Thread by @canna_brain

Very excited that this collaborative paper with @Heilig_Lab and the amazing @MayoOnTheBrain is finally out. Its a big one too! The first demonstration that pharmacological inhibition of FAAH in humans dampens stress responses and augments fear extinction sciencedirect.com/science/articl…

@Heilig_Lab @MayoOnTheBrain With all of the negative attention paid to failure of rodent-human translational studies, I think its important to highlight successes. I am going to have a thread now detailing some of the background to this to provide an example of how translational science can work.

@Heilig_Lab @MayoOnTheBrain In 2003, the Piomelli lab first published a paper developing the first FAAH inhibitor and demonstrated that inhibition of FAAH and elevation of AEA signaling can reduce anxiety in rodent models nature.com/articles/nm803

@Heilig_Lab @MayoOnTheBrain Around that same time period, @MarsicanoLab and work from Kerry Ressler found that endocannabinoids, particularly AEA, were important for fear extinction nature.com/articles/natur… and nature.com/articles/13006…

@Heilig_Lab @MayoOnTheBrain @MarsicanoLab Soon after, research from @SachinPatelLab and @HillardCece found that stress can result in reduced AEA levels within the amygdala onlinelibrary.wiley.com/doi/abs/10.111…

@Heilig_Lab @MayoOnTheBrain @MarsicanoLab @SachinPatelLab @HillardCece Several years went by as people were looking at these variables in independence, but it was a study from the Haller group that tied things together and found that FAAH inhibition was really only effective at reducing anxiety under conditions of stress link.springer.com/article/10.100…

@Heilig_Lab @MayoOnTheBrain @MarsicanoLab @SachinPatelLab @HillardCece Around the same time, work I was doing with @HillardCece found that stress rapidly increased FAAH activity in the amygdala, which could explain both why AEA levels declined from stress and why FAAH inhibitors were more effective under stressful conditions nature.com/articles/npp20…

@Heilig_Lab @MayoOnTheBrain @MarsicanoLab @SachinPatelLab @HillardCece 2009 was a significant year for this area, as work from Ahmad Hariri's group that year was also the first human evidence for support of this as they found that humans with the FAAH C385A SNP had reduced amygdala reactivity to threat and reduced anxiety linkinghub.elsevier.com/retrieve/pii/S…

@Heilig_Lab @MayoOnTheBrain @MarsicanoLab @SachinPatelLab @HillardCece It was a few years before another major finding came in here, which was from @gunduzozge and Andrew Holmes lab in collaboration with @SachinPatelLab showing that inhibition of FAAH, particularly within the amygdala, enhanced fear extinction nature.com/articles/mp201…

@Heilig_Lab @MayoOnTheBrain @MarsicanoLab @SachinPatelLab @HillardCece @gunduzozge Around that same time, work from my PDF with Bruce McEwen came out also showing that under conditions of chronic stress, up regulation of FAAH and impaired AEA signaling mediated structural changes within the amygdala and the development of anxiety nature.com/articles/mp201…

@Heilig_Lab @MayoOnTheBrain @MarsicanoLab @SachinPatelLab @HillardCece @gunduzozge After this, interest was brewing in this area and with @gunduzozge and Andrew Holmes and Bruce McEwen, we put together a conceptual framework of how we envisioned AEA signaling in the amygdala regulated stress, fear and anxiety linkinghub.elsevier.com/retrieve/pii/S…

@Heilig_Lab @MayoOnTheBrain @MarsicanoLab @SachinPatelLab @HillardCece @gunduzozge In 2015, another big advance was made when Francis Lee and BJ Casey worked to develop a mouse model of the FAAH C385A SNP and replicated and extended previous work by demonstrating that this SNP, in mice and humans, associated with reduced anxiety and fear dx.doi.org/10.1038/ncomms…

@Heilig_Lab @MayoOnTheBrain @MarsicanoLab @SachinPatelLab @HillardCece @gunduzozge In 2015, my lab also demonstrated that it was the stress-induced release of CRH (or CRF) that mediated the rapid induction of FAAH activity and loss of AEA signaling in the amygdala that promoted the generation of anxiety jneurosci.org/cgi/pmidlookup…

@Heilig_Lab @MayoOnTheBrain @MarsicanoLab @SachinPatelLab @HillardCece @gunduzozge Support for the idea that FAAH may regulate stress and fear in humans accumulated during this period, but was primarily limited to studies of the FAAH C385A SNP, which was found to have developmental effects on PFC-amygdala circuit in work from @dylanggee pnas.org/cgi/pmidlookup…

@Heilig_Lab @MayoOnTheBrain @MarsicanoLab @SachinPatelLab @HillardCece @gunduzozge @dylanggee A lot of this was tied together by work from @Heilig_Lab and @MayoOnTheBrain who found in humans that stress reduced AEA and that the FAAH SNP prevented this drop in AEA and replicated the enhanced fear extinction of this SNP nature.com/articles/s4138…

@Heilig_Lab @MayoOnTheBrain @MarsicanoLab @SachinPatelLab @HillardCece @gunduzozge @dylanggee All of this rodent-human research had created a compelling argument, but what was really missing was the pharmacological data in humans that replicated the rodent effects and demonstrated that the FAAH C385A SNP effects weren't just due to neurodevelopment effects of the SNP.

@Heilig_Lab @MayoOnTheBrain @MarsicanoLab @SachinPatelLab @HillardCece @gunduzozge @dylanggee And this is where this paper came in and put it all together, showing that indeed inhibition of FAAH in humans was capable of dampening several behavioral and physiological responses to stress and enhance fear extinction--a nice validation of about 18 years of preclinical work!

@Heilig_Lab @MayoOnTheBrain @MarsicanoLab @SachinPatelLab @HillardCece @gunduzozge @dylanggee There are dozens of other studies along the way that helped to build this story and argument, and replication of effects is super important in building a strong scientific argument, so I apologize if I missed any key ones, this thread is on the fly.

@Heilig_Lab @MayoOnTheBrain @MarsicanoLab @SachinPatelLab @HillardCece @gunduzozge @dylanggee But I want to end with again highlighting the importance of translational work and push back on the tired argument that preclinical work is not driving novel therapeutics in humans. This whole story built out of rodent work from a few labs and one day may lead to novel treatments

And massive props to great scientists like @Heilig_Lab and @MayoOnTheBrain who believe in translational science and push projects like this forward, without scientists like this a lot of our preclinical findings would never be realized or move forward in humans.