Endocannabinoid signaling in psychiatric disorders: a review of positron emission tomography studies

Matthew E. Sloan, Caroline W. Grant, Joshua L. Gowin, Vijay A. Ramchandani and Bernard Le Foll

Acta Pharmacologica Sinica, 2018, 0, 1–9;

https://doi.org/10.1038/s41401-018-0081-z

 

Endocannabinoid signaling is implicated in an array of psychopathologies ranging from anxiety to psychosis and addiction. In recent years, radiotracers targeting the endocannabinoid system have been used in positron emission tomography (PET) studies to determine whether individuals with psychiatric disorders display altered endocannabinoid signaling. We comprehensively reviewed PET studies examining differences in endocannabinoid signaling between individuals with psychiatric illness and healthy controls. Published studies evaluated individuals with five psychiatric disorders: cannabis use disorder, alcohol use disorder, schizophrenia, post-traumatic stress disorder, and eating disorders. Most studies employed radiotracers targeting cannabinoid receptor 1 (CB1). Cannabis users consistently demonstrated decreased CB1 binding compared to controls, with normalization following short periods of abstinence. Findings in those with alcohol use disorder and schizophrenia were less consistent, with some studies demonstrating increased CB1 binding and others demonstrating decreased CB1 binding. Evidence of aberrant CB1 binding was also found in individuals with anorexia nervosa and post-traumatic stress disorder, but limited data have been published to date. Thus, existing evidence suggests that alterations in endocannabinoid signaling are present in a range of psychiatric disorders. Although recent efforts have largely focused on evaluating CB1 binding, the synthesis of new radiotracers targeting enzymes involved in endocannabinoid degradation, such as fatty acid amide hydrolase, will allow for other facets of endocannabinoid signaling to be evaluated in future studies.

Keywords : positron emission tomography; cannabinoid receptors; endocannabinoids; fatty acid amide hydrolase; monoacylglycerol lipases; cannabis use disorder; alcoholism; schizophrenia; post-traumatic stress disorders; feeding and eating disorders

 

INTRODUCTION

The endocannabinoid system is one of the most widely distributed neurotransmitter systems in the human brain [1, 2]. Cannabinoid receptor 1 (CB1), the main receptor involved in central endo-cannabinoid signaling, modulates synaptic circuits that play a prominent role in psychopathology. For example, in the basolateral amygdala, CB1 activation facilitates the extinction of aversive memories by inducing long-term depression of GABAergic synapses [3]. In the medial prefrontal cortex, CB1 receptors regulate stress reactivity by terminating stressinduced corticosterone release [4]. In the ventral striatum and midbrain, CB1 activation is thought to be responsible for cannabis’ rewarding properties [5], and blockade of the CB1 receptor leads to reductions in self-administration of cannabis and other drugs of abuse [6], possibly by decreasing druginduced dopamine release [7, 8]. Given the diverse role of endocannabinoid signaling in these and other brain regions, the endocannabinoid system had been proposed as a pharmacological target for a range of psychiatric disorders, including mood disorders [9], anxiety disorders [10], and substance use disorders [11]. However, there is limited knowledge as to whether these disorders are associated with altered endocannabinoid signaling in humans.

To better determine whether psychiatric disorders are associated with endocannabinoid signaling abnormalities in the brain, we comprehensively reviewed human positron emission tomography (PET) studies employing radiotracers targeting the endocannabinoid system. We specifically selected studies that compared individuals with psychiatric disorders to healthy controls. If differences were present, we sought to determine whether these differences were global or regional. A literature search found relevant studies for five psychiatric disorders: cannabis use disorder, alcohol use disorder, schizophrenia, posttraumatic stress disorder (PTSD), and eating disorders (for details regarding the search strategy, see Supplemental methods). Studies investigating patients with neurological or neurodegenerative diseases, including temporal lobe epilepsy [12], migraine [13], Alzheimer’s disease [14], and Parkinson’s disease [15], were excluded from our review. Important details from each study, including the sex distribution of the sample, sample size, and method used to estimate receptor availability, are displayed in the accompanying tables.

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EndocannabinoidSignaling_Psych_Disorders