Mismatch negativity (MMN) is a candidate endophenotype for schizophrenia subserved by N-methyl-D-aspartate receptor (NMDAR) function and there is increasing evidence that prolonged cannabis use adversely affects MMN generation. Few human studies have investigated the acute effects of cannabinoids on brain-based biomarkers of NMDAR function and synaptic plasticity.

The current study investigated the acute effects of Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD) alone and in combination on the mismatch negativity (MMN).

In a randomised, double-blind, crossover placebo-controlled study, 18 frequent and 18 less-frequent cannabis users underwent 5 randomised drug sessions administered via vaporiser: (1) placebo; (2) THC 8 mg; (3) CBD 400 mg; (4) THC 8 mg + CBD 4 mg [THC + CBD_low]; (5) THC 12 mg + CBD 400 mg [THC + CBD_high]. Participants completed a multifeature MMN auditory oddball paradigm with duration, frequency and intensity deviants (6% each).

Relative to placebo, both THC and CBD were observed to increase duration and intensity MMN amplitude in less-frequent users, and THC also increased frequency MMN in this group. The addition of low-dose CBD added to THC attenuated the effect of THC on duration and intensity MMN amplitude in less-frequent users. The same pattern of effects was observed following high-dose CBD added to THC on duration and frequency MMN in frequent users.

The pattern of effects following CBD combined with THC on MMN may be subserved by different underlying neurobiological interactions within the endocannabinoid system that vary as a function of prior cannabis exposure. These results highlight the complex interplay between the acute effects of exogenous cannabinoids and NMDAR function. Further research is needed to determine how this process normalises after the acute effects dissipate and following repeated acute exposure.

Relapse prevention remains a major challenge in psychiatry, thus indicating that the established treatment methods combining psychotherapy with neuropharmacological interventions are not entirely effective. In recent years, several intervention strategies have been devised that are aimed at improving psychiatric treatment by providing a complementary set of add-on tools that can be used by clinicians to improve current patient assessment. Among these, cognitive event-related potentials (ERPs) have been indexed as valuable biomarkers of the pathophysiological mechanisms of various mental illnesses. However, despite decades of research, their clinical utility is still controversial and a matter of debate. In this opinion review, I present the main arguments supporting the use of cognitive ERPs in the management of psychiatric disorders, stressing why it is currently still not the case despite the vast number of ERP studies to date. I also propose a clinically-oriented suitable way in which this technique could - in my opinion - be effectively incorporated into individual patient care by promotion of the use of individual ERP test-retest sessions and the use of a multi-component approach.

Involuntary attention allows for the detection and processing of novel and potentially relevant stimuli that lie outside of cognitive focus. These processes comprise change detection in sensory contexts, automatic orientation toward this change, and the selection of adaptive responses, including reorientation to the original goal in cases when the detected change is not relevant for task demands. These processes have been studied using the Event-Related Potential (ERP) technique and have been associated to the Mismatch Negativity (MMN), the P3a, and the Reorienting Negativity (RON) electrophysiological components, respectively. This has allowed for the objective evaluation of the impact of different neuropsychiatric pathologies on involuntary attention. Additionally, these ERP have been proposed as alternative measures for the early detection of disease and the tracking of its progression. The objective of this review was to integrate the results reported to date about MMN, P3a, and RON in different neurological and psychiatric disorders. We included experimental studies with clinical populations that reported at least two of these three components in the same experimental paradigm. Overall, involuntary attention seems to reflect the state of cognitive integrity in different pathologies in adults. However, if the main goal for these ERP is to consider them as biomarkers, more research about their pathophysiological specificity in each disorder is needed, as well as improvement in the general experimental conditions under which these components are elicited. Nevertheless, these ERP represent a valuable neurophysiological tool for early detection and follow-up of diverse clinical populations.

The high prevalence of concomitant cannabis and nicotine use has implications for sensory and cognitive processing. While nicotine tends to enhance function in these domains, cannabis use has been associated with both sensory and cognitive impairments, though the underlying mechanisms are unclear. Additionally, the interaction of the nicotinic (nAChR) and cannabinoid (CB₁) receptor systems has received limited study in terms of sensory/cognitive processes. This study involving healthy volunteers assessed the acute separate and combined effects of nabilone (a CB₁ agonist) and nicotine on sensory processing as assessed by auditory deviance detection and indexed by the mismatch negativity (MMN) event-related potential. It was hypothesized that nabilone would impair auditory discriminability as shown by diminished MMN amplitudes, but not when administered in combination with nicotine. 20 male non-smokers and non-cannabis-users were assessed using a 5-stimulus 'optimal' multi-feature MMN paradigm within a randomized, placebo controlled design (placebo; nabilone [0.5 mg]; nicotine [6 mg]; and nicotine + nabilone). Treatment effects were region- and deviant-dependent. At the temporal regions (mastoid sites), MMN was reduced by nabilone and nicotine separately, whereas co-administration resulted in no impairment. At the frontal region, MMN was enhanced by co-administration of nicotine and nabilone, with no MMN effects being found with separate treatment. These neural effects have relevance for sensory/cognitive processes influenced by separate and simultaneous use of cannabis and tobacco and may have treatment implications for disorders associated with sensory dysfunction and impairments in endocannabinoid and nicotinic cholinergic neurotransmission.

