Patrik Roser

Potential antipsychotic properties of central cannabinoid (CB1) receptor antagonists

Δ9-Tetrahydrocannabinol (Δ9-THC), the principal psychoactive constituent of the Cannabis sativa plant, and other agonists at the central cannabinoid (CB1) receptor may induce characteristic psychomotor effects, psychotic reactions and cognitive impairment resembling schizophrenia. These effects of Δ9-THC can be reduced in animal and human models of psychopathology by two exogenous cannabinoids, cannabidiol (CBD) and SR141716. CBD is the second most abundant constituent of Cannabis sativa that has weak partial antagonistic properties at the CB1 receptor. CBD inhibits the reuptake and hydrolysis of anandamide, the most important endogenous CB1 receptor agonist, and exhibits neuroprotective antioxidant activity. SR141716 is a potent and selective CB1 receptor antagonist. Since both CBD and SR141716 can reverse many of the biochemical, physiological and behavioural effects of CB1 receptor agonists, it has been proposed that both CBD and SR141716 have antipsychotic properties. Various experimental studies in animals, healthy human volunteers, and schizophrenic patients support this notion. Moreover, recent studies suggest that cannabinoids such as CBD and SR141716 have a pharmacological profile similar to that of atypical antipsychotic drugs. In this review, both preclinical and clinical studies investigating the potential antipsychotic effects of both CBD and SR141716 are presented together with the possible underlying mechanisms of action.

Effects of acute oral Δ9-tetrahydrocannabinol and standardized cannabis extract on the auditory P300 event-related potential in healthy volunteers

Reduced amplitudes of auditory evoked P300 are a robust finding in schizophrenic patients, indicating deficient attentional resource allocation and active working memory. Delta9-Tetrahydrocannabinol (Delta9-THC), the main active constituent of Cannabis sativa, has been known to acutely impair cognitive abilities in several domains, particularly in memory and attention. Given the psychotic-like effects of Delta9-THC, a cannabinoid hypothesis of schizophrenia has been proposed. This prospective, double-blind, placebo-controlled cross-over study investigated the acute effects of cannabinoids on P300 amplitude in 20 healthy volunteers (age 28.2+/-3.1 years, 10 male) by comparing Delta9-THC and standardized cannabis extract containing Delta9-THC and cannabidiol (CBD). P300 waves were recorded during a choice reaction task. As expected, Delta9-THC revealed a significant reduction of P300 amplitude at midline frontal, central, and parietal electrodes. CBD has been known to abolish many of the psychotropic effects of Delta9-THC, but, unexpectedly, failed to demonstrate a reversal of Delta9-THC-induced P300 reduction. Moreover, there were no correlations between cannabinoid plasma concentrations and P300 parameters. These data suggest that Delta(9)-THC may lead to acute impairment of attentional functioning and working memory. It can be speculated whether the lack of effect of CBD may be due to an insufficient dose used or to an involvement of neurotransmitter systems in P300 generation which are not influenced by CBD.

Randomized, Double-blind, Placebo-controlled Study About the Effects of Cannabidiol (cbd) on the Pharmacokinetics of Δ9-tetrahydrocannabinol (thc) After Oral Application of Thc Verses Standardized Cannabis Extract

Cannabidiol (CBD) is known to modify the effects of Δ9-tetrahydrocannabinol (THC) by decreasing anxiety and antagonizing other THC-effects. As a reason, pharmacodynamic as well as pharmacokinetic mechanisms were suggested. In context of the use of cannabis-based medicine extracts for therapeutic purposes, a study was performed in a double-blind and placebo-controlled cross-over design in which each of 24 volunteers (12 male and 12 female, age 18-45 years) obtained soft-gelatin capsules with 10 mg THC (THC-set), cannabis extract containing 10 mg THC +5.4 mg CBD (CAN-set) or placebo in weekly intervals. Blood samples were taken 30 minutes before and 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 9 hours and 24 hours after the intake. The concentrations of THC, of its metabolites 11-OH-THC, THC-COOH and of CBD in the plasma samples were determined by automatic solid phase extraction, derivatization with N,O-bis(trimethylsilyl)triflouroacetamide and gas chromatography-mass spectrometry. The concentration versus time curves (maximum concentrations Cmax, corresponding time tmax and areas under the curves AUC) were evaluated by statistical methods with respect to equivalence or differences between the CAN-set and the THC-set. Furthermore, the intra-individual ratios of Cmax and AUC for 11-OH-THC/THC, THC-COOH/THC and THC-COOH/11-OH-THC were compared between the THC-set and the CAN-set. Despite the large variation of the data, evidence emerged from the total of the results that CBD partially inhibits the CYP 2C catalyzed hydroxylation of THC to 11-OH-THC. The probability for this inhibition is particularly high for oral intake because THC and CBD attain relatively high concentrations in the liver and because of the high first-pass metabolism of THC. However, the effect of CBD is small in comparison to the variability caused by other factors. Therefore, a pharmacokinetic reason for the differences determined between pure THC and cannabis extract is improbable at the doses chosen in this study. Significantly higher AUC and Cmax and shorter tmax were found for females as compared with males.

