Chronic cannabis use alters dACC-striatal glutamatergic balance.

Prefrontal and striatal glutamate plays an important role in modulating striatal dopamine levels and an imbalance in regional glutamate has been identified in several psychiatric conditions. We hypothesized that this imbalance also exists in cannabis use disorder (CUD). We recently quantified the difference in glutamate of dorsal anterior cingulate (dACC) and striatum regions in the frontostriatal pathway using proton MRS at baseline and on verified abstinent days 7 and 21 in chronic users of cannabis (n = 20) in comparison with age- and sex- matched non-using controls (n = 10). In addition, the Barratt Impulsiveness Scale-11 (BIS) was collected as a measure of inhibitory impulse control of the participants. We found that the difference in glutamate concentrations between the dACC and striatum (ΔdACC-strGlu) of the controls was significantly higher than that of cannabis users across the study timeline (F(1,28) = 18.32, p < 0.0005). The group difference was not affected by age, sex, or alcohol/cigarette consumption. On abstinent day 7, ΔdACC-strGlu was significantly correlated with the corresponding ΔdACC-strGABA among the users (r = 0.837, p < 0.00001). On day 21, ΔdACC-strGlu was negatively associated with monthly cannabis use days (Spearman's rho = -0.444, p = 0.05). Self-reported BIS and its subscales were significantly altered among the users compared to the controls across the study timeline (total F(1,28) = 7.0, p = 0.013; non-planning F(1,28) = 16.1, p < 0.0005; motor F(1,28) = 5.9, p = 0.022; cognitive F(1,28) = 6.1, p = 0.019). These data provide preliminary evidence that chronic cannabis use may lead to a dACC-striatal glutamate imbalance in conjunction with poor impulse control.

Multi-modal assessment of reward functioning in adolescent anhedonia.

BACKGROUND: Anhedonia is a core symptom of depression that predicts worse treatment outcomes. Dysfunction in neural reward circuits is thought to contribute to anhedonia. However, whether laboratory-based assessments of anhedonia and reward-related neural function translate to adolescents' subjective affective experiences in real-world contexts remains unclear. METHODS: We recruited a sample of adolescents (n = 82; ages 12-18; mean = 15.83) who varied in anhedonia and measured the relationships among clinician-rated and self-reported anhedonia, behaviorally assessed reward learning ability, neural response to monetary reward and loss (as assessed with functional magnetic resonance imaging), and repeated ecological momentary assessment (EMA) of positive affect (PA) and negative affect (NA) in daily life. RESULTS: Anhedonia was associated with lower mean PA and higher mean NA across the 5-day EMA period. Anhedonia was not related to impaired behavioral reward learning, but low PA was associated with reduced nucleus accumbens response during reward anticipation and reduced medial prefrontal cortex (mPFC) response during reward outcome. Greater mean NA was associated with increased mPFC response to loss outcome. CONCLUSIONS: Traditional laboratory-based measures of anhedonia were associated with lower subjective PA and higher subjective NA in youths' daily lives. Lower subjective PA and higher subjective NA were associated with decreased reward-related striatal functioning. Higher NA was also related to increased mPFC activity to loss. Collectively, these findings demonstrate that laboratory-based measures of anhedonia translate to real-world contexts and that subjective ratings of PA and NA may be associated with neural response to reward and loss.

Lower dACC glutamate in cannabis users during early phase abstinence.

Glutamate plays an important role in continued use of and relapse to abused substances. However, its involvement in cannabis withdrawal is still unclear. We hypothesize that regional glutamate is associated with the cannabis withdrawal syndrome and recently examined possible association of glutamate with cannabis withdrawal, using magnetic resonance spectroscopy (MRS), in non-treatment-seeking cannabis users. We recruited 26 frequent cannabis users and 11 age-matched non-using controls. Of the 37, 20 users (8f/12m) and 10 controls (5f/5m) completed a verified 21-day abstinence protocol. Dorsal anterior cingulate cortex (dACC) glutamate and γ-amino butyric acid (GABA) were measured with proton MRS at baseline and on abstinent days 7 and 21 in conjunction with measures of cannabis withdrawal and craving (MCQ), sleep difficulties (PSQI) and mood state. We used ANOVA to examine group differences in glutamate and GABA from baseline through day 21 and used linear regression to evaluate correlations between intra-individual glutamate and withdrawal symptoms. We found that self-reported anxiety severity (HAMA) was correlated with urinary THC/Cr ratios at baseline (r = 0.768, p = 0.000076) and abstinent day 7 (r = 0.5636, p = 0.0097), dACC glutamate was significantly lower in the users compared with the controls from baseline through day 21 (F = 5.90, p = 0.022), changes in glutamate between baseline and abstinent day 21 had a significantly negative correlation with corresponding changes in craving (r = -0.72, p = 0.005) after adjusting for age, consumption of alcohol/cigarettes, sleep difficulties, and urinary THC levels. These findings provide preliminary evidence that dACC glutamate is associated with the cannabis withdrawal syndrome.

