Up and down regulation of serotonin receptors

[Fantasian]

There is alot of talk about down regulation of receptors due to MDMA or ecstasy use. Meaning due to the receptors being bombarded by the neurotransmitter serotonin the receptors shrink away from the synapse causing a decreased effect of a release of serotonin in the brain leading to a diminished experience if not enough time is given post use. Also it has been noted that post depression people generally feel uplifted and strengthened commonly using the phrase getting thru it made me stronger! Possibly due to up regulation.

Im interested does anyone know how long it takes for up and down regulation to occur on the serotonin receptors?

Are we talking days? weeks? even years?

Im interested for particularly in relation to how long prior to consuming MDMA it would be advised to stop with 5HTP supplementation and if periods of 5HTP supplementation longer than 2 weeks can cause down regulation.

[KyleM]

From what SWIM has researched into this, the receptors will down-regulate from excessive binding and then what causes them to up-regulate again is not necessarily time itself, but has more to do with lowered supply/diminished levels of serotonin. So basically SWIY has very low serotonin after MDMA use and the brain's receptors will respond to SWIY's homeostatic needs by up-regulating. If SWIY takes large amounts of 5-HTP immedietly after MDMA use and then doesn't use MDMA for a while, the brain may think it has an adequate supply and not up-regulate the receptors so easily if at all. Where as if SWIY waited a couple weeks for them to up-regulate and then took a large amount of 5-HTP and took MDMA before the receptors could respond by down-regulating again, SWIY may have an unusually intense experience again. SWIM thinks that it takes about the same time for the receptors to up-regulate from serotonin depletion as it does to down-regulate from largly elevated levels, so if it takes 2 weeks to up-regulate then it probably takes about that time to down-regulate if SWIY were to take large amounts of 5-HTP. In conclusion to this portion, it may be possible that people with naturally high serotonin levels have much more trouble experiencing MDMA than those with naturally low levels.

SWIM's research has led him to believe that it is the 5-HT2A receptors that are mainly responsible for the wonderful effects of MDMA (mostly in the cortex/prefrontal cortex of the brain). 5-HT2A binding in the cortex is known to stimulate oxytocin (love hormone) release in the hypothalumus. The 5-HT2A receptor is known for being the most difficult receptor to upregulate, as they do not upregulate with 5-HT2A antagonists consistently (only 2 known antagonists up-regulate 5-HT2A receptors, MDL 11,939 and SR 46349B/eplivanserin). Good luck finding either of those 2 chemicals.

What controls 5-HT2A regulation in the cortex may be more related to stress hormones and estrogen levels than other means. It has been proven that when an individual is under stress, cortisol is released from the adrenal cortex, binds to glucocorticoid receptors and in results in up-regulation of 5-HT2A in the cortex and down-regulation of 5-HT1A in the hippocampus, and also up-regulation of oxytocin receptors (estrogen is also known to have similar results, which is why many females are more sensitive to MDMA than men). This may explain why people with PTSD are so sensitive to MDMA's rewarding effects. Stress levels must be significant over long periods of time in order to produce significant up-regulation, so one stressful day won't be enough. There are a couple available stress hormones if SWIY can find them; cortisol (hydrocortisone), corticosterone, dexamethasone (40x potency of cortisol), and a few others.
Note: taking stress hormones can lead to dependency, depression and many other problems, so be careful. This helps explain also why people who are under alot of stress often turn to drugs, the effects are much more rewarding than for those who are not.

Reputation Comments on this post:

	Great info
	Good info.
	Thanks for the info shared in this thread. Good research.
	Good post - cite sources, too please.

[Fantasian]

very interesting information, could you link to a source please

[KyleM]

SWIM is new on this forum, is there not a rule against posting sources here? If not SWIm has plenty, or PM SWIM and SWIM will send as much as you need.

[Broshious]

Originally Posted by KyleM

SWIM is new on this forum, is there not a rule against posting sources here? If not SWIm has plenty, or PM SWIM and SWIM will send as much as you need.

Sources for purchasing anything is what is against the rules not sources of information.

