatively spliced D domain of tenascin C in preclinical colitis models using near infrared (NIR) labeled targeted molecular imaging agents.Methods Human IgG and scFv fusion proteins specific to the alternatively spliced D domain of tenascin C were generated. Immunohistochemistry identified disease-specific expression of this extracellular matrix in mouse colitis models. Proteins were labeled with the NIR fluorophore IRDye 800CW via amine chemistry and intravenously dosed to evaluate targeting specificity in preclinical rodent and primate colitis models.Results The NIR labeled proteins successfully targeted colonic lesions in a murine model of colitis and appeared as distinct punctate spots. Co-administration of a blocking dose reduced the whole colon standardized uptake of the fluorescent dose >7-fold in mouse models. Estimates suggest local expression at >100 nM in diseased mouse colon. Macroscopic targeting specificity was not observed in diseased primate colon. Cellular level specificity was assessed via microscopy and immunohistochemistry.Conclusion Our imaging data suggest the alternatively spliced D domain of tenascin C is a promising target for delivery-based applications in inflammatory bowel diseases.

BACKGROUND. Distress tolerance (DT) has been implicated as an important factor in the experience of negative affect (NA) and cannabis craving. However, previous research is limited by its use of laboratory paradigms that may not replicate in naturalistic settings. The current study examined how DT influenced reactivity to NA cues in daily life in a sample of frequent (≥3 times per week) cannabis-using emerging adults (age 18-21). METHODS. Using cue-reactivity ecological momentary assessment (CREMA), 63 (54% female; 85.7% white; M(age) = 19.62) participants reported on their cannabis craving and affect (sadness, relaxation) four semi-random times per day for two weeks (56 possible CREMA sessions/participant). We assessed affect and cannabis craving before and after exposure to neutral and NA cues. Multilevel modeling was used to examine within- and between-participant effects of cues, DT, and sex, as well as within- and between-participant average pre-cue affect and craving, on post-cue affect and craving. RESULTS. NA cues consistently predicted higher-than-normal post-cue sadness and lower relaxation, but not greater-than-normal post-cue craving. Cue type interacted with sex and DT to predict post-cue sadness, but not craving. Female participants and those reporting low DT reported higher sadness following NA cues compared to males and those with high DT, respectively. CONCLUSIONS. Frequent cannabis-using emerging adults differed in affect, but not cannabis craving, reactivity to NA cues as a function of sex and DT. Our results were partially consistent with prior human laboratory and CREMA research finding greater reactivity to NA cues among females and individuals with low DT.

The hypothalamic-pituitary-adrenal (HPA) axis is a critical hormonal system involved in stress response. A number of studies have investigated the HPA axis response of drug-dependent individuals to stressors. Stress-induced vulnerabilities in the HPA axis may differ in response to chronic use of different substances, possibly leading to different target therapies. There has not been a direct comparison of HPA axis and subjective response between individuals with different types of substance use disorders following a laboratory stress intervention.The primary goal of the current study was to compare subjective and neuroendocrine response to the Trier Social Stress Task (TSST) across multiple primary types of substance use disorders and investigate differential response between males and females.Four hundred participants were drawn from seven studies completed at the Medical University of South Carolina between 2011 and 2021. The TSST was utilized across studies and subjective and neuroendocrine responses measured following completion. Generalized linear mixed effects models and area under the response curve analysis were used to compare both substance type and sex differences.The study groups involving individuals with cocaine use disorder had blunted stress, craving and cortisol response following the TSST as compared to other substance use groups. Females in the cocaine groups reported higher subjective stress but lower cortisol than males.The study results indicate that there may be differential effects of substances on the HPA axis, with cocaine using individuals exhibiting more blunting of the HPA axis response as compared to users of other substances.

