Is DXM actually the safer dissociative / rapid acting antidepressant!?

[dopamimetic]

Sub-anaesthetic doses of ketamine lead to changes in the expression of parvalbumin interneurons and significant changes in nitrergic and GABAergic (downregulation) systems as well as, especially after chronic dosing, upregulated NADPH oxidase and overall increase in glutamate levels in the brain.

Now, the NADPH oxidase plays a crucial role which I do not yet understand fully, but it does inactivate oxolacetate, which lowers glutamate levels, and it is a major factor in the production of superoxides, which may be responsible for the loss of parvalbumin & GABAergic neurons.

The rapid-acting antidepressant activities of ketamine have been associated with this mechanism, as well as psychotic after-effects.
But now the interesting part: Dextromethorphan is a NADPH oxidase inhibitor, active at low, sub-psychotomimetic and sub-dissociative dosages and it's not the DXO, but the actual DXM which does that. It has been studied for protective effects in Parkinson's and even to that ugly neurotoxin MPTP+ with success and a good safety profile. And DXM has a very pronounced, long-lasting antidepressant 'afterglow' that it shouldn't have if the above was true.

Also, wouldn't this mean that (besides of it's obvious, powerful adverse effects like the SNRI activity & sigma agonism) DXM would in fact make a somewhat 'safer' dissociative not inducing these long-term changes in the brain!?

Repeated application of ketamine to rats induces changes in the hippocampal expression of parvalbumin, neuronal nitric oxide synthase and cFOS similar to those found in human schizophrenia.
Loss of phenotype of parvalbumin interneurons in rat prefrontal cortex is involved in antidepressant- and propsychotic-like behaviors following acute and repeated ketamine administration.
IL-6 mediated degeneration of forebrain GABAergic interneurons and cognitive impairment in aged mice through activation of neuronal NADPH oxidase. <-- link to the inflammation model of anxiety & depression
Neuroprotective effect of dextromethorphan in the MPTP Parkinson's disease model: role of NADPH oxidase

But then again, to confuse:
Subchronic phencyclidine treatment in adult mice increases GABAergic transmission and LTP threshold in the hippocampus.

 

[belligerent drunk]

Correct me if I'm wrong, but isn't therapeutic ketamine used like once in 2 weeks or a similar long period? The first study gave ketamine to the rats every day for 5 days, so I'm not sure it's comparable to every 2 weeks in humans. Also, are the changes reversible? If so, I would expect that given ketamine's short half-life, such seldom administration wouldn't cause a progressive change in parvalbumin, GABA etc. Interesting stuff nonetheless, NMDA enthusiast

 

[dopamimetic]

Yeah, when used like this for refractory depression in sub-dissociative doses 2-4x per month the changes will be minimal, but they will be there - could be that this specific NADPH oxidase upregulation requires higher doses or more frequent administration to happen at a significant degree, and the AD activity is - as speculated - about NMDAr/AMPAr regulation.

But it will be of concern for recreational users, as well as these using ketamine (as an adjunct mostly) for pain. Here a decrease in GABA is the last one will want. So co-administering apocynin (a nice vanillin-related compound!) could be very interesting, I'd love to try this out. Or low-dose DXM, as it seems to be somewhat potent at inhibiting NADPH oxidase, maybe 1-2x 22mg per day would be enough and below any psychoactive threshold for normal metabolizers (maybe a little SSRI activity but not that much).

These changes will probably be reversible in adult humans, as most changes that are as long as they are not too overwhelming (but then again, the superoxide is somewhat toxic, or at least related to toxicity). They can induce disturbing or even disabling after effects (depending on the genetics, some become energized, other irritable and/or anxious, others psychotic... many don't realize anything at all). I don't really know any speculations about how long it will take either to induce the effects and how long the brain will need to re-adjust, and if taking something like apocynin / DXM might help even afterwards (it should, if the NADPH oxidase is actually upregulated).

An interesting thing is that N-acetyl cysteine, which metabolizes to glutathione, and helps to protect against oxidative stress etc. has a proven effect against depression, schizophrenia etc.. It lowers the effective dosages of various antidepressants and is even powerful when taken alone at dosages high enough. I've noticed personally that the nootropic antioxidant Emoxypine has some great benefits in alleviating headaches, fatigue and especially rebound / after effects / tolerance to dopaminergic things.

--

Also this raises again my theory, that not all depressant non-responders will respond to ketamine either. I don't get that lasting effect from ketamine, but paradoxically benefit from the actual action (or intoxication, if you want to call it so, but when dosed right, it's not intoxicating really) of dissociatives, the very most effective being MXE - and so it's not about dopamine, MXE does not have DA affinity afaik, and 3-MeO-PCP makes me just uncomfortably manic. With K (due to its short half live) this is most pronounced, but also from MXE I get some kind of excitatory rebound, worsening my anxiety and ADHD symptoms it relieved while active. Interestingly, DXM very much did do the trick, especially after some days of (low) dosing ... leading to a 3-7 days long period of really sunny mood and that 'okay, so must a normal human being feel' thing. But it had weird side effects from its other mechanisms, MXE is so much cleaner, so MXE + apocynin would make a great experiment. Unfortunately MXE is fuckin' prohibited and out of reach now.. so I'm hoping for 2'-OxO-PCE (if the MeO mainly pushed the affinity to SERT & maybe lead to an insignificant metabolite with slight opioid activity, then it could make a good candidate).

