What’s Your FAAH Type? Endocannabinoid Enzyme Variants in Humans
Did you know a lot of us have different endocannabinoid enzymes? Just like different eye color, hair color, and skin tone, there are two different versions of the gene that encodes the enzyme FAAH, which breaks down anandamide. One version works better than the other and leads to greater levels of anandamide. Read the blog for a closer look at what we know so far about these variants.
The AlphaFold structure of human FAAH form 1 with a magnification of the lower loop at the location of the Proline129Threonine variant. Up to around half of some populations will have at least one form of this FAAH enzyme in our genomes, which changes our levels of anandamide.
I love when the community sparks a special interest and this blog is about the work of Len May, who was introduced to me by my collaborators and friends The Beard Bros. After years of working with the endocannabinoid enzymes, I had never thought to take a deeper look into the different genetic variants of the human enzymes. But a significant number of us (over half in some populations!) carry at least one of the variant versions of human FAAH, fatty acid amide hydrolase, the enzyme that breaks down anandamide (AEA). And this publication shows that the presence of one of the variants of FAAH led to higher anandamide levels and greater severity of PTSD symptoms. So lets take a deeper look at what causes this at the atomic scale.
The Difference in the DNA
We each inherit a single chromosome from each of our parents, leading to 23 pairs of chromosomes and two versions for each gene. In some of us the DNA will have a “C” and others will have an “A.” While the “C” type of gene is way more common, a large number of people will have at least one chromosome with the “A”-containing FAAH gene (called rs324420). Though the exact interplay between the two different FAAH genes isn’t well understood like eye-color or hair color in which we know there are dominant and recessive versions of genes for different factors, the early data points to the presence of the “A” allele, or gene type, as significant. This means that any of us with the “A” allele likely have elevated levels of anandamide.
But what does this difference in the DNA actually do? It changes an important amino acid in the FAAH enzyme, a proline (see figure above) changes into a threonine. There are two things I find interesting about this change. The first is that it’s location is at the bottom of the enzyme in a loop domain. Loops are unstructured parts of enzymes that are typically flexible parts, so to change a section of a loop could change a normally flexible piece into something different that can affect many different parts of the enzyme, including the binding site. The second is that proline is the only tertiary amino acid and is conformationally constrained or rigid, so changing it to threonine increases flexibility at the loop and introduces an extra oxygen atom, increasing polarity. It’s only one small change, but this small change causes big effects.
Though not much is known about any structural or functional changes to the FAAH enzyme - something I’m super curious to explore - there is early evidence that this mutation decreases the expression levels of FAAH, meaning there is less of it around, leading to decreased breakdown of anandamide and increasing anandamide levels. In humans, this has been associated with:
alcohol, smoking, and other dependence-behaviors including cannabis
increased anxiety and/or stress levels (with conflicting data)
increased PTSD symptoms
increased gastrointestinal issues
increased myocardial infarction
better athletic performance
increased epilepsy
decreased pain sensitivity
For me, it tracks that this means that there is a difference in the therapeutic benefits, optimal dosages, and dose schedules for medical cannabis for people with the “A” alleles. I was shocked to hear from Len how many people are “A” allele carriers and how different demographics of people will have different proportions of “A” carriers. I’m also super interested in looking into what this change means at the binding site, because we have a catalog of known FAAH inhibitors, some of which have made it all the way to clinical trial. I’m also curious to know if there are ways to predict adverse reactions to other pharmaceuticals that have an effect on the endocannabinoid system, like the SSRIs.
Then there’s the CB1 receptor variant… but that’s for another blog.
REFERENCES
Leen, N.; de Weijer, A.; Boks, M.; Baas, J.; Vermetten, E.; Geuze, E. The Role of Genetic Variations in the FAAH Rs324420 Polymorphism and Its Interaction with CRHR1 Rs110402 and CNR1 Rs2180619 in Anxiety And- Trauma Related Symptoms After Military Deployment. Chronic Stress 2024, 8, 24705470241285828. https://doi.org/10.1177/24705470241285828.
Marusak, H. A.; Ely, S. L.; Zundel, C. G.; Gowatch, L. C.; Shampine, M.; Carpenter, C.; Tamimi, R.; Jaster, A. M.; Shakir, T.; May, L.; deRoon-Cassini, T. A.; Hillard, C. J. Endocannabinoid Dysregulation and PTSD in Urban Adolescents: Associations with Anandamide Concentrations and FAAH Genotype. Psychopharmacology 2024. https://doi.org/10.1007/s00213-024-06717-3.
Sipe, J. C.; Chiang, K.; Gerber, A. L.; Beutler, E.; Cravatt, B. F. A Missense Mutation in Human Fatty Acid Amide Hydrolase Associated with Problem Drug Use. Proc Natl Acad Sci U S A 2002, 99 (12), 8394–8399. https://doi.org/10.1073/pnas.082235799.
Silva, H.-H.; Tavares, V.; Neto, B. V.; Cerqueira, F.; Medeiros, R.; Silva, M.-R. G. FAAH Rs324420 Polymorphism: Biological Pathways, Impact on Elite Athletic Performance and Insights for Sport Medicine. Genes 2023, 14 (10), 1946. https://doi.org/10.3390/genes14101946.