Selective translocator protein (TSPO) agonists

Given that there is anecdotal evidence of lorazepam (Ativan) causing rapid temporary improvement of ME symptoms, even in very severe cases, I’ve wondered why ME researchers aren’t looking more closely at researching selective translocator protein (TSPO) agonists. TSPO is also known as the peripheral benzodiazepine receptor (PBR) and is primarily found on the inner and outer mitochondrial membrane.

A few selective TSPO/PBR agonist compounds exist in research, and they do not have affinity for the central GABAA receptor, therefore they do not have the negative effects benzodiazepines have so drugs selectively targeting TSPO could potentially be taken long term.

A few examples are Ro5-4864, Emapunil, and SSR-180,575

By researching these compounds in ME/CFS we could discover if indeed the effect lorazepam has on ME symptoms is due to TSPO agonism and the resulting effects on mitochondria, glial cells, adrenals and steroids, inflammation, etc. and not due to central GABAA binding. In addition, these could be a tool to help us understand the pathophysiology of ME and a potential target for ME/CFS treatment and drug development.

 

I read that clorazepam (Klonopin) has no affinity for the TSPO/PBR receptor. Have severe patients reported the same significant temporary improvement from clorazepam as for lorazepam? That would help answer one of the questions I wrote in the OP.

 

It might be useful to get a sense for how many patients the anecdotal evidence holds true? It's so easy to get a skewed idea of the extent of the impact.

I have two friends with ME who, like me, have been prescribed lorazepam. It had exactly the effect you'd expect: feeling weak, drugged, sleepy, and unresponsive.

I took it for several years – I was given it as a teenager, without any warning that it was extremely addictive as well as completely inappropriate for someone not suffering any symptoms that warranted its use. Unsurprisingly, my ME symptoms improved a great deal after managing to withdraw from it. The friend who used it for dental treatment found it made her feel so awful that it was preferable to conquer her phobia.

These are only anecdotes, of course, but they ought to be weighed against those from people who feel better. It may be relevant that only one of the friends I mention has severe ME – the other two tend to slide up and down the mild/moderate scale over time.

 

Yes totally, maybe too when a person deteriorates to severe or very severe ME the pathophysiology takes on new aspects, and lorazepam might only benefit here.

 

There is some discussion in this paper about the future of constructing neuropsychotropic drugs in the series of TSPO ligands (I've only read the abstract)
https://pubmed.ncbi.nlm.nih.gov/32881658/

 

Jonas Berquist has done steroidomics in ME/CFS and presented at the Stanford Symposium and elsewhere on the topic. I don't think it's published info.
https://www.omf.ngo/second-annual-symposium-transcripts/

Many papers describe how TSPO is involved in this pathway.