[KyleM]

Here are a few, SWIM has been researching this for over 2 years and will need come more time to relocate every source.

http://www.ajnr.org/cgi/content/full...resourcetype=1

http://jpet.aspetjournals.org/cgi/co...ull/299/3/1066

http://lecerveau.mcgill.ca/flash/cap...health_age.pdf

http://ajp.psychiatryonline.org/cgi/...full/159/3/419

http://www.reuniting.info/science/ox...n_love_ecstasy

http://www.jneurosci.org/cgi/content/full/21/10/3572

http://www.fpg.unc.edu/~images/pdfs/snapshots/sn9-oxytocin.pdf

http://www.psych.ubc.ca/~bglab/articles/Brotto,%20Gorzalka,%20&%20Hanson%20(1998).pdf

Here is another interesting one about the relationship between stress hormones and drug abuse.

http://jpet.aspetjournals.org/cgi/co...full/301/3/785

And this may provide some insight as to why piracetam may enhance MDMA. Remember that corticosterone is the dominent stress hormone in rats; cortisol in humans, so it could be assumed that something that stimulates corticosterone in rats will stimulate cortisol in humans.

http://www.medscape.com/medline/abstract/9749752

[Broshious]

Originally Posted by KyleM

From what SWIM has researched into this, the receptors will down-regulate from excessive binding and then what causes them to up-regulate again is not necessarily time itself, but has more to do with lowered supply/diminished levels of serotonin. So basically SWIY has very low serotonin after MDMA use and the brain's receptors will respond to SWIY's homeostatic needs by up-regulating. If SWIY takes large amounts of 5-HTP immedietly after MDMA use and then doesn't use MDMA for a while, the brain may think it has an adequate supply and not up-regulate the receptors so easily if at all. Where as if SWIY waited a couple weeks for them to up-regulate and then took a large amount of 5-HTP and took MDMA before the receptors could respond by down-regulating again, SWIY may have an unusually intense experience again. SWIM thinks that it takes about the same time for the receptors to up-regulate from serotonin depletion as it does to down-regulate from largly elevated levels, so if it takes 2 weeks to up-regulate then it probably takes about that time to down-regulate if SWIY were to take large amounts of 5-HTP. In conclusion to this portion, it may be possible that people with naturally high serotonin levels have much more trouble experiencing MDMA than those with naturally low levels.

SWIM's research has led him to believe that it is the 5-HT2A receptors that are mainly responsible for the wonderful effects of MDMA (mostly in the cortex/prefrontal cortex of the brain). 5-HT2A binding in the cortex is known to stimulate oxytocin (love hormone) release in the hypothalumus. The 5-HT2A receptor is known for being the most difficult receptor to upregulate, as they do not upregulate with 5-HT2A antagonists consistently (only 2 known antagonists up-regulate 5-HT2A receptors, MDL 11,939 and SR 46349B/eplivanserin). Good luck finding either of those 2 chemicals.

What controls 5-HT2A regulation in the cortex may be more related to stress hormones and estrogen levels than other means. It has been proven that when an individual is under stress, cortisol is released from the adrenal cortex, binds to glucocorticoid receptors and in results in up-regulation of 5-HT2A in the cortex and down-regulation of 5-HT1A in the hippocampus, and also and up-regulation of oxytocin receptors (estrogen is also known to have similar results, which is why many females are more sensitive to MDMA than men). This may explain why people with PTSD are so sensitive to MDMA's rewarding effects. Stress levels must be significant over long periods of time in order to produce significant up-regulation, so one stressful day won't be enough. There are a couple available stress hormones if SWIY can find them; cortisol (hydrocortisone), corticosterone, dexamethasone (40x potency of cortisol), and a few others.
Note: taking stress hormones can lead to dependency, depression and many other problems, so be careful. This helps explain also why people who are under alot of stress often turn to drugs, the effects are much more rewarding than for those who are not.

From "A role for oxytocin and 5-HT(1A) receptors in the prosocial effects of 3,4 methylenedioxymethamphetamine ("ecstasy")":

"Taken together, these results suggest that oxytocin release, stimulated by MDMA through 5-HT(1A) receptors, may play a key role in the prosocial effects of MDMA and underlie some of the reinforcing effects of the drug."

