Up and down regulation of serotonin receptors

[medievil]

what do you think about reverse tolerance? it occurs with every drug out there and i beleive it can be achieved with low doses of MDMA

this also occurs with for example 2cb, wich is an agonist of 5ht2a and in low doses is reported to be much like MDMA, ppl also report needing to use less and less of the same dose, so whay about upregulation those receptors with those compounds?

[KyleM]

Originally Posted by medievil

what do you think about reverse tolerance? it occurs with every drug out there and i beleive it can be achieved with low doses of MDMA

SWIM thinks SWIY means that if SWIY conditions himself to low doses of a drug for a while then taking a higher dose will have much more of a profound effect because SWIY is now accustomed to a small dose. In theory it sounds good, but if SWIY can stop thinking of MDMA as the drug, but as a "tool" instead and serotonin as "the drug", then the easiest way to lower tolerance to MDMA is to make serotonin less available by not having as much. But having no tolerance to serotonin won't allow you to roll without a decent amount of serotonin, so it may seem like a catch-22, which makes it very difficult to regain magic once it's gone. Once the tolerance is lowered you need less of the "tool" and more of "the drug". 5-HTP is essential after tolerance is gone, but is often neglected.

Originally Posted by medievil

this also occurs with for example 2cb, wich is an agonist of 5ht2a and in low doses is reported to be much like MDMA, ppl also report needing to use less and less of the same dose, so whay about upregulation those receptors with those compounds?

A general rule with most 5-HT receptors is that agonists down-regulate, antagonists up-regulate. This is where 5-HT2A is unlike other receptors because both will downregulate, with the exception of the 2 SWIM previously mentioned. So the answer is no, it will not upregulate. Sensitivity to other 5-HT2A agonists most likely works differently than serotonin (which is obviously an agonist at every 5-HT receptor).

A single neuron will fire based on the combination of all neurotransmitters bound to all receptors at that given time. So now SWIY should consider this: Is there a difference in effect in having 10 serotonin molecules binding to 10 5-HT2A receptors on a single neuron, and 1 serotonin molecule binding to 1 5-HT2A receptor on ten different neurons. Yes there is; the second will probably not produce as noticeable because the neurons are probably accustomed to having only a couple serotonin molecules binding to it in a normal day and not many on one neuron. But when we get into hallucinogens, now there are completely foreign molecules binding to the receptors, so one molecule per neuron on many neurons may cause significant effects, but will still be different than alot of these foreign molecules on fewer neurons. In the case of hallucinogens SWIM can not say that different is better like it is with serotonin, but it is definitely different. So SWIY will probably not ever become completely tolerant to hallucinogens, but the effects will most likely evolve. But that's getting into a completely different topic now.

Reputation Comments on this post:

informative posts, all of 'em in this thread

[medievil]

So the answer is no, it will not upregulate.

how do you explain the reverse tolerance phenomen to those compounds then? many ppl report they have to use less and less to get the same effect

[Fantasian]

Originally Posted by medievil

how do you explain the reverse tolerance phenomen to those compounds then? many ppl report they have to use less and less to get the same effect

and many many more report they have to use more, most E-tards or pillheads will take pills in double figures in a night. If what you say is correct people would be taking halves and quarters.

[medievil]

Originally Posted by Fantasian

and many many more report they have to use more, most E-tards or pillheads will take pills in double figures in a night. If what you say is correct people would be taking halves and quarters.

it depends, MJ has a reverse tolerance too, the dose and how many times you take compounds like 2cb make the difference
for example, most ppl that smoke like 2 times a week have a reverse tolerance, and most that smoke daily report a normal tolerance

offcourse ppl take more pills, i was wondering if a dose of like 50 mg works to induce a reverse tolerance, i know recreational doses induce a tolerance

[KyleM]

Originally Posted by medievil

it depends, MJ has a reverse tolerance too, the dose and how many times you take compounds like 2cb make the difference
for example, most ppl that smoke like 2 times a week have a reverse tolerance, and most that smoke daily report a normal tolerance

offcourse ppl take more pills, i was wondering if a dose of like 50 mg works to induce a reverse tolerance, i know recreational doses induce a tolerance

How can SWIY possibly know what kind of tolerance "most ppl" have? Everyone has a different brain chemistry and the exact amounts/potencies of marijuana (or ecstasy pills for that matter) consumed cannot be determined either. This really is getting off topic though, but if SWIY is determined then he should experiment with it himself and share his results on the forum.

