Spadin-derived PE 22-28 keeps popping up in my feed, anyone following the TREK-1 angle?

Question

Saw this peptide mentioned a few times this month in cognitive research writeups and it caught my eye because the mechanism is so different from the usual SSRI story. Blocking TREK-1 potassium channels to push serotonin signalling and neurogenesis sounds almost too tidy but the animal data on spadin and its derivatives is genuinely interesting, and the idea of something that works faster than traditional antidepressants is what keeps pulling me back to this space. What gives me pause is that it's still firmly preclinical, no real human safety data, and short half-life. I keep thinking about how that pattern has played out with other "exciting" neuropeptides that looked great in mice then just disappeared. So I'm curious if anyone here has been tracking the actual research pipeline or knows of any early human work in the works. Also for context I did try Adamax intranasally for a few weeks and liked the focus bump, but that's a totally different mechanism. This one feels more like a mood and plasticity play if it ever becomes real. Anyone else following TREK-1 stuff or am I going down another rabbit hole 😅

casey613 · Accepted Answer

Yeah the TREK-1 angle is interesting lah but I'm also treating it like another preclinical shiny thing for now. I've watched a few "fast acting antidepressant" candidates come and go over the years and the jump from rodent to human kills most of them, either the half life turns out to be a non starter or the safety window is way narrower than the animal papers suggested. The spadin derived stuff does look cleaner than some of the older candidates though, more selective target and the neurogenesis piece at least has a plausible story behind it. Have you seen anything on the actual peptide stability or any prodrug work? That's usually the bottleneck for these things if they want oral or even decent intranasal delivery. Without that it kinda dies on the vine regardless of how good the mechanism looks. Steady topic to follow but I wouldn't hold my breath for human trials this cycle, not until someone publishes a proper pharmacokinetic study.

elle_z · Answer

Yeah that's exactly my worry, the rodent to human jump has killed so many "fast acting" candidates I've gotten excited about 😅 the spadin derived stuff does feel a bit cleaner mechanism wise but I've learned not to trust that alone. Re stability, nothing concrete, just mentions in reviews that the native peptide degrades fast in plasma, which is why people are looking at shorter analogues like PE 22-28 to begin with. I'll keep digging, if I find a proper paper on the half life extension work I'll drop it here. Also yes adamax intranasal was a nothingburger for me, total waste ⚡

scientist_sanjay · Answer

Yeah that tracks with me. The rodent to human jump is where most of these "fast acting" candidates die, and half-life issues keep biting people who actually try them. I haven't seen proper stability data on pe 22-28 specifically. Have you come across anything on whether the spadin backbone holds up better than earlier derivatives? That's the part i'm most curious about.

elle_z · Answer

Yeah the rodent to human cliff is exactly what worries me too, so many of these just vanish after phase 1. I've only seen one stability paper that compared spadin to a few derivatives and the backbone held up ok in plasma but they didn't test pe 22-28 directly, that was more about earlier analogues. Honestly that's a gap I wish someone would publish on. Where are you seeing most of your updates on this, just conference abstracts or actual journals?

Spadin-derived PE 22-28 keeps popping up in my feed, anyone following the TREK-1 angle?

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