There has been a considerable rise in cannabis consumption in recent years, with estimates of 200 million individual users globally. Importantly, 3% of these individuals have cannabis use disorder (CUD), with this prevalence increasing to 33% amongst regular users, making it one of the most common substances use disorders (SUDs) worldwide. CUD is associated with substantial health, societal, and economic costs, and worsening of other psychiatric disorders. Despite this clinical burden, effective treatment options are limited. No pharmacological treatments have emerged as clearly efficacious, and psychotherapeutic interventions have shown tempered results. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain-based approach in which alternating magnetic fields are applied to the scalp to induce electrical currents in cortical tissue. As it can modulate neural circuits implicated in neuropsychiatric disorders, it is a promising brain-based approach in the treatment of addictions. Evidence has indicated its efficacy in reducing drug craving and consumption across numerous SUDs, although research into cannabis has been largely unexplored. Recently, a novel circular rTMS coil, the MagVenture MMC-140, has been developed with the capacity to modulate both the bilateral prefrontal cortex (PFC) and insula, both of which are implicated in the neurocircuitry of craving and executive function. As such, it shows potential for CUD treatment. This proof-of-concept clinical trial will evaluate the feasibility and tolerability of a 4-week course of rTMS to the PFC/insula using MMC-140 as a treatment for CUD. Feasibility of both high frequency (HF; excitatory) and low frequency (LF; inhibitory) stimulation parameters will be evaluated. In addition, pre/post rTMS changes in cannabis use outcomes (e.g., consumption, craving, and withdrawal), executive function, and PFC/insula functional connectivity will be explored. By comprehensively investigating clinical, cognitive, and neuroimaging effects of rTMS, this study could pave the way for the first brain-based intervention in CUD that could be widely adopted into clinical settings using a novel, cost-effective and accessible rTMS device.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
46
rTMS is a non-invasive neuromodulatory technique that applies alternating magnetic fields to the scalp to induce electric currents in localized cortical tissue. The intervention (LF or HF rTMS) will be administered daily 5 days/week for 4 weeks, using the MagVenture MMC-140 circular coil, with the brain regions targeted as the bilateral prefrontal cortex and the insula.
Centre for Addiction and Mental Health
Toronto, Ontario, Canada
RECRUITINGFeasibility of study completion as assessed by completion rates
Feasibility is determined by completion of the study and all associated study assessments, without withdrawing or being withdrawn from the study. Withdrawal from the study can be dropping out for any reason, including intolerability, serious adverse events, or inability to adhere to study procedures.
Time frame: The timeframe is through study completion, beginning from baseline to end of rTMS treatment week 4, an average of 8 weeks, the event determined by withdrawal from the study.
Tolerability of Intervention as assessed by adverse event reporting
This will be assessed through a side effect report at each treatment session. Safety monitoring will be implemented through the documentation and monitoring of adverse events (AEs) and serious adverse events (SAEs) using incidence tables by severity, relationship to treatment and baseline parameters.
Time frame: The timeframe is through study completion, beginning from baseline to end of rTMS treatment week 4, an average of 8 weeks. The events being counts of adverse events or serious adverse events.
Cannabis Use
Determined through self-report on the Timeline Followback (TLFB). Endpoints of interest will include percentage of days per week using cannabis, number of use sessions per day, 7-day point prevalence abstinence. Semi-quantitative analysis of cannabis use will be obtained through a THC Pre-Dosage Test (Narcocheck ®, Villejuif, France) to confirm.
Time frame: Baseline (pre-rTMS), Weekly (end of each week of rTMS), Follow-up (4-weeks post-rTMS), up to a total time frame of 8 weeks. Events are counted as self reported instances of cannabis use on the Timeline Followback.
Cannabis Craving
Changes in cannabis craving assessed through the Marijuana Craving Questionnaire (MCQ). Minimum score is 3 and maximum score is 84. Higher scores indicate greater cannabis craving (worse outcome).