BACKGROUND AND OBJECTIVES Characteristics of sleep concerns and their relationship to mental health in heterogeneous substance use disorder (SUD) treatment settings are not well understood. The purpose of this preliminary study was to assess sleep using subjective and objective measures at two time points during SUD treatment and compare sleep changes to changes in mental health measures. METHODS Treatment-seeking participants completed an assessment battery at the beginning of treatment (Time 1, N = 30) and again upon treatment completion (Time 2, approximately 4 weeks later, N = 22). The majority of participants were White (80%), male (63%), and presenting for alcohol use disorder (60.0%), though almost half reported polysubstance abuse (43%). Comorbidity was common (53%). Sleep and mental health questionnaires with 1 week of actigraphy and sleep diaries were completed at both time points. RESULTS Most participants met the criteria for a sleep disorder and mean scores on questionnaires showed poor sleep quality, insomnia symptoms, and frequent nightmares, with sleep quality and insomnia improving over time but remaining clinically significant. Nightmares did not improve. Actigraphy indicated poor sleep at both time points. Improvement in insomnia was related to improvement in measures of mental health while changes in actigraphy variables were not related to these measures. DISCUSSION AND CONCLUSIONS Multiple types of sleep disturbance are prevalent in this population, with nightmares persisting throughout treatment and insomnia symptoms showing a relationship with mental health symptoms. SCIENTIFIC SIGNIFICANCE This was the first study to longitudinally assess mental health with subjective and objective measures of sleep across multiple types of SUDs in a community SUD treatment setting.

Opioid Use Disorders (OUDs) and drug overdose deaths are increasing at alarmingly high rates in the United States. Stress and dysregulation in biologic stress response systems such as the hypothalamic-pituitary-adrenal axis and noradrenergic system appear to play an important role in the pathophysiology of substance use disorders and relapse to drug use, particularly for women. Alpha-2 adrenergic agonist medications effectively decrease noradrenergic activity and have demonstrated benefit in preventing relapse to substance use and decreasing stress-reactivity and craving in cocaine- and nicotine-dependent women, compared to men. Alpha-2 adrenergic agonists may help decrease stress reactivity in individuals with OUDs and prevent relapse to drug use, but gender differences have yet to be systematically explored. We describe the rationale, study design and methodology of a randomized, double-blind, placebo-controlled clinical trial examining gender differences in stress, craving and drug use among adult men and women with OUD taking methadone or buprenorphine and randomly assigned to an alpha-2 adrenergic agonist, lofexidine, compared to placebo. In addition, we describe methods for measuring daily stress, craving and drug use in participant's natural environment as well as participant's physiological (i.e., heart rate, cortisol) and psychological (i.e., stress, craving) response to laboratory social and drug cue stressors. Lastly, we detail methods adopted to sustain research activity while following guidelines for the COVID-19 pandemic. ClinicalTrials.gov Registration Number: NCT03718065.

OBJECTIVE: U.S. Food and Drug Administration (FDA)–approved medications exist for the treatment of alcohol use disorders. However, their effectiveness depends on proper adherence to the prescribed regimen. Differences in adherence across medications may have implications for clinical outcomes and may provide helpful information in considering treatment options. This study aims to identify significant differences in adherence if present. METHOD: A retrospective chart review was conducted in the Veterans Integrated Service Networks (VISN)-7 region of Veterans Affairs hospital and community-based outpatient clinics within South Carolina and Georgia. Prescriptions of FDA-approved alcohol use disorder medications from 2010 through 2015 were reviewed. Adherence was determined by the proportion of days the veteran had oral or injectable medication available over a 6-month period as noted by medication fills (reported as 0%–100% medication availability). We compared adherence for specific medications using chi-square, t test, logistic regression for dichotomous outcomes, and linear regression for continuous outcomes. RESULTS: A total of 715 subjects and 807 medication trials were included. Mean adherence (percentage of days that medication was available) was 41.3% for disulfiram, 44.7% for acamprosate, 49.8% for oral naltrexone, and 54.6% for extended-release injectable naltrexone. The mean adherence was significantly different between disulfiram and oral naltrexone (p = .002) as well as disulfiram and extended-release injectable naltrexone (p = .004). Adherence of 80% was achieved in 11.9%, 19.4%, 22.7%, and 24.4% of treatment courses with disulfiram, acamprosate, naltrexone, and extended-release injectable naltrexone, respectively. These differences were significant for disulfiram versus oral naltrexone (p = .004) and disulfiram versus extended-release injectable naltrexone (p = .05). CONCLUSIONS: These results demonstrate that overall adherence to medication-assisted treatment for alcohol use disorder is low across all medications. When directly compared, disulfiram had significantly lower adherence than both oral and extended-release injectable naltrexone.

