This suggests to me that it is the opioid tolerance itself that determines cocaine sensitivity. To test this, I'd like to see a study that administers a KOR agonist after tolerance to opioids has been established, and see if this reverses cocaine sensitivity.

Fascinating. I'd expect mu and delta opioids to reduce cortisol, if only indirectly via relaxation.

Likewise, it is important to understand the mechanism by which kappa agonism increases cortisol. Kappa is known for its dysphoric effects, which would naturally increase cortisol. However, kappa agonism is also consistent with extreme euphoria. This is known from reports with Salvia divinorum and Tabernanthe iboga. Whether this euphoria decreases cortisol or if it is, rather, a form of eustress is a very interesting question.

This is incredibly useful information.

I noticed my extract had some bitter taste and some earthy notes. I don't know what salvinorin and chlorophyll taste like, but I assume the taste comes from other impurities. However, I extracted for many minutes (10 or so); next time, I should do only the 3 minutes suggested here (3 times 1 minute).

This may partly represent the salvia "afterglow". It also demonstrates how rapidly tolerance-like mechanism can occur.

I find it odd that 0.32 mg/kg had little prolonged effect when twice that dose had a very large effect. I'd expect more of a gradient. The graph (figure 4) shows a nonsignificant drop in KOR binding of ~13% at 1 hour at 0.32 mg/kg, which I'm certain would become statistically significant in a larger sample. Still, that's nowhere near the 45% seen at 0.6 mg/kg. At 0.18 mg/kg, we see ~9%.

I calculated the human equivalent dose to be 6.8mg (0.6mg0.16270). This is an very high dose, so likely does not represent an accurate dose conversion.

Just confirming what I believed to be the case. I couldn't remember whether I'd read results of this specific sort, so I figured I should look it up. Chronic KOR agonism appears to be an ideal opioid hack.

This could potentially be explained due to variation in Tmax. That is to say, it may not be that half life varies dramatically. Rather, absorption into the bloodstream after intramuscular injection may be the cause. I'm no expert on IM injections.

I think this may be the best review of salvinorin A that I have ever looked at. I definitely need to sit down and read the full article at some point.

Fascinating and useful stuff. This is close to what I was expecting. Though, I was expecting chronic exposure to upregulate dopamine beyond baseline. If I'm understanding this correctly, it was upregulated in the sense that it enhanced the dopaminergic effects of cocaine. I've not yet read the full study.

If they mean what I think they mean, then this implies that chronic KOR is useful. I'll need to check citation 27.

PAT is apparently an herbal medicine I should look into. They also imply that KOR agonists act as I expect they do, but I'll need to read the full study to be sure.

Edit: yup, it appears that chronic KOR agonism is probably a good idea.

from full text "Utility of KOR agonists is a promising pharmacological tool for attenuating morphine tolerance (Pan, 1998), however, it is difficult to find effective KOR agonists that are devoid of dysphoric and psychotomimetic adverse effects in humans"

This is the cited study.