A phase 1/2 trial to assess safety and efficacy of a vaporized 5-methoxy-N,N-dimethyltryptamine formulation (GH001) in patients with treatment-resistant depression.

Background: Treatment-resistant depression (TRD) is a substantial public health burden, but current treatments have limited effectiveness. The aim was to investigate the safety and potential antidepressant effects of the serotonergic psychedelic drug 5-MeO-DMT in a vaporized formulation (GH001) in adult patients with TRD. Methods: The Phase 1 part (n = 8) of the trial investigated two single dose levels of GH001 (12 mg, 18 mg) with a primary endpoint of safety, and the Phase 2 part (n = 8) investigated an individualized dosing regimen (IDR) with up to three increasing doses of GH001 (6 mg, 12 mg, and 18 mg) within a single day, with a primary endpoint of efficacy, as assessed by the proportion of patients in remission (MADRS ≤ 10) on day 7. Results: Administration of GH001 via inhalation was well tolerated. The proportion of patients in remission (MADRS ≤ 10) at day 7 was 2/4 (50%) and 1/4 (25%) in the 12 mg and 18 mg groups of Phase 1, respectively, and 7/8 (87.5%) in the IDR group of Phase 2, meeting its primary endpoint (p < 0.0001). All remissions were observed from day 1, with 6/10 remissions observed from 2 h. The mean MADRS change from baseline to day 7 was -21.0 (-65%) and - 12.5 (-40%) for the 12 and 18 mg groups, respectively, and - 24.4 (-76%) for the IDR. Conclusion: Administration of GH001 to a cohort of 16 patients with TRD was well tolerated and provided potent and ultra-rapid antidepressant effects. Individualized dosing with up to three doses of GH001 on a single day was superior to single dose administration.Clinical Trial registration: Clinicaltrials.gov Identifier NCT04698603.

A replication study of JTC bias, genetic liability for psychosis and delusional ideation.

BACKGROUND: This study attempted to replicate whether a bias in probabilistic reasoning, or 'jumping to conclusions'(JTC) bias is associated with being a sibling of a patient with schizophrenia spectrum disorder; and if so, whether this association is contingent on subthreshold delusional ideation. METHODS: Data were derived from the EUGEI project, a 25-centre, 15-country effort to study psychosis spectrum disorder. The current analyses included 1261 patients with schizophrenia spectrum disorder, 1282 siblings of patients and 1525 healthy comparison subjects, recruited in Spain (five centres), Turkey (three centres) and Serbia (one centre). The beads task was used to assess JTC bias. Lifetime experience of delusional ideation and hallucinatory experiences was assessed using the Community Assessment of Psychic Experiences. General cognitive abilities were taken into account in the analyses. RESULTS: JTC bias was positively associated not only with patient status but also with sibling status [adjusted relative risk (aRR) ratio : 4.23 CI 95% 3.46-5.17 for siblings and aRR: 5.07 CI 95% 4.13-6.23 for patients]. The association between JTC bias and sibling status was stronger in those with higher levels of delusional ideation (aRR interaction in siblings: 3.77 CI 95% 1.67-8.51, and in patients: 2.15 CI 95% 0.94-4.92). The association between JTC bias and sibling status was not stronger in those with higher levels of hallucinatory experiences. CONCLUSIONS: These findings replicate earlier findings that JTC bias is associated with familial liability for psychosis and that this is contingent on the degree of delusional ideation but not hallucinations.

The jumping to conclusions reasoning bias as a cognitive factor contributing to psychosis progression and persistence: findings from NEMESIS-2.