Objective To evaluate the effects of use of the Kaiser Neonatal Early-Onset Sepsis Calculator (NEOSC) on NICU admissions, laboratory testing, antibiotic exposure, and exclusive breastfeeding (EBF) rates in full-term neonates exposed to chorioamnionitis. Design Quality improvement project with review of retrospective data. Setting/Local Problem In this single-site, community hospital with approximately 4,000 births per year, all neonates exposed to chorioamnionitis required NICU admission, laboratory evaluation, and empiric antibiotics. Participants Term neonates born to mothers diagnosed with chorioamnionitis identified through the International Classification of Diseases, Tenth Revision codes based on the discharge diagnosis. Intervention/Measurements The baseline retrospective analysis included calculation of sepsis risk with the Kaiser NEOSC through a chart review of neonates exposed to chorioamnionitis from January 1, 2015, to December 31, 2016. We compared the risk for sepsis with actual laboratory testing and antibiotic use and examined EBF before implementation of the use of the NEOSC. Implementation began January 2017; postintervention data were examined at 6 months and 1 year. All cases of neonates exposed to chorioamnionitis after the intervention were reviewed for use of the NEOSC, NICU admission/readmission for sepsis, laboratory testing, use of antibiotics, and EBF. Results In the 12 months after NEOSC use was implemented, NICU admissions, laboratory testing, and antibiotic use decreased. Among all neonates exposed to chorioamnionitis after implementation (N = 74), 68 (93%) were not admitted to the NICU, and only 8 (11%) required laboratory evaluation. Rates of EBF in neonates exposed to chorioamnionitis increased from less than 10% to greater than 50% after implementation. The length of the NICU stay for neonates exposed to chorioamnionitis decreased from an average of 138 to 12 days with no negative consequences. Conclusion Most neonates exposed to chorioamnionitis appeared well and did not require NICU admission, laboratory testing, or antibiotic therapy. Rates of EBF improved after use of NEOSC was implemented. The practice change helped prevent adverse consequences, such as painful interventions and separation of the mother and neonate. No neonates were readmitted for sepsis.

Cell saver blood is typically washed with normal saline (NS); however, recent studies have reported decreased red blood cell hemolysis and increased platelet function when a more physiologic washing solution, such as Plasma-Lyte A (PL-A) is used. We evaluated the in vitro and in vivo effects of NS compared to PL-A as washing solutions for cell saver blood in pediatric cardiac surgery. Cell saver blood was re-infused for up to 24 hours post-collection. Laboratory and clinical data were collected from infants receiving cell saver washed with either NS (n = 20) or PL-A (n = 21). Compositions of the cell saver blood were compared between groups at 5 in vitro time points and in vivo patient blood at 24 hours post-bypass. Although there were differences in in vitro laboratory values between groups; 24 hours post-bypass, in vivo results were similar. Our data supports 24-hour reinfusion of cell saver washed with either NS versus PL-A in pediatric cardiac surgery patients, and provides data on the differences in cell saver composition to guide future studies.

Background Little is known about chronic cannabis smoking-associated oral microbiome and its effects on central nervous system (CNS) functions. Results In the current study, we have analyzed the saliva microbiome in individuals who chronically smoked cannabis with cannabis use disorder and in non-smoking controls. We found that cannabis smoking in humans was associated with oral microbial dysbiosis. The most increased oral bacteria were Streptococcus and Actinomyces genus and the most decreased bacteria were Neisseria genus in chronic cannabis smokers compared to those in non-smokers. To investigate the function of cannabis use-associated microbiome, mice were orally exposured to Actinomyces. meyeri, Actinomyces. odontolyticus, or Neisseria. elongate through oral gavage twice per week for six months which mimics human conditions. Strikingly, oral exposure of Actinomyces meyeri, an oral pathobiont, but not the other two control bactreria, decreased global activity and increased β-amyloid 42 protein production in the mouse brains. Conclusions This is the first study to reveal that cannabis-associated enrichment of Actinomyces meyeri may contribute to a hallmark of neuropathology.