Clinical utility of a hybrid secondary and relapse prevention program in adults with mild intellectual disability in community residential and day habilitation settings.

BACKGROUND: Despite evidence that standard substance use disorder (SUD) treatment may be less effective in people with intellectual disability (ID), there is an absence of appropriate clinical tools with which to support them. OBJECTIVES: This study examined the clinical utility of an alcohol and other drug refusal skills intervention designed to be cognitively accessible to adults with ID METHODS: Thirty individuals at high risk for or in recovery from a SUD in developmental disability services (DDS) community residential and day habilitation settings participated in the two-week refusal skills group. Measures included pretest versus posttest improvement in refusal skill competency and baseline performance on a standardized verbal learning test. RESULTS: There was a strong effect for refusal skill acquisition (p < .001); and the magnitude of skill acquisition was predicted by group attendance (p < .001) and not by individual differences in verbal learning ability (p = .074) or efficiency (p = .35). CONCLUSIONS: The Refusal Skills Group is developmentally appropriate for people with mild ID in that: (1) they can learn and demonstrate refusal skills and (2) their skill acquisition is predicted more strongly by exposure to the intervention than by individual differences in learning characteristics. Delivering refusal skills in DDS settings familiar to clients increased their access to services and minimized disruption to their usual routines and schedules.

Clathrin-nanoparticles deliver BDNF to hippocampus and enhance neurogenesis, synaptogenesis and cognition in HIV/neuroAIDS mouse model.

Brain derived neurotrophic factor (BDNF) promotes the growth, differentiation, maintenance and survival of neurons. These attributes make BDNF a potentially powerful therapeutic agent. However, its charge, instability in blood, and poor blood brain barrier (BBB) penetrability have impeded its development. Here, we show that engineered clathrin triskelia (CT) conjugated to BDNF (BDNF-CT) and delivered intranasally increased hippocampal BDNF concentrations 400-fold above that achieved previously with intranasal BDNF alone. We also show that BDNF-CT targeted Tropomyosin receptor kinase B (TrkB) and increased TrkB expression and downstream signaling in iTat mouse brains. Mice were induced to conditionally express neurotoxic HIV Transactivator-of-Transcription (Tat) protein that decreases BDNF. Down-regulation of BDNF is correlated with increased severity of HIV/neuroAIDS. BDNF-CT enhanced neurorestorative effects in the hippocampus including newborn cell proliferation and survival, granule cell neurogenesis, synaptogenesis and increased dendritic integrity. BDNF-CT exerted cognitive-enhancing effects by reducing Tat-induced learning and memory deficits. These results show that CT bionanoparticles efficiently deliver BDNF to the brain, making them potentially powerful tools in regenerative medicine.

Elevated striatal glutamate + glutamine in recreational cannabis users during abstinence.

Cannabis withdrawal symptoms contribute to relapse, but the underlying mechanism remains unclear. We hypothesize that cannabis withdrawal may be associated with a reset of regional γ-amino butyric acid (GABA) and glutamate concentrations secondary to changes in the endocannabinoid system during abstinence and conducted a study on this issue. We used magnetic resonance spectroscopy (MRS) to detect the associated changes of these neurochemicals in twenty-six frequent, recreational cannabis users and eleven age-matched non-using controls. Twenty users (8F/12M) and ten control (5F/5M) participants completed a verified 21-day abstinence period. Striatal GABA and glutamine concentrations were measured at baseline and on abstinence days 7 and 21 in conjunction with measures of cannabis withdrawal symptoms and mood state. Cannabis users reported increased self-reported ratings of cannabis-withdrawal-symptoms on abstinence day 7 relative to controls. Striatal glutamate + glutamine (Glx) group concentrations were elevated in cannabis users at baseline and abstinence days 7 and 21 (F = 7.16, p = 0.012), and changes in GABA concentration and withdrawal symptoms between baseline and abstinence day 7 were positively correlated (r = 0.550, p = 0.010). In addition, baseline striatal GABA concentrations were negatively correlated with withdrawal symptoms on abstinence day 7 (r = -0.680, p = 0.003). Our data demonstrate that striatal Glx was elevated in cannabis users and baseline striatal GABA correlated with withdrawal during the abstinence. In addition, striatal GABA may temporally correlate with self-reported withdrawal symptoms during the initial days of abrupt cannabis abstinence. These findings provide preliminary evidence that striatal GABA and Glx are associated with the severity of cannabis withdrawal.

