Summary of Research Synopsis

Title: Repetitive Transcranial Magnetic Stimulation of the Frontopolar Cortex for Cannabis Use Disorder: A Randomised Sham-Controlled Trial

1. Background and Rationale

Cannabis Use Disorder (CUD) is a growing global concern, affecting up to 30% of cannabis users and contributing significantly to public health challenges. In India, cannabis is the most commonly used illicit substance, with a noticeable increase in treatment-seeking individuals. Current treatment strategies, primarily pharmacotherapy and behavioural interventions like CBT and MET, offer limited long-term effectiveness and are often associated with high relapse and dropout rates.

Neurobiologically, addiction is linked to dysfunction in the prefrontal cortex (PFC), which governs impulse control, decision-making, and goal-setting. Within the PFC, the frontopolar cortex (FPC or Brodmann Area 10) is particularly involved in higher-order cognitive processes, including metacognition and future planning—functions that are often impaired in individuals with CUD.

Repetitive Transcranial Magnetic Stimulation (rTMS), a non-invasive neuromodulation technique, has shown promise in reducing craving and improving executive function in other substance use disorders. While most rTMS research has targeted the dorsolateral prefrontal cortex (DLPFC), outcomes have been inconsistent. This study proposes targeting the FPC, hypothesizing that its unique cognitive role may offer more robust outcomes in treating CUD.

2. Objectives and Hypotheses

Primary Objective:
- Assess the efficacy of twice-daily high-frequency rTMS targeting the left FPC in reducing craving and cannabis use.

Secondary Objectives:
- Evaluate improvements in executive functioning, delay discounting, and emotional regulation.
- Assess functional outcomes and quality of life.
- Determine treatment durability and relapse prevention.
- Compare tolerability and safety between active and sham stimulation.

Hypotheses:
- Active rTMS to the FPC will significantly reduce cannabis craving and use compared to sham.
- It will improve executive and emotional functioning and be safe and well-tolerated.

3. Methodology

Design: A randomized, double-blind, sham-controlled trial with two arms:
- Active rTMS Group: High-frequency stimulation to the left FPC.
- Sham Group: Mimicked stimulation without magnetic pulse delivery.

Participants: 88 individuals aged 18–60, diagnosed with moderate to severe CUD, recruited from KIMS Bhubaneswar. Key exclusions include history of epilepsy, comorbid psychiatric disorders, metal implants, and pregnancy.

Randomization & Blinding: Computer-generated block randomization with allocation concealed. All participants, TMS operators, and assessors will be blinded to treatment groups.

Intervention Protocol:
- 20 sessions over 2 weeks (twice daily on weekdays).
- Active rTMS: 10 Hz, 110% RMT, targeting Fp1 site (FPC).
- Sham rTMS: Identical setup using inactive coil or angled coil with sensory mimicry.

Safety Monitoring: Pre/post-session symptom checklists, pregnancy tests, emergency protocols, and defined withdrawal criteria.

4. Outcome Measures and Data Analysis

Primary Outcomes:
- Cannabis craving measured weekly using the Marijuana Craving Questionnaire (MCQ-17).
- Cannabis use evaluated via Timeline Follow-Back (TLFB) and urine THC tests.

Secondary Outcomes:
- Executive Function: Go/No-Go, Delay Discounting, BIS-11.
- Emotion Regulation: DERS.
- Functioning: WHODAS 2.0.
- Relapse: Self-report and urine test-confirmed.

Sample Size: Based on a moderate effect size, 88 participants (44 per group) are targeted.

Data Collection & Analysis: Standardized tools at baseline, weeks 2, 4, 8, and 12. Analyses using repeated-measures ANOVA and ITT principles.

5. Significance

This study is the first randomized controlled trial to explore the potential of frontopolar rTMS for treating CUD. By focusing on a cortical region critical for long-term planning and self-regulation, it aims to address fundamental cognitive deficits contributing to chronic cannabis use. If successful, it could pave the way for more effective, neuroscience-informed interventions for substance use disorders.