A substantial body of credible evidence has accumulated that suggest that cannabis use is an important potentially preventable risk factor for the development of psychotic illness and its worse prognosis following the onset of psychosis. Here we summarize the relevant evidence to argue that the time has come to investigate the neurobiological effects of cannabis in patients with psychotic disorders. In the first section we summarize evidence from longitudinal studies that controlled for a range of potential confounders of the association of cannabis use with increased risk of developing psychotic disorders, increased risk of hospitalization, frequent and longer hospital stays, and failure of treatment with medications for psychosis in those with established illness. Although some evidence has emerged that cannabis-using and non-using patients with psychotic disorders may have distinct patterns of neurocognitive and neurodevelopmental impairments, the biological underpinnings of the effects of cannabis remain to be fully elucidated. In the second and third sections we undertake a systematic review of 70 studies, including over 3000 patients with psychotic disorders or at increased risk of psychotic disorder, in order to delineate potential neurobiological and neurochemical mechanisms that may underlie the effects of cannabis in psychotic disorders and suggest avenues for future research.

Substance use disorders (SUDs) have a devastating impact on society and place a heavy burden on health care systems. Given that alcohol, tobacco, and cannabis use have the highest prevalence, further understanding of the underlying pathophysiology of these SUDs is crucial. Electroencephalography is an inexpensive, temporally superior, and translatable technique which enables investigation of the pathobiology of SUDs through the evaluation of various event-related potential components, including mismatch negativity (MMN). The goals of this review were to investigate the effects of acute and chronic alcohol, tobacco, and cannabis use on MMN among nonpsychiatric populations and patients with comorbid psychosis. A literature search was performed using the database PubMed, and 36 articles met our inclusion and exclusion criteria. We found a pattern of attenuation of MMN amplitude among patients with alcoholism across acute and chronic alcohol use, and this dysregulation was not heritable. Reports were limited, and results were mixed on the effects of acute and chronic tobacco and cannabis use on MMN. Reports on comorbid SUDs and psychosis were even fewer, and also presented mixed findings. These preliminary results suggest that MMN deficits may be associated with SUDs, specifically alcohol use disorder, and serve as a possible biomarker for treating these common disorders.

Mismatch negativity (MMN) is among the best established biomarkers of cortical dysfunction in schizophrenia. MMN generators are localized primarily to primary and secondary auditory regions, and are known to reflect activity mediated by cortical N-methyl-d-aspartate-type glutamate receptors (NMDAR). Nevertheless, mechanisms underlying MMN generation at the local circuit level remain incompletely understood. This review synthesizes recent advances in circuit-level conceptualization of MMN based upon neuro-oscillatory findings. In the neuro-oscillatory (aka event-related spectral perturbation, ERSP) approach, responses to sensory stimuli are decomposed into underlying frequency bands prior to analysis. MMN reflects activity primarily in theta (4-7Hz) frequency band, which is thought to depend primarily upon interplay between cortical pyramidal neurons and somatostatin (SST)-type local circuit GABAergic interneurons. Schizophrenia-related deficits in theta generation are also observed not only in MMN, but also in other auditory and visual contexts. At the local circuit level, SST interneurons are known to maintain tonic inhibition over cortical pyramidal interneurons. SST interneurons, in turn, are inhibited by a class of interneurons expressing vasoactive intestinal polypeptide (VIP). In rodents, SST interneurons have been shown to respond differentially to deviant vs. standard stimuli, and inhibition of SST interneurons has been found to selectively inhibit deviance-related activity in rodent visual cortex. Here we propose that deficits in theta frequency generation, as exemplified by MMN, may contribute significantly to cortical dysfunction in schizophrenia, and may be tied to impaired interplay between cortical pyramidal neurons and local circuit SST-type GABAergic interneurons.

