Healing a desensitized serotonin receptor system

[5ht2Antogonist]

So.. let's say you upregulated your serotonin receptors by taking modest amount of LSD and now you got tolerance.
Well, let's also say that what you thought you had taken at the time turned out to be an NBOMe.
And you wanna know why Psilocybin doesn't work on you anymore.

Desensitized receptors which are never coming back ?
Mutation on the receptor site ?

The thing is, I guess there're always ways to recover. I'm sure of this. Whether by having MAOI's in your system and upregulating almost entire neurotransmitter system or ... well idk much guys..

That's why I'm posting this thread and I HAVE been staying away from all the substances (even including synthetic cannabinoids)

I'm not trying to solve this problem with more psychedelics either.. I just need an explanation that might give me a clue about what may have happened to the "desensitized receptors" afterwards.

(the part where I said I'm stayin away from synth. cannabinoids was a joke LMAO )

(NEVER COMBINE MAOI'S WITH DRUGS.)

 

[Cotcha Yankinov]

Some forms of tolerance may not have to do with the receptors themselves but rather changes in the downstream signaling cascades that the receptors use to create a change in neuron function (and hence psychoactive effects). There could be other forms of tolerance that are more difficult to conceptualize than direct 5-HT2A downregulation/desensitization as well.

For example, if psychedelics work via 5-HT2A mediated glutamate release in some areas of the cortex, then glutamate receptor downregulation could be another source of tolerance (if 5-HT2A activation is leading to glutamate release, and the psychoactive effects are downstream of that).

Even chronic antagonism of 5-HT2A will desensitize/downregulate 5-HT2A.

 

[5ht2Antogonist]

Some forms of tolerance may not have to do with the receptors themselves but rather changes in the downstream signaling cascades that the receptors use to create a change in neuron function (and hence psychoactive effects). There could be other forms of tolerance that are more difficult to conceptualize than direct 5-HT2A downregulation/desensitization as well.

For example, if psychedelics work via 5-HT2A mediated glutamate release in some areas of the cortex, then glutamate receptor downregulation could be another source of tolerance (if 5-HT2A activation is leading to glutamate release, and the psychoactive effects are downstream of that).

Even chronic antagonism of 5-HT2A will desensitize/downregulate 5-HT2A.

Wow, thank you for the valuable information Cotcha! I wish there was a VOTE +1 button instead of QUOTE

 

[5ht2Antogonist]

Some forms of tolerance may not have to do with the receptors themselves but rather changes in the downstream signaling cascades that the receptors use to create a change in neuron function (and hence psychoactive effects). There could be other forms of tolerance that are more difficult to conceptualize than direct 5-HT2A downregulation/desensitization as well.

For example, if psychedelics work via 5-HT2A mediated glutamate release in some areas of the cortex, then glutamate receptor downregulation could be another source of tolerance (if 5-HT2A activation is leading to glutamate release, and the psychoactive effects are downstream of that).

Even chronic antagonism of 5-HT2A will desensitize/downregulate 5-HT2A.

So.. should I search for ways to "regulate" or "re-set" the glutamate release back to what it was before? And is there any reason to the saying

"Psychedelics may bring about latent mental illness in some individuals"

Some people are just predestined, to getting schizophrenia even after the first use?

There definitely must be ways to restore the glutamate levels in my opinion.

 

[Cotcha Yankinov]

I have no idea whats mediating some of the tolerance issues, I wouldn't even know where to begin. But as I mentioned about 5-HT2A antagonism leading to desensitization of 5-HT2A, we can at least rule out using 5-HT2A antagonism to attempt upregulation of 5-HT2A.

It may be helpful to think of a possible mechanism of tolerance that is a sort of network wide/cell ensemble tolerance. There could be cell ensembles that have to function a certain way to produce the psychedelic state. There may also be cell ensembles that can oppose the psychedelic state. Maybe the oppositional cell ensembles could strengthen during repeated psychedelic states (as a homeostatic mechanism, to return the brain to normal function) in some people and result in resistance to the psychedelic state.

Maybe full agonists are better at inducing such homeostatic mechanisms in cell ensembles due to their different effects on signaling cascades downstream of the 5-HT2A. It would make sense that the brain would be better at desensitizing the response to a molecule that is signaling like serotonin does (as a full agonist), and that it may not be so good as desensitizing against a partial agonist that may not be as good at activating the signaling cascades necessary to induce this theoretical form of tolerance.

RE: schizophrenia, excess signaling at 5-HT2A and the farm downstream complications may result in cellular changes (such as decreased expression of GAD67 and parvalbumin in GABA interneurons) that those with mental illness are already predisposed to. In the case of MDMA, the reduction of GAD67/Parvalbumin expression that can be observed in animals given binge administration of MDMA seems to be downstream of 5-HT2A mediated glutamate release. The NMDA (glutamate) antagonists like ketamine also seem to induce (a bit reversible) changes in GAD67 and parvalbumin expression, and NMDA antagonist tolerance is sort of weird.

Any questions are welcome,
CY

 

[MeDieViL]

If im correct st johns worth upregulates 5ht2a and 5ht2c, some folks for drugs forum used it in high doses to reverse tolerance to mdma for 2 weeks in really high doses with some succes, the evidence is only anecdotal but its documented that it upregulates those serotonin receptors, therefor perhaps worth a try.

Its entirely true that the the development of tolerance can have something to do with downstream changes, such as glutamate, perhaps looking at dmt which apperantly doesnt have tolerance issues, correct me if im wrong, can give us some insights.

Its a fact that in daily low doses, psychedelics dont show any tolerance to their therepeutic effects, eg people using LSD or another psychedelic for depression, the tolerance only seems to occur to the hallucinogenic effects.