The endocannabinoid system as a putative target for the development of novel drugs for the treatment of psychiatric illnesses.

Cannabis is well established to impact affective states, emotion and perceptual processing, primarily through its interactions with the endocannabinoid system. While cannabis use is quite prevalent in many individuals afflicted with psychiatric illnesses, there is considerable controversy as to whether cannabis may worsen these conditions or provide some form of therapeutic benefit. The development of pharmacological agents which interact with components of the endocannabinoid system in more localized and discrete ways then via phytocannabinoids found in cannabis, has allowed the investigation if direct targeting of the endocannabinoid system itself may represent a novel approach to treat psychiatric illness without the potential untoward side effects associated with cannabis. Herein we review the current body of literature regarding the various pharmacological tools that have been developed to target the endocannabinoid system, their impact in preclinical models of psychiatric illness and the recent data emerging of their utilization in clinical trials for psychiatric illnesses, with a specific focus on substance use disorders, trauma-related disorders, and autism. We highlight several candidate drugs which target endocannabinoid function, particularly inhibitors of endocannabinoid metabolism or modulators of cannabinoid receptor signaling, which have emerged as potential candidates for the treatment of psychiatric conditions, particularly substance use disorder, anxiety and trauma-related disorders and autism spectrum disorders. Although there needs to be ongoing clinical work to establish the potential utility of endocannabinoid-based drugs for the treatment of psychiatric illnesses, the current data available is quite promising and shows indications of several potential candidate diseases which may benefit from this approach.

A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism.

The social impairments of autism spectrum disorder (ASD) have a major impact on quality of life, yet there are no medications that effectively treat these core social behavior deficits. Preclinical research suggests that arginine vasopressin (AVP), a neuropeptide involved in promoting mammalian social behaviors, may be a possible treatment for ASD. Using a double-blind, randomized, placebo-controlled, parallel study design, we tested the efficacy and tolerability of a 4-week intranasal AVP daily treatment in 30 children with ASD. AVP-treated participants aged 6 to 9.5 years received the maximum daily target dose of 24 International Units (IU); participants aged 9.6 to 12.9 years received the maximum daily target dose of 32 IU. Intranasal AVP treatment compared to placebo enhanced social abilities as assessed by change from baseline in this phase 2 trial's primary outcome measure, the Social Responsiveness Scale, 2nd Edition total score (SRS-2 T score; F 1,20 = 9.853; P = 0.0052; ηp 2 = 33.0%; Cohen's d = 1.40). AVP treatment also diminished anxiety symptoms and some repetitive behaviors. Most of these findings were more pronounced when we accounted for pretreatment AVP concentrations in blood. AVP was well tolerated with minimal side effects. No AVP-treated participants dropped out of the trial, and there were no differences in the rate of adverse events reported between treatment conditions. Last, no changes from baseline were observed in vital signs, electrocardiogram tracings, height and body weight, or clinical chemistry measurements after 4 weeks of AVP treatment. These preliminary findings suggest that AVP has potential for treating social impairments in children with ASD.

Plasma anandamide concentrations are lower in children with autism spectrum disorder.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by restricted, stereotyped behaviors and impairments in social communication. Although the underlying biological mechanisms of ASD remain poorly understood, recent preclinical research has implicated the endogenous cannabinoid (or endocannabinoid), anandamide, as a significant neuromodulator in rodent models of ASD. Despite this promising preclinical evidence, no clinical studies to date have tested whether endocannabinoids are dysregulated in individuals with ASD. Here, we addressed this critical gap in knowledge by optimizing liquid chromatography-tandem mass spectrometry methodology to quantitatively analyze anandamide concentrations in banked blood samples collected from a cohort of children with and without ASD (N = 112). Findings: Anandamide concentrations significantly differentiated ASD cases (N = 59) from controls (N = 53), such that children with lower anandamide concentrations were more likely to have ASD (p = 0.041). In keeping with this notion, anandamide concentrations were also significantly lower in ASD compared to control children (p = 0.034). Conclusions: These findings are the first empirical human data to translate preclinical rodent findings to confirm a link between plasma anandamide concentrations in children with ASD. Although preliminary, these data suggest that impaired anandamide signaling may be involved in the pathophysiology of ASD.

Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism.

