Technical: Could SSRIs reduce tolerance? (TheDEA look at this?)

Whilst chronic SSRI administration increases tolerance to MDMA (due to receptor downregulation), is it possible to use SSRIs to decrease tolerance?

Many of the effects of MDMA are due to its long half-life. Whilst the subject high lasts 3-5 hours, MDMA's long half-life (~9 hours) ensures that it continues to exert an effect long after the party has ended.

If AUC (Area Under the Curve) determines effect (i.e. neglecting receptor adaptation) then it can be shown that a majority of MDMA's effect actually occurs after the high ends.

Assume exponential clearance, with a half life of 9 hours (i.e. amount = exp(-k*x), where k = ln(2)/9.

A quick integral shows the total area under the curve from x=0 out to x=infinity ~ 12.984

The integral from x=6 out to x=infinity = 8.179

The ratio gives 0.629 implying 63% of MDMA's total effect occurs after the high. Neurotoxicity implications aside, as well as downregulation (which would lower the effect of the later tail), would this imply that the administration of a SSRI with a very very short half life could, in theory, reduce tolerance? Effexor (Venlafaxine) springs to mind (though a SNRI, it has SSRI properties). Failing that, fluvoxamine has a 16 hour half life.

Any comments?

Also: if anyone wants a link to a MAPLE evaluation or a handwritten version please ask, and I'll write out the maths.

While I can't fault your maths, I think you have to factor in too that there is a "cut off point" where the MDMA reaches below a threshold level and no longer has any effect. I'm not sure what that is, but I think its about 25~30mg.
Thus if you would now have to factor in the initial dose (say 75 or to make it easy mathswise 100mg) than then discount the area under the curve after a certain number of time (in the case of a 100mg initial dose and 25mg being the threshold, it'd be 2 half lives). Thus that would decrease the "after effect" MDMA has on the body which seems to be more inline with how it feels (ie no effects felt after 18 hours after dosing).
That would detract slightly from your argument but not a lot. I'd do the maths myself but windows calculator won't let me do exponentials of negative numbers and I can't be bothered to go find my calculator (if I even have it still).

You do make a good point and perhaps someone with slightly better neurochemical knowledge than me could shed some light on it

VelocideX said:

Whilst chronic SSRI administration increases tolerance to MDMA (due to receptor downregulation).

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I believe that MDMA becomes in effective at first due to the fact that the 5HT reuptake receptors are blocked (effectively preventing MDMA from taking over the 5HT reuptake receptors).

There is more to it, of course, as you have suggested since once SSRI treatment is discontinued MDMA is still not effective until upregulation occurs. I am probably missing something somewhere, but I don't see how SSRIs could decrease tolerance for MDMA.

Your calculus is correct, but you'd better make it very clear to everyone what you mean by "effect". Many of us here understand this term to mean "a noticeable or measurable change in behavior or perception." Whereas you're using it in the more scientific sense, to mean the sum of all results the drug produces, from the start of intoxication to finish, including those that aren't subjectively noticeable.

I thought of a good analogy that might illustrate your point, which I think is sound, better. Suppose you get a small amount of some corrosive chemical on your skin. If you don't do anything about it, it'll continue to eat into your skin and destroy it until there's too little of the chemical left to have a reaction, or until your skin secretes something that puts a stop to it. This could be a long time, and the chemical could do a lot of damage.

But what if, instead, after touching the chemical, you got to a hospital as fast as you could. The doctor treats your skin with something that ends the chemical reaction and prevents further damage. Even if more than half of the original amount of the chemical has already reacted with your skin, the total damage wouldn't be nearly as high as if you left it untreated and let the reaction run until finished!

The one thing I don't understand is why would the half life of the SSRI be an issue? I'm working on the assumption that the MDMA user is a moderate one (once a month on average), the SSRI had a half life of one day, and a single dose of the SSRI is taken at the end of a roll. There would be less than 10^-9 of the original dose left after 30 days. Virtually nil.

Here's the big question on everybody's mind, though:
If a SSRI dose extinguishes, if you will, MDMA, it obviously eliminates any afterglow. But by doing this, does it bring the user right back to his/her normal state, or would it just skip over the afterglow and bring on Suicide Tuesday in short order? What would be its, colloquially speaking, "effect"?