Acute effects of Δ9-tetrahydrocannabinol and standardized cannabis extract on the auditory evoked mismatch negativity

Reduced amplitudes of auditory evoked mismatch negativity (MMN) have often been found in schizophrenic patients, indicating deficient auditory information processing and working memory. Cannabis-induced psychotic states may resemble schizophrenia. Currently, there are discussions focusing on the close relationship between cannabis, the endocannabinoid and dopaminergic system, and the onset of schizophrenic psychosis. This study investigated the effects of cannabis on MMN amplitude in 22 healthy volunteers (age 28+/-6 years, 11 male) by comparing Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and standardized cannabis extract containing Delta(9)-THC and cannabidiol (CBD) in a prospective, double-blind, placebo-controlled cross-over design. The MMNs resulting from 1000 auditory stimuli were recorded by 32 channel EEG. The standard stimuli were 1000 Hz, 80 dB SPL, and 100 ms duration. The deviant stimuli differed in frequency (1500 Hz). Significantly greater MMN amplitude values at central electrodes were found under cannabis extract, but not under Delta(9)-THC. There were no significant differences between MMN amplitudes at frontal electrodes. MMN amplitudes at central electrodes were significantly correlated with 11-OH-THC concentration, the most important psychoactive metabolite of Delta(9)-THC. Since the main difference between Delta(9)-THC and standardized cannabis extract is CBD, which seems to have neuroprotective and anti-psychotic properties, it can be speculated whether the greater MMN amplitude that may imply higher cortical activation and cognitive performance is related to the positive effects of CBD. This effect may be relevant for auditory cortex activity in particular because only MMN amplitudes at the central, but not at the frontal electrodes were enhanced under cannabis.

Association between a cannabinoid receptor gene (CNR1) polymorphism and cannabinoid-induced alterations of the auditory event-related P300 potential

Numerous studies demonstrated a close relationship between cannabis abuse and schizophrenia with similar impairments in cognitive processing, particularly in P300 generation. Recently, an (AAT)n triplet repeat polymorphism within the cannabinoid receptor gene CNR1 has been found to be associated with both schizophrenia and substance dependence, and to modulate the P300 potential. As previously reported, both acute oral Δ(9)-tetrahydrocannabinol (Δ(9)-THC), the main psychoactive constituent of cannabis, and standardized cannabis extract containing Δ(9)-THC and cannabidiol (CBD) revealed a significant reduction of P300 amplitudes in healthy subjects but did not show any differences among each other. The aim of this study was to investigate whether the (AAT)n polymorphism differentially modulates the effects of Δ(9)-THC and cannabis extract on P300 generation in 20 healthy volunteers during an auditory choice reaction task. For the >10/>10 genotype, there was a significant decrease of P300 amplitude as well as a significant prolongation of P300 latency under pure Δ(9)-THC but not under cannabis extract. Moreover, we found a significant correlation between the number of AAT repeats and P300 variables for the Δ(9)-THC condition. Our data thus indicate that the CNR1 gene seems to be involved in the regulation of the P300 wave as a marker of selective attention and working memory. Moreover, it appears that variations within CNR1 may differentially alter the sensitivity to the acute effects of cannabinoids on P300 generation in healthy subjects.