Dronabinol inhibits alveolar bone remodeling in tooth movement of rats.

INTRODUCTION: Orthodontic tooth movement is reliant on the process of bone remodeling, and a variety of medications impact the ability of teeth to move through bone. Marijuana is the most widely used recreational drug in the world, and early studies suggest the drug impacts bone remodeling as tetrahydrocannabinol binds to cannabinoid receptors which play a role in bone homeostasis. This study aimed to assess the impact of dronabinol on alveolar bone remodeling in rats with otherwise healthy tissue when subjected to orthodontic forces. METHODS: Thirty male Sprague Dawley rats were equally allocated into 2 groups. Orthodontic appliances were placed in all animals, which consisted of a nickel-titanium coil ligated from the maxillary first molar to the central incisor. The appliance was activated to deliver a force to move teeth together. Over 21 days, daily injections of either dronabinol or the control (solvent) were given to the rats. Cephalometric analysis, histology, and bone remodeling profiles of both groups were analyzed and compared. RESULTS: Teeth moved in both the dronabinol and control groups (P <0.05). Tooth movement in the control group followed the typical process of orthodontic tooth movement: periodontal width narrowing and bone resorption on the compression side of the tooth, with an overall decrease in the height of the alveolar bone. In contrast, the dronabinol group showed an abnormal response to tooth movement: no bone resorption on the compression side of the tooth, increased bone formation on the tension side, and the maintenance of the height of the alveolar crest. In the dronabinol group, there were also significantly more osteoclasts and osteoblasts in the alveolar bone than in the control group. CONCLUSIONS: These results demonstrate that dronabinol attenuates orthodontic tooth movement by decreasing bone resorption, which could have implications for other bone-related recovery processes.

Denoising scanner effects from multimodal MRI data using linked independent component analysis.

Pooling magnetic resonance imaging (MRI) data across research studies, or utilizing shared data from imaging repositories, presents exceptional opportunities to advance and enhance reproducibility of neuroscience research. However, scanner confounds hinder pooling data collected on different scanners or across software and hardware upgrades on the same scanner, even when all acquisition protocols are harmonized. These confounds reduce power and can lead to spurious findings. Unfortunately, methods to address this problem are scant. In this study, we propose a novel denoising approach that implements a data-driven linked independent component analysis (LICA) to identify scanner-related effects for removal from multimodal MRI to denoise scanner effects. We utilized multi-study data to test our proposed method that were collected on a single 3T scanner, pre- and post-software and major hardware upgrades and using different acquisition parameters. Our proposed denoising method shows a greater reduction of scanner-related variance compared with standard GLM confound regression or ICA-based single-modality denoising. Although we did not test it here, for combining data across different scanners, LICA should prove even better at identifying scanner effects as between-scanner variability is generally much larger than within-scanner variability. Our method has great promise for denoising scanner effects in multi-study and in large-scale multi-site studies that may be confounded by scanner differences.

Interactive effects of age and recent substance use on striatal shape morphology at substance use disorder treatment entry.

BACKGROUND: Striatal neuroadaptations are regarded to play an important role in the progression from voluntary to compulsive use of addictive substances and provide a promising target for the identification of neuroimaging biomarkers. Recent advances in surface-based computational analysis enable morphological assessment linking variations in global and local striatal shape to duration and magnitude of substance use with a degree of sensitivity that exceeds standard volumetric analysis. METHODS: This study used a new segmentation methodology coupled with local surface-based indices of surface area and displacement to provide a comprehensive structural characterization of the striatum in 34 patients entering treatment for substance use disorder (SUD) and 49 controls, and to examine the influence of recent substance use on abnormal age-related striatal deformation in SUD patients. RESULTS: Patients showed a small reduction in striatal volume and no difference in surface area or shape in comparison to controls. Between-group differences in shape were likely neutralized by the bidirectional influence of recent substance use on striatal shape in SUD patients. Specifically, there was an interaction between age and substance such that among older patients more drug use was associated with greater inward striatal contraction but more alcohol use was associated with greater outward expansion. CONCLUSIONS: This study builds on previous work and advances our understanding of the nature of striatal neuroadaptations as a potential biomarker of disease progression in addiction.

