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Serotonergic drugs and receptor down-regulation

Seattle_Stranger

Seattle_Stranger

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A fairly basic question for someone with advanced knowledge:

Is it safe to assume that if a drug is serotonergic, meaning it acts on the serotonin system either via releasing, re-uptake inhibition, or agonism, will some level of down-regulation occur?

More specifically, I have eaten mushrooms (a serotonin agonist) several times in the past few months (give or take 5 times, less than 2g each time), with 2 times being within the last week. I would like to take MDMA soon (releaser and SRI). I understand the two drugs are safe to take together or in close vicinity, however, having taken mushrooms twice in the last week, and then MDMA soon after, not to mention a handful of additional mushroom trips not long ago, should I worry about receptor down-regulation? Or does down-regulation require a lot of abuse to occur?

So my question is simply whether anyone has scientific proof that psilocybin results in significant receptor down-regulation or not, and if so, how much is too much?

I don't abuse anything else besides weed, and kratom every other day if that counts as abuse. Last time I rolled was several months ago.

I'm looking for scientific answers not so much personal experiences. Just because you ate shrooms for a week straight and "we're just fine, man" isn't proof that you didn't mess up your brain. :)

Thank you!
 
I'm gonna move this to the advanced drug discussion forum. I'm pretty sure it belongs there, and sorry to the mods if it doesn't.

Homeless --> ADD
 
Which receptors are you talking about?

The way the downregulation process works is like this. A neuron gets a signal and releases some neurotransmitter. Then the presence of a neurotransmitter (lets say 5HT for the sake of his discussion) in the synapse triggers receptors on other cells in the vicinity. If the signalling is prolonged or very frequent, the cells begin to adjust by destroying receptors or moving them inside. (Protiens like reuptake transporters don't do this to the best of my knowledge.)

Now, the serotonin system is not governed by one type of receptor. There are about 7 major types of receptors for serotonin and well over a dozen subtypes put together. Psilocybin works its magic by agonism at the 5-HT2A and 5-HT2C receptors, which downregulate very rapidly. MDMA, on the other hand, has some affinity at the 2 receptors psilocybin hits, but also binds to a different set of serotonin reeptors than psilocin - and also acts as a general releasing agent, increasing the level of serotonin body-wide. (All serotonin releasers are also reuptake inhibitors.)

In short - yes, there is cross tolerance between psilocin and MDMA. It should dissipate as fast as tolerance to psilocin dissipates - maybe a week or so at max. There will be less if you take the psilocin before the MDMA. In fact, they are perfectly safe to take together in reasonable dosages.
 
Is it safe to assume that if a drug is serotonergic, meaning it acts on the serotonin system either via releasing, re-uptake inhibition, or agonism, will some level of down-regulation occur?
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not all drugs cause down-regulation. St. John's Wort is used to upregulate 5HT receptors, some people even use it to return the magic of MDMA.
 
Thank you for the answers!! Very informative. :)

I have 'experimenting' with mushrooms quite a bit lately, using a very low dose (~1g) every time, on average every 2 weeks for the past 2 or so months. I also plan to use MDMA in the next ~2 weeks, just once. I'm just worried that all this serotonin action will result in down-regulation. My question is basically do I have anything to worry about from using low doses of shrooms so often? In a slightly un-related question, does frequent use of shrooms have any consequence on the adrenal system?

About the SJW, that's really interesting. I'm going to read up more about that!

Thank you!
 
Always take a good source of Magnesium when taking Amphetamines (Magnesium Glycinate) to help regulate your Calcium channels and slow tolerance. Also, I have found that a Piracetam/Choline/Acetyl L-Carnitine mix works great for potentiation along with some R-Alpha Lipoic Acid to protect against oxidative stress. As with everything, make sure you are not going crazy on your doses, spacing out your trips/rolls (1-2 weeks), and getting a good amount of sleep and exercise.
 
why are you worried about downregulation? they're just going to upregulate back to normal in time.. which is why psychedelic tolerance doesn't last that long, like a week or two at most. It isn't like you're causing "damage" or anything. (at least not with the mushrooms)
 
golden1 said:
why are you worried about downregulation? they're just going to upregulate back to normal in time.. which is why psychedelic tolerance doesn't last that long, like a week or two at most. It isn't like you're causing "damage" or anything. (at least not with the mushrooms)
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OP is probably wondering about tolerance in this instance, or maybe the overall health of his 5HT receptors.
 
freehugs said:
OP is probably wondering about tolerance in this instance, or maybe the overall health of his 5HT receptors.
Click to expand...