BACKGROUND: Contemporary models of psychosis implicate the importance of affective dysregulation and cognitive factors (e.g. biases and schemas) in the development and maintenance of psychotic symptoms, but studies testing proposed mechanisms remain limited. This study, uniquely using a prospective design, investigated whether the jumping to conclusions (JTC) reasoning bias contributes to psychosis progression and persistence. METHODS: Data were derived from the second Netherlands Mental Health Survey and Incidence Study (NEMESIS-2). The Composite International Diagnostic Interview and an add-on instrument were used to assess affective dysregulation (i.e. depression, anxiety and mania) and psychotic experiences (PEs), respectively. The beads task was used to assess JTC bias. Time series analyses were conducted using data from T1 and T2 (N = 8666), excluding individuals who reported high psychosis levels at T0. RESULTS: Although the prospective design resulted in low statistical power, the findings suggest that, compared to those without symptoms, individuals with lifetime affective dysregulation were more likely to progress from low/moderate psychosis levels (state of 'aberrant salience', one or two PEs) at T1 to high psychosis levels ('frank psychosis', three or more PEs or psychosis-related help-seeking behaviour) at T2 if the JTC bias was present [adj. relative risk ratio (RRR): 3.8, 95% confidence interval (CI) 0.8-18.6, p = 0.101]. Similarly, the JTC bias contributed to the persistence of high psychosis levels (adj. RRR: 12.7, 95% CI 0.7-239.6, p = 0.091). CONCLUSIONS: We found some evidence that the JTC bias may contribute to psychosis progression and persistence in individuals with affective dysregulation. However, well-powered prospective studies are needed to replicate these findings.

[18F]MK-9470 PET measurement of cannabinoid CB1 receptor availability in chronic cannabis users.

Δ(9) -Tetrahydrocannabinol, the main psychoactive component of cannabis, exerts its central effects through activation of the cerebral type 1 cannabinoid (CB1 ) receptor. Pre-clinical studies have provided evidence that chronic cannabis exposure is linked to decreased CB1 receptor expression and this is thought to be a component underlying drug tolerance and dependence. In this study, we make first use of the selective high-affinity positron emission tomography (PET) ligand [(18) F]MK-9470 to obtain in vivo measurements of cerebral CB1 receptor availability in 10 chronic cannabis users (age = 26.0 ± 4.1 years). Each patient underwent [(18) F]MK-9470 PET within the first week following the last cannabis consumption. A population of 10 age-matched healthy subjects (age = 23.0 ± 2.9 years) was used as control group. Parametric modified standardized uptake value images, reflecting CB1 receptor availability, were calculated. Statistical parametric mapping and volume-of-interest (VOI) analyses of CB1 receptor availability were performed. Compared with controls, cannabis users showed a global decrease in CB1 receptor availability (-11.7 percent). VOI-based analysis demonstrated that the CB1 receptor decrease was significant in the temporal lobe (-12.7 percent), anterior (-12.6 percent) and posterior cingulate cortex (-13.5 percent) and nucleus accumbens (-11.2 percent). Voxel-based analysis confirmed this decrease and regional pattern in CB1 receptor availability in cannabis users. These findings revealed that chronic cannabis use may alter specific regional CB1 receptor expression through neuroadaptive changes in CB1 receptor availability, opening the way for the examination of specific CB1 -cannabis addiction interactions which may predict future cannabis-related treatment outcome.

Does assessment type matter? A measurement invariance analysis of online and paper and pencil assessment of the Community Assessment of Psychic Experiences (CAPE).

