The FAAH (fatty acid amide hydrolase) enzyme system has provided a number of headlines over the years. FAAH itself is involved in the brain’s endocannabinoid system – it clears neurotransmitters like anandamide – and a number of other biologically important hydroxyethylamide and acyltaurines. So the potential for inhibitors of it in analgesia has attracted a lot of notice, as does any new mechanism for pain relief that offers a possible way out of the opioid class.
That history comes to mind when reading about this new report of a woman in Inverness who has a mutation affecting the expression of just that enzyme. The story, which has gotten a lot of press this week, is a fascinating one: the patient herself was noticed when she had (notoriously painful) hand surgery but didn’t ask for any pain medication post-operation. All she had was some paracetamol with no further complaints, and the hospital staff immediately flagged that as highly unusual. Examination showed that she was, in fact, extremely insensitive to pain of all sorts. The patient was (of course) aware this, since she had been injured numerous times over the years without particularly noticing until later (“multiple scars around the arms and on the back of her hands”), but she hadn’t been concerned. That, actually, was another thing that turned up on interviews and examinations: she wasn’t all that concerned about things in general, with notable lack of anxiety and fear responses.
Sequencing showed that she had an inactivating mutation (now named FAAH-OUT, which as someone living in the Boston area I can appreciate phonetically). Interestingly, it’s not in the the FAAH gene itself, but represents a short deletion some ways downstream of it. It’s believed that this must be part of a long noncoding RNA whose presence strongly affects the expression of FAAH – and indeed, blood assays showed that the patient had significantly higher levels of the amides that FAAH cleaves.
One might think that lower levels of pain and anxiety would be a good thing, but consider those multiple scars. There’s something a bit worrying about not noticing that you’ve been cut until you see dripping blood (or, as the report notes, walking around with osteoarthritris of the hip and not noticing any particular pain from the “severely degenerated” joint). And more subtly, there’s something a bit worrying about not worrying about any of these things over the years. Too much anxiety is crippling, but a tiny bit of it might come in useful now and then, rather like hot sauce. I use that analogy because the patient also reported being able to eat a mouthful of Scotch Bonnet peppers while only noticing a short-lived “pleasant glow” in the mouth(!) This is not a recommended experiment for those people with a functioning nociception system, although do shoot some video for everyone if you’re still foolish enough to try it. Another interesting effect: she also reported longstanding memory problems (forgetting words in the middle of sentences, losing keys, etc.)
Now, if this story had appeared some years ago, it would have set off a chase similar to the PCSK9 story, I feel sure. But we already knew about FAAH, and about FAAH inhibitors. There are a lot of them, and many of them have gone into clinical trials (here’s a recent one). None have progressed, to my knowledge, despite trials for arthritis pain, anxiety and depression, etc., which is rather interesting considering what one might conclude from the “human knockout” example. These rare human mutations are extremely interesting and important, but they do not necessarily provide a royal road to clinical success, either. And it goes in both directions – the knockout mouse literature is replete with examples of things that should have had an effect but produced apparently normal rodents because other systems compensated as the animals developed, and there are surely any number of humans walking around with unusual deletions who have never been noticed because they are also phenotypically nearly invisible.
I have to note that compound in France that precipitated a clinical trial disaster a few years ago, which was a rather nonselective FAAH inhibitor. That mechanism doesn’t seem to have been what led to the terrible effects on patients, though – witness the variety of other FAAH compounds that have gone into humans without any such incidents. Rather, the lack of selectivity along with an extremely ill-advised approach to pharmacodynamic data and human dosing seems to have been the underlying problem, although the exact mechanism that led to the stroke-like effects is (I believe) still unknown.
Finally, there’s another broadly similar enzyme, monoacylglycerol hydrolase (MAGL) that cleaves another class of endocannabinoid, but this system was not affected in the Inverness patient. MAGL is a story all its own – it came into view as a possible cancer target, has been looked at for its neurological effects (pain, depression etc., as in FAAH), and a functionally homologous enzyme in nematodes has just been reported as a longevity factor. That one was picked up when the Cravatt group’s known MAGL inhibitor probe extended lifespan, despite nematodes not actually having MAGL analog of their own! Inhibitors of this enzyme have been studied pretty intensively, but (as far as I’m aware) none of them have made it out of the clinic. Work is definitely still going on, though.
This whole area is notably difficult to get a handle on, and I haven’t even gotten into the metabolic implications of either enzyme. What you see is several levels of complexity: the enzymes involved each handle several different substrates, often in completely different tissues, and the products that they produce each do several different things. So you can’t expect a simple story to appear when you step in with a small-molecule inhibitor (or when you find a person with a mutation in part of the system, either). Evolution has shown no interest in presenting us with modular, well-isolated, plug-and-play systems, but rather repurposes, tacks on, makes do, and piles up complexity with no regard for those of us trying to untangle the results. . .