Circulating endocannabinoids and affect regulation in human subjects

Highlights

• The endocannabinoid (EC) system influences a wide variety of neurobiological processes.

• We examined the role of circulating endocannabinoids in 175 individuals with and without mood, anxiety, and/or personality disorders.

• Circulating anandamide (AEA) levels displayed an inverse relationship with a composite measure of affect regulation across all study participants.

• Basal circulating levels of ECs may play a role in emotionality across individuals regardless of defined psychiatric disorder.

Abstract

The endocannabinoid (EC) system influences a wide variety of neurobiological processes including affect and emotionality as well as other neuropsychiatric functions. In this study we examined the relationship of circulating endocannabinoids [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)] with affect and emotionality in 175 individuals with (n = 115) and without (n = 60) mood, anxiety, and/or personality disorders. Circulating AEA levels displayed a modest, though statistically significant, inverse relationship with a composite measure of affect regulation (β = − 0.264, p = 0.009), due to its relationship with affect intensity (β = − 0.225, p = 0.021) across all study participants. Neither AEA nor 2-AG level differed as a function of any syndromal/personality disorder and neither correlated significantly with state depression or state anxiety scores. These data suggest that circulating levels endocannabinoids may play a role in emotionality across individuals regardless of defined psychiatric disorder.

Introduction

Considerable data suggests that the endocannabinoid (EC) system influences a wide variety of neurobiological processes including affect and emotionality, the formation of memories, and the glucocorticoid-mediated stress response (Mechoulam and Parker, 2013). Thus, the EC system is an attractive area for research into the potential for pharmacotherapeutic targets for psychiatric illnesses (Rubino et al., 2015), particularly those involving disturbances of affect and emotion.

The EC system is composed of two eicosanoid ligands; anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and two main receptors: CB1 and CB2. CB1 receptors are the most abundant G-protein coupled receptor in the nervous system and are concentrated throughout cortical, subcortical and cerebellar structures, though it should be noted that they are also present, in fewer numbers, in the periphery (Mechoulam and Parker, 2013). CB1 receptors are predominately found on GABAergic and glutamatergic neurons and exert a presynaptic inhibitory response when activated by EC molecules, or exogenous agonists like THC, the active ingredient in cannabis (Howlett et al., 2002). CB2 receptors are less numerous and were initially thought to be confined to the macrophagic immune cells, though current research supports a wider distribution in the CNS, particularly in microglial cells, and that they are involved in an immune-mediated neuroprotective role against inflammation (Ashton et al., 2006).

AEA and 2-AG are eicosanoid neuromodulatory lipids derived from membrane phospholipids. Both act presynaptically at EC receptors and are synthesized when and where they are required (Mechoulam and Parker, 2013) as opposed to being stored in vesicles. Considerable data within animal models documents the relationship between perturbations in the EC system and the constellation of symptoms present in depression and anxiety. Studies demonstrate a correlation between CB1 receptor-deficiency and depressive symptoms measured in mice such as anhedonia, anxiety, and heightened stress-response (Valverde and Torrens, 2012). In line with this relationship, chronic stress has been shown to compromise EC signaling in the brain (Hill et al., 2005; Wang et al., 2012) and augmentation of EC signaling can mitigate many of the adverse effects of chronic stress, such as anhedonia and anxiety (Bortolato et al., 2007; Rossi et al., 2010; Hill et al., 2013; Lomazzo et al., 2015). This suggests that impairments in EC signaling could relate to the development of stress-related psychiatric illnesses. Consistent with this, circulating levels of AEA and 2-AG have both been found to be reduced in disorders like major depression (Hill et al., 2008) or post-traumatic stress disorder (PTSD; Hill et al., 2013; Neumeister et al., 2013), or following exposure to chronic stress (Yi et al., 2016). However, there also reports of elevations in AEA and 2-AG levels in conditions such as minor depression (Hill et al., 2008) or chronic PTSD (Hauer et al., 2013), implying that dysregulation of EC signaling, regardless of directionality, may differentially contribute to the complex nature of psychiatric illnesses.

Despite evidence correlating EC levels and psychiatric conditions and the promise this research entails, few studies have been done in human subjects. During the development of CB1 receptor antagonists in humans for obesity treatment, it became apparent that blockade of the CB1 receptor did increase the incidence of anxiety and depression (Hill and Gorzalka, 2009; Christensen et al., 2007), supporting the preclinical data indicating that disruption of EC signaling did indeed regulate emotional states in humans. There are no published studies as of yet which detail the impact of pharmacological interventions targeted at AEA or 2-AG on emotional states in humans. Despite the lack of pharmacological studies, there is a series of studies which have shown that genetic variance in the enzyme FAAH in humans, which results in increased AEA signaling, is associated with reduced anxiety and fear, blunted amygdala activation to threat and enhanced cortical innervation of the amygdala (Hariri et al., 2009; Gee et al., 2016). To build off of the relatively limited number of human studies investigating alterations in EC in psychiatric illness, we compared serum AEA and 2-AG levels in a large group of individuals with and without DSM-5 psychiatric diagnoses as well as examine their affective intensity and lability in an attempt to correlate EC levels with psychopathology. Though we saw no significant differences within categorical DSM-5 defined disorders, we did find significant differences when examining dimensional measures of affect intensity and lability in study participants with and without a history of lifetime diagnosis of a psychiatric condition or personality disorder.