This suggests that 5-HT(1A) and not 2A receptors are what are important.

[KyleM]

Well it is conclusive that MDMA-induced serotonin release will downregulate 5-HT2A receptors and many sources say 5-HT2A stimulation stimulates oxytocin. That doesn't necessarily mean it's the only receptor that will have that effect, but regardless the 5-HT2A receptor appears to be the most affected by MDMA usage. Ironically many antidepressants will increase binding at 5-HT2A and slowly cause the same downregulation caused by MDMA-induced release (only difference being that other antidepressants don't deplete serotonin and therefor may have long term 5-HT2A downregulation and 5-HT1A upregulation rather than temporary), meaning there must be some therapeutic value with 5-HT binding at the 5-HT2A receptor. A way to test this would be to investigate whether individuals who have been taking 5-HTP and other sertonergic antidepressants for extended periods of time have difficulty experiencing MDMA.

[Broshious]

Originally Posted by KyleM

Well it is conclusive that MDMA-induced serotonin release will downregulate 5-HT2A receptors and many sources say 5-HT2A stimulation stimulates oxytocin. That doesn't necessarily mean it's the only receptor that will have that effect, but regardless the 5-HT2A receptor appears to be the most affected by MDMA usage. Ironically many antidepressants will increase binding at 5-HT2A and slowly cause the same downregulation caused by MDMA-induced release (only difference being that other antidepressants don't deplete serotonin and therefor may have long term 5-HT2A downregulation and 5-HT1A upregulation rather than temporary), meaning there must be some therapeutic value with 5-HT binding at the 5-HT2A receptor. A way to test this would be to investigate whether individuals who have been taking 5-HTP and other sertonergic antidepressants for extended periods of time have difficulty experiencing MDMA.

I probably should've posted the whole abstract my bad:

"The drug 3,4 methylenedioxymethamphetamine (MDMA; ecstasy) has a widely documented ability to increase feelings of love and closeness toward others. The present study investigated whether oxytocin, a neuropeptide involved in affiliative behavior, may play a role in this effect. A moderate (5 mg/kg, i.p.) dose of MDMA increased social interaction in male Wistar rats, primarily by increasing the amount of time rats spent lying adjacent to each other. MDMA (5 mg/kg) activated oxytocin-containing neurons in the supraoptic and paraventricular nuclei of the hypothalamus, as shown by Fos immunohistochemistry. MDMA (5 mg/kg i.p.) also increased plasma oxytocin levels and this effect was prevented by pre-treatment with the 5-HT(1A) antagonist N-[2-[4-(2-methyoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt (WAY 100,635; 1 mg/kg i.p.). The oxytocin receptor antagonist tocinoic acid (20 microg, i.c.v.) had no effect on social behavior when given alone but significantly attenuated the facilitation of social interaction produced by MDMA (5 mg/kg). The 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)-tetraline) (8-OH-DPAT, 0.25 mg/kg, i.p.) increased social behavior in a similar way to MDMA and this effect was also significantly attenuated by tocinoic acid. Taken together, these results suggest that oxytocin release, stimulated by MDMA through 5-HT(1A) receptors, may play a key role in the prosocial effects of MDMA and underlie some of the reinforcing effects of the drug."



And here's another that seems to say that 5-HT(2A) is not responsible:

Serotonin (1A) receptor involvement in acute 3,4-methylenedioxymethamphetamine (MDMA) facilitation of social interaction in the rat.