[medievil]

How can SWIY possibly know what kind of tolerance "most ppl" have?

swim thinks its weird you havent heared of this phenomenem, its often reported for 5ht2 agonists to need less and less of the same dose, swim beleives thats because 5ht2 receptor gets more sensitive, swim has no other explanation and this perfectly fits this discussion, swim also agrees we both need to try our own idea's

[Broshious]

Originally Posted by medievil

swim thinks its weird you havent heared of this phenomenem, its often reported for 5ht2 agonists to need less and less of the same dose, swim beleives thats because 5ht2 receptor gets more sensitive, swim has no other explanation and this perfectly fits this discussion, swim also agrees we both need to try our own idea's

Yeah I've heard of that before. Particularly with the 2C's. However, I'm pretty convinced that as far as MDMA goes 5HT2 is not as important as 5HT1A.

[KyleM]

Originally Posted by Broshious

Yeah I've heard of that before. Particularly with the 2C's. However, I'm pretty convinced that as far as MDMA goes 5HT2 is not as important as 5HT1A.

It just doesn't make any logical sense for the 5-HT1A to be majorly responsible. It is conclusive that 5-HT2A receptors down-regulate after MDMA use. In order for that to happen, there must be a significant amount of an agonist (in this case it's serotonin) binding to them. Logically, one could assume that MDMA causes large amounts of 5-HT to bind at this receptor. 5-HT1A receptors are significantly up-regulated with antidepressants while 5-HT2A are down-regulated. 5-HT is an agonist, therefor if the 5-HT1A receptors were responsible, then they would downregulate due to excessive agonist binding. So one could also assume that significant binding at this receptor is not happening. 5-HT1A receptors are relatively easy to upregulate, 5-HT2A receptors are relatively difficult. MDMA magic is relatively difficult to bring back...

SWIM will not rule out the possibility that 5-HT1As have some role in MDMA effects, but it is unlikely that they are majorly responsible. Just put all the pieces together. There will always be sources with conflicting info. MDMA neurotoxicity is a good example. SWIM can find a large number of scientific reports, not just NIDA or DEA bullshit, indicating significant brain damage from MDMA and SWIM can find other scientific sources that say the exact opposite. Ph.Ds disagree all the time. The point I'm making is SWIY will always be able to find a source that conflicts with every last aspect of what SWIM says.

[Broshious]

Originally Posted by KyleM

It just doesn't make any logical sense for the 5-HT1A to be majorly responsible. It is conclusive that 5-HT2A receptors down-regulate after MDMA use. In order for that to happen, there must be a significant amount of an agonist (in this case it's serotonin) binding to them. Logically, one could assume that MDMA causes large amounts of 5-HT to bind at this receptor. 5-HT1A receptors are significantly up-regulated with antidepressants while 5-HT2A are down-regulated. 5-HT is an agonist, therefor if the 5-HT1A receptors were responsible, then they would downregulate due to excessive agonist binding. So one could also assume that significant binding at this receptor is not happening. 5-HT1A receptors are relatively easy to upregulate, 5-HT2A receptors are relatively difficult. MDMA magic is relatively difficult to bring back...

SWIM will not rule out the possibility that 5-HT1As have some role in MDMA effects, but it is unlikely that they are majorly responsible. Just put all the pieces together. There will always be sources with conflicting info. MDMA neurotoxicity is a good example. SWIM can find a large number of scientific reports, not just NIDA or DEA bullshit, indicating significant brain damage from MDMA and SWIM can find other scientific sources that say the exact opposite. Ph.Ds disagree all the time. The point I'm making is SWIY will always be able to find a source that conflicts with every last aspect of what SWIM says.

All of my information points to 5HT1A being responsible for Oxytocin release, and Oxytocin release is a big factor in MDMA effects.

Lots of other chems act on the 5-HT2s. LSD for example. I don't hear of people "losing the magic" with that.

I agree that we can both find things to support out positions, and there's a good chance that we'll never know what exactly makes MDMA so special.

Also, since we both seem to believe in our respective methods fairly strongly, due to the ever lovely placebo effect, we should both see good results regardless of the actual truth.

[medievil]

Originally Posted by KyleM

It just doesn't make any logical sense for the 5-HT1A to be majorly responsible. It is conclusive that 5-HT2A receptors down-regulate after MDMA use. In order for that to happen, there must be a significant amount of an agonist (in this case it's serotonin) binding to them. Logically, one could assume that MDMA causes large amounts of 5-HT to bind at this receptor. 5-HT1A receptors are significantly up-regulated with antidepressants while 5-HT2A are down-regulated. 5-HT is an agonist, therefor if the 5-HT1A receptors were responsible, then they would downregulate due to excessive agonist binding. So one could also assume that significant binding at this receptor is not happening. 5-HT1A receptors are relatively easy to upregulate, 5-HT2A receptors are relatively difficult. MDMA magic is relatively difficult to bring back...