Craving and Cue Reactivity in Nicotine-Dependent Tobacco Smokers Is Associated With Different Insula Networks.

BACKGROUND: The insula has a well-established role in nicotine dependence and is a node of the salience network, which integrates internal and external information to guide behavior. Recent findings reveal that internal and external processing occurs in the ventral anterior insula (vAI) and dorsal anterior insula (dAI), respectively. Whether vAI/dAI network connectivity differentially reflects internally generated craving and externally triggered smoking cue reactivity was tested. METHODS: Thirty-six male and female nicotine-dependent individuals smoked 1 hour before functional magnetic resonance imaging. Baseline craving was measured, followed by resting-state and smoking cue reactivity scans and then another assessment of craving. Craving and cue reactivity interactions were measured by focusing on specific nodes of the salience network: the vAI/dAI and anterior cingulate cortex. RESULTS: Resting-state vAI/dAI networks overlapped with the prototypical salience network, yet they possessed distinct patterns, linking the vAI with nodes of the internally focused default mode network and the dAI with nodes of the external, goal-related frontoparietal network. Internally generated baseline craving was associated with enhanced vAI connectivity, whereas rostral anterior cingulate cortex reactivity to external smoking cues was associated with greater dAI connectivity. We also found that cue reactivity in the rostral anterior cingulate cortex was associated with a rise in subjective cue-induced craving, whereas baseline subjective craving did not influence brain cue reactivity. CONCLUSIONS: These data show that brain reactivity to smoking cues is associated with a subsequent increase in craving. In addition, separate insula networks have a role in an individual's vulnerability to internally related craving and externally triggered cue reactivity, which could guide the development of new, neurobiologically targeted therapies.

A Preliminary Examination of Nicotine-Free Electronic Cigarette Use During Cessation From Combustible Cigarettes.

Despite the availability of smoking cessation strategies, smoking cue-induced craving remains a relatively untreated relapse risk factor. Utilizing nicotine-free electronic cigarettes (e-cigarettes) to extinguish the motivational influence of smoking cues may be a viable approach to address cue reactivity. In this pilot study, 26 daily tobacco smokers used nicotine-free e-cigarettes while being maintained on daily transdermal sustained-release nicotine replacement therapy (NRT) to mitigate pharmacological withdrawal. Sensitivity to cue-induced craving, measured by the rise in craving after a visual cue exposure task, was assessed at a baseline visit after smoking as usual and again after 2 weeks of nicotine-free e-cigarette and NRT use. Participants' pattern and amount of tobacco cigarette smoking were evaluated on both visits and 1 month posttreatment. Cue-induced craving significantly decreased after the 2-week intervention, yet withdrawal scores increased during this time. One month after study completion, participants continued to report significantly lower overall cigarette craving and conventional tobacco cigarette use. Including the 34.8% that were totally abstinent, 65.2% reported smoking fewer than 10 cigarettes per week (compared to 87.2 per week at baseline for the entire group). A linear regression revealed that greater baseline cue-induced craving predicted better outcomes, whereas more withdrawal at the e-cigarette visit was related to more smoking at 1 month. This proof-of-concept pilot study suggests that the addition of ad libitum nicotine-free e-cigarettes to an existing strategy of transdermal NRT may attenuate cue-induced craving for tobacco smoking. A larger sample that is powered for detecting additional factors and longer-term outcomes is warranted.

Cutting-Edge Search for Safer Opioid Pain Relief: Retrospective Review of Salvinorin A and Its Analogs.

