John D. Cahill

Δ9-THC Disrupts Gamma (γ)-Band Neural Oscillations in Humans.

Gamma (γ)-band oscillations play a key role in perception, associative learning, and conscious awareness and have been shown to be disrupted by cannabinoids in animal studies. The goal of this study was to determine whether cannabinoids disrupt γ-oscillations in humans and whether these effects relate to their psychosis-relevant behavioral effects. The acute, dose-related effects of Δ-9-tetrahydrocannabinol (Δ9-THC) on the auditory steady-state response (ASSR) were studied in humans (n=20) who completed 3 test days during which they received intravenous Δ9-THC (placebo, 0.015, and 0.03 mg/kg) in a double-blind, randomized, crossover, and counterbalanced design. Electroencephalography (EEG) was recorded while subjects listened to auditory click trains presented at 20, 30, and 40 Hz. Psychosis-relevant effects were measured with the Positive and Negative Syndrome scale (PANSS). Δ9-THC (0.03 mg/kg) reduced intertrial coherence (ITC) in the 40 Hz condition compared with 0.015 mg/kg and placebo. No significant effects were detected for 30 and 20 Hz stimulation. Furthermore, there was a negative correlation between 40 Hz ITC and PANSS subscales and total scores under the influence of Δ9-THC. Δ9-THC (0.03 mg/kg) reduced evoked power during 40 Hz stimulation at a trend level. Recent users of cannabis showed blunted Δ9-THC effects on ITC and evoked power. We show for the first time in humans that cannabinoids disrupt γ-band neural oscillations. Furthermore, there is a relationship between disruption of γ-band neural oscillations and psychosis-relevant phenomena induced by cannabinoids. These findings add to a growing literature suggesting some overlap between the acute effects of cannabinoids and the behavioral and psychophysiological alterations observed in psychotic disorders.

ASCP Corner: The Endocannabinoid System and Schizophrenia: Links to the Underlying Pathophysiology and to Novel Treatment Approaches

patients, Wong et al23 found that elevated cannabinoid-1 receptor density in the frontal, middle, and posterior cingulate regions correlated with psychopathology. Cannabinoid-1 receptor gene polymorphisms may be associated with schizophrenia. Cannabinoid-1 receptor gene3 (CNR1) polymorphisms have been associated with schizophrenia in some studies,24,25 but not in others.26,27 While this inconsistency might reflect demographic differences in the study populations, another possibility is the heterogeneity of the illness.

The Psychiatric Consequences of Cannabinoids

With rising rates of cannabis use in the general population and an increasing number of US states legalizing both recreational and medical cannabis use, it is important to be informed about the adverse consequences of cannabinoids. This Commentary provides an overview of the psychiatric effects of plant-based and synthetic cannabinoids, differentiating acute effects from effects associated with persistent use. Cannabinoids produce multiphasic and dose-dependent effects on anxiety, mood, and perception, in addition to impairing cognition and psychomotor function. Generally, in healthy individuals, the acute negative psychiatric effects of cannabinoids are rated as milder in severity compared with those in individuals with pre-existing psychiatric disorders. With chronic exposure to cannabinoids, the probability of developing tolerance and dependence can increase. A problematic pattern of cannabis use can lead to clinically significant impairment and distress. Cessation of cannabis use in individuals who are tolerant and dependent can lead to a withdrawal syndrome. Studies report long-term cannabis exposure has been linked to psychiatric disorders, such as anxiety, psychotic and mood disorders. Limitations to the existing evidence notwithstanding, the plausibility of a causal relationship between cannabinoid exposure and persistent negative psychiatric outcomes, and the potential for long-term brain changes by regular exposure, especially for adolescents, are sufficient to warrant discussions with clinicians and the public. Implications for clinicians who certify, prescribe, or care for patients receiving cannabinoids are discussed, and a case is made for further research to better understand the impact of legalization on public mental health.

Testing differences in the activity of event-related potential sources: Important implications for clinical researchers

http://dx.doi.org/10.1016/j.clinph.2014.04.008 1388-2457/ 2014 International Federation of Clinical Neurophysiology. Source analysis of electroencephalographic (EEG) data is an increasingly popular tool that allows investigators to estimate the location, direction, and strength of the electric currents within the brain. Clinical researchers have increasingly exploited userfriendly Linear Distributed Source Model (LDSM) software packages (such as sLORETA-KEY) to extend classical event-related potential (ERP) experiments. However, methodological biases and inferential errors may have occurred. Spatial solutions tend to be accurately reported, but, use of standard methods to quantify source activity can introduce error into group/condition comparisons of ‘‘ERP generators’’, especially when the experimental effect is hypothesized to alter ERP peak amplitude or latency. Since 2010 alone, this journal has published a number of clinical studies reporting source localization of ERPs in which one cannot exclude one or more of these methodological or inferential issues (outlined in Table 1). We illustrate the potential pitfalls with proposed solutions. In LDSMs-based analyses, either cortical grey matter is divided into a number of voxels or cortical surface is modeled as a mesh with a number of vertices, each of which is assigned a three dimensional vector representing electric activity (EAV), a current density vector in the first case, or an electric dipole in the second. The length (norm) and orientation of an EAV correspond, respectively, to the magnitude and direction of flow of the reconstructed current (Pascual-Marqui, 2002). Grossly, positive scalp potentials would result from currents flowing towards scalp sensors, whereas negative scalp potentials would result from currents flowing away from these sensors. As EEG signals are purported to result from the summed field potentials generated by cortical neurons whose dendritic trees are perpendicular to the cortical surface, EAVs are frequently constrained to be oriented in this direction (Grech et al., 2008). To facilitate statistical comparison and graphical representation, it is common to then reduce each EAV (possessing three values per voxel or vertex) to its norm (|x|, a single positive number). Consequently, information about the direction of flow of current is lost. The norm solution, favored by popular software packages, is therefore not a complete reconstruction of the activity underlying the signals recorded at the scalp; instead, it only yields the magnitude of the activity. Although a perfectly valid measure in itself, source magnitude may be insensitive to some facets of underlying neural processes and cannot be directly related to the scalp ERPs. A temporal window centered on the peak of the scalp ERP is defined. Sources at each time point within this window are reconstructed and averaged across time to yield what is interpreted as the ‘ERP source’.