Objectives RBCs are known to undergo deleterious changes during storage, known as storage lesions, which have been shown to result in decreased oxygen-carrying capacity. However, there is inadequate literature describing the effects of stored RBC allogeneic transfusion on oxygen parameters in vivo. The oxygen standard parameters were retrospectively assessed before and after RBC transfusion. Methods Patients who received 1 RBC transfusion were assessed for hemoglobin (Hb) levels, peripheral capillary oxygen saturation (Spo2), and partial pressure of arterial oxygen (Pao2) from 12 hours before and 24 hours after transfusion. Results In total, 78 patients who were monitored by Spo2 and 28 patients monitored by Pao2 were included in this analysis. Following RBC transfusion, Hb levels increased significantly (P Conclusions This single-center, retrospective study revealed evidence of significantly decreased oxygenation and tissue perfusion after single-unit RBC transfusion, despite corrected Hb levels.

There is considerable variability in the use of outcome measures in clinical trials for cannabis use disorder (CUD), and a lack of consensus regarding optimal outcomes may have hindered development and approval of new pharmacotherapies. The goal of this paper is to summarize an evaluation of assessment measures and clinical endpoints for CUD clinical trials, and propose a research agenda and priorities to improve CUD clinical outcome assessments. The primary recommendation is that sustained abstinence from cannabis should not be considered the primary outcome for all CUD clinical trials as it has multiple limitations. However, there are multiple challenges to the development of a reliable and valid indicator of cannabis reduction, including the lack of a standard unit of measure for the various forms of cannabis and products and the limitations of currently available biological and self-report assessments. Development of a core toolkit of assessments is needed to both allow flexibility for study design, while facilitating interpretation of outcomes across trials. Four primary agenda items for future research are identified to expedite development of improved clinical outcome assessments for this toolkit: (1) determine whether minimally invasive biologic assays could identify an acute level of cannabis use associated with psychomotor impairment or other cannabis-related harms; (2) create an indicator of quantity of cannabis use that is consistent across product types; (3) examine the presence of cannabis-specific functional outcomes; and (4) identify an optimal duration to assess changes in CUD diagnostic criteria.

Background: The role and mechanism of drug use or abuse in Antiretroviral Therapy (ART)-treated HIV disease are not completely known. Methods: To investigate the impact of drug use on HIV pathogenesis without confounding by HIV replication and ART adherence, we first analyzed the data from our clinical database in 103 HIV+ subjects with viral-suppressed ART treatment by a multiple regression test. Results: We found that HIV+ drug users had lower CD4+ T cell counts but higher CD8+ T cell counts compared to HIV+ non-drug users, and both drug use and nadir CD4+ T cell counts was independently associated with CD4+ T cell recovery after controlling for sex and age. Next, we enrolled individuals from four study groups, HIV-negative and HIV+ subjects without any substance use, HIV-negative and HIV+ subjects with current illicit drug use (either non-injection cocaine or cannabis). All HIV+ subjects were viral-suppressed with ART treatment (≥ 2 years). Notably, HIV+ drug users had increased plasma anti-CD4 IgG levels compared to the other three study groups which were inversely correlated with decreased CD4+ T cell counts only in HIV+ drug users. There was a significant increase in CD4+ T cell recovery following ART in HIV+ non-drug users but not in HIV+ drug users. Anti-CD4 IgGs purified from plasma of HIV+ drug users induced CD4+ T cell death in vitro through Antibody-Dependent Cytotoxicity (ADCC). Conclusion: These results suggest that drug use prevents immune reconstitution in HIV-infected individuals despite long-term ART treatment and viral suppression.

