Shifting Brain Excitation-Inhibition Balance in Autism Spectrum Disorder

• ClinicalTrials.gov Identifier: NCT03537950
• Recruitment Status: Unknown
• First Posted: May 25, 2018
• Last Update Posted: May 25, 2018
• Sponsor: King's College London
• Information provided by (Responsible Party): Dr Grainne McAlonan, King's College London

Tracking Information

• First Submitted Date: April 17, 2018
• First Posted Date: May 25, 2018
• Last Update Posted Date: May 25, 2018
• Actual Study Start Date: August 22, 2016
• Actual Primary Completion Date: February 16, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 15, 2018)

Brain biochemistry response to pharmacological stimulation [ Time Frame: In the months 1-2 following the last day of scanning. ]

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.

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: May 15, 2018)

• Measurement of low frequency brain activity using resting state fMRI [ Time Frame: In the months 3-4 following the last day of scanning ]
  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.
• Measurement of brain functional connectivity using resting state fMRI [ Time Frame: In the months 5-6 following the last day of scanning ]
  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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Shifting Brain Excitation-Inhibition Balance in Autism Spectrum Disorder
• Official Title: Shifting Brain Excitation-Inhibition Balance Through the Endocannabinoid System in Men With Autism Spectrum Disorder (ASD) and in Healthy Controls
• Brief Summary: 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: 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.
• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention 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 (Participant, Investigator)
Masking Description:

Participants and investigators were blinded to the drug condition.

Primary Purpose: Basic Science

• Condition: Autism Spectrum Disorder

Intervention

• Drug: PLC
  Single oral dose of PLC.
  Other Name: Placebo
• Drug: CBD
  Single oral dose of cannabidiol (CBD) - 600mg.
  Other Name: Cannabidiol
• Drug: CBDV
  Single oral dose of cannabidivarin (CBDV) - 600mg.
  Other Name: Cannabidivarin

Study Arms

• Experimental: PLC, CBD, CBDV
  Dose order: PLC, CBD, CBDV
  Interventions:

  • Drug: PLC
  • Drug: CBD
  • Drug: CBDV
• Experimental: PLC, CBDV, CBD
  Dose order: PL, CBDV, CBD
  Interventions:

  • Drug: PLC
  • Drug: CBD
  • Drug: CBDV
• Experimental: CBD, PLC, CBDV
  Dose order: CBD, PLC, CBDV
  Interventions:

  • Drug: PLC
  • Drug: CBD
  • Drug: CBDV
• Experimental: CBD, CBDV, PLC
  Dose order: CBD, CBDV, PLC
  Interventions:

  • Drug: PLC
  • Drug: CBD
  • Drug: CBDV
• Experimental: CBDV, PLC, CBD
  Dose order: CBDV, PLC, CBD
  Interventions:

  • Drug: PLC
  • Drug: CBD
  • Drug: CBDV
• Experimental: CBDV, CBD, PLC
  Dose order: CBDV, CBD, PLC
  Interventions:

  • Drug: PLC
  • Drug: CBD
  • Drug: CBDV

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Unknown status
• Actual Enrollment (submitted: May 15, 2018): 38
• Original Actual Enrollment: Same as current
• Estimated Study Completion Date: April 27, 2019
• Actual Primary Completion Date: February 16, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years to 50 Years (Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT03537950
• Other Study ID Numbers: HR15-162744
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Dr Grainne McAlonan, King's College London
• Study Sponsor: King's College London
• Collaborators: Not Provided

Investigators

• Principal Investigator: Grainne McAlonan, PhD; King's College London

• PRS Account: King's College London
• Verification Date: May 2018