Cannabinoids in psychosis: Mechanisms and Therapeutics
Lead Research Organisation:
King's College London
Department Name: Institute of Psychiatry
Abstract
Barely a week goes by without another scare story about cannabis and mental health. This has arisen, partly, because of research findings that forms rich in ?9-tetrahydrocannibinol (THC) can induce psychosis, confer risk for the genesis of schizophrenia, trigger relapse in patients and worsen outcome.
Schizophrenic illness affects ~1% of the population and onset is typically in early adulthood. It is a frightening disorder, impacting on the highest faculties of the nervous system. Family life, close relationships, education and employment are often devastated and the suicide rate is 100x that of the general population.
Somewhat ironically, the Cannabis plant (in its natural habitat) contains not just a pro-psychotic agent, ?9-tetrahydrocannibinol (THC) but a highly promising anti-psychotic molecule; cannabidiol (CBD). Pilot work in our laboratory suggests CBD can inhibit THC-psychosis. This is significant because current anti-psychotic medicines do not appear to offer any protection against THC-psychosis.
In this proposal I aim to demonstrate (statistically) that CBD is effective in blocking THC-psychosis and that, in this regard, it is superior to currently available medicines. This will have important implications, for psychiatric therapeutics and public health and will also expand our knowledge of the effects of these compounds in man.
A parallel aim is to explore how THC acts in the brain to trigger psychosis. Using EEG recording I will investigate if THC disrupts neural rhythms in the cortex. Such disruption appears to be associated with classic schizophrenic symptoms, especially those in which there is failure to distinguish between self and other. It will be very interesting if THC disrupts neural rhythms in the same fashion.
Schizophrenic illness affects ~1% of the population and onset is typically in early adulthood. It is a frightening disorder, impacting on the highest faculties of the nervous system. Family life, close relationships, education and employment are often devastated and the suicide rate is 100x that of the general population.
Somewhat ironically, the Cannabis plant (in its natural habitat) contains not just a pro-psychotic agent, ?9-tetrahydrocannibinol (THC) but a highly promising anti-psychotic molecule; cannabidiol (CBD). Pilot work in our laboratory suggests CBD can inhibit THC-psychosis. This is significant because current anti-psychotic medicines do not appear to offer any protection against THC-psychosis.
In this proposal I aim to demonstrate (statistically) that CBD is effective in blocking THC-psychosis and that, in this regard, it is superior to currently available medicines. This will have important implications, for psychiatric therapeutics and public health and will also expand our knowledge of the effects of these compounds in man.
A parallel aim is to explore how THC acts in the brain to trigger psychosis. Using EEG recording I will investigate if THC disrupts neural rhythms in the cortex. Such disruption appears to be associated with classic schizophrenic symptoms, especially those in which there is failure to distinguish between self and other. It will be very interesting if THC disrupts neural rhythms in the same fashion.
Technical Summary
Aims:
In my previous work I have confirmed that synthetic intravenous (IV) ?9-tetrahydrocannibinol (THC) induces acute psychosis and cognitive deficits in healthy subjects. During the Fellowship I wish to build on these initial findings in two ways. This first aim has therapeutic implications. I intend to build upon pilot data to test the hypothesis that cannabidiol (CBD) will inhibit THC-psychosis. Subsequently, in a formal clinical trial, I will compare the efficacy of CBD versus a currently used antipsychotic medicine (risperidone) in blocking THC-psychopathology. The second aim of this fellowship is to further explore the mechanisms underlying THC-psychosis: Using EEG, I propose to test the hypothesis that THC decreases the consistency of fine-grained neural oscillations which occur ~150ms before a self-generated motor act.
Objectives
The first objective is to demonstrate that CBD inhibits THC-psychosis in healthy subjects. As the effect-size appears large, only a small sample (N=~8) is anticipated. This study, (study A), is not covered by the clinical trials directive and the projected timeline is 4 months. The efficacy of CBD v risperidone against THC-psychosis will be compared in a larger study (N=16), conducted under the MHRA directive (Study B) and the projected timeline is 12 months. In the EEG investigation (Study C), protocols developed in the pilot study will be used. Over 12-months I will investigate, in 15 healthy volunteers, the effect of THC on the consistency of neural oscillations, which occur milliseconds before a specific willed act.
