NMDA antagonists for tolerance (part 2)

[MagickalKat777]

I was on clonazepam for about 6 months, though the dose was relatively low (0.5mg at night).. I've always had paradoxical reactions to benzos though and think the clonazepam was making me worse the whole time, but it was being masked by another drug.

This could be the reason you have paradoxical reactions to magnesium.

I have the exact same issue - ironically with Klonopin as well.

I can't handle any form of magnesium in any significant amount other than what I get from dietary sources.

 

[doctordog]

What a bummer. I was really hoping Memantine would work out for my OCD. Is there anyway around the NMDA-paradoxical-reaction issue?

 

[MagickalKat777]

What a bummer. I was really hoping Memantine would work out for my OCD. Is there anyway around the NMDA-paradoxical-reaction issue?

Do you take anything else? I've not heard much about paradoxical reactions with memantine. What doses are we talking? You should always ramp memantine up gradually. The first week or two on it feel flat out weird - like you're on the verge of coming up on an awkward high that never manifests - but its goes away fairly quickly.

 

[doctordog]

So you've tried Memantine and could tolerate it, unlike Magnesium?

I don't take anything right now, and when I tried Memantine it was as monotherapy. I titrated from 2.5mg to 15mg, and gave every dose at least a week, but my anxiety just became insanely bad, especially once I graduated past 10mg. Below 10mg, it felt kinda like a long-acting Ritalin or something.. good for depression and socializing, but not very good for anxiety either.

It's really frustrating, because I have OCD, ADD and depression and hoped Memantine would be the magic bullet, and might allow me to tolerate stimulants. I tried Riluzole too (which antagonizes NMDA indirectly, I think) and also became more anxious.

I've wondered if revisiting Memantine with an SSRI on board would change my reaction.

 

[ebola?]

Well that explains why phenobarbital is so successful at getting people off of benzodiazepines.

Er...no, its strong agonism at the GABAA barbiturate site more readily explains such.

I,m taking memantine for prevent tolerance from ritalin. It works for 3 months, then i have to stop memantine for a week, then restart memantine a low dose and titrate slowly again.

It could alternately be that tolerance to the therapeutic effects of Ritalin took 3 months to accrue.

ebola

 

[MagickalKat777]

So you've tried Memantine and could tolerate it, unlike Magnesium?

I don't take anything right now, and when I tried Memantine it was as monotherapy. I titrated from 2.5mg to 15mg, and gave every dose at least a week, but my anxiety just became insanely bad, especially once I graduated past 10mg. Below 10mg, it felt kinda like a long-acting Ritalin or something.. good for depression and socializing, but not very good for anxiety either.

It's really frustrating, because I have OCD, ADD and depression and hoped Memantine would be the magic bullet, and might allow me to tolerate stimulants. I tried Riluzole too (which antagonizes NMDA indirectly, I think) and also became more anxious.

I've wondered if revisiting Memantine with an SSRI on board would change my reaction.

I tolerated memantine just fine short of a few side effects. I suppose that increased pulse and such could be an anxiety response but it only seemed to occur when I mixed memantine with other things and wasn't particularly unnerving, quite unlike regular anxiety. Those doses that you started on are insanely low. Are you sure that you didn't get anxious on your own? It may well have been that the low dose was not sufficient enough for NMDA antagonism as well - its not an especially potent NMDA antagonist.

As for the SSRIs, I wouldn't know. I won't ever put those poisonous things in me again. The only chemical anti-depressant I could see myself using is tianeptine/Stablon. All the rest of it is garbage.

 

[doctordog]

I tolerated memantine just fine short of a few side effects. I suppose that increased pulse and such could be an anxiety response but it only seemed to occur when I mixed memantine with other things and wasn't particularly unnerving, quite unlike regular anxiety. Those doses that you started on are insanely low. Are you sure that you didn't get anxious on your own? It may well have been that the low dose was not sufficient enough for NMDA antagonism as well - its not an especially potent NMDA antagonist.

No, I'm sure it was the Memantine .. I tried it on a couple of occasions to make sure and the anxiety felt very artificial, akin to a Ritalin overdose as I mentioned.