This, mostly the latter. Health is key here. I don't want my receptors down-regulating resulting in all sorts of depression, anxiety and other issues. :(

That, and I am always interested in simply staying informed! :)
 
golden1 said:
why are you worried about downregulation? they're just going to upregulate back to normal in time.. which is why psychedelic tolerance doesn't last that long, like a week or two at most. It isn't like you're causing "damage" or anything. (at least not with the mushrooms)
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^ This.

Don't do mushrooms/MDMA all the time, keep your doses modest, and you shouldn't have to worry about "downregulation". MDMA is going to be the "worst offender" for this (being a broad releasing agent) but after a day or 2 of high-protien meals and good excercise you should be feeling fine.

Generally people who blame "receptor downregulation" for depression/anxiety have participated in binge use of one or more drugs, recklessly high doses, or in bad situations.
 
I just want to restate the amazing results I have been getting from Piracetam! When taken with choline and Acetl L-Carnitine pre and post rolls, MDMA's effects are potentiated and it's negative side effects disappear completely! My head is clear and cognition is increased! Also, I have not tried it yet, but apparently it goes very well with psilocybin. That along with Magnesium to prevent tolerance, and MDMA is no longer a hindrance the days following it's use.
 
I keep hearing so much about piracetam. I think I'm going to have to take the dive and grab some.

I personally dislike MDMA simply because it's so bad for you all around. I love the effects of it (obviously), but I normally avoid it and go for something like kratom or mushrooms instead. I haven't taken MDMA in a few months, and I didn't roll very much when I did, so MDMA over-usage is not and never will be an issue.

Having said that, I use kratom almost every other day, and I wonder about it's serotonergic properties. Something tells me there's more than just opioid activity because kratom delivers a very empathetic high not unlike a low dose of MDMA. In high enough doses I find it even gets slightly psychedelic with minor CEV's and mushroom-like thought patterns, so I have a high suspicion that there's something 5-HT going on in there, even if very little. Does anyone have real data to share on this subject?

In addition, like I said I have been playing with mushrooms a bit lately, a couple times a month. I would like to continue messing with them, but just don't want to overdo it. I guess the bottom line of my questions is whether or not doing mushrooms every couple of weeks will result in bad things. The kratom thing is a bonus! :)

Thanks again for all the answers. Loving all the info!!
 
Would taking St. Johns Wort while on a psychedelic cause any sort of problems? I take a daily regiment of it, and the last two times I have tripped (LSD and aMT) I have decided against taking it while on the chemical because I don't know how it will effect me.
 
freehugs said:
Would taking St. Johns Wort while on a psychedelic cause any sort of problems? I take a daily regiment of it, and the last two times I have tripped (LSD and aMT) I have decided against taking it while on the chemical because I don't know how it will effect me.
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it mightt.
because its a mild MAO inhibitor. i think as long as you take em like 6 hours apart you should be fine.
 
Fyasko. said:
it mightt.
because its a mild MAO inhibitor. i think as long as you take em like 6 hours apart you should be fine.
Click to expand...
Ok thanks for the reply. I took it this morning, about8 hours ago, so lets see if my trip is any stronger tonight.
 
Ok I have a question. I was researching aMT, and found that it releases as much serotonin as mdma, but over a longer period of time.

So would this mean that the same amount of downregulation occurs because they both release the same amount? Or does mdma cause quicker downregulation because it releases it all at once?
 
freehugs said:
Would taking St. Johns Wort while on a psychedelic cause any sort of problems? I take a daily regiment of it, and the last two times I have tripped (LSD and aMT) I have decided against taking it while on the chemical because I don't know how it will effect me.
Click to expand...

I took two caps of St. Johns Wort with 2C-D at the end of a methylone trip without problem, but I don't say it's safe!
 
Fyasko. said:
it mightt.
because its a mild MAO inhibitor. i think as long as you take em like 6 hours apart you should be fine.
Click to expand...

If it's a MAOI then it will potentiate the effects of psychedelics since MAO breaks down dopamine,serotonin etc, if I recall correctly. I also have experienced this from my ayahuasca + acid experience, the blotters kicked in almost immediately(less then 5 minutes, no placebo since I felt immediate altered body/temperature sensation) merely cause I had taken lots of MAOI
 
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