SWIM will not rule out the possibility that 5-HT1As have some role in MDMA effects, but it is unlikely that they are majorly responsible. Just put all the pieces together. There will always be sources with conflicting info. MDMA neurotoxicity is a good example. SWIM can find a large number of scientific reports, not just NIDA or DEA bullshit, indicating significant brain damage from MDMA and SWIM can find other scientific sources that say the exact opposite. Ph.Ds disagree all the time. The point I'm making is SWIY will always be able to find a source that conflicts with every last aspect of what SWIM says.

my personal beleive is that 5ht1a's cause the oxytocin reelease, while 5ht2a's cause all the rest of the effect
2cb is reported to be a great rave drug, very powerfull like mdma (but i gues not as good), while it does not cause a release of oxytocin
2cb is an agonist of the 5ht2a receptor

and if you know that 2c's seem to have a reverse tolerance effect, i assume that this causes this receptor to upregulate

[medievil]

and what about oxytocin receptor downregulation? swim is just saying something, but could be possible

KyleM
swiy said ssri's upregulate the 1 receptor, do you know anything about other compounds, the best way to find the answer is to experiment

[medievil]

2CB revitalised my ecstasy experience

I have been using ecstasy for about 4 years now, and like so many others, I have never had that wonderful fresh experience for the last three years. I used to blame it on the quality of the pills, but then I talked to new people on the scene who did manage to have the most wonderful experiences, and they had taken exactly the same as I had. So I had to admit that it was something to do with me, and told myself that I had damaged myself and would never be able to feel that true ecstasy bliss again.
Then I made a chance discovery. I had only one E left which I knew it was too weak to do much on its own. But I also had some 2CB tablets, those very small white ones (sold as a treatment for male impotence!) which are 5mg each. So I decided to boost the low dose E with 10mg 2CB.
The result was incredible! It really was just like I remember from the good old days. As good as my very first E trip!
I spread the news among my friends, since 2CB is not hard to get here, and they all reported the same.
South African man

so extra 5ht2 stimulation brings the magic back?

[Broshious]

Originally Posted by medievil

so extra 5ht2 stimulation brings the magic back?

That is interesting. I wish in the study I found where they gave people a 5HT2A/5HT2C antagonist along with MDMA that one of the questions was about the "magic".

[KyleM]

Read this: http://www.jneurosci.org/cgi/content/full/21/10/3572
There are sources that indicate 5-HT2A stimulate oxytocin, and some that indicate 5-HT1A. MDMA downregulates the 5-HT2A receptors, therefor it's probably oxytocin stimulated by the 5-HT2A.

And because serotonin stimulates oxytocin, does not mean other agaonists will necessarily do that same thing, or at least to the same degree. The natural serotonin will result in much more euphoria than another 5-HT2A agonist.

Oxytocin receptors will downregulate with excessive binding as well. Their expression may be increased with estrogen and glucocorticoids, as well as oxytocin antagonists.

And with the 2Cs, as I said before, this is a foreign substance, there doesn't necessarily need to be many molecules binding to on a single neuron, like serotonin. Downregulation doesn't mean SWIY loses all his/her 5-HT2A receptors, but there are much fewer of them on each affected neuron. So other 5-HT2A agonist will still find receptors to bind to. Downregulation may allow the other 5-HT2A agonists to reach a greater number of neurons, but have less binding on an individual one. This does not work with serotonin because it's natural and SWIY's brain is used to having a small amount of binding at a large number of neurons throughout the day. In this case SWIY needs more binding on each individual neuron, this is where SWIY will need more receptors.

With hallucinogens, more agonism at fewer neurons will most likely include fewer, but more profound hallucinations, and less agonism at many neurons may produce more, but less profound hallucinations. SWIM hopes this helps...

[Fantasian]

So does SWIY have an answer that is possible to upregulate whichever receptor is responisble? or is the process too difficult at this point?

[Broshious]

Originally Posted by Fantasian

So does SWIY have an answer that is possible to upregulate whichever receptor is responisble? or is the process too difficult at this point?

I have seen one rather confusing paper pointing to Inositol up-regulating 5-HT2 receptors.

[medievil]

so estrogen upregulates oxytocin receptors and 5ht2a receptors

i'm very interested in clomid, it antagonizes the effect of estrogen in the body, the body compensates with more estrogen ==> more serotonin receptors (anecdotally intensifies experience)

Kyle, are oxytocin receptores also very hard to upregulate?

