Psychedelics and serotonin

[Malafight82]

I'm relatively new to using various substances and wanted to get some insight on how it works from chemical point of view. I know that LSD binds to serotonin in simillar manner as MDMA does, but I've never heard people having a comedown after LSD like they do after extasy. Also, Ive never heard about anything simillar to 3 months rule in case of psychedelics unlike taking a break with MDMA. My question comes down to, should I take into consideration that I've rolled on M in the near past when wanting to take LSD and vice versa?

 

[TripSitterNZ]

Psychedelics don't release serotonin like mdma does. Psychedelics don't do physical damage to the brain and will never have come downs like mdma. LSD tolerance lasts about a week maybe two weeks depending on the person. But you can take LSD weekly fine and be okay.

 

[t_wrex]

MDMA is significantly more taxing on your serotonin system because it causes excessive forced release of serotonin (and dopamine and norepinephrine). LSD doesn't release serotonin, but it binds to serotonin receptors, preventing the existing serotonin from being taken back up and causing it to slowly accumulate in the brain. Both drugs cause an eventual increase in serotonin levels, but MDMA to a much larger degree, hence why it has a larger comedown/hangover, and also why there is the "3 month rule" for it but not for LSD, AND also why it becomes neurotoxic at higher/longer term doses but LSD does not.

In my experience, after I have taken excessively large doses of LSD over the course of 2 or 3 days, I have absolutely felt a comedown, but it still didn't compare to that of MDMA.

Anecdotal reports suggest that there is minimal cross-tolerance between the two drugs, since they work in different ways, but then again there are also reports of people claiming that there is cross tolerance. I'm not sure pharmacologically whether it's true or not.

 

[Xorkoth]

MDMA is a serotonin releaser, which means it causes your brain to deplete its stores of serotonin in a flood that makes you feel great but then leaves you feeling bad. Whereas LSD and other classical psychedelics are serotonin agonists, which means that the molecule imitates serotonin in your receptors. It doesn't release actual serotonin, which is why the effects are so much different from MDMA, and also why you do not experience a come-down/crash. In fact, most users report a positive afterglow effect after LSD/psychedelics.

 

[Hodor]

LSD doesn't release serotonin, but it binds to serotonin receptors, preventing the existing serotonin from being taken back up and causing it to slowly accumulate in the brain.

You're mixing up a serotonin reuptake inhibitor (which binds to the serotonin transporter, causing serotonin to accumulate in the synapse) and a serotonin agonist (which directly activates the receptor).

LSD is one such serotonin agonist, i.e. binds to and activates serotonin receptors, and it is much better at this than serotonin itself to boot. Hence why people can get high off of a few micrograms of this substance. It is also selective for certain subtypes of serotonin receptors. See, your body has a comparatively small numbers of neurotransmitters, but it has to control a vast range of processes. This is done by having multiple subtypes of serotonin receptor, that, when activated, pass on different signals. Since specific parts of your brain/body will preferentially produce specific subtypes, this allows you to use the same type of signalling molecule to do different things in different body parts.

So when enough serotonin receptors of the "5HT2a"-subtype are activated, you start tripping balls. Activating 5HT3 gives you a violent urge to throw up. Activating 5HT2c causes anxiety and a loss of appetite, and so on and so forth. While all serotonin receptors naturally can be activated by serotonin, certain exogenous chemicals can bind to and activate one or more subtypes selectively, with little to no effects on others. Psychedelics, for example, are good at activating 5HT2a; and LSD is *especially* good at it, because the molecule can actually get stuck inside the receptor, keeping it activated until the body recognizes it as defective and recycles it.

As for MDMA, its primary effect is to get neurons to release serotonin into the synapses, resulting in the empathogenic effect. However, MDMA (and even more so its metabolite, MDA) also act as agonists at the 5HT2a receptor, eliciting additional psychedelic effects.
Our nervous systems, however, have evolved to be self-regulating. If receptors are continously activated, they are downregulated, which is why psychedelic tolerance builds almost instantly. However, this generally doesn't result in a crash, because psychedelics are mostly only affecting a specific type of serotonin receptor. With a serotonin releasing agent like MDMA, on the other hand, you're not just generally downregulating all your serotonin receptors, but you're actually releasing so much serotonin that much of it has to be destroyed instead of retrieved for later re-use. This means that until your stores of serotonin have been replenished, you're going to be seriously serotonin-deprived, and consequently feeling like shit.

 

[SunriseChampion]

With a serotonin releasing agent like MDMA, on the other hand, you're not just generally downregulating all your serotonin receptors, but you're actually releasing so much serotonin that much of it has to be destroyed instead of retrieved for later re-use. This means that until your stores of serotonin have been replenished, you're going to be seriously serotonin-deprived, and consequently feeling like shit.

I have a question in regards to this. Why is it that some people only experience positive or benign after-effects from MDMA use?
For example, I have never experienced anything but an afterglow after using MDMA, even in the handful of cases where I used what I would consider too much in one go; ie, ~120mg + ~120mg at T: +3h.

