Does Reverse Tolerance Return??

[Infamybrian]

Hi guys, I just decided to join the kava forums. Lots of great information on kava stains however, I couldn't find any information on reverse tolerance being a permanent thing. I tried kava for the first time 4 months ago and it was a great experience. It did take awhile to really get the feeling of kava(I have experience with lots of substances btw), but i find it to be a effective cannabis replacement.

So After clearing half of my Solomon from N@H i feel in love with the feeling. 4 months later(my wallets been bone dry) I picked up 1/2 pound of Konaik and i'm curious if reverse tolerance stays with you, or does your resistance to build up? I'd like to make this bag last for atleast 2 weeks of nightly sessions. Thanks in advance for the answers.

 

[JonT]

The answer may be as simple as "it depends". Some people get RT and some don't. I never did. I don't think there's any real studies on the phenomenon, so we are left with just anecdotes.

 

[sɥɐʞɐs]

i've noticed, when i first started and only drank for a little while each year, i had to put in a bit more time to get the full effects. Having done that sporadically for many years, i then took several years off with no kava at all. When I came back to it this time around, there wasn't as long of a wait and I could feel it pretty well even on the 1st day back. Now that I've been drinking it consistently, I have fairly consistent experiences. If I run out of kava for a week or so...I can still tell that it doesn't hit quite as fully as it does the 2nd and 3rd day back. But that's much quicker than it seemed when I first started.

 

[infraredz]

I've never had any RT come back after taking breaks (sometimes as long as a few months). Once I broke through that RT years ago, I have never once felt the need to increase my amount from the standard that I settled on (8tbsp for most kava). Even after a few months off (like now), I still feel the same intensity and scope of effects I would if I had been drinking it daily.

 

[infraredz]

Also, as far as what causes the reverse tolerance...

If kava's MOA is indeed through the modulation of GABA-a receptors, specifically through positive allosteric modulators at receptor sites causing upregulation (although not exclusively) than it would seem logical to assume that repeated administration will cause an increasing intensity of effect (at least in the GABAergic sense) wherein due to upregulation, there is an increase in the amount of GABA receptors on the cellular surface and therefore, the active ligands in kavalactones are able to bind to (and therefore exert their effect) to a greater degree.

During downregulation (tolerance) of μ-opioid agonists [for example], part of the physioslogical change involves receptor phosphorylation due to G protein-coupled cellular kinases which significantly impedes that receptor's signaling and effectively causes less effective binding of the associated ligands. Then, there is of course the downregulation of actual receptor sites which both lead to tolerance, dependence and a decrease in "effect".
It's possible that some similar mechanism is also responsible, albeit in a different way since we're talking about the reverse of the above example.

There is also a lot of research that shows that proteins (Delta FosB and RGS9-2, a regulator of G protein signaling) are involved with tolerance and addiction. This protein Delta FosB, has been theorized to activate genes that increase the person's sensitivity to a given drug. Delta FosB slowly accumulates in the body and remains active far longer than CREB (a protein involved with transcription). This then causes a hypersensitivity and is a leading area of research in drug addiction. There has even been some evidence that FosB can cause actual structural changes in the brain (nucleus accumbens I think) although I can't remember much about that part.

Here are some of the bookmarks I found regarding this (in no particular order)
[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC58680/]
[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2796570/]
[http://www.ncbi.nlm.nih.gov/pubmed/14746512]
[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667282/]
[http://www.ncbi.nlm.nih.gov/pubmed/18184321]
[http://www.ncbi.nlm.nih.gov/pubmed/17880927]
[http://www.ncbi.nlm.nih.gov/pubmed/18184321]
[http://www.jbc.org/content/280/10/8951.long]
[http://www.ncbi.nlm.nih.gov/pubmed/15829256]
[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3394094/]
[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2634932/]

All that being said, we still don't know why kava does this

 

[HeadHodge]

@infraredz

Don't know if any of what you said is true or not but that was absolutely awesome!! I really dig trying to understand how things work.