NMDA antagonist neurotoxicity, 5-HT2A receptors, and Mirtazapine

[mecaib]

Hello,

I've got a question for you guys.

It has become well-known that 5-HT2A receptor agonists prevent NMDA antagonist neurotoxicity in rats:
http://www.nature.com/npp/journal/v18/n1/abs/1395108a.html

I plan to take a dissociative soon. I take 30mgs mirtazapine each night. The dissociative will be DXM, which has been shown to not cause vacuolation in the rat brain.

That study was probably conducted with DXM HBr, not DXM polistirex, which is what I'll be taking.

I wonder if taking a potent 5-HT2A receptor antagonist such as mirtazapine in conjunction with an NMDA antagonist could increase the chance of Olney's Lesions, even if said dissociative has been shown to not cause neuronal death? Or do you think the risk will remain the same?

Your thoughts on this matter are humbly requested. Perhaps such discussions will lead to actual research in the future.

I'm sorry in advance if this has all been covered before!

~mec

 

[Pothedd]

Hey guys I noticed this thread nobody ever posted a response to. That just doesn't seem right, even if the situation doesn't seem harmful.

Anyway, I know it's been almost a year since the OP posted this but hey, here's my two cents.
Personally I haven't experienced or observed symptoms of olney's lesions in anyone else after heavy dxm use, and don't believe anything of the sort to take place in the human brain with its usage.

And I haven't come across anything that would indicate this would be any different with the addition of mirtazapine.
Personally I have found that a normal dose of remeron will put me to sleep nicely, if I'm tripping on dxm and need to do so.
All sources on the web suggest that mirtazapine may help combat some of the effects of "street" hallucinogens, but I think it just puts you to sleep so you stop trippin'. lol...

 

[villiers]

only in rats

As far as i know Olney's Lesions was never shown to occur in primates, only in rats due to their different metabolism.

 

[smellytim]

^ what he said. olneys lesions have never been proven to appear in humans as far as i know.
one dose of DXM really shouldnt cause anything anyway. just try to avoid using it more than once every two weeks or so...

 

[Pothedd]

^I second that^

 

[The Smoking Man]

As everyone else said, Olney's Lesions haven't been shown to occur in the primate brain. I can imagine the NMDA receptor upregulation from overexposure to NMDA antagonists would cause excitotoxic brain damage, though.

 

[P A]

Were the serotonergically preventable lesion even to occur in teenaged OTC drug abusers, I'm not aware of a single study demonstrating what deceivingly appears to be the corollary - do 5-HT2A antagonists dose-dependently augment the lesion to the same extent that the agonists prevent it? Given the highly complex and constitutive activity of the 2A receptors [especially in the human brain], I'd say it's hardly clear-cut. Seeing as how OP is still posting, and appears free of complaint, I guess we can assume the trip wasn't a complete disaster...

Also, here's a study demonstrating the counter-intuitive opposite - a handful of serotonin antagonists significantly dampening the toxicity of dizocilpine:

Atypical Antipsychotics and a Src Kinase Inhibitor (PP1) Prevent Cortical Injury Produced by the Psychomimetic, Noncompetitive NMDA Receptor Antagonist MK-801

Abstract

Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine, ketamine, and MK-801 produce schizophrenia-like psychosis in humans. The same NMDA antagonists injure retrosplenial cortical neurons in adult rats. We examined the effects of atypical antipsychotics and an inhibitor of nonreceptor tyrosine kinase pp60 (Src) on the cortical injury produced by MK-801. An atypical antipsychotic (either clozapine, ziprasidone, olanzapine, quetiapine, or risperidone) or vehicle was administered to adult female Sprague–Dawley rats. PP1 (Src inhibitor), PP3 (nonfunctional analog of PP1) or vehicle (DMSO) was administered to another group of animals. After pretreatment, animals were injected with MK-801, killed 24 h after the MK-801, and injury to retrosplenial cortex assessed by neuronal Hsp70 protein expression. All atypical antipsychotics examined significantly attenuated MK-801-induced cortical damage. PP1 protected compared to vehicle, whereas PP3 did not protect. The ED50s (decrease injury by 50%) were as follows: PP1 <0.1 mg/kg; olanzapine 0.8 mg/kg; risperdal 1 mg/kg; clozapine 3 mg/kg; ziprasidone 32 mg/kg; and quetiapine 45 mg/kg. The data show that the atypical antipsychotics tested as well as a Src kinase inhibitor prevent the injury produced by the psychomimetic MK-801, and the potency of the atypical antipsychotics for preventing cortical injury was roughly similar to the potency of these drugs for treating psychosis in patients.

