Reversing tolerance with psychedelics/MDMA?

[EMLonergan]

If psychedelics are 5HT2a agonists, and tolerance results from 5HT2a downregulation, is it possible to cause an upregulation through chemical methods in order to eliminate tolerance? Wouldn't this also lead to increased MDMA effects, since 5HT2a also plays a role in the magic of MDMA experiences?

Do you think 5HT2a antagonists such as MDL 11,939 or Eplivanserin would do the trick? If not, is there any other possible way of causing this?

Here's the post on another forum that got me curious:

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.

Read more: http://www.drugs-forum.com/forum/showthread.php?t=36636#ixzz1p8zhXBPk

 

[bremes]

I've heard that melatonin upregulates 5-ht2a.

 

[atrollappears]

Actually, 5-HT2A antagonists downregulate the receptor. Go figure.

In any case, long-term MDMA tolerance isn't the result of 5-HT2A downregulation, the receptor density/sensitivity returns to normal rather quickly. That's why psychedelics don't have long-term tolerance.

Edit: Forgot to mention, 5-HT2A density is actually slightly increased in MDMA users IIRC.

 

[Lopez]

aren't NMDA antagonists known for their ability to prevent, reverse, and sometimes even reset tolerance?

otherwise, don't roll more than once a week in order to prevent upregulation.

 

[Amu]

Actually, 5-HT2A antagonists downregulate the receptor. Go figure.

In any case, long-term MDMA tolerance isn't the result of 5-HT2A downregulation, the receptor density/sensitivity returns to normal rather quickly. That's why psychedelics don't have long-term tolerance.

Edit: Forgot to mention, 5-HT2A density is actually slightly increased in MDMA users IIRC.

Which receptors are you implying are the true cause of MDMA tolerance? Dopamine?

 

[atrollappears]

Which receptors are you implying are the true cause of MDMA tolerance? Dopamine?

I don't think it's any receptors, just like with long-term regular amphetamine tolerance. I'd guess it has to do with more complex changes regarding the behavior of serotonin vesicles, and probably also SERT downregulation. It's hard to say for sure though.

 

[Nephtys]

I don't think it's any receptors, just like with long-term regular amphetamine tolerance. I'd guess it has to do with more complex changes regarding the behavior of serotonin vesicles, and probably also SERT downregulation. It's hard to say for sure though.

Isn't long-term tolerance a kind of protective mechanism from the brain?

 

[atrollappears]

Isn't long-term tolerance a kind of protective mechanism from the brain?

It's just the brain trying to maintain homeostasis. We behave the way we do for a reason: it's been successful at keeping us alive and getting us successful offspring. So, the brain has been programmed to try to maintain those normal behaviors. Drugs, as I'm sure you are aware, don't usually induce the best survival traits.

 

[EMLonergan]

I'm wondering if there is any possible way to chemically induce a decrease in MDMA tolerance.

 

[sekio]

I'm wondering if there is any possible way to chemically induce a decrease in MDMA tolerance.

Essentially, no.

 

[EMLonergan]

Essentially, no.

Well, Piracetam is known for its ability to potentiate the dopaminergic effects of any dopamine reducing agent due to its inhibition of DA reuptake. Even though there might be no way of reducing tolerance by upregulating receptors, it should be possible in theory to potentiate a serotonergic effect in an analogous way to piracetam's dopamine-enhancing effects, no?

 

[sekio]

In theoy, yes, but in practical usage nobody has found an effective way to totally reverse or prevent tolerance to monoamine-releasing drugs. (amphetamines, MDMA)

There are definitely things you can do to help prevent tolerance buildup (NMDA receptor antagonists, low doses, infrequent usage) but once it has been developed the only thing that actually helps is time.

Dopamine reuptake inhibitors are cheating, they cause tolerance too. (see: cocaine, methylphenidate, mdpv) In general anything that elevates postsynaptic monoamine levels will cause tolerance.

Reuptake inhibition combined with release agents can actually block the releasing effects, see MDMA+SSRI.

 

[EMLonergan]

In theoy, yes, but in practical usage nobody has found an effective way to totally reverse or prevent tolerance to monoamine-releasing drugs. (amphetamines, MDMA)

There are definitely things you can do to help prevent tolerance buildup (NMDA receptor antagonists, low doses, infrequent usage) but once it has been developed the only thing that actually helps is time.

Dopamine reuptake inhibitors are cheating, they cause tolerance too. (see: cocaine, methylphenidate, mdpv) In general anything that elevates postsynaptic monoamine levels will cause tolerance.

