Although there is emergent evidence illustrating neural sensitivity to cannabis cues in cannabis users, the specificity of this effect to cannabis cues as opposed to a generalized hyper‐sensitivity to hedonic stimuli has not yet been directly tested. Using fMRI, we presented 53 daily, long‐term cannabis users and 68 non‐using controls visual and tactile cues for cannabis, a natural reward, and, a sensory‐perceptual control object to evaluate brain response to hedonic stimuli in cannabis users. The results showed an interaction between group and reward type such that the users had greater response during cannabis cues relative to natural reward cues (i.e., fruit) in the orbitofrontal cortex, striatum, anterior cingulate gyrus, and ventral tegmental area compared to non‐users (cluster‐threshold z = 2.3, P < 0.05). In the users, there were positive brain‐behavior correlations between neural response to cannabis cues in fronto‐striatal‐temporal regions and subjective craving, marijuana‐related problems, withdrawal symptoms, and levels of THC metabolites (cluster‐threshold z = 2.3, P < 0.05). These findings demonstrate hyper‐responsivity, and, specificity of brain response to cannabis cues in long‐term cannabis users that are above that of response to natural reward cues. These observations are concordant with incentive sensitization models suggesting sensitization of mesocorticolimbic regions and disruption of natural reward processes following drug use. Although the cross‐sectional nature of this study does not provide information on causality, the positive correlations between neural response and indicators of cannabis use (i.e., THC levels) suggest that alterations in the reward system are, in part, related to cannabis use. Hum Brain Mapp 37:3431–3443, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Combined use of marijuana (MJ) and tobacco is highly prevalent in today's population. Individual use of either substance is linked to structural brain changes and altered cognitive function, especially with consistent reports of hippocampal volume deficits and poorer memory performance. However, the combined effects of MJ and tobacco on hippocampal structure and on learning and memory processes remain unknown. In this study, we examined both the individual and combined effects of MJ and tobacco on hippocampal volumes and memory performance in four groups of adults taken from two larger studies: MJ-only users (n=36), nicotine-only (Nic-only, n=19), combined marijuana and nicotine users (MJ+Nic, n=19) and non-using healthy controls (n=16). Total bilateral hippocampal volumes and memory performance (WMS-III logical memory) were compared across groups controlling for total brain size and recent alcohol use. Results found MJ and MJ+Nic groups had smaller total hippocampal volumes compared to Nic-only and controls. No significant difference between groups was found between immediate and delayed story recall. However, the controls showed a trend for larger hippocampal volumes being associated with better memory scores, while MJ+Nic users showed a unique inversion, whereby smaller hippocampal volume was associated with better memory. Overall, results suggest abnormalities in the brain-behavior relationships underlying memory processes with combined use of marijuana and nicotine use. Further research will need to address these complex interactions between MJ and nicotine.

Human African trypanosomiasis (HAT) is a fatal infectious disease caused by the eukaryotic pathogen Trypanosoma brucei. Available treatments are difficult to administer and have significant safety issues. S-Adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme in the parasite polyamine biosynthetic pathway. Previous attempts to develop TbAdoMetDC inhibitors into anti-HAT therapies failed due to poor brain exposure. Here, we describe a large screening campaign of two small-molecule libraries (∼400,000 compounds) employing a new high-throughput (∼7 s per sample) mass spectrometry-based assay for AdoMetDC activity. As a result of primary screening, followed by hit confirmation and validation, we identified 13 new classes of reversible TbAdoMetDC inhibitors with low-micromolar potency (IC50) against both TbAdoMetDC and T. brucei parasite cells. The majority of these compounds were >10-fold selective against the human enzyme. Importantly, compounds from four classes demonstrated high propensity to cross the blood-brain barrier in a cell monolayer assay. Biochemical analysis demonstrated that compounds from eight classes inhibited intracellular TbAdoMetDC in the parasite, though evidence for a secondary off-target component was also present. The discovery of several new TbAdoMetDC inhibitor chemotypes provides new hits for lead optimization programs aimed to deliver a novel treatment for HAT.

Background Exteroception involves processes related to the perception of environmental stimuli important for an organism's ability to adapt to its environment. As such, exteroception plays a critical role in conditioned response. In addiction, behavioral and neuroimaging studies show that the conditioned response to drug-related cues is often associated with alterations in brain regions including the precuneus/posterior cingulate cortex, an important node within the default mode network dedicated to processes such as self-monitoring. Objective This review aimed to summarize the growing, but largely fragmented, literature that supports a central role of exteroceptive processes in addiction. Methods We performed a systematic review of empirical research via PubMed and Google Scholar with keywords including ‘addiction’, ‘exteroception’, ‘precuneus’, and ‘self-awareness’, to identify human behavioral and neuroimaging studies that report mechanisms of self-awareness in healthy populations, and altered selfawareness processes, specifically exteroception, in addicted populations. Results Results demonstrate that exteroceptive processes play a critical role in conditioned cue response in addiction and serve as targets for interventions such as mindfulness training. Further, a hub of the default mode network, namely, the precuneus, is (i) consistently implicated in exteroceptive processes, and (ii) widely demonstrated to have increased activation and connectivity in addicted populations. Conclusion Heightened exteroceptive processes may underlie cue-elicited craving, which in turn may lead to the maintenance and worsening of substance use disorders. An exteroception model of addiction provides a testable framework from which novel targets for interventions can be identified.

BackgroundTetrahydrocannabinol (Δ9-THC), the primary ingredient in marijuana, exerts its effects across several neurological and biological systems that interact with the endocrine system. Thus, differential effects of Δ9-THC are likely to exist based on sex and hormone levels.MethodsWe reviewed the existing literature to determine sex-based effects of Δ9-THC on neural structure and functioning.ResultsThe literature demonstrates differences in male and female marijuana users on brain structure, reward processing, attention, motor coordination, and sensitivity to withdrawal. However, inconsistencies exist in the literature regarding how marijuana affects men and women differentially, and more work is needed to understand these mechanisms. While extant literature remains inconclusive, differentiation between male and female marijuana users is likely due to neurological sexual dimorphism and differential social factors at play during development and adulthood.ConclusionsSex has important implications for marijuana use and the development of cannabis use disorders and should be considered in the development of prevention and treatment strategies.