Over the years, pain has contributed to low life quality, poor health, and economic loss. Opioids are very effective analgesic drugs for treating mild, moderate, or severe pain. Therapeutic application of opioids has been limited by short and long-term side effects. These side effects and opioid-overuse crisis has intensified interest in the search for new molecular targets and drugs. The present review focuses on salvinorin A and its analogs with the aim of exploring their structural and pharmacological profiles as clues for the development of safer analgesics. Ethnopharmacological reports and growing preclinical data have demonstrated the antinociceptive effect of salvinorin A and some of its analogs. The pharmacology of analogs modified at C-2 dominates the literature when compared to the ones from other positions. The distinctive binding affinity of these analogs seems to correlate with their chemical structure and in vivo antinociceptive effects. The high susceptibility of salvinorin A to chemical modification makes it an important pharmacological tool for cellular probing and developing analogs with promising analgesic effects. Additional research is still needed to draw reliable conclusions on the therapeutic potential of salvinorin A and its analogs.

Early onset cigarette smokers exhibit greater P300 reactivity to smoking-related stimuli and report greater craving.

Adolescence is a period during which a number of critical neuromaturation processes occur and the vulnerability for developing nicotine dependence is extremely high. Thus, early-onset (EO; age < 16 years old), relative to late-onset (LO; age ≥ 16 years old), tobacco smoking may be uniquely deleterious for developmentally immature systems that regulate neural signaling reactivity. This study investigated how age of tobacco smoking onset affects neurophysiological measures of smoking cue reactivity and reported craving in adult smokers. EO smokers (EOS; n = 8; 4 females), LO smokers (LOS; n = 10; 5 females), and healthy non-smokers (HNS; n = 10; 5 females) participated in an event-related potential (ERP) cue reactivity study with tactile and image stimuli. Participants handled neutral objects during one interval and smoking-related objects during a second interval. After each interval, they viewed smoking-related, neutral, or arousing images using an oddball paradigm. P300 ERPs and craving for tobacco were recorded during each session. P300 amplitudes were significantly higher in central midline (Cz) channel to smoking, but not neutral or arousing, images after handling smoking objects. Specifically, Cz P300 smoking amplitudes were significantly greater in EOS, relative to LOS and HNS, and associated with greater craving at baseline. There were no other group differences in mood or craving. EOS exhibited greater P300 reactivity to smoking-related stimuli, relative to LOS, suggesting a more sensitized neural response. EO smoking during early neuromaturation may alter neurophysiological signaling involved in responding to smoking-related stimuli, which could impact the outcome of smoking cessation interventions.

Early onset tobacco cigarette smokers exhibit deficits in response inhibition and sustained attention.

BACKGROUND: Initiation of cigarette smoking during adolescence coincides with structural and cognitive neuromaturation. Thus, early onset smokers (EOS; initiated <16 years old) may be at unique risk of altered development of executive function relative to late onset smokers (LOS; initiated >16 years old). This study quantified the effects of age of smoking onset on response impulsivity and inhibitory control using a novel smoking Go/NoGo task (Luijten et al., 2011). METHODS: Nicotine deprived adult EOS (n = 10) and LOS (n = 10) and adult healthy non-smokers (HNS; n = 10) were shown smoking-related and neutral images with either a blue (Go) or yellow (NoGo) frame. Participants were instructed to respond to blue-framed Go trials quickly and accurately, and withhold responding for yellow-framed NoGo trials. RESULTS: EOS made more Go response accuracy errors (p ≤ 0.02) and failed more frequently to inhibit responses to NoGo trials (p < 0.02) than LOS and HNS. EOS also made more errors in inhibiting responses to smoking-related (p ≤ 0.02) and neutral (p ≤ 0.02) NoGo trials. EOS reported greater baseline craving for cigarette smoking than LOS (p < 0.04), and craving was significantly associated with greater omission errors (p ≤ 0.04). CONCLUSIONS: EOS exhibited greater difficulty than LOS in responding accurately to Go stimuli and withholding responses to both smoking and neutral NoGo stimuli, indicating greater response impulsivity, poor attention, and deficits in response inhibition. These findings suggest that EO smoking, in particular, contributes to diminished task-related attention and inhibitory control behaviors in adulthood and provide support for the tobacco-induced neurotoxicity of adolescent cognitive development (TINACD) theory (DeBry and Tiffany, 2008).

Reduced interhemispheric executive control network coupling in men during early cocaine abstinence: A pilot study.