 

[mecaib]

Thank you guys for giving this thread some exposure! I'm glad to hear that primates don't (appear to) incur brain lesions from NMDA antagonists like rats do, but I wonder what other kinds of damage might occur.

Seeing as how OP is still posting, and appears free of complaint, I guess we can assume the trip wasn't a complete disaster...

Yeah, I can't say I feel brain-damaged, but who knows? Here's the trip report I made after starting this thread.

Some of the reasons for taking the trip were wrong, but were not completely responsible for the negative effects I experienced. The bad sensations seem to be a hallmark of all my higher-dose DXM trips.

I haven't had another DXM trip since that one, but I have taken very minute amounts (<60mg) to boost/level my mood. It seems contradictory, but DXM serves as an antidepressant and a mood-stabilizer for me. The best after-effects only come after I trip on DXM, which still makes this thread relevant to me.

Unfortunately, every time I trip on it, I can feel lesions forming. I can even see them. It must be an hallucination, but I can never quite get over it! I would much rather get some good mushrooms or acid, but they are so rare in my area, at least for people in my age group and social circle.

 

[P A]

Oops. Embarrassing - I completely forgot one of mirtazapine's hallmark properties, alongside its relevance to NAN. Part of Remeron's therapeutic efficacy is mediated via alpha-2A adrenoceptor blockade, a mechanism theorized to greatly exacerbate any extant toxicity, given that administration of postsynaptic a2A ligands (guanfacine, clonidine) substantially reduces the incidence of Olney's lesions in rats. Since mirtazapine has reportedly higher affinity for a2A than any of the other few monoamine receptor sites to which it binds, this activity could theoretically be some cause for concern. On the other hand, because no conclusive NAN research has been, nor is being, conducted (WHY?) in humans, and there still isn't any indication that the lesion occurs in "higher" mammalian brains with considerably slower rates of metabolism than rats', there's no reasonable possibility of closure on the subject presently. If I were regularly taking mirtazapine, I guess I would prefer to err on the side of caution and co-administer some guanfacine with the methorphan to mitigate any additive influence.

If the NMDA antagonist lesion refuses to manifest in monkey brains in the presence of dxm alone, could the addition of an exacerbatory pro-toxin 'unmask' the progressive impact? I wouldn't risk it.

Unfortunately, every time I trip on it, I can feel lesions forming. I can even see them

This is why we refer to these drugs as "hallucinogens."

 

[Amu]

Old thread, but do note that mirtazapine has high affinity for alpha-2 autoreceptors, and will not decrease alpha-2 receptor functioning in clinically relevant doses, as it increases NE transmission, many studies have shown this property, such as http://www.ncbi.nlm.nih.gov/pubmed/11111835

Thus, I would draw a preliminary conclusion that mirtazapine will not cause greater toxicity with concurrent use of NMDA antagonists in doses used for depression, and might actually might prevent said neurotoxicity similar to how guanfacine does so

 

[SpunkySkunk347]

Hello,

I've got a question for you guys.

It has become well-known that 5-HT2A receptor agonists prevent NMDA antagonist neurotoxicity in rats:
http://www.nature.com/npp/journal/v18/n1/abs/1395108a.html

I plan to take a dissociative soon. I take 30mgs mirtazapine each night. The dissociative will be DXM, which has been shown to not cause vacuolation in the rat brain.

That study was probably conducted with DXM HBr, not DXM polistirex, which is what I'll be taking.

I wonder if taking a potent 5-HT2A receptor antagonist such as mirtazapine in conjunction with an NMDA antagonist could increase the chance of Olney's Lesions, even if said dissociative has been shown to not cause neuronal death? Or do you think the risk will remain the same?

Your thoughts on this matter are humbly requested. Perhaps such discussions will lead to actual research in the future.

I'm sorry in advance if this has all been covered before!

~mec

The main risk you are running with mixing the two is serotonin syndrome, not Olney's lesions. Taking any serotonin/norepinephrine/dopamine reuptake inhibitor with dextromethorphan is very dangerous.

From what I've read, Olney's lesions are only a serious possibility with massive "3rd plateau" doses of DXM, like 600mg and higher.
Apparently, taking doses higher than 1000mg a couple of times has a much higher possibility of causing lesions than chronically taking small 300-500mg doses. For example, you could take 300mg of DXM every other weekend for months and be more or less okay; but taking, say, 1500mg just once could cause serious damage.

But anyways, the most important issue here is that you DO NOT mix DXM with mirtazapine -- very dangerous. Just don't do it.
You need to wait at least a week or two after taking mirtazapine before taking DXM. Please, people die from interactions like these. And although you may not die, you could be doing some serious damage to yourself. And even if you recklessly disregard the possibility of causing damage, the combination of the two drugs is probably going to be very uncomfortable and could be the worst 8 hours of your life.

