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Long term Cannabinoid Use and why it's impossible to wean off them

You are correct. Inhibitory neurotransmitters and ions such as potassium, or sodium blockade can be both inhibitory and excitatory - it doesn't discriminate - ie it inhibits the release of GABA as well.

This is why certain prescription anticonvulsant can cause myoclonus, by binding to sodium channels which inhibit the release of inhibitory and excitatory neurotransmitters or by directly inhibiting the release of glutamate and GABA concurrently
 
Even some D2r's can be inhibitory.

But my point was that some CB1r's are coupled to inhibitory G proteins while others can be coupled to excitatory G proteins - because the G proteins can vary from cell type to cell type you're not always going to find that ligand xyz is a partial agonist etc. across every study - it can vary with cell types. Affinity is what will remain constant, and I'm still wondering if we had any info on how slow the dissociation rate is and if it can even be towards pseudo irreversible or irreversible with some of these synthetic cannabinoids
 
No, all D2s are inhibitory.

Did you understand my article? It's like the 5-HT2a/mGlu2 receptor complex that is activated by LSD.


I understood your point. I said the same thing didn't I?
 
You are probably correct about D2 (My fried brain can't remember where I heard about D2r's being coupled to excitatory pathways in some instances, it might have actually been with the heterodimers).

My point is we shouldn't say something like "THC is a partial agonist" etc, instead we should say "THC binds to CB1 coupled to Gi/o/adenylate cyclase in this cell type" etc. to be more precise, because there is variation in availability of G proteins in cell types and hence variability in whether we measure increased IPSP's and such.

I might have found why I was getting the idea that D2 activation can end up being excitatory in some cases, and you might try to make a conclusion taking your article and this one together http://www.ncbi.nlm.nih.gov/pubmed/27089415 - " CB1 agonist HU210 or D2 agonist quinpirole alone inhibited forskolin-activated cAMP accumulation, whereas HU210 plus quinpirole increased cAMP accumulation above basal."

So one possibility is that the formation of CB1/D2 heterodimers results in a receptor complex that leads to increased cAMP. You might have a situation where you reach a critical mass - heterodimers form slowly until a couple months into synthetic cannabinoid use, heterodimers start mediating more overall neuronal excitation, and once that ball gets rolling it might be hard to stop. You might also have a sort of inverse situation with increasing excitability of inhibitory interneurons, and then compensation downstream etc.

It could be possible that for whatever reason a synthetic cannabinoid is more conducive to heterodimer formation, or it is causing enough dopamine efflux to encourage heterodimer formation more so than THC.
 
No Your assumption of it leading to neuronal excitation would be due to simply the fact of neuronal downregulation isn't it?

No there isn't variation in cell D2 receptors: they are the same receptors; yet you are the same about they availability; but receptors are receptors...
 
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theGirlWithBlueHair said:
No Your assumption of it leading to neuronal excitation would be due to simply the fact of neuronal downregulation isn't it?

No there isn't variation in cell D2 receptors: they are the same receptors; yet you are the same about they availability; but receptors are receptors...
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I'm not sure to which study you are referring to regarding downregulation, the study I posted suggests that there are variations in G protein signaling and that that is responsible for the noted differences in cAMP.

What I'm trying to get at here is that receptors aren't just receptors, G proteins can be segregated inside a cell such so that in different cell types the same receptor being activated by the same ligand has more efficacy at different G proteins and hence will lead to a difference physiological response by the cell, both in terms of inhibitory/excitatory potential generation and also changes to the cell itself.
 
Yes but all D2 receptors are inhibitory, they activate GIRK channels. The only way they are excitatory is when they indirectly activate low voltage gated t-type calcium channels and cause subsequent depolarizations because of this.


I don't need to refer to a study regarding downregulation. People experience ensuing excitation during a couple months of use is because of downregulation of their D2 receptors, which are inhibitory, and they have less of them. So it makes sense, right?

It makes a heterodimer with the 5-HT 2A receptor too, so downregulation of that heterodimer as well as downregulation of regular CB1/CB2 receptors would cause excitation? it's a dependency state.
 
theGirlWithBlueHair said:
Ugh what don't you get, it was for the experience TO SMOKE PURE THC it was worth smoking the other stuff

The dab contains other cannabinoids that interfere alter the high and you should understand this

You are clearly not understanding

I was interested in the effects of pure THC by itself without the other cannabinoids in it to alter the high... so I didn't give a fuck about the other shit in the pills because I only did it once so stop lecturing me about it
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If there was 'other shit' in the pills, you weren't smoking pure THC plain and simple. Unless of course you extracted and purified, in which case I stand corrected. And honestly, I don't think people are lecturing you so much as correcting you and disabusing you of wrong assumptions.

