Shifting Brain Excitation-Inhibition Balance in Autism Spectrum Disorder

Study Overview
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Brief Summary
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This study investigates brain response to single acute dose of cannabidiol, cannabidivarin, and placebo in healthy men with and without autism spectrum disorder

Detailed Description
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Previous research suggests that cannabidiol (CBD) and cannabidivarin (CBDV) could have the potential to shift brain excitation and inhibition (E-I) in the healthy brain and in neurodevelopmental psychiatric conditions, where this balance is disrupted, such as autism spectrum disorder (ASD). However, no study to date has investigated this. Therefore, in this study, we invited 20 healthy men with and without ASD. Each participant received each drug once (600mg CBD/CBDV, or matched placebo) and magnetic resonance imaging was used to obtain measures of brain biochemistry, activity, and connectivity. We further obtained questionnaires, task data, saliva, urine and blood samples, and conducted visual tasks using eye tracking, electroencephalography, and retinal imaging.

Official Title
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Shifting Brain Excitation-Inhibition Balance Through the Endocannabinoid System in Men With Autism Spectrum Disorder (ASD) and in Healthy Controls

Conditions
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Autism Spectrum Disorder

Intervention / Treatment
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* Drug: PLC
* Drug: CBD
* Drug: CBDV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: men pass diagnostic threshold for ASD on the ADI-R (if informant is available) currently symptomatic on ADOS age 18-50 years can give informed consent IQ>70 (on a standard instrument such as WASI) medication-free in the month preceding participation (but regular medication with drug, which does not affect glutamate or GABA directly may be permitted) willing to provide urine samples to screen for use of illicit substances prior to each scan Exclusion Criteria: IQ<70 history of psychosis, co-morbid major mental illness, significant physical illness (heart disease, high blood pressure, seizures) habitual substance misuse (including alcohol) known allergy to cannabis ASD caused by a known genetic syndrome e.g. Fragile X or 22q11 deletion syndrome, past/present treatment for epilepsy Women will be excluded from this pilot study to reduce heterogeneity in a small sample; avoid the issues around exposing women of reproductive age to a drug; and because pregnancy is a routine exclusion criteria for research MRI. Lastly, ASD is more common in men.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Repeated-measures cross-over study, where each subject received each of three pharmacological probes once (order of drug administration was pseudorandomised)
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PLC, CBD, CBDV<br>Dose order: PLC, CBD, CBDV | Drug: PLC<br>* Single oral dose of PLC.<br>* Other names: Placebo;Drug: CBD<br>* Single oral dose of cannabidiol (CBD) - 600mg.<br>* Other names: Cannabidiol;Drug: CBDV<br>* Single oral dose of cannabidivarin (CBDV) - 600mg.<br>* Other names: Cannabidivarin;|
| Experimental: PLC, CBDV, CBD<br>Dose order: PL, CBDV, CBD | Drug: PLC<br>* Single oral dose of PLC.<br>* Other names: Placebo;Drug: CBD<br>* Single oral dose of cannabidiol (CBD) - 600mg.<br>* Other names: Cannabidiol;Drug: CBDV<br>* Single oral dose of cannabidivarin (CBDV) - 600mg.<br>* Other names: Cannabidivarin;|
| Experimental: CBD, PLC, CBDV<br>Dose order: CBD, PLC, CBDV | Drug: PLC<br>* Single oral dose of PLC.<br>* Other names: Placebo;Drug: CBD<br>* Single oral dose of cannabidiol (CBD) - 600mg.<br>* Other names: Cannabidiol;Drug: CBDV<br>* Single oral dose of cannabidivarin (CBDV) - 600mg.<br>* Other names: Cannabidivarin;|
| Experimental: CBD, CBDV, PLC<br>Dose order: CBD, CBDV, PLC | Drug: PLC<br>* Single oral dose of PLC.<br>* Other names: Placebo;Drug: CBD<br>* Single oral dose of cannabidiol (CBD) - 600mg.<br>* Other names: Cannabidiol;Drug: CBDV<br>* Single oral dose of cannabidivarin (CBDV) - 600mg.<br>* Other names: Cannabidivarin;|
| Experimental: CBDV, PLC, CBD<br>Dose order: CBDV, PLC, CBD | Drug: PLC<br>* Single oral dose of PLC.<br>* Other names: Placebo;Drug: CBD<br>* Single oral dose of cannabidiol (CBD) - 600mg.<br>* Other names: Cannabidiol;Drug: CBDV<br>* Single oral dose of cannabidivarin (CBDV) - 600mg.<br>* Other names: Cannabidivarin;|
| Experimental: CBDV, CBD, PLC<br>Dose order: CBDV, CBD, PLC | Drug: PLC<br>* Single oral dose of PLC.<br>* Other names: Placebo;Drug: CBD<br>* Single oral dose of cannabidiol (CBD) - 600mg.<br>* Other names: Cannabidiol;Drug: CBDV<br>* Single oral dose of cannabidivarin (CBDV) - 600mg.<br>* Other names: Cannabidivarin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brain biochemistry response to pharmacological stimulation | The measure of brain biochemistry response to PLC, CBD, and CBDV includes the following: Assessment of the ratio of brain excitation and inhibition (measured as the balance of excitatory and inhibitory neurotransmitters) using using proton magnetic resonance spectroscopy [1H]MRS. | In the months 1-2 following the last day of scanning. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of low frequency brain activity using resting state fMRI | In the third and fourth month following the day of the last scan, we will measure whole brain low frequency brain activity using resting state functional magnetic resonance imaging. Measure of activity: fractional amplitude of low frequency fluctuations. | In the months 3-4 following the last day of scanning | 
| Measurement of brain functional connectivity using resting state fMRI | In the fifth and sixth month following the day of the last scan, we will measure whole brain resting state functional connectivity using resting state functional magnetic resonance imaging. Measure of connectivity: correlation between pairs of regions. | In the months 5-6 following the last day of scanning | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cannabidiol, Cannabidivarin, E-I balance, pharmacological imaging