Long-term cannabis use may confer cognitive deficits and increased risk of psychosis. However, the relationship between cannabis use and schizophrenia is complex. In particular, little is known about the effects of chronic cannabis use on the attention-related electric brain response in schizophrenia. We investigated auditory novelty and oddball P300 evoked potentials in a mixed sample of first-episode and chronic schizophrenic patients and healthy controls with (SZCA, n = 20; COCA, n = 20, abstinence ≥28 days) or without (SZ, n = 20; CO, n = 20) chronic cannabis use. Duration of regular cannabis use was 8.3 ± 5.6 (SZCA) and 9.1 ± 7.1 (COCA) years. In general, schizophrenic patients showed reduced P300 amplitudes. Cannabis use was associated with both a reduced early and late left-hemispheric novelty P300. There was a significant 'diagnosis × cannabis' interaction for the left-hemispheric late novelty P300 in that cannabis use was associated with a reduced amplitude in the otherwise healthy but not in the schizophrenic group compared with their relative control groups (corrected p < 0.02; p > 0.9, respectively). The left-hemispheric late novelty P300 in the otherwise healthy cannabis group correlated inversely with amount and duration of cannabis use (r = -0.50, p = 0.024; r = -0.57, p = 0.009, respectively). Our study confirms attentional deficits with chronic cannabis use. However, cannabis use may lead to different cognitive sequelae in patients with schizophrenia and in healthy controls, possibly reflecting preexisting alterations in the endocannabinoid system in schizophrenia.

Some of the most compelling evidence supporting an association between cannabinoid agonists and psychosis comes from controlled laboratory studies in humans. Randomized, double-blind, placebo-controlled, crossover laboratory studies demonstrate that cannabinoid agonists, including phytocannabinoids and synthetic cannabinoids, produce a wide range of positive, negative, and cognitive symptoms and psychophysiologic deficits in healthy human subjects that resemble the phenomenology of schizophrenia. These effects are time locked to drug administration, are dose related, and are transient and rarely necessitate intervention. The magnitude of effects is similar to the effects of ketamine but qualitatively distinct from other psychotomimetic drugs, including ketamine, amphetamine, and salvinorin A. Cannabinoid agonists have also been shown to transiently exacerbate symptoms in individuals with schizophrenia in laboratory studies. Patients with schizophrenia are more vulnerable than healthy control subjects to the acute behavioral and cognitive effects of cannabinoid agonists and experience transient exacerbation of symptoms despite treatment with antipsychotic medications. Furthermore, laboratory studies have failed to demonstrate any "beneficial" effects of cannabinoid agonists in individuals with schizophrenia-challenging the cannabis self-medication hypothesis. Emerging evidence suggests that polymorphisms of several genes related to dopamine metabolism (e.g., COMT, DAT1, and AKT1) may moderate the effects of cannabinoid agonists in laboratory studies. Cannabinoid agonists induce dopamine release, although the magnitude of release does not appear to be commensurate to the magnitude and spectrum of their acute psychotomimetic effects. Interactions between the endocannabinoid, gamma-aminobutyric acid, and glutamate systems and their individual and interactive effects on neural oscillations provide a plausible mechanism underlying the psychotomimetic effects of cannabinoids.

Cannabis use is associated with the development of psychotic symptoms and increased risk for schizophrenia. The mismatch negativity (MMN) is a brain event-related potential marker of change detection thought to index glutamatergic N-methyl-D-aspartate receptor-mediated neurotransmission, which is known to be deficient in schizophrenia. This study examined auditory MMN in otherwise healthy chronic cannabis users compared with nonuser control subjects.

Forty-two chronic cannabis users and 44 nonuser healthy control subjects completed a multi-feature MMN paradigm, which included duration, frequency, and intensity deviants (deviants 6%; standards 82%). The MMN was compared between users and control subjects as well as between long- and short-term users and age- and gender-matched control subjects. Associations between MMN, cannabis use measures, and symptoms were examined.

The MMN amplitude was significantly reduced to frequency but not duration or intensity deviants in overall cannabis users relative to control subjects. Frequency MMN was similarly attenuated in short- and long-term users relative to control subjects. Long-term users also exhibited reduced duration MMN relative to control subjects and short-term users and this was correlated with increased duration of exposure to cannabis and increased psychotic-like experiences during intoxication. In short-term users, a younger age of onset of regular cannabis use and greater frequency of use were associated with greater psychotic-like experiences and symptomatic distress.

These results suggest impaired sensory memory that might reflect N-methyl-D-aspartate receptor dysfunction in chronic cannabis users. The pattern of MMN alterations in cannabis users differed from that typically observed in patients with schizophrenia, indicating overlapping but distinct underlying pathology.