Edit: Looks like I'm 2 years late. Hope the kid was alright. This thread really isn't ADD material anyways. And please, to any young or inexperienced drug users lurking the forums reading this, STOP taking drugs while you are on prescription medication.

 

[Pothedd]

Nobody's died from mixing mirtazapine and dxm. I've been on remeron for years, and was on dxm for years, with no adverse effects. In fact, DXM stopped the restless leg syndrome caused by remeron, and provided relief so I could either sleep or stay awake. It was my choice.
Remeron's effect on serotonin is nearly negligible, and I have been prescribed it alongside an SSRI for years. Serotonin syndrome doesn't seem to be a very likely outcome of this combination, and there hasn't been a documented case of serotonin syndrome caused by a mixture of mirtazapine with anything.

 

[Amu]

The main risk you are running with mixing the two is serotonin syndrome, not Olney's lesions. Taking any serotonin/norepinephrine/dopamine reuptake inhibitor with dextromethorphan is very dangerous.

From what I've read, Olney's lesions are only a serious possibility with massive "3rd plateau" doses of DXM, like 600mg and higher.
Apparently, taking doses higher than 1000mg a couple of times has a much higher possibility of causing lesions than chronically taking small 300-500mg doses. For example, you could take 300mg of DXM every other weekend for months and be more or less okay; but taking, say, 1500mg just once could cause serious damage.

But anyways, the most important issue here is that you DO NOT mix DXM with mirtazapine -- very dangerous. Just don't do it.
You need to wait at least a week or two after taking mirtazapine before taking DXM. Please, people die from interactions like these. And although you may not die, you could be doing some serious damage to yourself. And even if you recklessly disregard the possibility of causing damage, the combination of the two drugs is probably going to be very uncomfortable and could be the worst 8 hours of your life.

Edit: Looks like I'm 2 years late. Hope the kid was alright. This thread really isn't ADD material anyways. And please, to any young or inexperienced drug users lurking the forums reading this, STOP taking drugs while you are on prescription medication.

I disagree with this, although harm reduction is important and the general mission of this website, it should not be achieved via misinformation. Mirtazapine and DXM are not "very dangerous" to take together at clinically relevant doses, and the former might be neuroprotective, as I've explained. I know you are trying to be cautious here, and I appreciate that, but we need to be precise and reasonable with neurotoxicology at the same time.

 

[SpunkySkunk347]

Even though mirtazapine may have weak serotonergic activity, it can still be enough to push an individual into serotonin toxicity -- mixing drugs can cause the substances involved to be stronger or weaker than they normally are; its like compounding problems exponentially.

Also, the sedation caused by mirtazapine (due to H1 antagonism I believe) is also dangerous to mix with DXM. People around here die all the time from mixing DXM with anti-histamines, anti-depressants, and sleep aids. Most of them are teens too, its horrible - when information exists that could have saved them.

"Nah youll be alright, I've mixed them before and have been fine" isn't enough. Doctors prescribe mirtazapine with anti-depressants while knowing there's a risk, but thats mixing two reuptake inhibitors, under medical supervision -- DXm if i remember correctly actually causes a serotonin release as well as inhibiting reuptake. Its just basic pharmacology 101.

Most anti-depressants inhibit certain enzymes metabolizing DXM, so I'll admit that mirtazapine is safer in that regard that it doesn't inhibit enzymes, but still

Maybe there will only be a 1 in 100 chance that an interaction occurs, but why risk it? Why can't a person wait to take the DXM when they're not on remeron or just do something else entirely? Is getting high off a nasty drug really that important?

 

[Amu]

Even though mirtazapine may have weak serotonergic activity, it can still be enough to push an individual into serotonin toxicity -- mixing drugs can cause the substances involved to be stronger or weaker than they normally are; its like compounding problems exponentially.

This is actually not the case, mirtazapine has an extremely low risk of causing serotonin toxicity, and is actually used to prevent it, so it could save his life instead.

Also, the sedation caused by mirtazapine (due to H1 antagonism I believe) is also dangerous to mix with DXM. People around here die all the time from mixing DXM with anti-histamines, anti-depressants, and sleep aids. Most of them are teens too, its horrible - when information exists that could have saved them.

Yes that's true, though I assume the OP is aware of the sedation and won't be driving on the combo

Maybe there will only be a 1 in 100 chance that an interaction occurs, but why risk it? Why can't a person wait to take the DXM when they're not on remeron or just do something else entirely? Is getting high off a nasty drug really that important?