I find that postloading with an SSRI just cuts me back to my normal (if not slightly tired) state. The "anti-depressant" effect helps to counter act the possible "Terruble Tuesdays" but like you say, also blocks any afterglow.

Perhaps I should have clarified some of my points. I'm basing this idea on the premise that MDMA has negative influences that are NOT related to downregulation (e.g. oxidative stress, SERT damage, etc).

In regards to the threshold, whilst MDMA does have a threshold of ~30mg or so, it still continues to exert an effect below that point. Whilst it may not be perceptible, it nevertheless induces oxidative stress and serotonin release etc, and so I don't think it could be discounted.

The reason for a short half-life SSRI is that a long-half life SSRI will INCREASE tolerance. If you take prozac, some 50% of the active metabolite will still be present by the next weekend, thus blocking MDMA's effect (its perceived as an increase in tolerance). With shorter half lives, the drug will have cleared the system but will have induced significant downregulation due to its presence... while the drug may not be there, residual downregulation effects will be. Thus you want the drug to clear your system quite quickly so it has a minimal chance to induce downregulation...

So, if I understand you correctly, you are suggesting that short term use of short half-life SSRIs could possibly decrease tolerance because the drug would not have produced a downregulation in the HT5 receptors, and would not be present to physically block the MDMA from intercepting the receptors.

It's an interesting concept, and seems like something that would merit experimentation (albeit, subjective experimentation).

if you assume 30mg as a threshold dose, and an initial 100mg dose (im making huge assumptions here about how much gets through the first pass etc), then you solve the equation to find that 30% of the initial dose remains at 15.6 hours.

do the integrals from 0 to 15.6 and 6 to 15.6 and take the ratio and its about 0.47, which is still almost half the effect.

yeah thats essentially what i'm saying....
its just something ive noticed. i postload with effexor, and find that even 4 days later i dont have a tolerance (or not one i can perceive anyway)

the maths here is very reductive and only supposed to be illustrative, but it supports my belief that a significant fraction of the negative effects of MDMA are caused after the high stops. This is supported by that bit of research (cant be bothered looking) about SSRIs attenuating neurotoxicity (note: NOT preventing, merely reducing) when taken 3-6 hours later etc.

Velocide, I can't in good conscience keep from mentioning the fact that SSRIs and amphetamine-class drugs should NEVER be taken simultaneously. I assume you already are well aware of the dangers of mixing these.

Does this mean you are lucky enough to get a continuous supply of speed-free pills, as evidenced by a test kit? I sure hope so for your sake! I would hop on the net and order me some generic effexor from one of those dodgy pharmeceutical sites right away, if only for the fact that where I am (Taiwan), people prefer their pills on the speedy side. I don't think I've ever had a pill here that wasn't decidedly speedy.

Or is it possible that SSRIs work in different ways, and not all of them are neurotoxic when combined with a bit of speed? I was always led to assume this was true of all SSRIs, regardless of their chemical composition. Perhaps you could enlighten me on this one.

MyDoorsAreOpen, Velocide is talking about taking an SSRI 4~6 hours after taking MDMA, which would result in the MDMA high being completely stopped in its tracks. The reason they shouldn't be taken at the same time is no high from the MDMA will be felt due to the SSRI's seratonin affecting properties. No real harm will come from doing that (less than taking just MDMA really). Are you thinking of MAOIs? They should never be mixed with MDMA.

No, I'm talking about the harmful interaction of speed, often present in pills alongside MDMA, and SSRIs.

^^^ What are the dangers you talk about? I was under the impression that whilst it is not a good idea to mix amphetamines and ssri's, it is not considered particularly dangerous.

Very interesting theory VelocideX

But I have a question; what causes downregulation? Is it a long exposure to a somewhat high level of neurotransmitters, or is it especially the 'peak' that causes this downregulation? I'd say that in the latter case the effect of the SSRIpostload would be far less then in the first case?

MyDoorsAreOpen said:

No, I'm talking about the harmful interaction of speed, often present in pills alongside MDMA, and SSRIs.

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Speed mainly effects dopamine, while SSRIs by their name/nature effect Seratonin. There would be some, but little, interaction between them I'd imagine.

