With the increasing push to legalize cannabis in Western nations, there is a need to gauge the potential impact of this policy change on vulnerable populations, such as those with mental illness, including schizophrenia, mood and anxiety disorders. This is particularly important as there are strong motives in these individuals to seek short-term reward (e.g., "getting high"). Nonetheless, data to support the beneficial effects of cannabis use in psychiatric populations are limited, and potential harms in patients with psychotic and mood disorders have been increasingly documented. This article reviews the effects of cannabis in people with mental illness. Then, we provide a reconciliation of the addiction vulnerability and allostatic hypotheses to explain addiction comorbidity in mentally ill cannabis users, as well as to further aid in developing a rational framework for assessment and treatment of problematic cannabis use in these patients.

Impulsivity is strongly associated with substance use disorders (SUDs). Our review discusses impulsivity as an underlying vulnerability marker for SUDs, and treatment of co‐occurring impulsivity in SUDs. Three factors should be considered for the complex relationship between impulsivity and a SUD: (1) the trait effect of impulsivity, centering on decreased cognitive and response inhibition, (2) the state effect resulting from either acute or chronic substance use on brain structure and function, and (3) the genetic and environmental factors (e.g., age and sex) may influence impulsive behavior associated with SUDs. Both subjective and objective measures are used to assess impulsivity. Together, treatment developments (pharmacological, behavioral, and neurophysiological) should consider these clinically relevant dimensions assessed by a variety of measures, which have implications for treatment matching in individuals with SUD. Despite its heterogeneity, impulsivity is a marker associated with SUDs and may be understood as an imbalance of bottom‐up and top‐down neural systems. Further investigation of these relationships may lead to more effective SUD treatments.

Purpose of review: To provide an overview of the underlying neurobiology of tobacco smoking in schizophrenia, and implications for treatment of this comorbidity.Recent findings: Explanations for heavy tobacco smoking in schizophrenia include pro-cognitive effects of nicotine, and remediation of the underlying pathophysiology of schizophrenia. Nicotine may ameliorate neurochemical deficits through nicotine acetylcholine receptors (nAChRs) located on the dopamine, glutamate, and GABA neurons. Neurophysiological indices including electroencephalography, electromyography, and smooth pursuit eye movement (SPEM) paradigms may be biomarkers for underlying neuronal imbalances that contribute to the specific risk of tobacco smoking initiation, maintenance, and difficulty quitting within schizophrenia. Moreover, several social factors including socioeconomic factors and permissive smoking culture in mental health facilities, may contribute to the smoking behaviors (initiation, maintenance, and inability to quit smoking) within this disorder.Summary: Tobacco smoking may alleviate specific symptoms associated with schizophrenia. Understanding the neurobiological underpinnings and psychosocial determinants of this comorbidity may better explain these potential beneficial effects, while also providing important insights into effective treatments for smoking cessation.

Cannabis use disorder (CUD) occurs at high rates in schizophrenia, which negatively impacts its clinical prognosis. These patients have greater difficulty quitting cannabis which may reflect putative deficits in the dorsolateral prefrontal cortex (DLPFC), a potential target for treatment development. We examined the effects of active versus sham high-frequency (20-Hz) repetitive transcranial magnetic stimulation (rTMS) on cannabis use in outpatients with schizophrenia and CUD. Secondary outcomes included cannabis craving/withdrawal, psychiatric symptoms, cognition and tobacco use. Twenty-four outpatients with schizophrenia and CUD were enrolled in a preliminary double-blind, sham-controlled randomized trial. Nineteen participants were randomized to receive active (n = 9) or sham (n = 10) rTMS (20-Hz) applied bilaterally to the DLPFC 5x/week for 4 weeks. Cannabis use was monitored twice weekly. A cognitive battery was administered pre- and post-treatment. rTMS was safe and well-tolerated with high treatment retention (~90%). Contrast estimates suggested greater reduction in self-reported cannabis use (measured in grams/day) in the active versus sham group (Estimate = 0.33, p = 0.21; Cohen’s d = 0.72), suggesting a clinically relevant effect of rTMS. A trend toward greater reduction in craving (Estimate = 3.92, p = 0.06), and significant reductions in PANSS positive (Estimate = 2.42, p = 0.02) and total (Estimate = 5.03, p = 0.02) symptom scores were found in the active versus sham group. Active rTMS also improved attention (Estimate = 6.58, p < 0.05), and suppressed increased tobacco use that was associated with cannabis reductions (Treatment x Time: p = 0.01). Our preliminary findings suggest that rTMS to the DLPFC is safe and potentially efficacious for treating CUD in schizophrenia.