Selenoprotein S (Seps1) is an endoplasmic reticulum (ER) resident antioxidant implicated in ER stress and inflammation. In human vastus lateralis and mouse hindlimb muscles, Seps1 localization and expression were fiber-type specific. In male Seps1+/− heterozygous mice, spontaneous physical activity was reduced compared with wild-type littermates ( d = 1.10, P = 0.029). A similar trend was also observed in Seps1−/− knockout mice ( d = 1.12, P = 0.051). Whole body metabolism, body composition, extensor digitorum longus (EDL), and soleus mass and myofiber diameter were unaffected by genotype. However, in isolated fast EDL muscles from Seps1−/− knockout mice, the force frequency curve (FFC; 1–120 Hz) was shifted downward versus EDL muscles from wild-type littermates ( d = 0.55, P = 0.002), suggestive of reduced strength. During 4 min of intermittent, submaximal (60 Hz) stimulation, the genetic deletion or reduction of Seps1 decreased EDL force production ( d = 0.52, P < 0.001). Furthermore, at the start of the intermittent stimulation protocol, when compared with the 60-Hz stimulation of the FFC, EDL muscles from Seps1−/− knockout or Seps1+/− heterozygous mice produced 10% less force than those from wild-type littermates ( d = 0.31, P < 0.001 and d = 0.39, P = 0.015). This functional impairment was associated with reduced mRNA transcript abundance of thioredoxin-1 ( Trx1), thioredoxin interacting protein ( Txnip), and the ER stress markers Chop and Grp94, whereas, in slow soleus muscles, Seps1 deletion did not compromise contractile function and Trx1 ( d = 1.38, P = 0.012) and Txnip ( d = 1.27, P = 0.025) gene expression was increased. Seps1 is a novel regulator of contractile function and cellular stress responses in fast-twitch muscles.

The high prevalence of women in substance use treatment programs with children, and the co-occurring negative physical and mental health outcomes associated with substance use, led to the development of integrated substance use treatment programs that target a range of women-specific issues. Integrated programs typically offer some type of parenting component, although the level of parenting services varies widely. Existing reviews have found positive child and parent outcomes following integrated treatment programs in general, although studies were not selected on the basis of whether they included parenting interventions. Due to the large percentage of substance using parents and research that parenting interventions contribute to decreased maternal substance use, this critical review examines parental outcomes of published studies on integrated programs that specifically include a parenting intervention component, as well as moderators of parenting and parental substance use/relapse. Across the 15 studies identified, this systematic review primarily focused on 8 parenting outcomes, including program retention, substance use, parenting stress, psychosocial adjustment, depression, child abuse potential, parenting behaviors, and parent-child interaction; as well as 5 additional secondary outcomes. The review discusses results on each of these outcomes, as well as retention rates across the parenting interventions.

Background The agreement between self-reported cannabis abstinence with urine cannabinoid concentrations in a clinical trials setting is not well characterized. We assessed the agreement between various cannabinoid cutoffs and self-reported abstinence across three clinical trials, one including contingency management for abstinence. Methods Three cannabis cessation clinical trials where participants reported use and provided weekly urine samples for cannabis and creatinine concentration measurements were included. Bootstrapped data were assessed for agreement between self-reported 7+ day abstinence and urine cannabinoid tests using generalized linear mixed effects models for clustered binary outcomes. One study implemented contingency management for cannabis abstinence. Four hundred and seventy-three participants with 3787 valid urine specimens were included. Urine was analyzed for 11-nor-9-carboxy-Δ9-tetrahydrocannabinol and creatinine using immunoassay methods Biological cutoffs of 50, 100, and 200 ng/ml, as well as changes in CN normalized THCCOOH (25%/50% decrease), were assessed for agreement with self-reported abstinence during the three clinical trials. Results Agreement between measured THCCOOH and self-reported abstinence increases with increasing cutoff concentrations, while the agreement with self-reported non-abstinence decreases with increasing cutoff concentrations. Combining THCCOOH cutoffs with recent changes in CN-THCCOOH provides a better agreement in those self-reporting abstinence. Participants in the studies that received CM for abstinence had a lower agreement between self-reported abstinence and returned to use than those in studies that did not have a contingency management component. Conclusion Using combinations of biological measurements and self-reported abstinence, confirmation of study related abstinence may be verifiable earlier and with greater accuracy than relying on a single measurement.

