Cannabis is one of the most widely used psychoactive substances globally, with its prevalence increasing due to widespread legalization and expanding medical applications. Cannabis use disorder is characterized by an individual's inability to regulate cannabis consumption despite experiencing adverse consequences (Brubacher et al., 2022). The therapeutic potential of cannabinoids is well-documented, particularly in the management of chronic pain, epilepsy, multiple sclerosis, and appetite stimulation (Romero-Sandoval et al., 2017), (Morano et al., 2020), (Nielsen et al., 2018), and (Badowski and Smith, 2020).

Cannabinoids exert their effects primarily through interaction with cannabinoid receptor type 1 (CB1) and type 2 (CB2), which are key components of the endocannabinoid system—a complex network distributed throughout the body that plays a vital role in maintaining homeostasis. Neurochemical evidence suggests a significant interaction between the endocannabinoid system and inhibitory neural circuits. In particular, regions such as the hippocampus and nucleus accumbens exhibit intricate interplay between the endocannabinoid and γ-aminobutyric acid (GABA) systems, which may underlie the neurocognitive and addictive effects of cannabis (Hoffman and Lupica, 2000).

In addition to their well-established therapeutic roles, cannabinoids have recently been implicated in the pathophysiology of neurodegenerative disorders. Dysregulation of the endocannabinoid system is now recognized as a potential contributor to conditions such as amyotrophic lateral sclerosis (ALS), where therapeutic targeting of the broader “endocannabinoidome”—including receptors, ligands, and metabolic enzymes—has shown promising results (Dubbioso et al., 2024). This broader context supports the rationale for examining cortical inhibition and excitability in cannabis users, as alterations in endocannabinoid signaling may intersect with GABAergic function and cortical motor system integrity.

Importantly, the impact of cannabinoids on GABAergic neurons appears to vary depending on the specific GABA receptor subtype and brain region involved, indicating a complex and region-specific neurochemical interaction. Despite its potential significance, the influence of cannabis on GABAergic neurotransmission in humans has not been extensively studied. One promising method for investigating cortical GABAergic function is transcranial magnetic stimulation (TMS). TMS protocols have been used to evaluate the activity of GABAA and GABAB receptors in the human motor cortex (Chen, 2000; Fitzgerald et al., 2002). Furthermore, recent research indicates that non-invasive brain stimulation may modulate attentional networks via neuropeptides such as orexin, which could interact with inhibitory processes like the cortical silent period (CSP) and short-interval intracortical inhibition (SICI), particularly in substance users with altered GABAergic signaling (Moscatelli et al., 2024).

The motor cortex is an ideal model for investigating cortical function due to its accessibility and well-established physiological characteristics. Cortical excitability, commonly assessed through transcranial magnetic stimulation (TMS), offers valuable insight into the interplay between excitatory and inhibitory neural processes (Cuypers and Marsman, 2021). Key parameters such as the Resting Motor Threshold (RMT), Active Motor Threshold (AMT), and Motor Evoked Potential Amplitude (MEP-A) provide direct measures of corticospinal excitability. In contrast, inhibitory indices like the Cortical Silent Period (CSP) and Short-Interval Intracortical Inhibition (SICI) reflect the integrity of inhibitory neurotransmission. Specifically, CSP represents the suppression of voluntary muscle activity and is considered a marker of GABAB receptor-mediated inhibition, while SICI, which utilizes a conditioning-test stimulus paradigm, is linked to GABAA receptor activity (Khedr et al., 2016, 2020).

Cannabis use has been associated with widespread alterations in neurotransmitter systems, particularly the endocannabinoid system, which plays a critical role in regulating synaptic transmission and maintaining neural homeostasis. These neurochemical changes can significantly influence cortical dynamics, especially in motor regions, potentially affecting both excitatory and inhibitory balance. For example, studies have demonstrated that cannabis users exhibit diminished cortical inhibition, most notably through reductions in SICI—a finding suggestive of disrupted GABAergic function(Ngoy et al., 2024), Nevertheless, the precise effects of cannabis on neurophysiological measures of cortical function remain incompletely understood. In addition, the potential associations between cannabis-induced alterations in cortical excitability and mental health outcomes—such as anxiety, depression, and somatization—are underexplored and warrant further investigation. A clearer understanding of these relationships could elucidate the neurobiological underpinnings of cannabis-related cognitive and emotional dysfunction.

This study seeks to address these gaps by exploring the impact of cannabis use on cortical excitability and inhibitory function, as well as the association of these neurophysiological parameters with psychological symptoms. Using a case-control design, we compared cortical excitability measures between cannabis users and non-users to determine how cannabis modulates motor cortical function. We hypothesize that cannabis use is associated with alterations in motor cortical excitability and inhibition, which may contribute to or reflect underlying psychiatric symptoms. Furthermore, we aim to identify potential correlations between these neurophysiological findings and clinical measures of anxiety, depression, and somatization, thereby providing a more comprehensive understanding of cannabis-related brain dysfunction.