The current study assessed whether various co-administered serotonin (5-HT) receptor antagonists could prevent some of the acute behavioral effects of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") in rats. In the social interaction test, MDMA (5 mg/kg) significantly increased the duration of total social interaction between two conspecifics meeting for the first time. Microanalysis showed that MDMA increased adjacent lying and approach behaviours while reducing anogenital sniffing. MDMA (5 mg/kg) also caused elements of the serotonin syndrome including low body posture and piloerection. In the emergence test, MDMA significantly increased hide time and emergence latency indicating increased anxiety-like behavior. Pretreatment with the 5HT 1A receptor antagonist, WAY 100635 (1 mg/kg), prevented MDMA-induced increases in social interaction and markers of the serotonin syndrome while the 5-HT 1B receptor antagonist GR 55562 (1 mg/kg) and 5-HT 2A receptor antagonist ketanserin (1 mg/kg) were ineffective. The 5-HT 2B/2C receptor antagonist, SB 206553 (2 mg/kg), prevented MDMA-induced prosocial effects but caused pronounced thigmotaxis (hyperactivity at the periphery of the testing chamber). The anxiogenic effect of MDMA on the emergence test was not prevented by pretreatment with any of the 5-HT receptor antagonists tested. These results indicate that prosocial effect of MDMA may involve 5-HT 1A and possibly 5-HT 2B/2C receptors. In contrast, MDMA-induced generalised anxiety, as measured by the emergence test, seems unlikely to involve the 5-HT 1A, 5-HT 1B or 5-HT 2A, 5-HT 2B or 5-HT 2C receptors.


(Edit)And here's a study done on actual humans for a change:

Psychological and physiological effects of MDMA ("Ecstasy") after pretreatment with the 5-HT(2) antagonist ketanserin in healthy humans.

"MDMA (3,4-methylenedioxymethamphetamine, "Ecstasy") mainly releases serotonin and dopamine. In animals, pretreatment with 5-HT(2) antagonists has been shown to attenuate neurochemical and behavioral effects of MDMA. In humans, the role of 5-HT(2) receptors in the action of MDMA has not been studied. We investigated the effect of pretreatment with the 5-HT(2A/C) antagonist ketanserin (50 mg p.o.) on subjective responses to MDMA (1.5 mg/kg p.o.) in 14 healthy volunteers using a double-blind placebo-controlled within-subject design. Subjective effects were rated by psychometric rating scales. Physiological effects measured were blood pressure, heart rate, and body temperature. Adverse effects were assessed during the sessions, and after one and three days. Ketanserin attenuated MDMA-induced perceptual changes, emotional excitation, and acute adverse responses but had little effect on MDMA-induced positive mood, well-being, extroversion, and short-term sequelae. Body temperature was lower under MDMA plus ketanserin compared to MDMA alone. The results suggest a contributing role for 5-HT(2) receptors in the action of MDMA in humans."

As all of that is basically gibberish to me I'd love to hear your thoughts.

[Fantasian]

Originally Posted by KyleM

There are a couple available stress hormones if SWIY can find them; cortisol (hydrocortisone), corticosterone, dexamethasone (40x potency of cortisol), and a few others.
Note: taking stress hormones can lead to dependency, depression and many other problems, so be careful. This helps explain also why people who are under alot of stress often turn to drugs, the effects are much more rewarding than for those who are not.

From SWIM's knowledge would it be advantagous if SWIF had access to these to try the process. WHat dosages was SWIM use of Cortisol? What side effects would occur etc? What dangers are there?

Edit:
Also i recently read this information
"B. Up and down regulation of serotonin

MDMA causes post-synaptic serotonin 5-HT2 receptors in the brain to up-regulate or down-regulate according to the dose. Up and down-regulation are normal adaptive responses to increased transmission through the serotonin receptors, as a result of MDMA-stimulated serotonin release.

§ Small doses of MDMA (equivalent to a human dose of <1mg/kg) cause up-regulation. This appears to stimulate the development of new serotonin neurons."

Does this mean small dosages of MDMA cause upregulation therefore if used over time would cause an anti tolerance effect?

[medievil]

Does this mean small dosages of MDMA cause upregulation therefore if used over time would cause an anti tolerance effect?

yes, if thos receptors actually upgrade

[Fantasian]

Originally Posted by medievil

yes, if thos receptors actually upgrade

yeah i realised that, sorry i should have been more specific, is there much evidence that small doses of MDMA cause upregulation anywhere?