An increasing proportion of the world has legalized cannabis for medicinal or recreational use. The legalization trend appears to be continuing. These changes in the legislative landscape may have important health, treatment, and research implications. This review discusses public health outcomes that may be impacted by increases in cannabis availability and use. It additionally considers potential research and treatment priorities in the face of widespread cannabis legalization.

The material properties of natural tissues, such as skeletal muscle, are highly sophisticated and are synthetically challenging to mimic. Using natural biomacromolecules to functionalize self-assembled peptide (SAP) hydrogels has the potential to increase the utility of these materials by more closely reproducing the natural cellular environment. Here, to demonstrate that a conserved co-assembly pathway can retain distinct function, the biocompatible peptide derivative Fmoc-FRGDF was co-assembled with either a sulfated polysaccharide, fucoidan, or the provisional matrix proteoglycan, versican. Our results demonstrate that thermodynamically driven co-assembly with biologically active macromolecules is facile, stable, and does not affect the final assembled nanostructure. Biologically, the incorporation of these functionally distinct molecules had no effect on C2C12 myoblast proliferation and viability but strongly altered their morphology. The surface area of myoblasts cultured on the fucoidan scaffold was reduced at 24 and 72 h post seeding, with a reduction in the formation of multinucleated syncytia. Myoblasts cultured on versican scaffolds were smaller compared to cells grown on the empty vector scaffolds at 24 h but not 72 h post seeding, with multinucleated syncytia formation being unaffected. This work allows programmed and distinct morphological effects of cell behavior, paving the way for further mechanistic studies.

Background Quantifying cannabis use is complex due to a lack of a standardized packaging system that contains specified amounts of constituents. A laboratory procedure has been developed for estimating physical quantity of cannabis use by utilizing a surrogate substance to represent cannabis, and weighing the amount of the surrogate to determine typical use in grams. Method This secondary analysis utilized data from a multi-site, randomized, controlled pharmacological trial for adult cannabis use disorder (N = 300), sponsored by the National Drug Abuse Treatment Clinical Trials Network, to test the incremental validity of this procedure. In conjunction with the Timeline Followback, this physical scale-based procedure was used to determine whether average grams per cannabis administration predicted urine cannabinoid levels (11-nor-9-carboxy-Δ9-tetrahydrocannabinol) and problems due to use, after accounting for self-reported number of days used (in the past 30 days) and number of administrations per day in a 12-week clinical trial for cannabis use disorder. Results Likelihood ratio tests suggest that model fit was significantly improved when grams per administration and relevant interactions were included in the model predicting urine cannabinoid level (X2 = 98.3; p Conclusions This study provides support for the use of a scale-based method for quantifying cannabis use in grams. This methodology may be useful when precise quantification is necessary (e.g., measuring reduction in use in a clinical trial).

Background An efficacious pharmacotherapy for cannabis use disorder (CUD) has yet to be established. This study preliminarily evaluated the safety and efficacy of varenicline for CUD in a proof-of-concept clinical trial. Methods Participants in this 6-week randomized, placebo-controlled pilot trial received either varenicline (n = 35) or placebo (n = 37), added to a brief motivational enhancement therapy intervention. Outcomes included cannabis withdrawal, cannabis abstinence, urine cannabinoid levels, percent cannabis use days, and cannabis sessions per day. Results Both treatment groups noted significant decreases in self-reported cannabis withdrawal, percentage of days used, and use sessions per day during treatment compared to baseline. While this pilot trial was not powered to detect statistically significant between-group differences, participants randomized to varenicline evidenced numerically greater rates of self-reported abstinence at the final study visit [Week 6 intent-to-treat (ITT): Varenicline: 17.1% vs. Placebo: 5.4%; RR = 3.2 (95% CI: 0.7,14.7)]. End-of-treatment urine creatinine corrected cannabinoid levels were numerically lower in the varenicline group and higher in the placebo group compared to baseline [Change from baseline: Varenicline -1.7 ng/mg (95% CI: -4.1,0.8) vs. Placebo: 1.9 ng/mg (95% CI: -0.4,4.3); Δ = 3.5 (95% CI: 0.1,6.9)]. Adverse events related to study treatment did not reveal new safety signals. Conclusions Findings support the feasibility of conducting clinical trials of varenicline as a candidate pharmacotherapy for CUD, and indicate that a full-scale efficacy trial, powered based on effect sizes and variability yielded in this study, is warranted.