Tom
 
theGirlWithBlueHair said:
Yes but all D2 receptors are inhibitory, they activate GIRK channels. The only way they are excitatory is when they indirectly activate low voltage gated t-type calcium channels and cause subsequent depolarizations because of this.
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http://www.ncbi.nlm.nih.gov/pubmed/9204917 - "Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors augments cAMP accumulation in striatal neurons: evidence for a Gs linkage to the CB1 receptor." My pondering was if this increase in cAMP is because of a CB1/D2 heterodimer being formed. You'll notice the increase in cAMP was not sensitive to Ca2+. Are you saying you think knockdown of Gi/o via regular CB1 + D2 agonism is leading to more Gs signaling and hence cAMP increases? Seems to me heterodimer formation and hence altered efficacy concerning G proteins is more likely.

theGirlWithBlueHair said:
I don't need to refer to a study regarding downregulation. People experience ensuing excitation during a couple months of use is because of downregulation of their D2 receptors, which are inhibitory, and they have less of them. So it makes sense, right? [It makes a heterodimer with the 5-HT 2A receptor too, so downregulation of that heterodimer as well as downregulation of regular CB1/CB2 receptors would cause excitation? it's a dependency state./QUOTE]

In this case, if CB1 + D2 activation is leading to heterodimers that tend to increase cAMP, you might find that activation of inhibitory MSNs would increase with CB1 agonism, make of this what you will.

http://www.ncbi.nlm.nih.gov/pubmed/27089415 - "Combined CB1 plus D2 agonists in MN9D cells converted the CB1 agonist-mediated activation of Gi to inhibition of Gi. In these models, the CB1 agonist response was converted to an inverse agonist response at Gi activation. Cannabinoid agonist-stimulated cAMP accumulation can be best explained as reduced activation of Gi, thereby attenuating the tonic inhibitory influence of Gi on the major isoforms of adenylyl cyclase."
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That is mania of D2 Receptors: It is well known that their stimulant effect is from indirectly stimulating t type calcium channels.

they share the same GIRM channel that does this with GABA B Agonists and is responsible for their hypomanic effect
 
Dracarys said:
But they are relatively new, so we don't know if they may have side-effects that cannabis itself lacks. For instance, they may be hard for the liver or kidneys to process. That could be because of the chemical structure of a particular substance, wich is not reflected in the direct pharmacology in the sense of receptor affinity and so on.
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That's very true. I read a post or article on bluelight years ago that said that one of the major synthetic cannabinoid research chemicals is a carcinogen, and not the best thing to be smoking or putting into your body at all.

I have a friend that has been addicted to synthetic cannabinoid research chemicals. He got off them but slowly cut back, mixed them with herb or hash into joints, and then switched to smoking herb full time. Can you do this?
 
Once I start getting ill effects - which happens abruptly and unceremoniously - like I can smoke one hit and get normal typical effects at 1pm and then at 1:20pm it starts getting me sick and ill every time I take a hit so I can no longer consume the substance, hence withdrawals begin
 
w01fg4ng said:
well it's much easier today with places like bluelight to know better than to assume such things.

I come from an era where people would tell you that smoking seeds makes you impotent and false information like that was often excepted as true because fact checking was extremely difficult.

i don't think this generation has much of an excuse to believe such things like all synthetic cannabinoids is as safe as natural cannabinoids. The information is literally right in front of your face...too easy.
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qft
 
theGirlWithBlueHair said:
Do you know why I might suddenly, out of nowhere get the effects - I used them with typical effects and had been using them almost every 15 -30 min for 3 months - and suddenly they are making me sick and I can not wean?
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You seem like a lever pushing lab rat crackhead LMAO

Every 15-30 Minutes of synthetic cannabinoids? What the actual fuck?
 
I think they are making you sick because you are using like a crackhead.

In an 8 hour day, say, that would be 32 individual times that you ingest these drugs. Just 8 Hours. Add 4 more hours, 16 more ingestions.

Consider that. It is probably your body recovering from the abuse you have been putting it through, for THREE MONTHS STRAIGHT, in your words, not withdrawing.
 
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