[KyleM]

Well MDMA also stimulates cortisol release, plus the decreased serotonin leads to up-regulation and decreased sensitivity. But sensitivity means nothing without serotonin, so basically you could be hypersensitive, but have so little serotonin that there is not enough binding to produce significant firing of the cell. The opposite being so much serotonin and so few receptors, that SWIY could have a massive release of serotonin from MDMA and still there is not enough receptors available to bind to in order to cause euphoria. Ideally SWIY would produce 5-HT2A hypersensitivity by maintaining low 5-HT and then taking massive loads of 5-HTP over a short period of time; and if SWIY takes a decent dose of MDMA during this window of opportunity (before 5-HT2A downregulate) then there are levels of rolling never thought imaginable.

[medievil]

MDMA does not deplete serotonin, thats an old myth, neurotxic doses only deplete max 10 or 20%
the real issue with MDMA is that serotonin receptors downregulate, every drug that has a tolerance has a reverse tolerance (needing less and less) (like cocaine, amphetamine, weed, etc...)
so i definatly beleive that low doses slowly reverse tolerance

[KyleM]

I have also read somewhere that MDMA depletes only a small percentage of your brain's 5-HT; it appears to be depleted in the cortex, but mostly the prefrontal cortex. So that 10% or so SWIY loses just may be most of the 5-HT in SWIY's prefrontal cortex that will allow him/her to roll. So 5-HT is depleted where it matters to MDMA. If you study the infamous NIDA postcards (which we all know only shows 5-HT loss, not damage) SWIY can clearly see most 5-HT loss is in the frontal cortex area and also somewhat throughout the rest of the cortex. Check out this powerpoint from MAPS too as well, it shows the also infamous "holes in the brain" photos (SWIY may have to reference a photo that labels the brain regions if SWIY does not already know them). As much a failure these photos are for the anti-drug warriors' cause, they do help the rest understand more about MDMA's functioning.

http://www.ecstasyabuse.net/images/h...stasybrain.gif

www.maps.org/avarchive/ms2005/rick-ms2005.ppt



Basically MDMA appears to target specific areas of the brain, not deplete the total supply of 5-HT the brain. With the tolerance issue, it depends on why you are tolerant in the first place, as you can see in SWIM's theory in his first post of this forum. In regards to other drugs, SWIM has also read somewhere that tolerance to most drugs is caused by down-regulation of the receptors that they act on. There are some drugs that bind to receptors and cause all the effects themselves (marijuana), and others that stimulate the release of a natural neurotransmitter, which in turn binds to a receptor and causes the desired effects (MDMA, methamphetamine). Basically the drug SWIY is feeling is serotonin/dopamine, etc., not MDMA entirely itself, so one may never be truly tolerant to MDMA, but rather his/her own serotonin or not have enough serotonin in the cortex to work with.

[Broshious]

Yes I've read the same thing. I even thought that MDMA(it may have been another drug) RAISED 5-HT in other parts of the brain but lowered it in some as you said. My question is how long that 10% loss takes to be replaced. It would seem like you're synthesizing 5-HT constantly so it shouldn't take too terribly long.

[KyleM]

MDMA itself will not raise supply of 5-HT, but it may work like other antidepressants which increase 5-HT1A density in hippocampus and decrease 5-HT2A in the cortex. It may take longer to replenish 5-HT after each MDMA session due to tryptophan hydroxylase inhibition over time. The first few times SWIY uses the drug, the 5-HT may be replenished much quicker than the latter times. This is where 5-HTP really comes into play because it is one step ahead of tryptophan hydroxylase in 5-HT synthesis.

[Fantasian]

Originally Posted by KyleM

MDMA itself will not raise supply of 5-HT, but it may work like other antidepressants which increase 5-HT1A density in hippocampus and decrease 5-HT2A in the cortex. It may take longer to replenish 5-HT after each MDMA session due to tryptophan hydroxylase inhibition over time. The first few times SWIY uses the drug, the 5-HT may be replenished much quicker than the latter times. This is where 5-HTP really comes into play because it is one step ahead of tryptophan hydroxylase in 5-HT synthesis.

So would small doses of MDMA cause new receptors to be made or cause some kind of upregulation? Or is there any other way except for using stress hormones like cortisol to cause upregulation?

