Signaling-specific inhibition of the CB receptor for cannabis use disorder: phase 1 and phase 2a randomized trials.

Cannabis use disorder (CUD) is widespread, and there is no pharmacotherapy to facilitate its treatment. AEF0117, the first of a new pharmacological class, is a signaling-specific inhibitor of the cannabinoid receptor 1 (CB-SSi). AEF0117 selectively inhibits a subset of intracellular effects resulting from Δ-tetrahydrocannabinol (THC) binding without modifying behavior per se.

The Relationship Between Circulating Endogenous Cannabinoids and the Effects of Smoked Cannabis.

The endogenous cannabinoid system (ECS), including the endocannabinoids (eCBs), anandamide (AEA), and 2-arachidonoylglycerol (2-AG), plays an integral role in psychophysiological functions. Although frequent cannabis use is associated with adaptations in the ECS, the impact of acute smoked cannabis administration on circulating eCBs, and the relationship between cannabis effects and circulating eCBs are poorly understood. This study measured the plasma levels of AEA, 2-AG, and Δ-9-tetrahydrocannabinol (THC), subjective drug-effects ratings, and cardiovascular measures at baseline and 15-180 min after cannabis users (=26) smoked 70% of a cannabis cigarette (5.

Paired inhibitory stimulation and gait training modulates supplemental motor area connectivity in freezing of gait.

Introduction: Freezing of gait (FOG) is a debilitating feature of Parkinson's disease (PD). Evidence suggests patients with FOG have increased cortical control of gait. The supplementary motor area (SMA) may be a key structure due to its connectivity with locomotor and cognitive networks.

Repetitive transcranial magnetic stimulation as a potential treatment approach for cannabis use disorder.

The expanding legalization of cannabis across the United States is associated with increases in cannabis use, and accordingly, an increase in the number and severity of individuals with cannabis use disorder (CUD). The lack of FDA-approved pharmacotherapies and modest efficacy of psychotherapeutic interventions means that many of those who seek treatment for CUD relapse within the first few months. Consequently, there is a pressing need for innovative, evidence-based treatment development for CUD.

State-Dependent Effects of Ventromedial Prefrontal Cortex Continuous Thetaburst Stimulation on Cocaine Cue Reactivity in Chronic Cocaine Users.

Cue-induced craving is a significant barrier to obtaining abstinence from cocaine. Neuroimaging research has shown that cocaine cue exposure evokes elevated activity in a network of frontal-striatal brain regions involved in drug craving and drug seeking. Prior research from our laboratory has demonstrated that when targeted at the medial prefrontal cortex (mPFC), continuous theta burst stimulation (cTBS), an inhibitory form of non-invasive brain stimulation, can decrease drug cue-related activity in the striatum in cocaine users and alcohol users.

Developing Repetitive Transcranial Magnetic Stimulation (rTMS) as a Treatment Tool for Cocaine Use Disorder: a Series of Six Translational Studies.

Purpose Of The Review: Cocaine dependence is a chronic and relapsing disorder which is particularly resistant to behavioral or pharmacologic treatment, and likely involves multiple dysfunctional frontal-striatal circuits. Through advances in preclinical research in the last decade, we now have an unprecedented understanding of the neural control of drug-taking behavior. In both rodent models and human clinical neuroimaging studies, it is apparent that medial frontal-striatal limbic circuits regulate drug cue-triggered behavior.

Transdiagnostic Effects of Ventromedial Prefrontal Cortex Transcranial Magnetic Stimulation on Cue Reactivity.

Background: Elevated frontal and striatal reactivity to drug cues is a transdiagnostic hallmark of substance use disorders. The goal of these experiments was to determine if it is possible to decrease frontal and striatal reactivity to drug cues in both cocaine users and heavy alcohol users through continuous theta burst stimulation (cTBS) to the left ventromedial prefrontal cortex (VMPFC).

Methods: Two single-blinded, within-subject, active sham-controlled experiments were performed wherein neural reactivity to drug/alcohol cues versus neutral cues was evaluated immediately before and after receiving real or sham cTBS (110% resting motor threshold, 3600 pulses, Fp1 location; N = 49: 25 cocaine users [experiment 1], 24 alcohol users [experiment 2]; 196 total functional magnetic resonance imaging scans).

Author Correction: Gray and white matter integrity influence TMS signal propagation: a multimodal evaluation in cocaine-dependent individuals.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Gray and white matter integrity influence TMS signal propagation: a multimodal evaluation in cocaine-dependent individuals.

Transcranial magnetic stimulation (TMS) can stimulate cortical and subcortical brain regions. However, in order to reach subcortical targets, intact monosynaptic connections are required. The goal of this investigation was to evaluate the contribution of white matter integrity and gray matter volume to frontal pole TMS-evoked striatal activity in a large cohort of chronic cocaine users.

Left frontal pole theta burst stimulation decreases orbitofrontal and insula activity in cocaine users and alcohol users.

Background: Preclinical research has demonstrated a causal relationship between medial prefrontal cortex activity and cocaine self-administration. As a step towards translating those data to a neural circuit-based intervention for patients, this study sought to determine if continuous theta burst stimulation (cTBS) to the left frontal pole (FP), would attenuate frontal-striatal activity in two substance-dependent populations.

Methods: Forty-nine substance dependent individuals (25 cocaine, 24 alcohol) completed a single-blind, sham-controlled, crossover study wherein they received 6 trains of real or sham cTBS (110% resting motor threshold, FP1) each visit.

Functional independence in resting-state connectivity facilitates higher-order cognition.

Growing evidence suggests that intrinsic functional connectivity (i.e. highly structured patterns of communication between brain regions during wakeful rest) may encode cognitive ability.

Task-dependent recruitment of intrinsic brain networks reflects normative variance in cognition.

Background: Functional neuroimaging has great potential to inform clinical decisions, whether by identifying neural biomarkers of illness progression and severity, predicting therapeutic response, or selecting suitable patients for surgical interventions. Yet a persisting barrier to functional neuroimaging's clinical translation is our incomplete understanding of how normative variance in cognition, personality, and behavior shape the brain's structural and functional organization. We propose that modeling individual differences in these brain-behavior relationships is crucial for improving the accuracy of neuroimaging biomarkers for neurologic and psychiatric disorders.

Merging clinical neuropsychology and functional neuroimaging to evaluate the construct validity and neural network engagement of the n-back task.

The n-back task is a widely used neuroimaging paradigm for studying the neural basis of working memory (WM); however, its neuropsychometric properties have received little empirical investigation. The present study merged clinical neuropsychology and functional magnetic resonance imaging (fMRI) to explore the construct validity of the letter variant of the n-back task (LNB) and to further identify the task-evoked networks involved in WM. Construct validity of the LNB task was investigated using a bootstrapping approach to correlate LNB task performance across clinically validated neuropsychological measures of WM to establish convergent validity, as well as measures of related but distinct cognitive constructs (i.