Endogenous cannabinoids and suicide

To the Editor

The neurobiological underpinnings of suicidal behavior have been hard to determine, although abnormalities in a wide array of biological systems that could contribute to the development of suicidality have been proposed. Over the past 10–15 years, researchers began to study and discuss a possible role of endogenous cannabinoids (endocannabinoids) in the pathophysiology of suicidal behavior.

The endocannabinoid system consists of two eicosanoid ligands derived from membrane phospholipids: anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and two main receptors: CB1 and CB2 (Coccaro et al., 2018; Vinod, 2012). CB1 receptors are broadly expressed on nearly all types of neurons in the brain, including serotonergic, noradrenergic, dopaminergic, GABAergic and glutamatergic terminals. Endocannabinoid signaling at the synapse results in suppression of neurotransmitter release from the axon terminal.

Information on the role of endocannabinoids in the neurobiology of suicide is limited. Upregulation of CB1 receptors in the prefrontal cortex of depressed suicide victims was found (Vinod, 2012). Another post-mortem study revealed elevated levels of the CB1 receptor and CB1-receptor-mediated G-protein signaling in the dorsolateral prefrontal cortex (DLPFC) of alcoholic suicide victims compared with alcoholic non-suicide subjects (Vinod, 2012). Higher levels of AEA and 2-AG were also observed in the DLPFC of suicide victims with alcoholism in this study.

Deficiencies in endocannabinoid signaling contribute to the development of stress-related psychiatric disorders associated with suicidal behavior including mood disorders, posttraumatic stress disorder (PTSD) and alcohol use disorder (Coccaro et al., 2018; Micale and Drago, 2018; Vinod, 2012). Blood levels of AEA and 2-AG are decreased in major depression, PTSD or after exposure to chronic stress. There are also reports of elevations in AEA and 2-AG blood levels in minor depression and chronic PTSD. Abnormal endocannabinoid signaling has also been implicated in the pathophysiology of anxiety and psychotic disorders. Possibly, abnormalities in endocannabinoid signaling, irrespective of directionality, contribute to the pathophysiology of psychiatric disorders and suicidal behavior.

Endocannabinoid levels are increased in response to acute stress, while poor recruitment of endocannabinoid signaling in response to acute stress, or low basal endocannabinoids concentrations in the blood have been linked to excessive stress-induced activation of the hypothalamic–pituitary–adrenal (HPA) system (Micale and Drago, 2018). HPA axis dysregulation is one of the key endophenotypes of suicidal behavior. Considerable evidence suggests that suicidal behavior is associated with hyperactivity of the HPA axis. The endocannabinoid–HPA interaction may play an important role in the neurobiology of suicidal behavior.

In summary, endocannabinoids may be involved in the pathophysiology of suicidal behavior. Further studies of the role of endocannabinoids in the neurobiology of suicide are needed.