[Broshious]

Originally Posted by Fantasian

So would small doses of MDMA cause new receptors to be made or cause some kind of upregulation? Or is there any other way except for using stress hormones like cortisol to cause upregulation?

I read about Inositol possibly causing an increased sensitivity of 5-HT2A receptors. Not sure what the difference is between increased sensitivity and up-regulation.

[KyleM]

It would cause upregulation of existing receptors. The easiest way to do this take MDMA weekly in small/normal doses. This will maintain low 5-HT and lower tryptophan hydroxylase; basically the idea is to not allow the 5-HT to resupply and lower tolerance. Once this is achieved, SWIY would require 5-HTP to rapidly build 5-HT levels (SWIM had success with 500mg/day in divided doses for 7 days). SWIY would not want to maintain these high levels very long because the receptors will significantly downregulate after a couple weeks, so SWIY would need MDMA as soon as the 5-HT is rapidly built.

The stress hormones should literally be a last resort, mainly for those who have a natural tolerance to 5-HT due to high levels or built high tolerance from long-term antidepressant/5-HTP use. In my previous post I explained how MDMA is much more rewarding for those who had a lot of stress/depression in their life before they took MDMA their first time. The good reputation of MDMA's abilities has reached far beyond that group of people now, so there are many people who grew up without ever being seriously depressed or nearly as stressed as others, or just have naturally high serotonin trying this drug now and it's not as good for them. Stress hormones here would emulate the stress others, who had good experiences from MDMA, had in their lives in order to make their brains more sensitive to it. Does SWIM recomend SWIY doing this? No, but it really depends on how badly someone wants to get high.

For those who have had good experiences, try 5-HTP before going to anything drastic like stress hormones.

[KyleM]

Originally Posted by Broshious

I read about Inositol possibly causing an increased sensitivity of 5-HT2A receptors. Not sure what the difference is between increased sensitivity and up-regulation.

up-regulation = increased sensitivity and vice-versa

[medievil]

The easiest way to do this take MDMA weekly in small/normal doses.

i dont think that will work because you are going to downregulate those receptors every week, unless you take that dose that upregulates receptors

i also support the standpount of thedea.org th

[medievil]

i also support the standpount of thedea.org that serotonin depletion is never an issue, and that your brain easily makes more serotonin then normally when you take mdma weekly

i beleive the best bet is inducing the reverse tolerance phenomen that occurs with like every other drug out there

[medievil]

its also interesting to note that the biggest effect of tolerance is the day after, so if a low dose causes a reverse tolerance, your brain would be most sensitive to serotonin the day after

if that is true then this anecdotal report makes sense



Lately i've noticed my rolls aren't as good as they used to be... thought i might be "lossing my magic" but i found out the more often i do it, like take one one day then actually go to the clubs and roll the next day, i get a roll going on like i used to. But even at three the first day doesn't do ne thing. How safe is it to take one and then my two the next day? and does ne one else experiance this.

[KyleM]

Originally Posted by medievil

i dont think that will work because you are going to downregulate those receptors every week, unless you take that dose that upregulates receptors

The idea is that when SWIY stops taking his/her small weekly doses, the resulting up-regulation, from maintaining very low supply of serotonin, will be greater than the initial downregulation.

This is basically part 1 of a 2-part way to return the magic. Part 1 being to upregulate as much 5-HT2A receptors as possible and after that is completed, part 2 is to replenish the serotonin as quickly as possible. It must be done in that order. This may take time, money, and many dissapointing MDMA sessions in the meantime, but the rewards just may well be worth all of it.

Originally Posted by medievil

i also support the standpount of thedea.org that serotonin depletion is never an issue, and that your brain easily makes more serotonin then normally when you take mdma weekly

i beleive the best bet is inducing the reverse tolerance phenomen that occurs with like every other drug out there

Serotonin depletion is an issue, as I stated previously. After the first couple sessions with MDMA, the brain will replenish much quicker than later ones. There is evidence of reduced tryptophan hydroxylase activity after many doses of MDMA.