The ECS from Another Perspective. FAAH-OUT!
By Stacey Marie Kerr MD, Hawaiian Ethos Medical Advisor
The more we learn about the endocannabinoid system, the smarter we get about utilizing what we know to improve people’s health. After a disastrous attempt by a pharmaceutical company to change the way some ECS enzymes work, research in this field slowed down. Recently, Jo Cameron, a 71-year-old Scottish woman and her endocannabinoid system led us to discover something interesting that may benefit others in the not-so-distant future. Jo Cameron feels very little pain—a result of a genetic mutation that allows her endocannabinoid system to work overtime. Studying her DNA, scientists realized that her bliss is all about the enzymes and the genes that code for them.
enzymes are the key
Identifying enzymes, figuring out what they do, and learning how to manipulate them can lead to significant advances in medicine. Enzymes are chemicals the body makes to cause cellular reactions. If we control the activity of enzymes, we can control the reactions. Here’s an example: Many anti-depressants work by inhibiting enzymes that remove our natural anti-depressants from circulation, allowing those natural anti-depressants to circulate longer, work better, and keep us happier. It made sense for the pharmaceutical industry to look at the chemical enzyme that clears anandamide from circulation; if we can inhibit that enzyme then we can keep anandamide working longer…all to our blissful benefit.
the ecs and the enzymes that control it
Anandamide is an endocannabinoid; think of it as our own internally-made THC. FAAH is the enzyme that degrades anandamide and takes it out of circulation when it’s no longer needed, so FAAH would be the enzyme to target. Every body system needs balance, and FAAH is the way we keep anandamide levels at an appropriate level – not too much, not too little.
In addition to keeping anandamide in balance, FAAH also degrades and keeps some other neurotransmitters in balance. One of these other neurotransmitters, PEA (Palmitoylethanolamide), also plays a role in this story.
PEA is a supplement you can easily buy online, advertised as a natural cure for pain. It is commonly used to manage inflammation. Although PEA does not bind to cannabinoid receptors, it enhances the activity of anandamide through the entourage effect. PEA has been shown to have anti-inflammatory and anti-pain effects. [1,2] This is a good chemical to have circulating at significant levels!
Many people inhale, ingest, and apply THC and PEA to their bodies in an effort to treat pain and anxiety. But what if you could keep the anandamide and PEA circulating in your body longer rather than, or in addition to, adding more? Looking at these physical ailments from another perspective, scientists investigated the enzyme that breaks down the neurotransmitters already present in our bodies. If we slow down the degradation and removal of these, would we have more anandamide and PEA in circulation and thus, less pain and anxiety?
Total faah blockade
Pharmaceutical researchers considered this possibility and set to work developing a FAAH blocking medicine. They found when FAAH is blocked there may be more anandamide and PEA available, but there are also some side effects that could be disastrous.
From the New England Journal of Medicine, November 2016:
“In a phase 1 study…..an orally administered reversible FAAH inhibitor was given to healthy volunteers to assess safety…..An acute and rapidly progressive neurologic syndrome developed in three of the four participants starting on the fifth day of drug administration. The main clinical features were headache, a cerebellar syndrome, memory impairment, and altered consciousness. Magnetic resonance imaging showed bilateral and symmetric cerebral lesions... One patient became brain dead; the condition of two patients subsequently improved, but one patient had residual memory impairment, and the other patient had a residual cerebellar syndrome. One patient remained asymptomatic.” [3]
This study was immediately terminated.
Faah genetic mutations
Enter Jo, a Scottish woman who feels almost no pain or anxiety. She never panics, even when a situation is dangerous and calls for the fight-or-flight response. This exceptional woman has never required pain medication after surgeries, and prior to a total hip replacement she complained of no pain. The surgery was done only after x-rays revealed almost complete destruction of the hip joint. That much destruction and no pain?! How can that be?
When she broke her arm at age 8, she didn’t tell anyone because it wasn’t bothering her. “According to the study authors, she said she frequently experiences “long-standing memory lapses,” like forgetting words mid-sentence and misplacing keys. She also said that she never panics—not even in dangerous situations, like a recent car accident. Cameron’s mother and daughter do not share her pain insensitivity, but her son seems to have inherited it to a lesser degree.” (Smithsonian 3/28/19) [4]
Jo agreed to have her blood tested, so the geneticists went to work. They discovered that the amount of anandamide circulating through her blood was 70% more than most people, and her PEA amounts were triple that of others. No wonder she felt very little pain or anxiety! She lived in a dream-state many of us would envy. She was not ‘high’ all the time, just as someone who uses extreme doses of THC all the time may no longer get intoxicated. Her body was used to high levels of anandamide and she thought her situation was normal.
Theorizing that she must have less active FAAH than most people, the scientists focused on the gene that codes for and produces FAAH. They found a genetic mutation in the DNA of Jo’s FAAH gene, and while that mutation may have contributed to the situation, it was not the whole story.
faah-out
FAAH has a duplicate ‘pseudogene’, previously considered inactive and of no consequence. This pseudogene to FAAH was given the name FAAH-OUT, and it appears to regulate some of the activities of the FAAH gene itself. Jo’s FAAH OUT gene is also unique – it also has a genetic mutation.
Did the combination of mutations on both the FAAH parent gene and the FAAH OUT pseudogene prevent the FAAH enzyme they produced from fully functioning? If so, it would explain her elevated levels of anandamide and PEA.
Altered function of FAAH from genetic mutations, but not total blockade, appears to be a good thing. Maybe by further investigating the FAAH OUT gene we can come up with a way to safely treat pain and anxiety without the horrific side effects seen in the earlier FAAH research.
If the discovery of mutations in these two genes leads to a way to safely increase the amount of natural anandamide and PEA in our bodies, we could be better able to relieve the suffering of those with chronic pain and inflammation. All thanks to a relaxed, pain-free woman in Scotland. FAAH OUT!
Sources
1. Lo Verme, J.; Fu, J.; Astarita, G.; La Rana, G.; Russo, R.; Calignano, A.; Piomelli, D. (2005). "The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide". Molecular Pharmacology. 67 (1): 15–19. doi:10.1124/mol.104.006353. PMID 15465922.
2. Calignano a, L. R. G. (2001). "Antinociceptive activity of the endogenous fatty acid amide, palmitylethanolamide". Eur J Pharmacol. 419 (2–3): 191–198. doi:10.1016/S0014-2999(01)00988-8. PMID 11426841.
3. Kerbrat MD etal, “Acute Neurologic Disorder from an Inhibitor of Fatty Acid Amide Hydrolase” N Engl J Med 2016; 375:1717-1725 DOI: 10.1056/NEJMoa1604221
5. Habib, Abdella M. et al.” Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity” British Journal of Anaesthesia , 2019 Mar 28. pii: S0007-0912(19)30138-2 DOI: https://doi.org/10.1016/j.bja.2019.02.019