Canada reports some of the highest rates of cannabis use in our youth and young adult populations, among all the developed countries. Recent Health Canada surveys report that 27% of 16-19-year-olds and 32% of 20-24-year-olds have used cannabis in the past 30 days, with 16-24-year-olds showing the highest rates of daily or near-daily use. Unfortunately, cannabis use has also been found to be a risk factor for the development of a psychotic disorder in emerging adults, and in those who develop psychosis and continue cannabis use, there is a significant effect on long term outcomes. This includes the severity of symptoms, risks of relapse (being hospitalized) and not reaching a level of functioning that would be expected. Lifetime experience with cannabis is greater than 80% in young adults with early phase psychosis (EPP; the first 5 years of a psychosis illness) with up to 30% of Canadian EPP patients meeting criteria for a diagnosis of cannabis use disorder (CUD) at entry to care. A recent Canadian population-based study found that cannabis use disorder associated to psychosis has risen from 3.7% pre-2018 to 10.3% at present. There has been a significant increase in Δ9-tetrahydrocannabinol (THC) levels in cannabis products available globally over the years, with popular cannabis products available start as high as 18% THC in Canada. However high potency cannabis carries a more significant risk for psychosis development, as well as higher risk for cannabis dependence and other severe mental health issues.

A major gap in the research is a specific focus on cannabis potency on brain white matter (WM) in youth and young adults, and if there are any potential treatment strategies that could be used to influence any of these cannabis WM effects. To address this, a medication called metformin, that is already used in psychosis to help with side effects of antipsychotic medications, will be used as it has also shown promise to influence WM changes in other illnesses. This project is thus focused on naturalistic cannabis potency effects on WM in emerging adults in EPP (divided into three groups; those using high potency cannabis, low potency cannabis, and minimal cannabis use) and treating them with metformin for 6 months and assessing effects on neuroimaging, cognitive and clinical variables.

The purpose of this pilot feasibility study is to inform the development/refinement of an intervention protocol, and not to test potential effects or mechanisms as the sample size will have insufficient power to perform an in-depth analysis. The results of this work will inform our research strategy development and assess feasibility of our novel methodological approach.

Participants will:

1. Visit the clinic at baseline, 3 months (only Timeline Follow-Back Assessment administered), and 6 months post baseline to complete substance use and mental health questionnaires, and cognitive assessments
2. Complete an MRI scan at baseline and 6 months
3. Take Metformin every day for 6 months

Researchers will compare three groups of young adults with EPP: those using cannabis on a regular basis i) high potency (>15% THC) and ii) low potency (<15% THC) cannabis products and iii) patients with minimal-to-no cannabis use to see if there are differences in cannabis potency effects on white matter.

This study will collect four different types of variables: demographic (things that describe the participants), clinical (things that describe how ill the individuals are), substance use (things that measure how much or how reliant participants are on recreational substances), and neuropsychological (things that measure cognitive functioning such as attention, memory, verbal learning, and executive functioning).

Baseline demographics will include age, sex, gender and ethnicity. The Timeline Followback (TLFB) method will be used to collect detailed information about current cannabis use, which includes quantity, frequency, and potency (e.g., THC %, THC/CBD). Potency data will be self-report, verified whenever possible through the use of the Nova Scotia Liquor Corporation product website and other websites used for product purchase. Cannabis quantity and frequency will be assisted by visual aids. The TLFB has been validated for use among those with schizophrenia-spectrum disorders. The World Health Organization - Alcohol, Smoking, and Substance Involvement Screening Test (WHO-ASSIST) will be used to collect non-cannabis substance use data and the Cannabis Use Disorder Identification Test - Revised (CUDIT-R) will be used to measure problematic cannabis use. Overall psychosis symptoms will be measured by the Clinical Global Impression scale, for both severity and improvement (CGI-S, CGI-I). Cognitive data will be collected, focusing on tasks that are known to be affected by cannabis use (including high potency product). These include verbal learning and memory (California Verbal Learning Test-3; CVLT-3) and executive functioning (Trail Making Test B; TMT-B). In addition, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) will be used which includes domains of immediate memory, language, attention, and delayed memory.

Neuroimaging: Subjects will undergo a Magnetic Resonance Imaging (MRI) scan collecting T1-weighted structural, diffusion-weighted scans and magnetic resonance spectroscopy data at baseline and 6 months post baseline.

Interim and final assessments: The TLFB will be completed 3 months post baseline. At 6-months post baseline, all the above measures and imaging will be repeated (study end).

Inclusion Criteria:

• This study will enroll individuals 18-25 years of age from the Nova Scotia Early Psychosis Program

Exclusion Criteria:

• Current stimulant use disorder

Individual participant data (IPD) will not be shared due to ethical and privacy considerations outlined by the Nova Scotia Health Authority. Data sharing was not a requirement of the study's funding, and given the small sample size, there is a heightened risk of re-identification of participants. To protect participant confidentiality and adhere to institutional ethics guidelines, data will remain securely stored and will not be made available to external parties.