To quote the "Antidepressants and Recreational Drugs FAQ" :

Amphetamines (Methamphetamine, Adderall, Dexedrine), Ritalin (methylphenidate), Cocaine: The effects of these drugs on someone taking an SSRI will not be significantly different. With the amphetamines, especially methamphetamine, there will be less “loveyness” but overall, the high will remain unchanged. This is a safe combination overall, and you should still be able to get high from these stimulants while on an SSRI.

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If you want to discuss it more I'll split this thread (if I can work out how to do it properly) so that it doesn't go too far off topic.

VelocideX said:

yeah thats essentially what i'm saying....
its just something ive noticed. i postload with effexor, and find that even 4 days later i dont have a tolerance (or not one i can perceive anyway)

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Here is a wild thought. To the best of my knowledge, no one knows absolutely for sure what is causing the SERT damage:

One theory is that it is excessive dopamine which gets lodged into the reuptake receptor (which has always seemed somewhat strange to me because dopamine does not bear an affinity for them).

Another theory is that it is a metabolite produced from the MDMA which is causing the damage. But that would still need to suggest that the metabolite has an affinity for the receptor. Perhaps, but why necessarily that receptor? Why not some other one? A metabolite would be a different compound with different properties, so having the same receptor affinity would be quite a coincidence (it is still possible, but generally the chances are that it would not).

Given the remaining available MDMA, shown under the curve that you presented after the perceived roll, perhaps this is the culprit. This would still have the same receptor affinity, and perhaps a new MDMA molecule attaching to an exhausted receptor produces the effect of damaging it (or rendering it unable to respond to future MDMA exposure until it has returned to its baseline). This receptor exhaustion could also be the reason why short term re-exposure to MDMA tends to decrease one's sensitivity (and produce other side effects). It could simply be due to exhaustion which eventually could result in a longer and longer time that it takes for the receptor to return to baseline.

This would also explain why a short lived SSRI, such as Effexor, would be effective (as you have described) since it would remain in the receptor longer then the MDMA would remain in the system (but for a shorter half life then the dopamine - i.e., disproving the dopamine toxicity theory). The SSRI places no demands on the receptor, so it does not contribute to the exhaustion effect.

Although there is definitely be a need for the 5HT levels to return to normal, it seems to me that this could be occurring more rapidly then suggested (especially if the user is including 5HTP for several days afterwards). And the real culprit to tolerence is simply receptor exhaustion.

Any thoughts?

I'm not aware of any interaction between SSRIs and speed. From memory Venlafaxine's affinity for dopamine transporters is some ~100s of times less than for serotonin transporters. Hell you generally have to take high doses of venlafaxine to notice its NA reuptake inhibiting properties (Venlafaxine's affinity for SERT is 5x higher than for NA transporter)

I don't believe there's any dangerous interaction. Where are you getting your info from?

SSRIs reducing tolerance? SSRIs induce negative-feedback changes (initial loss of SERT density, post-synpatnic 5HT downregulation, decrease in TPH activity) in serotonergic neurons starting from the first dose. How would a drug which an extremely high affinity for SERT decrease tolerance for another drug with a very high affinity for SERT. If you're talking about using SSRIs to increase the density of SERT then you might have a point. However, with an increase in SERT comes a decrease in post-synaptic 5HT receptors. So each would cancel out the other.

Perhaps someone would care to explain this.

The only way (pharmacologically) I know of which probably could decrease MDMA tolerance would be long term use (6+ months) of a 5HT2 antagonist followed by short term concommitant use of an SSRI with a short half life (such as paroxetine). After use of these, the following can be expected to have occured:

a) Increased density of SERT
b) Increase sensitivity (supersensitivity) and/or number of post-synaptic 5HT2 receptors

However, the concommitant use of SSRIs and 5HT antagonists (or agonists) is contraindicated due to the risk of serotonin syndrome.


X

^^^ The changes you say that paroxetine brings on, are these changes permenant? Having taken this drug is your brain forever changed, or doesn it return to it's origon state eventually?

I was under the impression no lasting changes are made, and the only reason that you may be permently rid of you problem (for which you took the medication) was through phychologically over coming it. The drug merely helps you to see the light, as it were, and then you can stay there on your own.