New PTSD Research: ECS Modulation of Fear Extinction In Women

Days ago the British Journal of Pharmacology published "Sex-dependent effects of endocannabinoid modulation of conditioned fear extinction in rats" – research done by a team of Canadian, Italian, and Americans. The study examines how the Endocannabinoid System (ECS) varies between men and women in how we respond to fear – specifically those with PTSD. Researchers noted that women are twice as likely to experience an inability to extinguish fear responses within internal systems. They found that acute systemic inhibition of endocannabinoids didn't alter fear extinction in males – but that wasn't the case in the opposite sex.

This calls for much more research to find specific cannabinoid or plant based therapies for PTSD as the same manipulations in females produced "diverging effects". This proved the vast difference in how endocannabinoids and the receptor system vary between men/women in regards to handling a multitude of responses – including that to stress via ECS signalling.

In this study an increase of signals to the TRPV1 impaired fear memory extinction by inhibiting certain endocannabinoids – which was the tell tale sign that males/females differ – we simply don't react the same internally. Researchers noted specifically that "inhibition of 2-AG hydrolysis promoted active over passive fear responses acutely via activation of cannabinoid type-1 receptors. Measurement of AEA and 2-AG levels after extinction training revealed sex- and brain region-specific changes."

The non stop growing cannabinoid medicine research world has proven that the ECS is the key system in the human to control 'triggers' to our fear. The male ECS has shown to have a dramatic ability to squelch these feelings in relation to the female which explains why the diagnosis is much higher in women. Our bodies are all unique so not single research study has all the answers – there will be females that prove this theory wrong and males that do the same – but in general we have two very differing physiological compositions both internal and external.

It only takes a quick glance on the external to see the differences between a male and female – but internally the processes of our various systems including the ECS also vary much like the tell tale exterior which is easy to visibly see. While some may feel this study shows that females are more 'afraid' – others, including this researcher, feel that this study proves females to have a heightened awareness. Fear is not always a bad thing, but response to it will be the determining factor in how one survives a truly harrowing experience.

Sex‐dependent effects of endocannabinoid modulation of conditioned fear extinction in rats

Maria Morena Andrei S. Nastase Alessia Santori Benjamin F. Cravatt Rebecca M. Shansky Matthew N. HillFirst published: 13 December 2020 https://doi.org/10.1111/bph.15341

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bph.15341.

Abstract

Background and Purpose

Women are twice as likely as men to develop post‐traumatic stress disorder (PTSD) making the search for biological mechanisms underlying these gender disparities especially crucial. One of the hallmark symptoms of PTSD is an alteration in the ability to extinguish fear responses to trauma‐associated cues. In male rodents, the endocannabinoid system can modulate fear extinction and has been suggested as a therapeutic target for PTSD. However, whether and how the endocannabinoid system may modulate fear expression and extinction in females remains unknown.

Experimental Approach

To answer this question, we pharmacologically manipulated endocannabinoid signalling in male and female rats prior to extinction of auditory conditioned fear, and measured both passive (freezing) and active (darting) conditioned responses.

Key Results

Surprisingly, we found that acute systemic inhibition of the endocannabinoid anandamide (AEA) or 2‐arachidonoyl glycerol (2‐AG) hydrolysis did not significantly alter fear expression or extinction in males. However, the same manipulations in females produced diverging effects. Increased AEA signalling at vanilloid TRPV1 receptors impaired fear memory extinction. In contrast, inhibition of 2‐AG hydrolysis promoted active over passive fear responses acutely via activation of cannabinoid type‐1 receptors. Measurement of AEA and 2‐AG levels after extinction training revealed sex‐ and brain region‐specific changes.

Conclusion and Implications

We provide the first evidence that AEA and 2‐AG signalling affect fear expression and extinction in females in opposite directions. These findings are relevant to future research on sex differences in mechanisms of fear extinction and may help develop sex‐specific therapeutics to treat trauma‐related disorders.

The full publication is not yet available in the National Library of Medicine – it's that new.

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