BACKGROUND: Individuals who use cocaine have fewer cognitive resources needed to maintain abstinence. This is evidenced by blunted brain function during cognitive control tasks and reduced communication between brain regions associated with cognitive function. For instance, relapse vulnerability is heightened in individuals with less communication between the right and left frontoparietal executive control network (ECN). Given that recent cocaine use enhances such communication, it is plausible that recency of cocaine use influences interhemispheric ECN communication. However, it is unclear whether ECN communication weakens over the course of early cocaine abstinence, which may then enhance relapse risk. METHODS: In ten men with cocaine use disorder, we conducted a preliminary assessment of the relationship between the number of days since last cocaine use (1-3days) and interhemispheric ECN coupling using resting state functional magnetic resonance imaging (fMRI). RESULTS: Reduced interhemispheric ECN coupling was associated with increasing days since last cocaine use; weaker coupling was also associated with lower urine cocaine metabolite concentrations. This association was more prominent in prefrontal than parietal ECN-subregions. CONCLUSIONS: Preliminary results indicate that resting state interhemispheric ECN coupling weakens within the first few days following last cocaine use. Because of the known link between reduced ECN interhemispheric coupling and relapse vulnerability, these results suggest that relapse risk may increase the longer an individual abstains during an early quit attempt. Treatments focused on reversing this coupling deficit may facilitate abstinence.

Nabilone pharmacotherapy for cannabis dependence: A randomized, controlled pilot study.

BACKGROUND AND OBJECTIVES: We assessed the safety, tolerability, and preliminary efficacy of nabilone, a cannabinoid agonist, to treat cannabis dependence. METHODS: Eighteen adults with DSM-IV cannabis dependence were randomized to receive either 2 mg/day of nabilone (n = 10) or placebo (n = 8) for 10 weeks in addition to medication management. Twelve participants, six in each group, completed treatment. The safety and tolerability of nabilone was assessed at each visit. Any side effects from nabilone or the placebo were documented. Cannabis use outcomes were assessed via self-report of days of use and twice-weekly urine cannabinoid tests; secondary outcomes included cannabis craving and anxiety. RESULTS: We assessed safety and tolerability at each study visit. A total of eight adverse events, all mild or moderate, were reported in two participants in the nabilone group, and six events were reported in four participants in the placebo group during study treatment. A total of eight adverse events were reported in two participants in the nabilone group and six events were reported in four participants in the placebo group during study treatment. All reported adverse events were rated mild-to-moderate. There were no side effects deemed serious enough to be classified as an FDA-defined serious adverse event. In general, participants in both groups reported reduced cannabis use according to self-report over the course of the study, although these reductions were not statistically discernible. Moreover, there was no difference in cannabis use between the nabilone group and the placebo group as measured by self-report. DISCUSSION AND CONCLUSIONS: Nabilone pharmacotherapy was safe and well-tolerated in participants with cannabis dependence. Future studies might evaluate a higher dose of nabilone to determine its effects on cannabis use outcomes in participants with cannabis dependence. SCIENTIFIC SIGNIFICANCE: There remains a clear need for additional pharmacotherapy trials for cannabis dependence, and nabilone remains a candidate for such trials. (Am J Addict 2017;26:795-801).

Improved low-cost, MR-compatible olfactometer to deliver tobacco smoke odor.

We describe a low-cost, MRI-compatible olfactometer that delivers fresh cigarette smoke odor, a challenging odorant to present, as well as other odorants. This new olfactometer retains all of the advantages of an earlier design that was capable of only delivering volatile odors (Lowen & Lukas, Behavior Research Methods, 38, 307-313, 2006). The new system incorporates a novel switching mechanism that allows it to deliver fresh smoke generated from a burning cigarette during a stimulus presentation paradigm that might be employed in a cue-reactivity experiment. An evaluation study established that the olfactometer reliably delivered smoke to the participants and that tobacco smoke was discriminated from other odorants; there were no adverse reactions to the device.

Redox Dysregulation in Schizophrenia Revealed by in vivo NAD+/NADH Measurement.