That's true, but you have to honest about the risks, if you label every combination as "risky" and "avoid to be cautious" no one is going to take our advice seriously and harm reduction will be reduced. This is not MAO-A Inhibitor + MDMA, we can't be like the drug police and label everything dangerous. So every user should start with low doses of both and titrate up slowly after being informed of the risks. If they have a doctor that would help, but it's usually the case you can't tell your doctor about your desire to chug bottles of DXM

 

[SpunkySkunk347]

you have valid points, but DXM is notorious for having interactions far beyond most normal recreational drugs. There are many combos I wouldn't consider dangerous -- although they may be uncomfortable.

But mixing DXM with anything is setting a course through possibly dangerous uncharted waters. If its not dangerous, consider that the combination is probably going to be uncomfortable -- and maybe even downright scary.

I remember when I was on paroxetine and took 300mg of DXM; it was terrifying. I just thank god I had a full bottle of clonazepam with me at the time which I used to bring myself down. Sure, mirtazapine isn't paroxetine, and might be "safe" to mix with DXM, but I personally would be paranoid and scared if I took the two together; DXM is a substance that demands respect.

If you can forgive me for some personification, I reckon that DXM is compensating for its rep as being a drug for "naive teenagers who can't get real drugs" by scaring the fuck out of its users.

 

[Pothedd]

It's definitely not anything like an SSRI (such as paroxetine) mixed with DXM, which would be quite likely to cause a panic attack.
Seriously, try them together. I don't even take remeron anymore due to the dreams, and I haven't taken DXM in many many months, but I would definitely mix them again. Remeron is downright uncomfortable by itself. From what I remember, DXM completely relieved that.

You experienced a panic attack. Sure it's terrifying, but it's not serotonin syndrome. They are two very, VERY different issues. My girlfriend had a panic attack from a large dose of DXM on its own, which the doctor administered a shot of ativan for and she was all better.
You had benzos, which made your experience bearable, which indicates anxiety as the sole cause of your negative experience. Serotonin syndrome would require medical intervention by means of an antagonist.

Trust me, there is no indication that mirtazapine would be a dangerous combination with any serotonergic drug.

 

[SpunkySkunk347]

I know it was a panic attack, I have panic disorder. But they come in differnt flavors. My whole head felt like its was getting really warm and inflated, and there was this ringing/buzzing/vibrating feeling in my brain; there was definitely some serotonin toxicity going on - not just anxiety.
My thoughts felt like what I can only describe as "reactive" -- every little stimulus in my environment would trigger a conscious thought, which would then cascade into more thoughts. It felt uncontrollable. Definitely shouldn't have mixed DXM with an SSRI

I got to stop thinking back to these bad trips, its ruining my high right now and giving me anxiety just thinking about it

 

[Pothedd]

That sounds exactly like a terrible panic attack. I know how they are man. They suck. She may have been on SSRI's as well when she had that attack too. She was freaking out, throwing up, heart racing, thinking she was going to die. I was fine off the same dose, drove her to the emergency room, perfectly calm the whole time, but this was concentrated DXM and she had never had it in that form before. The quick comeup must've really fucked her up.

If you have a panic disorder though, DXM's probably not a very good idea, and definitely shouldn't be mixed with stimulating compounds.
But this is about mirtazapine, which is fine. I actually woke up in the middle of the night, tripping BALLS on DXM and mirtazapine, and it was like one long salvia trip, except with euphoria (instead of dysphoria, which salvia caused in me. made me want to kill myself).
That's all I'm getting at though. There's no known issue with this combination, and may actually be worth trying for some people.

 

[SpunkySkunk347]

That sounds exactly like a terrible panic attack. I know how they are man. They suck. She may have been on SSRI's as well when she had that attack too. She was freaking out, throwing up, heart racing, thinking she was going to die. I was fine off the same dose, drove her to the emergency room, perfectly calm the whole time, but this was concentrated DXM and she had never had it in that form before. The quick comeup must've really fucked her up.

If you have a panic disorder though, DXM's probably not a very good idea, and definitely shouldn't be mixed with stimulating compounds.
But this is about mirtazapine, which is fine. I actually woke up in the middle of the night, tripping BALLS on DXM and mirtazapine, and it was like one long salvia trip, except with euphoria (instead of dysphoria, which salvia caused in me. made me want to kill myself).
That's all I'm getting at though. There's no known issue with this combination, and may actually be worth trying for some people.

*sigh*
I had a panic attack yes, but there were additional effects from the DXM synergizing with the paroxetine as well. I don't feel like I'm playing real life super mario every time I get a panic attack