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Repetitive transcranial magnetic stimulation (rTMS) is a promising treatment for cannabis use disorder in schizophrenia; however, gaps in the literature remain as to the potential role of neurocognitive functioning in treatment response. We evaluated the moderating role of select cognitive functions including baseline executive functioning, verbal memory, and sustained attention, and we explore the mediating role of changes in task performance on changes in cannabis use in both active and sham rTMS groups. Participants underwent high-frequency (20 Hz) rTMS applied to the bilateral dorsolateral prefrontal cortex 5x/week for 4 weeks. Weekly self-report of cannabis use and semi-quantitative urinary carboxy-tetrahydrocannabinol levels were recorded. A neurocognitive battery assessing verbal memory, visuospatial working memory, verbal working memory, sustained attention, delayed discounting, and complex planning was administered pre- and post-treatment. Better baseline performance on tasks assessing sustained attention, delayed discounting, and complex planning moderated the extent to which participants in the active group reduced cannabis use. There were no significant indirect pathways between treatment, changes in neuropsychological performance, and changes in cannabis use; however, active rTMS improved complex planning and sustained attention. These preliminary findings suggest that there is a moderating role of sustained attention, delayed discounting, and complex planning on the effects of rTMS on cannabis use. Further, mediation models suggest rTMS may exert direct effects on cannabis use independent of its effects on cognitive functioning in people with SCZ. Trial Registration: clinicaltrials.gov: NCT03189810.

BackgroundSubstance use disorders (SUDs) are a common yet poorly studied comorbidity in individuals with psychotic disorders. The co-occurrence of the two complicates recovery and interferes with pharmacological and behavioral treatment response and adherence. Recently, researchers have been exploring both invasive and non-invasive neuromodulation techniques as potential treatment methods for SUDs. We review the evidence that neuromodulation may reduce substance craving and consumption in individuals with schizophrenia.MethodsA comprehensive literature search of PubMed, MEDLINE, and PsycINFO databases was conducted (N = 1,432). Of these, we identified seven studies examining the effects of repetitive transcranial magnetic stimulation (rTMS) and two studies using transcranial direct current stimulation (tDCS) on drug consumption and craving in schizophrenia or schizoaffective disorders.ResultsDespite the limited number of studies in this area, the evidence suggests that rTMS to the dorsolateral prefrontal cortex (DLPFC) may reduce cannabis and tobacco use in patients with schizophrenia and schizoaffective disorder. Findings with tDCS, however, were inconclusive.DiscussionOur systematic review suggests that rTMS applied to DLPFC is a safe and promising therapeutic technique for the management of comorbid schizophrenia and SUDs, with the majority of the evidence in tobacco use disorder. However, there was substantial heterogeneity in study methods, underscoring the need to optimize stimulation parameters (e.g., frequency, duration, and target regions). Larger clinical trials are needed to establish the efficacy of rTMS in reducing drug consumption and craving in psychotic patients, ideally in comparison to existing pharmacological and behavioral interventions.

Ketamine has been shown to be efficacious for the treatment of depression, specifically among individuals who do not respond to first-line treatments. There is still, however, a lack of clarity surrounding the clinical features and response periods across samples that respond to ketamine. This paper systematically reviews published randomized controlled trials that investigate ketamine as an antidepressant intervention in both unipolar and bipolar depression to determine the specific clinical features of the samples across different efficacy periods. Moreover, similarities and differences in clinical characteristics associated with acute versus longer-term drug response are discussed. Similarities across all samples suggest that the population that responds to ketamine’s antidepressant effect has experienced chronic, long-term depression, approaching ketamine treatment as a “last resort”. Moreover, differences between these groups suggest future research to investigate the potential of stronger efficacy towards depression in the context of bipolar disorder compared to major depression, and in participants who undergo antidepressant washout before ketamine administration. From these findings, suggestions for the future direction of ketamine research for depression are formed.