Autism spectrum disorder (ASD) is characterized by core social deficits. Prognosis is poor, in part, because existing medications target only associated ASD features. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may be a blood-based biomarker of social functioning and a possible treatment for ASD. However, prior OXT treatment trials have produced equivocal results, perhaps because of variability in patients' underlying neuropeptide biology, but this hypothesis has not been tested. Using a double-blind, randomized, placebo-controlled, parallel design, we tested the efficacy and tolerability of 4-wk intranasal OXT treatment (24 International Units, twice daily) in 32 children with ASD, aged 6-12 y. When pretreatment neuropeptide measures were included in the statistical model, OXT compared with placebo treatment significantly enhanced social abilities in children with ASD [as measured by the trial's primary outcome measure, the Social Responsiveness Scale (SRS)]. Importantly, pretreatment blood OXT concentrations also predicted treatment response, such that individuals with the lowest pretreatment OXT concentrations showed the greatest social improvement. OXT was well tolerated, and its effects were specific to social functioning, with no observed decrease in repetitive behaviors or anxiety. Finally, as with many trials, some placebo-treated participants showed improvement on the SRS. This enhanced social functioning was mirrored by a posttreatment increase in their blood OXT concentrations, suggesting that increased endogenous OXT secretion may underlie this improvement. These findings indicate that OXT treatment enhances social abilities in children with ASD and that individuals with pretreatment OXT signaling deficits may stand to benefit the most from OXT treatment.

Atypical sensory reactivity influences auditory attentional control in adults with autism spectrum disorders.

Frequent observations of atypical sensory reactivity in people with autism spectrum disorders (ASD) suggest that the perceptual experience of those on the Spectrum is dissimilar to neurotypicals. Moreover, variable attention abilities in people with ASD, ranging from good control to periods of high distractibility, may be related to atypical sensory reactivity. This study used auditory event-related potential (ERP) measures to evaluate top-down and bottom-up attentional processes as a function of perceptual load, and examined these factors with respect to sensory reactivity. Twenty-five age and IQ-matched participants (ASD: 22.5 year, SD = 4.1 year; Controls: 22.8 year, SD = 5.1 year) completed the Adolescent/Adult Sensory Profile prior to performing a modified 3-stimulus (target, non-target, and distractor) auditory oddball target detection task EEG was recorded during task completion. ERP analysis assessed early sensory processing (P50, ∼50 ms latency; N100, ∼100 ms latency), cognitive control (N200, ∼200 ms latency), and attentional processing (P3a and P3b, ∼300 ms latency). Behavioral data demonstrates participants with ASD and neurotypical performed similarly on auditory target detection, but diverged on sensory profiles. Target ERP measures associated with top-down control (P3b latency) significantly increased under greater load in controls, but not in participants with ASD. Early ERP responses associated with bottom-up attention (P50 amplitude) were positively correlated to increased sensory sensitivity. Findings suggest specific neural mechanisms for increased perceptual capacity and enhanced bottom-up processing of sensory stimuli in people with autism. Results from participants with ASD are consistent with load theory and enhanced perceptual functioning. Autism Res 2016, 9: 1079-1092. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

The Role of Right Inferior Parietal Cortex in Auditory Spatial Attention: A Repetitive Transcranial Magnetic Stimulation Study.

Behavioral studies support the concept of an auditory spatial attention gradient by demonstrating that attentional benefits progressively diminish as distance increases from an attended location. Damage to the right inferior parietal cortex can induce a rightward attention bias, which implicates this region in the construction of attention gradients. This study used event-related potentials (ERPs) to define attention-related gradients before and after repetitive transcranial magnetic stimulation (rTMS) to the right inferior parietal cortex. Subjects (n = 16) listened to noise bursts at five azimuth locations (left to right: -90°, -45°, 0° midline, +45°, +90°) and responded to stimuli at one target location (-90°, +90°, separate blocks). ERPs as a function of non-target location were examined before (baseline) and after 0.9 Hz rTMS. Results showed that ERP attention gradients were observed in three time windows (frontal 230-340, parietal 400-460, frontal 550-750 ms). Significant transient rTMS effects were seen in the first and third windows. The first window had a voltage decrease at the farthest location when attending to either the left or right side. The third window had on overall increase in positivity, but only when attending to the left side. These findings suggest that rTMS induced a small contraction in spatial attention gradients within the first time window. The asymmetric effect of attended location on gradients in the third time window may relate to neglect of the left hemispace after right parietal injury. Together, these results highlight the role of the right inferior parietal cortex in modulating frontal lobe attention network activity.