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Researchers discover how the brain turns chronic stress into pathological anxiety

anxiety research cannabinoid corticotropin-releasing factor amygdala endocannabinoid stress

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#1 Irishdude

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Posted 16 February 2017 - 11:34 AM


In a new study, researchers at The Scripps Research Institute (TSRI) have described how two important molecules in the brain work together to trigger intense anxiety.

The new findings in animal models point to a novel interaction in the regulation of the brain’s stress response that may underlie the pathological anxiety related to symptoms of post-traumatic stress disorder (PTSD).

“Anxiety and stress disorders affect millions of people worldwide,” explained study leader Marisa Roberto, a professor at TSRI. “Understanding the mechanisms underlying these disorders is important for identifying potential new targets for therapeutic use.”

The researchers focused on the endogenous cannabinoid (endocannabinoid or eCB) system, which include natural lipid signaling molecules that bind to cannabinoid receptors in the brain. Cannabinoid (type 1) receptors control stress-mediating circuits by inhibiting neurotransmitter release — a sort of gating mechanism to keep anxiety in check.

In contrast to the stress-reducing properties of endocannabinoids, a peptide molecule called corticotropin-releasing factor (CRF) activates the stress response and promotes increased sensitivity to stress and anxiety when activated over and over again.

In the new study, published today in the journal Biological Psychiatry, the researchers investigated the interaction between the stress-promoting (CRF) and stress-constraining (eCBs) mechanisms in the central nucleus of the amygdala, a critical brain region involved in mediating emotional reactions. The findings suggest that overactive CRF signaling in this region produces a wide range of effects that override the stress-reducing capabilities of a major eCB called N-arachidonoylethanolamine (anandamide), turning chronic stress into unchecked, or pathological, anxiety.

“Anxiety is something that everyone experiences on a day-to-day basis,” said study first author Luis A. Natividad, a research associate in the Roberto lab. “But it is unclear what changes this otherwise natural process into something debilitating.”

To answer this question, Roberto’s lab teamed up with Roberto Ciccocioppo’s lab at the University of Camerino, Italy, and the lab of TSRI Professor Loren (“Larry”) Parsons, a renowned leader in the fields of endocannabinoid signaling, stress and drug addiction who passed away in 2016.

The researchers studied rats that were genetically selected for higher alcohol drinking and also display an anxiety-like phenotype. These rats exhibit a mutation in a gene called Crhr1 that increases CRF (type 1) receptor signaling.

Using behavioral, neurochemical and electrophysiological approaches, the researchers found that increased CRF signaling led to elevated activity of the anandamide clearance enzyme fatty acid amide hydrolase (FAAH). Increased CRF was also associated with drops in anandamide levels in the central nucleus of the amygdala. Together, increased FAAH activity and decreased anandamide signaling reduce inhibitory control of excitatory neurotransmission in this critical region, and lower the brain’s ability to regulate stress and anxiety.

The researchers concluded that long-term dysregulation of CRF-FAAH mechanisms in the amygdala keeps anandamide from doing its job. Without anandamide to balance out the system, the brain is primed to react to stress.

Follow-up experiments showed that inhibiting FAAH could blunt CRF’s effects and reduce signs of anxiety in the rats.

Roberto said the next step will be to further study this rat model to better understand relationships between high anxiety and alcoholism. She added that the rat model could also be useful for studying PTSD, where high anxiety is connected to a higher risk of developing alcoholism.

“The results of our study may be useful, not only in understanding the neurobiological basis of alcoholism, anxiety and possibly PTSD, but also in developing more efficacious pharmacotherapies to treat these disorders,” added Ciccocioppo.

The researchers dedicated this study to Parsons. Natividad added a note on Parson’s influence on the research and on the TSRI campus:

“Larry’s guidance throughout the study was critical in bringing together a cohesive story exploring the relevance of endocannabinoid signaling with downstream neural processing in a way that is unique to the field and has translational relevance to the human condition. He serves as a role model for me not only as a scientist, but also in terms of being a good colleague, mentor and friend to those around him. I feel privileged to have been part of his lab, his teachings and mentorship. He will be dearly missed.” Reference

Interesting research. As a person who is prone to anxiety when under stress, I would love if someone more knowledgeable than I could chime in about how to disrupt FAAH and promote the cannabinoid gating receptors(?)