Reuptake inhibition combined with release agents can actually block the releasing effects, see MDMA+SSRI.

Do you have any idea why dopamine reuptake inhibition caused by piracetam will increase dopaminergic effects from dopamine releasers while serotonin reputake inhibition will inhibit the effects of serotonin releasing agents?

 

[sekio]

It has to do with transporter affinity.

SSRIs are designed to bind very tightly (low Ki) to the serotonin transporter and as a result they have 'binding preference' over MDMA (moderate Ki).

I would imagine that as a dopamine reuptake inhibitor piracetam is relatively weak (high Ki). Compare MDPV, cocaine, methylphenidate (low Ki).

 

[Tussmann]

It has to do with transporter affinity.

SSRIs are designed to bind very tightly (low Ki) to the serotonin transporter and as a result they have 'binding preference' over MDMA (moderate Ki).

I would imagine that as a dopamine reuptake inhibitor piracetam is relatively weak (high Ki). Compare MDPV, cocaine, methylphenidate (low Ki).

This is also why taking an SSRI during an MDMA comedown is the key to alleviating neurotoxicity.

 

[sekio]

As far as I know the transporters have fuckall to do with toxicity and mostof it comes from excessive reactive oxygen species being produced & elevated local temperature causing cell death/heat shock.

MDMA's long term neurotoxicity at reasonable dose levels has not been proven in man.

 

[Tussmann]

From what I understand MDMA becomes neurotoxic when all 5-HT has been depleted, and the SERT starts reuptaking DA (which is still available) back into the wrong synapse. Thus, dirty oxidative reactions occur and things get sour. So, something like an SSRI should blunt the mismatch reuptake -- I think there is a host of evidence to support this in animal models and human anecdotes...for what its worth.

Also, I was under the impression that MDMA had significant negative repercussions in user's verbal-fluency in the long run.

 

[Epsilon Alpha]

I've spent some time reviewing the available literature, but when I'm not typing this out on my phone I'll get more into detail. Suffice to say there are MANY processes going on in MDMA and amphetamine neurotoxicity. I've seen some results that suggest that there are various receptor mediated and possible epigenetic mechanism of apoptosis at play.

 

[atrollappears]

There are definitely things you can do to help prevent tolerance buildup (NMDA receptor antagonists, low doses, infrequent usage) but once it has been developed the only thing that actually helps is time.

NMDA antagonists (including magnesium) can, anecdotally, help reduce tolerance after it has been established with methylphenidate and amphetamine.

As far as I know the transporters have fuckall to do with toxicity and mostof it comes from excessive reactive oxygen species being produced & elevated local temperature causing cell death/heat shock.

Well the MDMA has to get into the neuron, via the transporters, to cause damage. Also, IIRC the elevated temperature matters because it decreases the effectiveness of the body's endogenous antioxidant system.

MDMA's long term neurotoxicity at reasonable dose levels has not been proven in man.

Important to note.

From what I understand MDMA becomes neurotoxic when all 5-HT has been depleted, and the SERT starts reuptaking DA (which is still available) back into the wrong synapse. Thus, dirty oxidative reactions occur and things get sour. So, something like an SSRI should blunt the mismatch reuptake -- I think there is a host of evidence to support this in animal models and human anecdotes...for what its worth.

Also, I was under the impression that MDMA had significant negative repercussions in user's verbal-fluency in the long run.

The dopamine theory has been largely discredited, and the oxidative stress theory which sekio mentioned is currently in vogue. However with MDMA induced neurotoxicity there is more going on than simple oxidative stress, including events in which the main endogenous antioxidant, glutathione, may actually be required for MDMA to damage neurons.

I've spent some time reviewing the available literature, but when I'm not typing this out on my phone I'll get more into detail. Suffice to say there are MANY processes going on in MDMA and amphetamine neurotoxicity. I've seen some results that suggest that there are various receptor mediated and possible epigenetic mechanism of apoptosis at play.

I'm very interested to hear what you think about MIN and its relation to (meth)amph toxicity. What's your take on how exactly the glutathione alpha-methyldopamine conjugates cause MDMA-like damage? Do you think it fits in the transporter? I would be surprised, but I don't see it causing that much damage outside the cell... Amino acid transporters maybe?

 

[Tussmann]

NMDA antagonists (including magnesium) can, anecdotally, help reduce tolerance after it has been established with methylphenidate and amphetamine.

If anything Mg is just good for overall health, but don't expect much in regards to NMDA antagonism and tolerance reduction. Like, you could cut a microscopic dose of DXM or memantine down and it would still yield a higher affinity than mg.