You have the mu-opioid receptors which are responsible for mediating all the wonderful, classical opiate effects; you just generally feel extremely comfortable and content when it's activated. Then you have delta-opioid receptors which I guess are responsible for mediating some portion of the pain relieving qualities of opioids.
But then there is the kappa-opioid receptor which the active drug contained within Salvia Divinorum binds to. Like what? Lmao that's kinda bizarre that an opioid receptor is mediating such wild effects. People don't generally think an opioid receptor being activated can make you believe you're in the humans-are-chairs dimension, but here we are. Also the weird, extreme feelings of dysphoria kappa activation can cause, like a feeling of impending doom. Polar opposite to the mu-receptors in possibly every way.
What's weirder is the body has a natural endogenous agonist for the kappa receptor. It's called dynorphin. Kind of like the opposite of endorphins. Like wtf, why would my body want to be activating the kappa opioid receptor ever at all. I feel like this thing needs more research.
Buprenorphine, the active drug in Suboxone, is actually a mixed opioid agonist/antagonist. It's a partial agonist at the mu-opioid receptor. This means it activates it to the extent it will stop withdrawals and cravings, but if you have an opioid tolerance it won't activate it enough to get you high. But it's also an antagonist at the kappa-opioid receptor.
You know the drug Naloxone? It's used to revive people from an opioid overdose. It works by being an antagonist at the mu receptors. That means it binds to the receptor but doesn't activate it. In doing so it reverses the effects of any opioids in your system such as respiratory depression. Since it is then taking up space on the receptor, the other opioid molecules in your body are then unable to bind to it themselves. This reverses the overdose.
As I said, Buprenorphine does this at the kappa receptor. That means people on Buprenorphine have blocked kappa-opioid receptors that their natural endogenous dynorphin can't bind to. What is the opposite of thinking you're a piece of furniture? Idk, but this suggests to me that if someone is having a bad Salvia trip, you could probably reverse it by quickly giving them Buprenorphine. The same way that Naloxone reverse mu-opioid overdoses.
But what's more interesting to me is wondering about the long term effects of never having Dynorphins binding to my kappa-opioid receptors. Why would I ever want Dynorphins to bind to it? People don't generally describe the Salvia experience as pleasant. Idk
Just wondering out loud here, the way drugs interact with your brain to significantly alter your consciousness is very fascinating to me
this is a fascinating avenue i've never considered and a great write-up. this is why i love neurochemistry. it seems to be one of those dark, unexplored frontiers of science that doesn't require insane math or massive, NASA budgets to explore.
as an aside my own personal, strong saliva trip was the worst experience i ever had with any substance. reality itself broke down, i was convinced i was dead, and was basically sent to some kind of hell dimension and flayed with burning pain. this was after the world flushed like a toliet. it was just intense, abject fear for what felt like hours. i was only in for 4 minutes, and my friends said i just sat there with my eyes wide and sweating. yeah, part of me wonders what the hell those receptors are actually for. if glutamate and NMDA can get you to "heaven" or an afterlife at least (ketamine, other dissos) then are these the receptors to send you to hell?
I haven't tried Salvia myself yet, but I have a morbid curiosity for it that I think will one day lead me to using it. I've always loved traditional psychedelics like LSD. I even loved the funky dissociative trips brought about by DXM. But everything I've heard about Salvia suggests it's another animal entirely.
Bizarrely, it's an opioid. Four years ago I got clean from opioids, though I still have a strong nostalgia when remembering their effects. It seems so alien to me that an opioid can do what Salvia does. I've read some research that suggests the kappa opioid receptor is involved in some way with making us feel fear. That makes a lot of sense I think.
I wish I could find some trip report from someone on Buprenorphine using Salvia. I'm on Buprenorphine, an antagonist of the kappa receptor. So I have some doubts Salvia would even work on me. If it does, then it would need to have a stronger binding affinity at the receptor then Buprenorphine, which is a tall order because Buprenorphine is known for holding onto receptors with absolutely wicked force. The only opioids that can casually push Buprenorphine off the mu-opioid receptor are those in the fentanyl family. Though, that isn't a guarantee it has the same strong binding affinity for antagonism at the kappa opioid receptors.
I feel like a strong part of the high that Buprenorphine can possibly produce isn't mediated by the mu opioid receptor at all. When I first got off opium, I tried using Buprenorphine instead, but it didn't work too well because of my insane tolerance to opiates. At this point, four years into daily Buprenorphine use though, I'm still getting a significant mood lift every time I take it. I think a lot of this might be due to antagonism of the kappa opioid receptor, basically producing the opposite effects as Salvia.
Also, regular opiates like Morphine and Heroin have the same kappa agonism ability as Salvia, just at a much lower potency. I would think opiate overdose would actually be a blissful way to die, but many people report intense feelings of extreme fear and panic when they overdose. This is probably mostly because they can't breathe, but I also suspect there is something going on with the kappa agonism at very high doses.