Edited by Irishdude, 16 February 2017 - 11:35 AM.

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#2 ta5

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Posted 16 February 2017 - 03:43 PM

I was looking at some of this a couple years ago. Here are my sketchy notes. I'm not prepared to defend this. I may have been confused. Some statements may be flat out wrong, but there may be some leads to look in to:


Ways to increase Anandamide (N-arachidonoylethanolamine)?:
    Maca (macamide potent inhibitor of anandamide cellular uptake) 
    Tylenol (AM404 is a metabolite of acetaminophen and AM404 inhibits FAAH)
    Fatty Acid Amide Hydrolase (FAAH) Enzyme Inhibitors:
    FAAH-like anandamide transporter (FLAT) inhibitors [2]
    Biochanin A, an isoflavanone, has been shown to be an effective peripheral inhibitor of FAAH[3]
    By increasing N-arachidonoyl phosphatidylethanolamine or by inhibiting amide hydrolase
    PEA potentiates AHA
    Ibuprofen is also a FAAH inhibitor
    DHA can increase anandamide levels

    Guineesine or guineensine from black pepper is an Anandamide reuptake inhibitor




"A diet with supplements of arachidonic acid, glycerol, chocolate, and/or NAPE, as well as pantothenic acid, in addition to regular exercise and the use of FAAH inhibitors such as paracemtol/AM-404 (or, again, chocolate)"


Foods that contain kaempferol: apples, grapes, tomatoes, green tea, potatoes, onions, broccoli, Brussels sprouts, squash, cucumbers, lettuce, green beans, peaches, blackberries, raspberries, and spinach.

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#3 jack black

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Posted 17 February 2017 - 12:57 PM

Good topic. Anyone having results using this method?
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#4 Mind_Paralysis

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Posted 25 February 2017 - 11:25 PM

Man, I need to have a closer look at this! I'm suffering from burnout at the moment, although I've gotten tremendously better, I still need to make sure that it never happens again - I can't afford to lose that much of myself again - it's a lot of work, rebuilding yourself from the ground up.


Interesting that they mention the endocannabinoid-system - endocannabinoid down-regulation as a result of receptor-overload from SCRI-effects are believed to be the method through which Paracetamol/Acetaminophen inhibits physical and EMOTIONAL pain.


Being less traumatized by traumatic and threatening things does seem a lot like greater stress-resistance to me - perhaps AM-404, the active metabolite from Paracetamol could then be used as a powerful anti-stress supplement?


Or am I misinterpreting the data?

#5 gamesguru

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Posted 26 February 2017 - 02:17 AM

exercise, kratom, alcohol and ketamine all affect endocannabinoid signalling, it definitely explains some of their anti-anxiety effects.


i also wouldn't get too wrapped up in anandamine, NADA (N-arachidonoyl dopamine, made from arachidonic acid and dopamine) is just as interesting.  TRPV1/vanilloid and CB1 agonist, PPAR-gamma and calcineurin inducer.


Voacanga africana and falcerinol are CB1 antagonists

#6 UltraCitron

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Posted 27 February 2017 - 06:01 AM

Smoke weed erryday. /s

Actually, I've been doing that lately. My baseline is significantly less stressed and less anxious. Piracetam seems to help with the memory and motivation issues, but they're still present and fairly annoying. It's a bit more difficult to get stuff done.

FAAH inhibitors are very intersting - get some of the stress and anxiety relieving effects of weed without the weed. Does anyone have experience with them?

#7 Irishdude

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Posted 01 March 2017 - 11:15 AM

I did a cursory search and couldn't turn up any anecdotes.




I feel the exact same way. I want to increase my resilience to stress over time. Exercise everyday is all I have come up with so far plus mindfulness which I am struggling to implement daily.

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#8 sativa

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Posted 15 July 2017 - 09:33 PM

Hey guys - check this!


49 Ways to Increase Natural Cannabinoids Without Smoking Pot (including ways that decrease cannabinoids) (https://selfhacked.com/blog/49-ways-increase-natural-cannabinoids-without-smoking-pot-including-ways-decrease-cannabinoids/)





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Also tagged with one or more of these keywords: anxiety research, cannabinoid, corticotropin-releasing factor, amygdala, endocannabinoid, stress

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