The CB1 Neutral Antagonist Tetrahydrocannabivarin Reduces Default Mode Network and Increases Executive Control Network Resting State Functional Connectivity in Healthy Volunteers

International Journal of Neuropsychopharmacology, 2016, 1–7 doi:10.1093/ijnp/pyv092 Research Article research article The CB1 Neutral Antagonist Tetrahydrocannabivarin Reduces Default Mode Network and Increases Executive Control Network Resting State Functional Connectivity in Healthy Volunteers Ewelina Rzepa, MSc; Luke Tudge, MSc; Ciara McCabe, PhD School of Psychology and Clinical Language Sciences, University of Reading, UK (Ms Rzepa, Mr Tudge, and Dr McCabe); Department of Psychiatry, Warneford Hospital, University of Oxford, UK (Dr McCabe). Correspondence: Ciara McCabe, PhD, Associate Professor in Neuroscience, School of Psychology and Clinical Language Sciences, University of Reading, Reading RG6 6AL (). Abstract Background: The cannabinoid cannabinoid type 1 (CB1) neutral antagonist tetrahydrocannabivarin (THCv) has been suggested as a possible treatment for obesity, but without the depressogenic side-effects of inverse antagonists such as Rimonabant. However, how THCv might affect the resting state functional connectivity of the human brain is as yet unknown. Method: We examined the effects of a single 10 mg oral dose of THCv and placebo in 20 healthy volunteers in a randomized, within-subject, double-blind design. Using resting state functional magnetic resonance imaging and seed-based connectivity analyses, we selected the amygdala, insula, orbitofrontal cortex, and dorsal medial prefrontal cortex (dmPFC) as regions of interest. Mood and subjective experience were also measured before and after drug administration using self-report scales. Results: Our results revealed, as expected, no significant differences in the subjective experience with a single dose of THCv. However, we found reduced resting state functional connectivity between the amygdala seed region and the default mode network and increased resting state functional connectivity between the amygdala seed region and the dorsal anterior cingulate cortex and between the dmPFC seed region and the inferior frontal gyrus/medial frontal gyrus. We also found a positive correlation under placebo for the amygdala-precuneus connectivity with the body mass index, although this correlation was not apparent under THCv. Conclusion: Our findings are the first to show that treatment with the CB1 neutral antagonist THCv decreases resting state functional connectivity in the default mode network and increases connectivity in the cognitive control network and dorsal visual stream network. This effect profile suggests possible therapeutic activity of THCv for obesity, where functional connectivity has been found to be altered in these regions. Keywords: Cannabinoids, default mode, fMRI, obesity, resting state, reward Introduction Despite severe health and economic consequences of excess body weight (Andreyeva et al., 2004), the neurobiological mechanism of disordered eating in humans remains unclear. The endocannabinnoid system in the human brain, which involves cannabinoid type 1 (CB1) receptors, has been implicated in reward processing in animals and humans (Solinas et al., 2007) Received: May 21, 2015; Revised: July 20, 2015; Accepted: August 5, 2015 © The Author 2015. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact 1 2 | International Journal of Neuropsychopharmacology, 2016 and in regulating feeding behavior by modulating brain reward signals related to appetite and the consumption of food (Solinas et al., 2008). For example, when tetrahydrocannabinol (THC), which is a psychoactive constituent of the cannabis plant and a partial agonist at the CB1 receptor, was administered in rats it led to an increase in the hedonic response to sucrose and a decrease in aversive reactions to bitter solutions (Jarrett et al., 2005). Moreover, Solinas and Goldberg reported that administration of THC, during food consumption, increased the motivation to respond for the food in rats (Solinas and Goldberg, 2005). Rimonabant, an antagonist and possible inverse agonist (Pertwee, 2005) at the CB1 receptor, was licensed in Europe for the treatment of obesity in 2006 but was withdrawn from clinical use in 2008 due to depression-like side effects. Rimonabant was found to promote weight loss by decreasing food intake (Scheen et al., 2006); however, it also presented with depressionand anxiety-related side effects. In an attempt to try and understand how these treatments might be having their effects, we did a study in 2010 that examined the neural response to reward and aversion in humans after a 7-day treatment with rimonabant (Horder et al., 2010). We found that rimonabant reduced neural responses to a pleasant chocolate taste in reward areas of the brain such as the ventral striatum and orbitofrontal cortex (OFC), whilst increasing brain responses to aversive sights and tastes in regions such as the lateral OFC (Horder et al., 2010). We concluded that although reduced food intake might be due to a reduced neural response to reward, this may also have been a mechanism by which depression side-effects were induced, given that reduced neural responses to reward have been found in depressed patients (Keedwell et al., 2005; Wacker et al., 2009) and in those at risk of depression (McCabe et al., 2009, 2012) and are thought to be a possible biomarker for depression (Hasler and Northoff, 2011). THCv, a neutral antagonist that acts on CB1 receptors, has been suggested as a potentially safer alternative with fewer side effects (Le Foll et al., 2009; Pacher and Kunos, 2013). Animal studies have shown that, like rimonabant, THCv reduces weight gain and food consumption but, unlike rimonabant, does not increase activity in the basolateral amygdala and ventral tagmental area: brain regions involved in emotion regulation (Meye et al., 2013). Moreover, our recent fMRI study, the first to investigate THCv effects on reward and aversion in the healthy human brain, found that relative to placebo, THCv increased activation to pleasant chocolate stimuli in the anterior cingulate cortex, caudate, putamen, and midbrain (Tudge et al., 2014), opposite to the profile of those at risk of depression (McCabe et al., 2009, 2012). Thus, our results supported the idea that THCv does not impair reward function, and this may be related to a potentially safer side-effect profile. We also found that THCv increased activation to the aversive stimulus in the amygdala, insula, and OFC (Tudge et al., 2014). We suggested this might be a mechanism to reduce food intake, by increasing the salience of food and perhaps then decreasing the time to satiety. This is plausible in light of a study by Tallett et al. (2008), which found (...truncated)