BACKGROUND: The psychometric properties of an online test are not necessarily identical to its paper and pencil original. The aim of this study is to test whether the factor structure of the Community Assessment of Psychic Experiences (CAPE) is measurement invariant with respect to online vs. paper and pencil assessment. METHOD: The factor structure of CAPE items assessed by paper and pencil (N = 796) was compared with the factor structure of CAPE items assessed by the Internet (N = 21,590) using formal tests for Measurement Invariance (MI). The effect size was calculated by estimating the Signed Item Difference in the Sample (SIDS) index and the Signed Test Difference in the Sample (STDS) for a hypothetical subject who scores 2 standard deviations above average on the latent dimensions. RESULTS: The more restricted Metric Invariance model showed a significantly worse fit compared to the less restricted Configural Invariance model (χ(2)(23) = 152.75, p<0.001). However, the SIDS indices appear to be small, with an average of -0.11. A STDS of -4.80 indicates that Internet sample members who score 2 standard deviations above average would be expected to score 4.80 points lower on the CAPE total scale (ranging from 42 to 114 points) than would members of the Paper sample with the same latent trait score. CONCLUSIONS: Our findings did not support measurement invariance with respect to assessment method. Because of the small effect sizes, the measurement differences between the online assessed CAPE and its paper and pencil original can be neglected without major consequences for research purposes. However, a person with a high vulnerability for psychotic symptoms would score 4.80 points lower on the total scale if the CAPE is assessed online compared to paper and pencil assessment. Therefore, for clinical purposes, one should be cautious with online assessment of the CAPE.

Delta-9-tetrahydrocannabinol-induced dopamine release as a function of psychosis risk: 18F-fallypride positron emission tomography study.

Cannabis use is associated with psychosis, particularly in those with expression of, or vulnerability for, psychotic illness. The biological underpinnings of these differential associations, however, remain largely unknown. We used Positron Emission Tomography and (18)F-fallypride to test the hypothesis that genetic risk for psychosis is expressed by differential induction of dopamine release by Δ(9)-THC (delta-9-tetrahydrocannabinol, the main psychoactive ingredient of cannabis). In a single dynamic PET scanning session, striatal dopamine release after pulmonary administration of Δ(9)-THC was measured in 9 healthy cannabis users (average risk psychotic disorder), 8 patients with psychotic disorder (high risk psychotic disorder) and 7 un-related first-degree relatives (intermediate risk psychotic disorder). PET data were analyzed applying the linear extension of the simplified reference region model (LSRRM), which accounts for time-dependent changes in (18)F-fallypride displacement. Voxel-based statistical maps, representing specific D2/3 binding changes, were computed to localize areas with increased ligand displacement after Δ(9)-THC administration, reflecting dopamine release. While Δ(9)-THC was not associated with dopamine release in the control group, significant ligand displacement induced by Δ(9)-THC in striatal subregions, indicative of dopamine release, was detected in both patients and relatives. This was most pronounced in caudate nucleus. This is the first study to demonstrate differential sensitivity to Δ(9)-THC in terms of increased endogenous dopamine release in individuals at risk for psychosis.

To cut a short test even shorter: reliability and validity of a brief assessment of intellectual ability in schizophrenia--a control-case family study.

BACKGROUND: The potential inclusion of cognitive assessments in the DSM-V and large time-consuming assessments drive a need for short tests of cognitive impairments. We examined the reliability and validity of a brief, 15-minute, version of the Wechsler Adult Intelligence Scale-III (WAIS-III). METHODS: The sample consisted of patients diagnosed with schizophrenia (n=75), their siblings without schizophrenia (n=74) and unrelated healthy controls (n=84). A short WAIS-III consists of the Digit Symbol Coding subtest, and every second (or third) item of Block Design, Information, and Arithmetic. Psychometric analyses were implemented using item-response theory (IRT) to determine the best minimal item short version, while maintaining the sensitivity and reliability of the IQ score. RESULTS: The proposed 15-minute WAIS-III gave reliable estimates of the Full Scale IQ (FSIQ) in all three groups in the sample. The 15-minute (select-item) version yielded an overall R of.95 (R(2)=.92) and IRT yielded an R of .96 (R(2)=.92). All four subtests performed well in differentiating patients, relatives, and healthy controls. Multivariate analysis showed a significant difference in FSIQ-estimate between patients, relatives, and healthy controls, F(2, 202) = 19.00, p < .0001. Regression modelling showed that the three versions of the WAIS had similar associations with functional outcome after a 3-year follow-up. CONCLUSIONS: Our proposed 15-minute version of the WAIS may serve as a useful screening device for general intellectual ability in research or clinical settings, and is recommended when a quick and accurate IQ estimate is desired.

Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study.

OBJECTIVE: To determine whether use of cannabis in adolescence increases the risk for psychotic outcomes by affecting the incidence and persistence of subclinical expression of psychosis in the general population (that is, expression of psychosis below the level required for a clinical diagnosis). DESIGN: Analysis of data from a prospective population based cohort study in Germany (early developmental stages of psychopathology study). SETTING: Population based cohort study in Germany. PARTICIPANTS: 1923 individuals from the general population, aged 14-24 at baseline. MAIN OUTCOME MEASURE: Incidence and persistence of subthreshold psychotic symptoms after use of cannabis in adolescence. Cannabis use and psychotic symptoms were assessed at three time points (baseline, T2 (3.5 years), T3 (8.4 years)) over a 10 year follow-up period with the Munich version of the composite international diagnostic interview (M-CIDI). RESULTS: In individuals who had no reported lifetime psychotic symptoms and no reported lifetime cannabis use at baseline, incident cannabis use over the period from baseline to T2 increased the risk of later incident psychotic symptoms over the period from T2 to T3 (adjusted odds ratio 1.9, 95% confidence interval 1.1 to 3.1; P=0.021). Furthermore, continued use of cannabis increased the risk of persistent psychotic symptoms over the period from T2 to T3 (2.2, 1.2 to 4.2; P=0.016). The incidence rate of psychotic symptoms over the period from baseline to T2 was 31% (152) in exposed individuals versus 20% (284) in non-exposed individuals; over the period from T2 to T3 these rates were 14% (108) and 8% (49), respectively. CONCLUSION: Cannabis use is a risk factor for the development of incident psychotic symptoms. Continued cannabis use might increase the risk for psychotic disorder by impacting on the persistence of symptoms.

Age at onset of psychotic disorder: cannabis, BDNF Val66Met, and sex-specific models of gene-environment interaction.

Discovering modifiable predictors for age at onset may help to identify predictors of transition to psychotic disorder in the "at-risk mental state." Inconsistent effects of sex, BDNF Val66Met (rs6265), and cannabis use on age of onset were previously reported. BDNF Val66Met and cannabis use before illness onset were retrospectively assessed in a sample of 585 patients with schizophrenia and their association with age at onset was evaluated. Cannabis use was significantly associated with earlier age at onset of psychotic disorder (AOP; average difference 2.7 years, P < 0.001), showing dose-response effects with higher frequency and earlier age at first use. There was a weak association between BDNF Val66Met genotype and AOP (difference 1.2 years; P = 0.050). No evidence was found for BDNF × cannabis interaction (interaction χ(2) (1) = 0.65, P = 0.420). However, a significant BDNF × cannabis × sex interaction was found (interaction χ(2) (1) = 4.99, P = 0.026). In female patients, cannabis use was associated with earlier AOP in BDNF Met-carriers (difference 7 years), but not in Val/Val-genotypes. In male patients, cannabis use was associated with earlier AOP irrespective of BDNF Val66Met genotype (difference 1.3 years). BDNF Val66Met genotype in the absence of cannabis use did not influence AOP, neither in female or male patients with psychotic disorder. Complex interactions between cannabis and BDNF may shape age at onset in female individuals at risk of psychotic disorder. No compelling evidence was found that BDNF genotype is associated with age at onset of psychotic disorder in the absence of cannabis use.

Does cannabidiol protect against the negative effects of THC?

A recent study by Morgan and colleagues found that cannabidiol attenuates the acute cognitive effects of delta-9-tetrahydrocannabinol (THC). This is of interest as THC has been associated with the detrimental effects of cannabis on mental health in at-risk users, and the potency of cannabis is increasing across Europe.

Does dopamine mediate the psychosis-inducing effects of cannabis? A review and integration of findings across disciplines.