Stress is a frequent precipitant of relapse to drug use. Pharmacotherapies targeting a diverse array of neural systems have been assayed for efficacy in attenuating stress-induced drug-seeking in both rodents and in humans, but none have shown enough evidence of utility to warrant routine use in the clinic. We posit that a critical barrier in effective translation is inattention to sex as a biological variable at all phases of the research process. In this review, we detail the neurobiological systems implicated in stress-induced relapse to cocaine, opioids, methamphetamine, and cannabis, as well as the pharmacotherapies that have been used to target these systems in rodent models, the human laboratory, and in clinical trials. In each of these areas we additionally describe the potential influences of biological sex on outcomes, and how inattention to fundamental sex differences can lead to biases during drug development that contribute to the limited success of large clinical trials. Based on these observations, we determine that of the pharmacotherapies discussed only α2-adrenergic receptor agonists and oxytocin have a body of research with sufficient consideration of biological sex to warrant further clinical evaluation. Pharmacotherapies that target β-adrenergic receptors, other neuroactive peptides, the hypothalamic-pituitary-adrenal axis, neuroactive steroids, and the endogenous opioid and cannabinoid systems require further assessment in females at the preclinical and human laboratory levels before progression to clinical trials can be recommended.

The medicinal use of marijuana has been legalized in 28 states, with a wide range of specificity for approved medical conditions. Even with the emergence of non–combustion-based delivery systems, in 2014, 90% of marijuana users used smoked marijuana. The purpose of this review is to summarize the data available on use of smoked marijuana for medical purposes. A literature search was performed to retrieve randomized controlled trials exploring the efficacy of smoked cannabis for treatment of a medical condition. Studies with the primary endpoint listed as the effect of smoked cannabis on a disease-specific characteristic were included. Open-label studies and studies using other administration methods were excluded. Seven studies met these criteria and were included in this review. Cannabis did not outperform placebo on experimentally evoked pain or times walk test. There is clear evidence that smoked cannabis reduces intraocular pressure, but the effect is too brief (< 4 hours) to be of therapeutic benefit for this chronic disorder. There was also consistent evidence that smoked marijuana, even at lower concentrations of tetrahydrocannabinol, increased total daily calorie intake and number of eating occasions. Neither of the studies with quality of life as secondary outcome measures revealed statistically significantly improved outcomes with cannabis use.

Cannabis use disorder (CUD) is a common condition with few treatments. Several studies in other substance use disorders have found that applying repetitive transcranial magnetic stimulation (rTMS) to the dorsolateral prefrontal cortex (DLPFC) decreases cue-elicited craving and possibly decreases use. To date, there have been no studies attempting to use rTMS in CUD.This study was conducted to determine if rTMS could be feasibly delivered to a group of non-treatment seeking CUD participants. Secondarily, the study aimed to estimate the effect of rTMS on craving.In a double-blind, sham-controlled, crossover design, a single session of active or sham rTMS (Left DLPFC, 10 Hz, 110% rMT, 4000 pulses) was delivered during a validated cannabis cue paradigm. Participants crossed over to complete the other condition one week later. The feasibility and tolerability were measured by the rate of retention, and the percentage of participants able to tolerate full dose rTMS, respectively. Craving was measured using the Marijuana Craving Questionnaire (MCQ).Eighteen non-treatment seeking CUD participants were recruited from the community; 16 (three women) completed the trial (89% retained for the three study visits). All of the treatment completers tolerated rTMS at full dose without adverse effects. There was not a significant reduction in the total MCQ when participants received active rTMS as compared to sham rTMS.rTMS can be safely and feasibly delivered to CUD participants, and treatment is well tolerated. A single session of rTMS applied to the DLPFC may not reduce cue-elicited craving in heavy cannabis users.