The dose-dependent psychomotor effects of intravenous delta-9-tetrahydrocannabinol (Δ9-THC) in humans

Background: Binding studies have demonstrated that levels of the cannabinoid receptor type-1 are highest in the basal ganglia and cerebellum, two areas critical for motor control. However, no studies have systematically examined the dose-related effects of intravenous delta-9-tetrahydrocannabinol, the primary cannabinoid receptor type-1 partial agonist in cannabis, on broad domains of psychomotor function in humans. Aims: Therefore, three domains of psychomotor function were assessed in former cannabis users (cannabis abstinent for a minimum of three months; n=23) in a three test-day, within-subject, double-blind, randomized, cross-over, and counterbalanced study during which they received intravenous delta-9-tetrahydrocannabinol (placebo, 0.015 mg/kg, and 0.03 mg/kg). Methods: Gross motor function was assessed via the Cambridge Neuropsychological Test Automated Battery Motor Screening Task, fine motor control via the Lafayette Instrument Grooved Pegboard task, and motor timing via a Paced Finger-Tapping Task. In addition, the Cambridge Neuropsychological Test Automated Battery Rapid Visual Processing Task was utilized to determine whether delta-9-tetrahydrocannabinol-induced motor deficits were confounded by disruptions in sustained attention. Results/outcomes: Delta-9-tetrahydrocannabinol resulted in robust dose-dependent deficits in fine motor control (Grooved Pegboard Task) and motor timing (Paced Finger-Tapping Task), while gross motor performance (Motor Screening Task) and sustained attention (Rapid Visual Processing Task) were unimpaired. Interestingly, despite the observed dose-dependent increases in motor impairment and blood levels of delta-9-tetrahydrocannabinol, subjects reported similar levels of intoxication in the two drug conditions. Conclusions/interpretation: These data suggest that while several domains of motor function are disrupted by delta-9-tetrahydrocannabinol, subjective feelings of intoxication are dissociable from cannabinoid-induced psychomotor effects. Results are discussed in terms of the potential neural mechanisms of delta-9-tetrahydrocannabinol in motor structures.

Building Early Intervention Services for Psychotic Disorders: A Primer for Early Adopters in the U.S.

Recent developments in the U.S. healthcare policy signal a growing commitment to early intervention for psychotic disorders. A growing international and U.S. research database supports the effectiveness of specialty team-based models adapted to care for young individuals with recent onset psychosis. The RAISE (Recovery After an Initial Schizophrenia Episode) initiative, sponsored by the NIMH (National Institute of Mental Health), has defined such Coordinated Specialty Care (CSC) services as a new benchmark for care across the U.S., and published a variety of resources to support dissemination. Funding initiatives led by the center for Substance Abuse and Mental Health Services (SAMHSA), and support from other national organizations, have catalyzed interest in community agencies across the country. We offer guidance to such early adopters and supplement extant resources with a focus on the process of setting up such programs. Adopters have numerous decisions to make. These include determining admission criteria, structuring care processes to maximize impact, choosing from several empirically based interventions, and resourcing workforce development. We provide a guide to salient resources, and lessons learned from a decade old CSC, to aid in these complex decisions. We end with a discussion of limitations in the current knowledge base, and the need for responsive research. Early intervention services can engender application of demonstrably effective treatment, while also providing platforms for research to improve and develop new treatments. Collaborations between a wide variety of government, academic and commercial stakeholders will be essential to realize the transformative public health impact of early intervention for psychotic disorders.

Psychopharmacology Prescribing Workshops: A Novel Method for Teaching Psychiatry Residents How to Talk to Patients About Medications

ObjectiveTraditional, lecture-based methods of teaching pharmacology may not translate into the skills needed to communicate effectively with patients about medications. In response, the authors developed an interactive course for third-year psychiatry residents to reinforce prescribing skills.MethodsResidents participate in a facilitated group discussion combined with a role-play exercise where they mock-prescribe medication to their peers. Each session is focused on one medication or class of medications with an emphasis on various aspects of informed consent (such as describing the indication, dosing, expected benefits, potential side effects, and necessary work-up and follow up). In the process of implementing the course at a second site, the original format was modified to include self-assessment measures and video examples of experienced faculty members prescribing to a simulated patient.ResultsThe course was initially developed at one site and has since been disseminated to a number of other institutions. Between 2010 and 2016, 144 residents participated in the course at the authors’ two institutions. Based upon pre/post surveys conducted with a subset of residents, the course significantly improved comfort with various aspects of prescribing. Although residents may also gain comfort in prescribing with experience (as the course coincides with the major outpatient clinical training year), improvement in comfort-level was also noted for medications that residents had relatively little experience initiating. At the end of the year, half of the residents indicated the course was one of their top three preferred methods for learning psychopharmacology in addition to direct clinical experience and supervision (with none listing didactics).ConclusionAn interactive prescribing workshop can improve resident comfort with prescribing and may be preferred over a traditional, lecture-based approach. The course may be particularly helpful for those medications that are less commonly used. Based upon our experience, this approach can be easily implemented across institutions..