[KyleM]

These will result in 5-HT2A up-regulation in the cortex:
-Glucocorticoids (cortisol, corticosterone, prednisone, prednisolone, betamethasone, dexamethasone)
-Anything that stimulates glucocorticoid release (piracetam, alcohol, stress, drug/alcohol withdrawl)
-Adrenocorticotropic hormone (ACTH)/cosyntropin (Synthetic ACTH) (Stimulates glucocorticoid release)
-Estrogen/estradiol
-MDL 11,939 & SR 46349B/eplivanserin (Only 2 antagonists that cause up-regulation, but will interfere with serotonin binding while taking them)
-Hypericum (St. John's Wort)
-Electroconvulsive Therapy (ECT)
-Sustained serotonin depletion in cortex

These will result in 5-HT2A down-regulation in cortex:
-5-HT2A agonists (serotonin, hallucinogens), antagonists (except the 2 listed above) and pretty much anything else that binds to the receptor)
-5-HTP/L-Tryptophan
-Antidepressants (SSRIs, MAOIs, Tricyclic, 5-HT releasers)
-Cocaine

When it comes to oxytocin, estrogen/estradiol/oestradiol will upregulate. Glucocorticoids are said to enhance oxytocin expression (Don't know whether this means up-regulation or increased oxytocin from 5-HT2A). There are 2 oxytocin receptor antagonists, Barusiban & Atosiban, but SWIM has not found anything conclusive indicating up- or down-regulation.

Broshious, can you try to find that confusing paper about inositol so I can read it?

[Alfa]

Originally Posted by KyleM

These will result in 5-HT2A up-regulation in the cortex:
-Glucocorticoids (cortisol, corticosterone, prednisone, prednisolone, betamethasone, dexamethasone)
-Anything that stimulates glucocorticoid release (piracetam, alcohol, stress, drug/alcohol withdrawl)
-Adrenocorticotropic hormone (ACTH)/cosyntropin (Synthetic ACTH) (Stimulates glucocorticoid release)
-Estrogen/estradiol
-MDL 11,939 & SR 46349B/eplivanserin (Only 2 antagonists that cause up-regulation, but will interfere with serotonin binding while taking them)
-Hypericum (St. John's Wort)
-Electroconvulsive Therapy (ECT)
-Sustained serotonin depletion in cortex

These will result in 5-HT2A down-regulation in cortex:
-5-HT2A agonists (serotonin, hallucinogens), antagonists (except the 2 listed above) and pretty much anything else that binds to the receptor)
-5-HTP/L-Tryptophan
-Antidepressants (SSRIs, MAOIs, Tricyclic, 5-HT releasers)
-Cocaine

When it comes to oxytocin, estrogen/estradiol/oestradiol will upregulate. Glucocorticoids are said to enhance oxytocin expression (Don't know whether this means up-regulation or increased oxytocin from 5-HT2A). There are 2 oxytocin receptor antagonists, Barusiban & Atosiban, but SWIM has not found anything conclusive indicating up- or down-regulation.

This is most interesting.

Could you please expand on MDL 11,939 & SR 46349B? Are there studies that support your statement? In what way will they interfere with serotonin binding?

[altnipper]

Just wondered if anyone knows o anyone who takes sjw the day after rolling, would this work to alleviate comdown depression etc. Swim uses 5htp and works really well, is it safe to use sjw that close to rolling also?

[Fantasian]

Originally Posted by altnipper

Just wondered if anyone knows o anyone who takes sjw the day after rolling, would this work to alleviate comdown depression etc. Swim uses 5htp and works really well, is it safe to use sjw that close to rolling also?

taking sjw within 2 weeks prior to rolling will significantly reduce the roll because of various ssri effects among others. Post roll one would assume it would be at least a little neuroprotective but dosages would vary. Most find 5HTP is enough.

[Alfa]

Originally Posted by altnipper

Just wondered if anyone knows o anyone who takes sjw the day after rolling

Please avoid using abbreviations like this. People will misunderstand you. If you expect someone to take the effort to write up a good reply, then at least take the effort to write normal words.

[altnipper]

sorry but it was written++++ times in the replies above, I thought the rules were that if it's mentioned before then it's ok to abbreviate, I mean people use 5htp all the time and mdma itself is an abbreviation, please don't talk to me like a kid - 'at least take the effort' you are not a headmaster mate, we are all on the same side.

[medievil]

hmm, hypericum, doesnt that look like the best option to you?
what doses are used of the herb, and how long do you need to take it?