 

[TripSitterNZ]

I have a question in regards to this. Why is it that some people only experience positive or benign after-effects from MDMA use?
For example, I have never experienced anything but an afterglow after using MDMA, even in the handful of cases where I used what I would consider too much in one go; ie, ~120mg + ~120mg at T: +3h.

because they have used it correctly and not abused it and took a normal dose of very pure mdma. But i am one of the people who abused high dose mdma on the weekly and the comedowns would last two weeks to a month if i took half a gram in a night.

 

[t_wrex]

You're mixing up a serotonin reuptake inhibitor (which binds to the serotonin transporter, causing serotonin to accumulate in the synapse) and a serotonin agonist (which directly activates the receptor).

LSD is one such serotonin agonist, i.e. binds to and activates serotonin receptors, and it is much better at this than serotonin itself to boot. Hence why people can get high off of a few micrograms of this substance. It is also selective for certain subtypes of serotonin receptors. See, your body has a comparatively small numbers of neurotransmitters, but it has to control a vast range of processes. This is done by having multiple subtypes of serotonin receptor, that, when activated, pass on different signals. Since specific parts of your brain/body will preferentially produce specific subtypes, this allows you to use the same type of signalling molecule to do different things in different body parts.

So when enough serotonin receptors of the "5HT2a"-subtype are activated, you start tripping balls. Activating 5HT3 gives you a violent urge to throw up. Activating 5HT2c causes anxiety and a loss of appetite, and so on and so forth. While all serotonin receptors naturally can be activated by serotonin, certain exogenous chemicals can bind to and activate one or more subtypes selectively, with little to no effects on others. Psychedelics, for example, are good at activating 5HT2a; and LSD is *especially* good at it, because the molecule can actually get stuck inside the receptor, keeping it activated until the body recognizes it as defective and recycles it.

As for MDMA, its primary effect is to get neurons to release serotonin into the synapses, resulting in the empathogenic effect. However, MDMA (and even more so its metabolite, MDA) also act as agonists at the 5HT2a receptor, eliciting additional psychedelic effects.
Our nervous systems, however, have evolved to be self-regulating. If receptors are continously activated, they are downregulated, which is why psychedelic tolerance builds almost instantly. However, this generally doesn't result in a crash, because psychedelics are mostly only affecting a specific type of serotonin receptor. With a serotonin releasing agent like MDMA, on the other hand, you're not just generally downregulating all your serotonin receptors, but you're actually releasing so much serotonin that much of it has to be destroyed instead of retrieved for later re-use. This means that until your stores of serotonin have been replenished, you're going to be seriously serotonin-deprived, and consequently feeling like shit.

Thanks. I always like getting schooled, and I'd be the first to admit that neurology/pharmacology isn't a particular forte of mine. As well, you seem to have many deeply detailed and accurate posts, kudos.

 

[t_wrex]

I have a question in regards to this. Why is it that some people only experience positive or benign after-effects from MDMA use?
For example, I have never experienced anything but an afterglow after using MDMA, even in the handful of cases where I used what I would consider too much in one go; ie, ~120mg + ~120mg at T: +3h.

Curious, how many times in your life would you say you've done MDMA? I've noticed that that first 7-8 times I had no comedown, but for the last few times I've done it I absolutely have noticed one.

 

[SunriseChampion]

Curious, how many times in your life would you say you've done MDMA? I've noticed that that first 7-8 times I had no comedown, but for the last few times I've done it I absolutely have noticed one.

That's a tough question to answer, mostly because the vast majority of my use was in 2004-2007. In fact, I've only done MDMA twice since 2010, and once was a very small amount (~75mg).

When I first used MDMA, it was about six times in two months, two episodes of which included redosing the same amount as initial at around T +2-3h. One of these episodes was a pretty unsafe ~150mg + ~150mg. I remember melting into the grass at sunrise with my eyes pretty far back in my dome. It was nice.....and the days after were nice as well. No crash whatsoever.

All of these episodes ended with a beautiful afterglow lasting anywhere from a day or two to almost two weeks. The one negative effect I noticed after a couple of uses was a weird craving for food for maybe a week after use. The only similar thing to this I've ever experienced was food cravings for three weeks after quitting smoking cigarettes last year.

The initial six or so uses of MDMA resulted in significantly powerful afterglows, likely owing to the then novelty of the experience. The subsequent three years of use resulted in decreased afterglow in terms of profundity, but still resulted in an augmented feeling of wellbeing for days to weeks after use.

The use between 2007 and 2010 is a bit muddled because it was usually combined with LSD or copious amounts of alcohol. The candyflipping had a beneficial outcome, post-high, whereas the alcohol coupled use had benign or neutral aftereffects.....a sort of dulled after-experience, as one might expect from alcohol having been involved.

Other than the period of initial use in 2004, none of my dosing was closer together than a couple of months, and in most cases was probably 4-6 months apart.

If I had to strain to remember in order to estimate the total number of times I've used MDMA, I would have to say it'd be in the 20-25 range, with an average amount used of ~120-150mg.


In your case, given that lately your after-effects have been trending towards the negative, is your dosing similar? Source the same or different?