General population epidemiological studies have consistently found that cannabis use increases the risk of developing psychotic disorders in a dose-dependent manner. While the epidemiological signal between cannabis and psychosis has gained considerable attention, the biological mechanism whereby cannabis increases risk for psychosis remains poorly understood. Animal research suggests that delta-9-tetrahydrocannabinol (THC, the main psychoactive component of cannabis) increases dopamine levels in several regions of the brain, including striatal and prefrontal areas. Since dopamine is hypothesized to represent a crucial common final pathway between brain biology and actual experience of psychosis, a focus on dopamine may initially be productive in the examination of the psychotomimetic effects of cannabis. Therefore, this review examines the evidence concerning the interactions between THC, endocannabinoids and dopamine in the cortical as well as subcortical regions implicated in psychosis, and considers possible mechanisms whereby cannabis-induced dopamine dysregulation may give rise to delusions and hallucinations. It is concluded that further study of the mechanisms underlying the link between cannabis and psychosis may be conducted productively from the perspective of progressive developmental sensitization, resulting from gene-environment interactions.

Psychosis reactivity to cannabis use in daily life: an experience sampling study.

BACKGROUND: Little is known about the experiential dynamics of the interaction between cannabis and vulnerability to psychosis. AIMS: To examine the effects of cannabis on psychotic symptoms and mood in patients with psychosis and healthy controls. METHOD: Patients with a psychotic disorder (n = 42) and healthy controls (n = 38) were followed in their daily lives using a structured time-sampling technique. RESULTS: Daily life cannabis use predicted subsequent increases in positive affect and in patients, but not in controls, decreases in negative affect. In patients, but not in controls, cannabis use predicted increased levels of hallucinatory experiences. Mood-enhancing properties of cannabis were acute, whereas psychosis-inducing effects were sub-acute. There was no direct evidence for self-medication effects in daily life. CONCLUSIONS: Patients with psychosis are more sensitive to both the psychosis-inducing and mood-enhancing effects of cannabis. The temporal dissociation between acute rewarding effects and sub-acute toxic influences may be instrumental in explaining the vicious circle of deleterious use in these patients.

Gene-environment interplay between cannabis and psychosis.

Cannabis use is considered a contributory cause of schizophrenia and psychotic illness. However, only a small proportion of cannabis users develop psychosis. This can partly be explained by the amount and duration of the consumption of cannabis and by its strength but also by the age at which individuals are first exposed to cannabis. Genetic factors, in particular, are likely to play a role in the short- and the long-term effects cannabis may have on psychosis outcome. This review will therefore consider the interplay between genes and exposure to cannabis in the development of psychotic symptoms and schizophrenia. Studies using genetic, epidemiological, experimental, and observational techniques will be discussed to investigate gene-environment correlation gene-environment interaction, and higher order interactions within the cannabis-psychosis association. Evidence suggests that mechanisms of gene-environment interaction are likely to underlie the association between cannabis and psychosis. In this respect, multiple variations within multiple genes--rather than single genetic polymorphisms--together with other environmental factors (eg, stress) may interact with cannabis to increase the risk of psychosis. Further research on these higher order interactions is needed to better understand the biological pathway by which cannabis use, in some individuals, may cause psychosis in the short- and long term.

Evidence that the COMT(Val158Met) polymorphism moderates sensitivity to stress in psychosis: an experience-sampling study.

Gene-environment interactions involving the catechol-O-methyltransferase Val(158)Met polymorphism (COMT(Val158Met)) have been implicated in the causation of psychosis. Evidence from general population studies suggests that Met/Met subjects are sensitive to stress, a trait associated with psychosis. We hypothesized that the Met allele would moderate the effects of stress on negative affect (NA) in controls, and on NA and psychosis in patients with a psychotic disorder. Thirty-one patients with a psychotic disorder and comorbid cannabis misuse and 25 healthy cannabis users were studied with the experience sampling method (ESM), a structured diary technique assessing current context and emotional and psychotic experiences in daily life. A significant interaction between COMT(Val158Met) genotype and ESM stress in the model of NA was found for patients (interaction chi(2) = 7.4, P = 0.02), but not for controls (interaction chi(2) = 3.8, P = 0.15). In the model of ESM psychosis, a significant interaction between COMT(Val158Met) genotype and ESM stress was also apparent (interaction chi(2) = 11.6, P < 0.01), with Met/Met patients showing the largest increase in psychotic experiences as well as NA in reaction to ESM stress. The findings suggest that the COMT(Val158Met) polymorphism moderates affective and psychotic responses to stress in patients with psychosis, providing evidence for gene-environment interaction mechanisms in the formation of psychotic symptoms.