That's a good point about the dose though. Maybe I'll try starting at 20mg next time.

 

[MagickalKat777]

That's a good point about the dose though. Maybe I'll try starting at 20mg next time.

I'm not suggesting that you go and take 20mg. It could very well be that you have an allergy or some other rare reaction with memantine and it has such a long half life that you would be going through it for quite some time if that is the case.

Have you ever tried ketamine or methoxetamine out of curiosity? Or just magnesium and memantine?

 

[doctordog]

Yeah, I wouldn't mess with Memantine again unless I had my anxiety under control, though it is interesting that I was using clonazepam and antihistamines at the time I was on it (both of which I now realize increase my anxiety/agitation).

Never messed with K or mxe .. mostly because I've never been given a chance.

You mean magnesium and memantine together, or as monotherapy? I've never tried the two together .. Memantine I was on with a low dose of clonazepam, and Magnesium I've used in combo with other supplements or drugs but never alone.

 

[MagickalKat777]

I was actually referring to whether or not you used any other NMDA antagonists which would be a no.

That said, antihistamines shoot my anxiety through the roof (diphenhydramine is the worst) and clonazepam does as well now. Maybe try memantine without being on those other meds.

 

[doctordog]

isn't DXM an NMDA antagonist? is it still available OTC (I'm in Australia)? maybe I should test out a small dose to see if it's NMDA antagonists in general..

yeah, I'll be working with a new psychiatrist soon .. if I can alleviate my anxiety, I'll be willing to mess with Memantine again.

have you had paradoxical reactions to anything other than clonazepam and magnesium?

 

[MagickalKat777]

Dextromethorphan is over the counter in most countries.

This is what Erowid has to say about it:

Australia #
DXM is legal as an over-the-counter cough suppressant, but import restrictions on DXM-only products may exist. We have been told that DXM over-the-counter products are limited to 3% or less DXM and one package may not contain over 600 mg of DXM. One visitor writes that the only product available that is DXM-Only is Robitussin Dry Cough Forte (3mg/ml). (thanks c, O, SG) (last updated sep 3 2012)

Check the active ingredients... your only option might be Robitussin DM which is a mix of DXM and guaifenesin - high doses of guaifenesin can make you vomit but so can DXM on its own. I used to use the DM formulation all the time.

That Dry Cough Forte sounds like the "Long Lasting Cough" that we have here in the states but I'm sure its expensive like it is here.

That said, the NMDA antagonism effects happen with as low as 15mg four times a day (every 6 hours).

EDIT: I looked up the Dry Cough Forte on the Australian Google and it is indeed the most ideal. I would look for that in the store. Your stuff over there even has less garbage in it than ours does here and it has the maximum 600mg in the 200mL bottle (30mg per 10mL). Look for that.

I did see something about a generic formulation of Delsym (dextromethorphan polistirex - basically extended release DXM) but I can't find it anywhere so you might look into that too as Delsym doesn't appear to be available in Australia.

 

[ebola?]

That said, the NMDA antagonism effects happen with as low as 15mg four times a day (every 6 hours).

How did you come up with this dosage? And what does this threshold even mean? NMDA antagonism is not a binary effect to be turned on or off. Rather, receptor occupancy and resulting effects scale upward smoothly with increasing dosages...

ebola

 

[doctordog]

thanks for all your help, Magickalkat! just one final question .. is NMDA antagonism linked to catecholamine release, which might explain potential anxiety?

I've poked around pubmed and found some abstracts that suggests it enhances striatal dopamine, though I have no idea what the subjective effects of that might present as. I had a lot more mental energy on Memantine, libido was enhanced, colors brighter etc. and it tended to potentiate other stimulants, rather than taking the edge off (which is what I was aiming for).

 

[MagickalKat777]

How did you come up with this dosage? And what does this threshold even mean? NMDA antagonism is not a binary effect to be turned on or off. Rather, receptor occupancy and resulting effects scale upward smoothly with increasing dosages...

ebola

Dosage based on purely reports of what has worked for others and my own personal experience. I've read the entire original thread and numerous other threads on the topic and while they all agree that Delsym is ideal, the general belief when using regular DXM is a 4x a day dose. I purposely am keeping dose recommendations low because a) it doesn't seem like much is needed for optimal NMDA antagonism and minimal side effects and b) doctordog seems to have a sensitivity. There isn't much in the way of studies for this, especially in humans.