Cannabis is the most commonly used illicit drug worldwide, with ~5 million daily users worldwide. Emerging evidence supports a number of associations between cannabis and psychosis/psychotic disorders, including schizophrenia. These associations-based on case-studies, surveys, epidemiological studies, and experimental studies indicate that cannabinoids can produce acute, transient effects; acute, persistent effects; and delayed, persistent effects that recapitulate the psychopathology and psychophysiology seen in schizophrenia. Acute exposure to both cannabis and synthetic cannabinoids (Spice/K2) can produce a full range of transient psychotomimetic symptoms, cognitive deficits, and psychophysiological abnormalities that bear a striking resemblance to symptoms of schizophrenia. In individuals with an established psychotic disorder, cannabinoids can exacerbate symptoms, trigger relapse, and have negative consequences on the course of the illness. Several factors appear to moderate these associations, including family history, genetic factors, history of childhood abuse, and the age at onset of cannabis use. Exposure to cannabinoids in adolescence confers a higher risk for psychosis outcomes in later life and the risk is dose-related. Individuals with polymorphisms of COMT and AKT1 genes may be at increased risk for psychotic disorders in association with cannabinoids, as are individuals with a family history of psychotic disorders or a history of childhood trauma. The relationship between cannabis and schizophrenia fulfills many but not all of the standard criteria for causality, including temporality, biological gradient, biological plausibility, experimental evidence, consistency, and coherence. At the present time, the evidence indicates that cannabis may be a component cause in the emergence of psychosis, and this warrants serious consideration from the point of view of public health policy.

Impaired mismatch negativity (MMN) is a robust finding in schizophrenia and, more recently, similar impairments have been reported in other psychotic- and affective-disorders (including at early stages of illness). Although cross-sectional studies have been numerous, there are few longitudinal studies that have explored the predictive value of this event-related potential in relation to clinical/functional outcomes. This study assessed changes in MMN (and the concomitant P3a) amplitude over time and aimed to determine the longitudinal relationship between MMN/P3a and functional outcomes in patients recruited during the early stage of a schizophrenia- or affective-spectrum disorder.

Sixty young patients with schizophrenia- and affective-spectrum disorders and 30 healthy controls underwent clinical, neuropsychological and neurophysiological assessment at baseline. Thirty-one patients returned for clinical and neuropsychological follow-up 12-30months later, with 28 of these patients also repeating neurophysiological assessment. On both occasions, MMN/P3a was elicited using a two-tone passive auditory paradigm with duration deviants.

Compared with controls, patients showed significantly impaired temporal MMN amplitudes and trend-level deficits in central MMN/P3a amplitudes at baseline. There were no significant differences for MMN measures between the diagnostic groups, whilst the schizophrenia-spectrum group showed reduced P3a amplitudes compared to those with affective-spectrum disorders. For those patients who returned for follow-up, reduced temporal MMN amplitude at baseline was significantly associated with greater levels of occupational disability, and showed trend-level associations with general and social disability at follow-up. Paired t-tests revealed that MMN amplitudes recorded at the central-midline site were significantly reduced in patients over time. Interestingly, those patients who did not return for follow-up showed reduced frontal MMN and fronto-central P3a amplitudes compared to their peers who did return for repeat assessment.

This study provides some evidence of the predictive utility of MMN at the early stages of schizophrenia- and affective-spectrum disorders and demonstrated that MMN impairments in such patients may worsen over time. Specifically, we found that young patients with the most impaired MMN amplitudes at baseline showed the most severe levels of disability at follow-up. Furthermore, in the subset of patients with repeat neurophysiological testing, central MMN was further impaired suggestive of neurodegenerative effects. MMN may serve as a neurophysiological biomarker to more accurately predict functional outcomes and prognosis, particularly at the early stages of illness.

After 30 years of consensus-derived diagnostic categories in mental health, it is time to head in new directions. Those categories placed great emphasis on enhanced reliability and the capacity to identify them via standardized checklists. Although this enhanced epidemiology and health services planning, it failed to link broad diagnostic groupings to underlying pathophysiology or specific treatment response.

It is time to adopt new goals that prioritize the validation of clinical entities and foster alternative strategies to support those goals. The value of new dimensions (notably clinical staging), that are both clinically relevant and directly related to emerging developmental and neurobiological research, is proposed. A strong emphasis on 'reverse translation' (that is, working back from the clinic to the laboratory) underpins these novel approaches. However, it relies on using diagnostic groupings that already have strong evidence of links to specific risk factors or patterns of treatment response.

The strategies described abandon the historical divides between clinical neurology, psychiatry and psychology and adopt the promotion of pathways to illness models.