Cannabidiol as an add-on therapy to overcome the slow-onset and, possibly, resistance to antidepressant treatment: involvement of NAPE-PLD in the medial prefrontal cortex

Author:

Scarante Franciele F.ORCID,Lopes Vinícius D.,Fusse Eduardo J.,Vicente Maria A.,Araújo Melissa R.,Scomparin Davi S.,Aguiar Rafael P.,Guimarães Francisco S.,Nardini Viviani,Sorgi Carlos Arterio,Faccioli Lucia H.,Hallak Jaime E. C.,Joca Samia,Mackie Kenneth,Zuardi Antonio Waldo,Crippa José Alexandre S.,Campos Alline C.

Abstract

AbstractAntidepressants such as serotonin uptake inhibitors are the first-line pharmacological treatment for chronic stress-related psychiatric disorders. However, their late-onset therapeutic action and frequent side effects, however, are important challenges for clinicians and patients. Besides, around 30% of major depression patients are considered treatment-resistant. Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid with a wide range of psychopharmacological effects, but its mechanism of action remains unclear. Here, we found that in male mice submitted to two different repeated stress protocols (chronic unpredictable and social defeat stress), low doses of CBD (7.5mg/Kg) caused an early-onset behavioral effect when combined to the antidepressant escitalopram (ESC-10mg/Kg). The behavioral effects of the ESC+CBD combination depended on the expression/activity of the N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD, responsible for synthesizing the endocannabinoid anandamide), but not the DAGLα, enzyme in the ventromedial prefrontal cortex. In addition, we described a case series with three treatment-resistant depression that were successfully treated with CBD as adjuvant therapy, as evaluated by standardized clinical rating scales. After 12 weeks of treatment, two patients were considered depression remitted (MADRS score lower than 10) while one patient successfully responded to CBD as add-on treatment (more than 50% decrease from the baseline MADRS). Our results suggest that CBD might be useful as an add-on therapy for optimizing the action of antidepressants. They also suggest that CBD’s beneficial actions depends on the facilitation of N-acylethanolamines actions in the medial prefrontal cortex.HighlightsIn mice, cannabidiol (CBD), but not escitalopram, induced a fast-onset anti-stress action.Combinations of sub-effective doses of CBD and escitalopram produce anti-stress effects after only 7 days.The Escitalopram + CBD treatment modulated synaptic protein markers in the medial prefrontal cortex.CRISPR-Cas9-mediated knockdown of NAPE-PLD in the medial PFC prevents the anti-stress effect of the Escitalopram + CBD.Adding CBD to an antidepressants regimen successfully treated three patients with treatment resistant depression.Graphical abstract

Publisher

Cold Spring Harbor Laboratory

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