Time frame: Baseline (pre-rTMS), Weekly (end of each week of rTMS), an average of 8 weeks from baseline assessment to end of rTMS, Follow-up (4-weeks post-rTMS),
Cannabis Withdrawal
Changes in cannabis withdrawal symptoms assessed through the Marijuana Withdrawal Checklist (MWC)
Time frame: Baseline (pre-rTMS), Weekly (end of each week of rTMS), an average of 8 weeks from baseline assessment to end of rTMS, Follow-up (4-weeks post-rTMS),
Prefrontal cortex and Insula Connectivity
Assessed by seed-based resting state connectivity on functional magnetic resonance imaging (fMRI). Seeds are defined as the medial prefrontal cortex, dorsolateral prefrontal cortex, and the insula. Measurement will be of change in strength of connectivity between these seeds pre- to post-rTMS, and comparing between groups (high or low frequency stimulation).
Time frame: Baseline (pre-rTMS), End of rTMS (end of treatment week 4 of rTMS)
Depression symptoms
Changes in depression symptoms assessed through the 17-item Hamilton Rating Scale for Depression (HRSD-17). Minimum score is 0, maximum score is 52, higher scores indicate greater depression (worse outcome)
Time frame: Baseline (pre-rTMS), Weekly (end of each week of rTMS), an average of 8 weeks from baseline assessment to end of rTMS, follow-up (4-weeks post-rTMS),
Anxiety symptoms
Changes in anxiety symptoms assessed through the Generalized Anxiety Disorder Scale 7 (GAD-7). Minimum score is 0, maximum score is 21, higher scores indicate greater anxiety (worse outcome).
Time frame: Baseline (pre-rTMS), Weekly (end of each week of rTMS), an average of 8 weeks from baseline assessment to end of rTMS, follow-up (4-weeks post-rTMS),
Trail Making Test
Changes on a neuropsychological assessment for attention, speed, and mental flexibility. Part A and Part B. Measurement: number of seconds required to complete the task. • Higher scores reveal greater impairment.
Time frame: Baseline (pre-rTMS), End of rTMS (end of treatment week 4 of rTMS), an average of 8 weeks from baseline assessment to end of rTMS, follow-up (4-weeks post-rTMS)
Digit Span
Changes on a neuropsychological assessment for working memory. Consists of 2 parts: Forwards and Backwards. Each item is scored 0, 1, or 2 points. (Depending on accuracy). • Lower scores reveal greater impairment. Minimum score 0. Maximum total score on Digit Span: 30 points
Time frame: Baseline (pre-rTMS), End of rTMS (end of treatment week 4 of rTMS), an average of 8 weeks from baseline assessment to end of rTMS, follow-up (4-weeks post-rTMS)
Hopkins Verbal Learning Test
Changes on a neuropsychological assessment for working memory. Consists of 3 parts: A (free recall), B (delayed recall), C (recognition). Less number of words remembered indicates worse outcome.
Time frame: Baseline (pre-rTMS), End of rTMS (end of treatment week 4 of rTMS), an average of 8 weeks from baseline assessment to end of rTMS, follow-up (4-weeks post-rTMS)
Continuous Performance Test
Changes on a neuropsychological assessment for sustained attention. Measurement \& Scoring Categories: Correct Detection (number of times the client responded to the target stimulus. Higher rates of correct detections indicate better attentional capacity), reaction times (Amount of time between the presentation of the stimulus and the client's response), omission errors (Number of times the target was presented, but the client did not respond/click the mouse. High omission rates indicate distractibility to stimuli or a sluggish response), commission errors (Number of times the client responded but no target was presented. A fast reaction time and high commission error rate points to difficulties with impulsivity. A slow reaction time with high commission and omission errors, indicates inattention in general).
Time frame: Baseline (pre-rTMS), End of rTMS (end of treatment week 4 of rTMS), an average of 8 weeks from baseline assessment to end of rTMS, follow-up (4-weeks post-rTMS)
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