Mental state decoding and mental state reasoning in recently detoxified alcohol-dependent individuals

Impaired social cognition has been associated with interpersonal problems and with the development of and relapse into alcohol abuse. In the present study, self-reported trait empathy, decoding of complex mental states and cognitive and affective mental state reasoning were assessed in alcohol-dependent participants, and the association with executive function and psychopathological characteristics was investigated. Twenty recently detoxified alcohol-dependent patients and 20 matched healthy controls were assessed with an abbreviated German version of the interpersonal reactivity index, the revised reading the mind in the eyes test, the faux pas story test, the trail making test and the letter-number-sequencing test. Patients were impaired relative to controls with regard to mental state decoding on the eyes test and showed reduced faux pas detection and impaired mental state reasoning reflected by lower faux pas understanding and faux pas empathy scores. There were no group differences regarding self-reported trait empathy. Performance on the sociocognitive measures was related to executive functioning and the severity of depressive symptoms. Although self-report measures might not always reliably detect impairments of social cognition, behavioural measures suggest pronounced impairments of mental state decoding and mental state reasoning in association with alcohol dependence. Findings ought to be incorporated into current treatment strategies.

Oxytocin influences avoidant reactions to social threat in adults with borderline personality disorder.

Borderline personality disorder (BPD) is characterized by interpersonal dysfunction, emotional instability, impulsivity, and risk‐taking behavior. Recent research has focused on the role of oxytocin in BPD, with mixed results as regards the processing of social stimuli.

The loudness dependence of auditory evoked potentials (LDAEP) as an indicator of serotonergic dysfunction in patients with predominant schizophrenic negative symptoms.

Besides the influence of dopaminergic neurotransmission on negative symptoms in schizophrenia, there is evidence that alterations of serotonin (5-HT) system functioning also play a crucial role in the pathophysiology of these disabling symptoms. From post mortem and genetic studies on patients with negative symptoms a 5-HT dysfunction is documented. In addition atypical neuroleptics and some antidepressants improve negative symptoms via serotonergic action. So far no research has been done to directly clarify the association between the serotonergic functioning and the extent of negative symptoms. Therefore, we examined the status of brain 5-HT level in negative symptoms in schizophrenia by means of the loudness dependence of auditory evoked potentials (LDAEP). The LDAEP provides a well established and non-invasive in vivo marker of the central 5-HT activity. We investigated 13 patients with schizophrenia with predominant negative symptoms treated with atypical neuroleptics and 13 healthy age and gender matched controls with a 32-channel EEG. The LDAEP of the N1/P2 component was evaluated by dipole source analysis and single electrode estimation at Cz. Psychopathological parameters, nicotine use and medication were assessed to control for additional influencing factors. Schizophrenic patients showed significantly higher LDAEP in both hemispheres than controls. Furthermore, the LDAEP in the right hemisphere in patients was related to higher scores in scales assessing negative symptoms. A relationship with positive symptoms was not found. These data might suggest a diminished central serotonergic neurotransmission in patients with predominant negative symptoms.

Nonverbal Behavior During Clinical Interviews: similarities and Dissimilarities Among Schizophrenia, Mania, and Depression

Abstract Research has shown that patients with schizophrenia and depression differ from nonclinical subjects in nonverbal behavior. In contrast, there is a paucity of studies addressing differences in nonverbal communication between diagnostic groups and as to what extent nonverbal communication feeds into standard ratings of psychopathology. Twenty-six patients with schizophrenia were compared with 24 patients with affective disorders (13 depressed, 11 manic) regarding their nonverbal behavior using the Ethological Coding System for Interviews. Symptom severity was rated using the Brief Psychiatric Rating Scale. Patients with mania displayed more illustrative gestures than did patients with schizophrenia or depression. Subtler behavioral differences between the groups occurred regarding assertive behaviors and displacement activities suggestive of hostility and motivational conflict, respectively. Distinct correlations between nonverbal communication and psychopathology ratings emerged in all three groups. Patients with schizophrenia, depression, and mania differ in nonverbal behavior. Nonverbal communication seems to be a significant contributor to clinicians’ intuitive ratings.

The "DGPPN-Cohort": A national collaboration initiative by the German Association for Psychiatry and Psychotherapy (DGPPN) for establishing a large-scale cohort of psychiatric patients.

The German Association for Psychiatry and Psychotherapy (DGPPN) has committed itself to establish a prospective national cohort of patients with major psychiatric disorders, the so-called DGPPN-Cohort. This project will enable the scientific exploitation of high-quality data and biomaterial from psychiatric patients for research. It will be set up using harmonised data sets and procedures for sample generation and guided by transparent rules for data access and data sharing regarding the central research database. While the main focus lies on biological research, it will be open to all kinds of scientific investigations, including epidemiological, clinical or health-service research.