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Effects of cannabinoids on resting state functional brain connectivity: a systematic review
Keywords
1. Introduction
Cannabinoid-based products are widely used globally and are becoming increasingly accessible, potent and diversified due to global trends towards the decriminalization of their use and sale (Scheim et al., 2020). Over the past decade, the concentration of cannabis’ main psychoactive compound ∆9-tetrahydrocannabinol (THC) in cannabis products has doubled (Chandra et al., 2019, Freeman et al., 2019b). Meanwhile, the concentration of cannabidiol (CBD), a non-intoxicating cannabinoid with putative therapeutic properties (Bergamaschi et al., 2011) remain stable over time (Freeman et al., 2021). These trends are concerning: THC has addictive (Volkow et al., 2016), intoxicating (Curran et al., 2016), anxiogenic (Crippa et al., 2009) and psychotogenic properties (Hindley et al., 2020). In contrast, CBD putatively mitigates such adverse effects of THC (Englund et al., 2013, Freeman et al., 2019a). Consequently, the burden of the adverse psychosocial outcomes associated with the recent increases of THC likely represent an increasing public health, social and economic problem in the forthcoming years (Hall et al., 2019).
The effects of cannabinoid intoxication have been attributed to the influence of cannabinoids on the brain. Indeed, when cannabis is consumed, THC binds to brain cannabinoid receptors that are densely innervated in selected cortical regions (e.g., prefrontal cortex, hippocampus, cerebellum; Glass et al., 1997; Hashimotodani et al., 2007; Mackie, 2008). These brain pathways are implicated in cognitive processes that are altered with cannabinoid intoxication (e.g., disinhibition, reward processing, motor coordination; Broyd et al., 2016; Dellazizzo et al., 2022; Kroon et al., 2021; Ramaekers et al., 2021); as well as mental health symptoms which transiently increase with cannabis intoxication (e.g., anxiety and psychotic symptoms; Barrett et al., 2018; Colizzi et al., 2016). From a neurobiological perspective, we are yet to uncover in detail the brain pathways underlying cannabinoid intoxication. Notably, the development of functional Magnetic Resonance Imaging (MRI) tools that map brain function in-vivo has generated increasingly sophisticated efforts to identify the neurobiology of cannabinoid intoxication.
Several systematic reviews have integrated findings from experimental fMRI studies in humans during THC and/or CBD intoxication, showing changes in prefrontal, striatal and other regions (Bloomfield et al., 2019, Freeman et al., 2019a, Gunasekera et al., 2020). However, findings have varied significantly across studies, with inconsistent direction and location of the findings (Bloomfield et al., 2019, Freeman et al., 2019a, Gunasekera et al., 2020). The inconsistent results might be (partly) explained by methodological issues. Specifically, several reviews have summarised findings from task-based fMRI while participants perform a variety of cognitive tasks, which may have introduced confounding due to the cognitive demands associated with the task (e.g. cognitive domain examined, task performance, strategy and effort) from that of cannabinoid intoxication (Fox and Greicius, 2010).
Other reviews have synthesised evidence that used heterogeneous neuroimaging techniques (e.g. fMRI, positron emission tomography, single photon emission computed tomography, arterial spin labelling). Thus, they cannot readily disentangle the impact of cannabinoids from that of distinct measures of brain functional integrity (Bloomfield et al., 2019, Freeman et al., 2019a, Gunasekera et al., 2020). In addition, the most up to date search in previous reviews include publications up to July 2019 (Gunasekera et al., 2020) and several new studies have been published since then (Mason et al., 2021, Pretzsch et al., 2019, Wall et al., 2022, Zaytseva et al., 2019).
We conducted the first systematic review of studies that investigated the brain functional changes that occur during acute cannabinoid intoxication by using resting state functional connectivity fMRI – which measures how strongly the function of different brain areas regions is correlated over time without cognitive confounds (van de Ven et al., 2004) - in contrast to task-based fMRI or other functional neuroimaging techniques. Indeed, resting-state fMRI measures spontaneous fluctuations of brain function while people do not overtly perform any cognitively demanding tasks, while they are at rest but awake in the scanner (van de Ven et al., 2004). This technique has been used to identify large-scale neural networks in normative samples and core alterations underlying disease (Fox and Greicius, 2010, Philippi et al., 2020). Resting state fMRI thus holds promise to unpack fundamental functional brain changes that occur with cannabinoid intoxication.
We selected the studies which have been published thus far, that investigated subjects of any age who are psychiatrically, neurologically healthy, and free of regular substance use (other than alcohol and nicotine). We paid specific attention to the influence of cannabinoids and their administration (type, dosage, routes of administration) on the putative resting state functional connectivity phenotype of cannabinoid intoxication (Freeman et al., 2020). We also overviewed the associations between the level of functional connectivity alterations and self-reported intoxication or cognitive performance or both. Finally, we detailed the methodologies used to examine resting state functional connectivity during cannabinoid intoxication to evaluate the standards of research in this area and inform directions for future work.
Youxin Sui
Chaojie Kan2,3†, 
Shizhe Zhu
Tianjiao Zhang
Ying Shen
Chuan Guo
Fuminari Kaneko
Keiichiro Shindo
Masaki Yoneta
Megumi Okawada