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Re: Tolerance is just so low!! SLS

Posted by undopaminergic on December 28, 2022, at 16:40:08

In reply to Re: Tolerance is just so low!! undopaminergic, posted by SLS on December 28, 2022, at 14:18:41

> > > > maybe...a non-antidepressant approach?
> > >
> > > Whatever works. It would be an instructional exercise to have people list those drugs or other substances that worked best for them.
> > >
> >
> > I won't try to go through them all, but my best combination was buprenorphine + methylphenidate. I felt I was in the process of getting on my feet again when the drugs were taken away from me.
> >
> > -undopaminergic
> What property of buprenorphine do you think mitigated your depressive symptoms? What led you to combine the two drugs?
> I found this:
> "Major Depressive Disorder and Kappa Opioid Receptor Antagonists"
> Buprenorphine is a partial agonist at the mu opioid receptor and an *antagonist* at the kappa receptor, which could explain the antidepressant properties of buprenorphine. Perhaps you can find another kappa receptor antagonist. I wouldn't know where to look.
> - Scott

I was largely guided by neuroscience. I think kappa-antagonism was the main factor in my success. (I did enjoy the initial mu-agonism as well.)

I had read abstracts suggesting that the dopamine elevation in the nucleus accumbens from buprenorphine (BUP) plus cocaine was superior to either of them alone, and, interestingly, BUP was as effective as morphine, despite the limited efficacy of BUP at the mu-opioid receptor. Of course, I substituted methylphenidate for cocaine.

I had also read that kappa-antagonism elevated dopamine release in the prefrontal cortex. Perhaps that is why the combination helped my ADHD.

> Perhaps you can find another kappa receptor antagonist. I wouldn't know where to look.

David Pearce (author of the Good Drug Guide) has been able to acquire and test JDTic, an orally and centrally active kappa-opioid antagonist. He implied that it did not do much for depression but did have nootropic effects.

Both kappa-agonists and kappa-antagonists reduce the amount of cocaine consumed by rodents. Kappa-antagonists are more effective. I propose that agonists reduce the experience of reward derived from cocaine, and that antagonists prevent the development of tolerance, allowing doses to remain low.

I had also read (or interpreted) that the use of stimulants (eg. cocaine) stimulated dynorphin (the endogenous kappa-agonist), and that dynorphin diminished (downregulated) the expression of direct (dopamine transporter) and indirect (dopamine D2-receptor) targets of the stimulants.





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