Design and Methods
Study A: A controlled, double-blind trial of the efficacy of CBD v placebo in blocking THC-induced psychosis and cognitive impairment. Participants will attend for 2 experimental sessions at least 3 weeks apart. ‘Pre-Treatments‘, CBD (5mg) or placebo, will be administered intravenously prior to IV THC (1.25mg) as per pilot studies.
Study B: A controlled, double-blind trial of the efficacy of oral CBD v risperidone v placebo in blocking IV THC (1.25mg) induced psychosis and cognitive impairment. To permit comparison, ‘pre-treatments‘ will be administered orally as matched gelatin capsules containing CBD (600mg) or risperidone (3mg). The order of pre-treatments will be randomised.
Study C: A placebo-controlled, double-blind investigation of whether IV THC (1.25mg) decreases the consistency of neural oscillations occurring ~150ms before a particular willed act. Participants (n=15) will attend for 2 experimental sessions and complete blocks of standard motor and vocal tasks. Simultaneous EEG data will be acquired on a Neuroscan Synamps amplifier, electrode caps and Acquire 4.3 software and analysed using Fieldtrip and Neuroscan.
Opportunities: Scientific and medical
To our knowledge this is the first study investigating if THC disrupts the consistency in the EEG signal each time a person prepares a specific act. Similarly, this is the first study to investigate whether CBD inhibits THC-induced psychopathology and the first to investigate atypical antipsychotics in this manner.
In my previous work I have confirmed that synthetic intravenous (IV) ?9-tetrahydrocannibinol (THC) induces acute psychosis and cognitive deficits in healthy subjects. During the Fellowship I wish to build on these initial findings in two ways. This first aim has therapeutic implications. I intend to build upon pilot data to test the hypothesis that cannabidiol (CBD) will inhibit THC-psychosis. Subsequently, in a formal clinical trial, I will compare the efficacy of CBD versus a currently used antipsychotic medicine (risperidone) in blocking THC-psychopathology. The second aim of this fellowship is to further explore the mechanisms underlying THC-psychosis: Using EEG, I propose to test the hypothesis that THC decreases the consistency of fine-grained neural oscillations which occur ~150ms before a self-generated motor act.
Objectives
The first objective is to demonstrate that CBD inhibits THC-psychosis in healthy subjects. As the effect-size appears large, only a small sample (N=~8) is anticipated. This study, (study A), is not covered by the clinical trials directive and the projected timeline is 4 months. The efficacy of CBD v risperidone against THC-psychosis will be compared in a larger study (N=16), conducted under the MHRA directive (Study B) and the projected timeline is 12 months. In the EEG investigation (Study C), protocols developed in the pilot study will be used. Over 12-months I will investigate, in 15 healthy volunteers, the effect of THC on the consistency of neural oscillations, which occur milliseconds before a specific willed act.
Design and Methods
Study A: A controlled, double-blind trial of the efficacy of CBD v placebo in blocking THC-induced psychosis and cognitive impairment. Participants will attend for 2 experimental sessions at least 3 weeks apart. ‘Pre-Treatments‘, CBD (5mg) or placebo, will be administered intravenously prior to IV THC (1.25mg) as per pilot studies.
Study B: A controlled, double-blind trial of the efficacy of oral CBD v risperidone v placebo in blocking IV THC (1.25mg) induced psychosis and cognitive impairment. To permit comparison, ‘pre-treatments‘ will be administered orally as matched gelatin capsules containing CBD (600mg) or risperidone (3mg). The order of pre-treatments will be randomised.
Study C: A placebo-controlled, double-blind investigation of whether IV THC (1.25mg) decreases the consistency of neural oscillations occurring ~150ms before a particular willed act. Participants (n=15) will attend for 2 experimental sessions and complete blocks of standard motor and vocal tasks. Simultaneous EEG data will be acquired on a Neuroscan Synamps amplifier, electrode caps and Acquire 4.3 software and analysed using Fieldtrip and Neuroscan.
Opportunities: Scientific and medical
To our knowledge this is the first study investigating if THC disrupts the consistency in the EEG signal each time a person prepares a specific act. Similarly, this is the first study to investigate whether CBD inhibits THC-induced psychopathology and the first to investigate atypical antipsychotics in this manner.