If we were working directly with dextrorphan, it would probably be a lot easier to figure all of this stuff out... Then again, DXO is not DXM. The two probably work in tandem pharmacologically to bring about the desirable effects.

thanks for all your help, Magickalkat! just one final question .. is NMDA antagonism linked to catecholamine release, which might explain potential anxiety?

I've poked around pubmed and found some abstracts that suggests it enhances striatal dopamine, though I have no idea what the subjective effects of that might present as. I had a lot more mental energy on Memantine, libido was enhanced, colors brighter etc. and it tended to potentiate other stimulants, rather than taking the edge off (which is what I was aiming for).

Looking up memantine and dopamine, it does appear that memantine is a D2(High) agonist with an affinity about the same as it has for NMDA. That's a curious thing to note and could explain the euphoria boost I noticed on alcohol and MDMA with memantine. Nice find.

http://www.ncbi.nlm.nih.gov/pubmed/18000814

Following this path, I looked up magnesium and found this:

http://www.ncbi.nlm.nih.gov/pubmed/2932536

Both magnesium and memantine have effects on D2 - memantine is an agonist at D2(High) and magnesium itself modulates D2 into its high-affinity state.

Dextromethorphan does not have this property. Dextrorphan does not have it either.

You may very well have just figured out why neither you nor I tolerated memantine or magnesium very well.

Neither dextromethorphan or dextrorphan have this property at all. Dextromethorphan is a serotonin reuptake inhibitor and has a list of other effects and an overall "dirty" profile compared to memantine but it doesn't touch dopamine. You may well be just fine with dextromethorphan like myself.

Dextromethorphan has been shown to possess the following properties, mainly in binding assays to various receptors of animal tissues. Low Ki values mean strong binding or high affinity; high Ki values mean weak binding to the target or low affinity:

Uncompetitive NMDA receptor (PCP site) antagonist (Ki = 7,253 nM).[23][24][25][26]
σ1 and σ2 sigma receptor agonist (Ki = 205 nM and 11,060 nM, respectively). In a comparative investigation of dimemorfan, dextromethorphan and dextrorphan in mouse cells, dextromethorpan binds with relatively high affinity to Sigma-1 receptors and with very low affinity to Sigma-2 receptors.[23]
α3β4-, α4β2-, and α7-nACh receptor (Ki = in the μM range) antagonist. Dextromethorphan binds to nicotinic receptors in frog eggs (Xenopus oocytes), human embryonic kidney cells and mouse tissue. It inhibits the antinociceptive (pain killing) action of nicotine in the tail-flick test in mice, where mouse tails are exposed to heat, which makes the mouse flick its tail if it feels pain.[27][28][29]
μ-, δ-, and κ-opioid receptor agonist (Ki = 1,280 nM, 11,500 nM, and 7,000 nM, respectively).[30]
SERT and NET inhibitor (Ki = 23 nM and 240 nM, respectively).[31][30][32][33]
NADPH oxidase inhibitor.[34]

Its affinities for some of the sites listed are relatively very low and are probably insignificant, such as binding to NMDA receptors and opioid receptors, even at high recreational doses.[citation needed] Instead of acting as a direct antagonist of the NMDA receptor itself, it is likely that dextromethorphan functions as a prodrug to its nearly 10-fold more potent metabolite dextrorphan, and this is the true mediator of its dissociative effects.[23] It is not entirely clear what role, if any, (+)-3-methoxymorphinan, dextromethorphan's other major metabolite, plays in its effects.[35]

http://en.wikipedia.org/wiki/Dextromethorphan

I guess now I know why memantine and amphetamines/phenethylamines didn't get along with me. Very nice find indeed!

 

[doctordog]

Interesting. I always thought Memantine's D2 affinity was negligible. Would be nice if there was a clean NMDA antagonist to mess around with.