Cannabis, the mind and society: the hash realities.

Cannabis has been known for at least 4,000 years to have profound effects on the mind--effects that have provoked dramatically divergent attitudes towards it. Some societies have regarded cannabis as a sacred boon for mankind that offers respite from the tribulations of everyday life, whereas others have demonized it as inevitably leading to 'reefer madness'. The debate between the protagonists and prohibitionists has recently been re-ignited, but unfortunately this debate continues mainly in ignorance of our new understanding of the effects of cannabis on the brain and of studies that have quantified the extent of the risks of long-term use.

COMT Val158Met moderation of stress-induced psychosis.

BACKGROUND: Exposure to stressful life events increases the risk of developing a psychotic disorder. Moreover, increased reactivity to stress seems to represent part of the vulnerability for psychosis. This study aimed to investigate whether a functional polymorphism in the catechol-O-methyltransferase (COMT Val(158)Met) gene moderates the psychosis-inducing effects of stress. METHOD: A semi-experimental stress exposure paradigm was used in a sample of 306 genotyped young men (aged 19-24 years), in whom measures of psychotic symptoms were obtained at recruitment in the Greek army (exposed condition) and again after 18 months of military training (unexposed condition). RESULTS: Stress exposure at army induction was associated with an increased level of psychotic symptoms. In addition, carriers of the COMT Val(158)Met Val allele were more susceptible to the effect of stress on the psychosis outcome than those with the Met/Met genotype (test for interaction: chi2 = 5.02, df = 1, p = 0.025). CONCLUSION: The COMT Val(158)Met genotype may moderate the effect of stress on psychotic symptoms.

Does normal developmental expression of psychosis combine with environmental risk to cause persistence of psychosis? A psychosis proneness-persistence model.

BACKGROUND: Research suggests that low-grade psychotic experiences in the general population are a common but transitory developmental phenomenon. Using two independent general population samples, the hypothesis was examined that common, non-clinical developmental expression of psychosis may become abnormally persistent when synergistically combined with developmental exposures that may impact on behavioural and neurotransmitter sensitization such as cannabis, trauma and urbanicity. METHOD: The amount of synergism was estimated from the additive statistical interaction between baseline cannabis use, childhood trauma and urbanicity on the one hand, and baseline psychotic experiences on the other, in predicting 3-year follow-up psychotic experiences, using data from two large, longitudinal, random population samples from the Netherlands [The Netherlands Mental Health Survey and Incidence Study (NEMESIS)] and Germany [The Early Developmental Stages of Psychopathology (EDSP) study]. RESULTS: The 3-year persistence rates of psychotic experiences were low at 26% in NEMESIS and 31% in EDSP. However, persistence rates were progressively higher with greater baseline number of environmental exposures in predicting follow-up psychotic experiences (chi2=6.9, df=1, p=0.009 in NEMESIS and chi2=4.2, df=1, p=0.04 in EDSP). Between 21% and 83% (NEMESIS) and 29% and 51% (EDSP) of the subjects exposed to both environmental exposures and psychotic experiences at baseline had persistence of psychotic experiences at follow-up because of the synergistic action of the two factors. CONCLUSION: The findings suggest that environmental risks for psychosis act additively, and that the level of environmental risk combines synergistically with non-clinical developmental expression of psychosis to cause abnormal persistence and, eventually, need for care.