Balance between the redox pair of nicotinamide adenine dinucleotides (oxidized NAD+ and reduced NADH), reflects the oxidative state of cells and the ability of biological systems to carry out energy production. A growing body of evidence suggests that an "immuno-oxidative" pathway including oxidative stress, mitochondrial dysfunction, neuroinflammation, and cell-mediated immune response may contribute to disruptions in brain activity in schizophrenia (SZ). The aim of this study is to assess possible redox imbalance in SZ patients by using a novel in vivo 31P MRS technique. The participants included 40 healthy controls, 21 chronic SZ, 13 first-episode (FE) SZ, and 18 FE bipolar disorder (BD) patients (as a psychiatric control group). All participants initially underwent structural imaging at a 3 Tesla (3 T) and 31P MRS measurements were performed on a 4 T MR scanner. NAD+ and NADH components were determined by nonlinear least-square fitting of the model simulated spectra; these incorporated prior chemical shift and coupling constant information to in vivo resonances obtained from 31P MRS experiments. We found a significant reduction in the NAD+/NADH ratio in chronically ill SZ patients compared to a matched healthy control group, and in FE SZ patients compared to both a matched FE BD patient group and a matched healthy control group. These findings provide evidence for redox imbalance in the brain in all phases of SZ, potentially reflecting oxidative stress.

The Grass Might Be Greener: Medical Marijuana Patients Exhibit Altered Brain Activity and Improved Executive Function after 3 Months of Treatment.

The vast majority of states have enacted full or partial medical marijuana (MMJ) programs, causing the number of patients seeking certification for MMJ use to increase dramatically in recent years. Despite increased use of MMJ across the nation, no studies thus far have examined the specific impact of MMJ on cognitive function and related brain activation. In the present study, MMJ patients seeking treatment for a variety of documented medical conditions were assessed prior to initiating MMJ treatment and after 3 months of treatment as part of a larger longitudinal study. In order to examine the effect of MMJ treatment on task-related brain activation, MMJ patients completed the Multi-Source Interference Test (MSIT) while undergoing functional magnetic resonance imaging (fMRI). We also collected data regarding conventional medication use, clinical state, and health-related measures at each visit. Following 3 months of treatment, MMJ patients demonstrated improved task performance accompanied by changes in brain activation patterns within the cingulate cortex and frontal regions. Interestingly, after MMJ treatment, brain activation patterns appeared more similar to those exhibited by healthy controls from previous studies than at pre-treatment, suggestive of a potential normalization of brain function relative to baseline. These findings suggest that MMJ use may result in different effects relative to recreational marijuana (MJ) use, as recreational consumers have been shown to exhibit decrements in task performance accompanied by altered brain activation. Moreover, patients in the current study also reported improvements in clinical state and health-related measures as well as notable decreases in prescription medication use, particularly opioids and benzodiapezines after 3 months of treatment. Further research is needed to clarify the specific neurobiologic impact, clinical efficacy, and unique effects of MMJ for a range of indications and how it compares to recreational MJ use.

Splendor in the Grass? A Pilot Study Assessing the Impact of Medical Marijuana on Executive Function.

Currently, 25 states and Washington DC have enacted full medical marijuana (MMJ) programs while 18 states allow limited access to MMJ products. Limited access states permit low (or zero) tetrahydrocannabinol (THC) and high cannabidiol (CBD) products to treat specified conditions such as uncontrolled epilepsy. Although MMJ products are derived from the same plant species as recreational MJ, they are often selected for their unique cannabinoid constituents and ratios, not typically sought by recreational users, which may impact neurocognitive outcomes. To date, few studies have investigated the potential impact of MMJ use on cognitive performance, despite a well-documented association between recreational marijuana (MJ) use and executive dysfunction. The current study assessed the impact of 3 months of MMJ treatment on executive function, exploring whether MMJ patients would experience improvement in cognitive functioning, perhaps related to primary symptom alleviation. As part of a larger longitudinal study, 24 patients certified for MMJ use completed baseline executive function assessments and 11 of these so far have returned for their first follow-up visit 3 months after initiating treatment. Results suggest that in general, MMJ patients experienced some improvement on measures of executive functioning, including the Stroop Color Word Test and Trail Making Test, mostly reflected as increased speed in completing tasks without a loss of accuracy. On self-report questionnaires, patients also indicated moderate improvements in clinical state, including reduced sleep disturbance, decreased symptoms of depression, attenuated impulsivity, and positive changes in some aspects of quality of life. Additionally, patients reported a notable decrease in their use of conventional pharmaceutical agents from baseline, with opiate use declining more than 42%. While intriguing, these findings are preliminary and warrant further investigation at additional time points and in larger sample sizes. Given the likelihood of increased MMJ use across the country, it is imperative to determine the potential impact of short- and long-term treatment on cognitive performance as well as the efficacy of MMJ treatment itself.