This would confirm the thing of rebound glutamate, GABA decrease and NADPH increase somewhat.

And it could add to the addictiveness K / MXE have for some, independent of any dopaminergic mechanisms ...

 

[belligerent drunk]

Personally the SERT/NET action of DXM puts me off a bit when thinking about long-term usage.

It's hard for me to speculate like this without raw data from human trials. Yes, superoxide is not exactly the thing you want to increase the production of, but you have to remember that all kinds of reactive oxygen species are created all the time - what matters is whether the increase in superoxide production is relevant especially when considering low doses several days/weeks apart.

How does glutathione help against depression and schizophrenia by the way?

 

[Skorpio]

Mxe does have DA affinity: http://www.sciencedirect.com/science/article/pii/S030698771200312X

It says it is a d2 agonist, but based on how pretty much all ayrlcyclohexylamines are dris but especially pce, and ketamine which both share structure with mxe, I feel like it is fairly safe to guess that the d2 agonism is via reuptake inhibition.

Until they screen it at Dat, this is all jus t guessing, but I think it is much more likely than it not being a dri.

Furthermore even if mxe isn't a dri, it still has dopamine activity

 

[dopamimetic]

Skorpio: Okay, that's new to me, thanks for the info! But somehow I'd say that MXE is much less potent at dopamine (agonism/reuptake inhibition) than the PCP's. Also if it's really plain D2 agonism, then the overall effects will differ from these of a DRI (compare e.g. pramipexole or even memantine to methylphenidate).

Do you have access to the full text of that paper, do they specify the affinity of MXE to the various receptors and especially D2? Because I'm taking memantine daily as a 'basic mood-stabilizer' which probably gets displaced when taking a more powerful dissociative, but since it's D2 affinity seems to be somewhat stronger than thought (it's equal to or slightly higher than it's NMDA antagonism- it just doesn't cause nasty dopamine agonist withdrawal because of the NMDA action) my brain will be used to some D2 agonism..

belligerent drunk: N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action It's also about glutamate & all that, but I don't understand it fully yet - free full text!

Afaik MXE has reasonable affinity to the SERT too, but it lacks the NE activity of DXM and maybe sigma activity which could contribute to the overall 'dirty' quality of DXM as well as the latter to the manic effects the PCPs have... Also MXE could well produce a minor, yet relevant, opioid-active metabolite at least in some. It's NMDA antagonism overpowers the opioid effects in that one will not really become dependent or get withdrawal even from chronic use (some very high dosing users got through a somewhat opioid-alike withdrawal though, but thinking of combined DA/SSRI withdrawal together with the rebound surge of glutamate, lowered GABA levels and just the psychological aspects of getting out of the comfortable psychedelic dissociation, I don't know..)

Some interesting anecdote from me though, I am somewhat sensitized to opioids since I've messed a bit with them last year. I sometimes get miosis (not really pinpoint pupils, but smaller than they should be) from low-ish doses of MXE as some others reported too. This together with some usual physical effects like constipation & the opposite when the substance wears off (no itching at all though, but I'm not that histamine sensitive either). It doesn't feel strong or concerning really, by far not comparable to any real opioid, but I've wondered nevertheless if and how much this contributes to the effects as well to the rebound of MXE (maybe this together with the 5-HT is what makes MXE so much more mellow and just normalizing instead of manic like 3-MeO-PCP).

Oh, and MXE sometimes really calms or even sedates me, in a very comfortable yet unique way... the most passable description would maybe be a combined GABAergic and dopaminergic feeling. This only happens when I should be tired (e.g. have been awake all day long) or my mind has been over-active and anxious etc..

 

[dopamimetic]

It's too early to conclude anything & of course I'm just one individual submitting anecdotal reports ...

... but I have really high hopes now that the DXM - NADPH oxidase inhibition does work and might be one of the keys to the puzzle I'm trying to get together. So I've literally abused a cough medicine with potent dissociative effects because of some weird side effect. How stupid okay, the dissociation and slightly psychedelic state of mind both have their own qualities that can help much when used correctly for therapeutic advancements etc.. and besides that, these states are just very interesting and intriguing to experience and research them ...but the NADPH oxidase could well have been the missing link.

So I don't know yet what it's about - if and how much NMDA antagonism and with which kinetics is required additional to the NADPH oxidase inhibition, if and how much SERT inhibition is required etc.. I hope of course that things will settle down over time when the cause gets treated and the neurons can self-regulate / self-heal mostly.. It seems, unfortunately , I won't be able to maintain this hypomanic thought-flowing everything-is-so-easy state of mind - that actually was quite real about enhancements, I had to look for delusions of course etc. but the speed at which I could learn new things, think about complex topics, make interconnections etc.. was just plainly amazing .. and with a surprisingly small error quote somewhat, based on that I'm just an amateur and all that..

Thought yesterday, hey, you took so many DXM in your adolescence, not really knowing about the possible side or long term effects ... and while it certainly was not the best to do, it does not seem to have caused relevant damage to my brain, cognition or emotion-processing. All these problems have been there before. If anything, then the drugs have made countless new connections, opened my eyes to the reality, gave me completely new perspectives and insights etc ... this can be overwhelming and leading to psychosis of course, but hm.. I'm not the psychotic guy. That's another story.

So I've bought a box of 30mg DXM HBr cough capsules yesterday. Took one in the evening, one more when I went to bed. Might have been placebo, but I fell asleep very quickly. Woke up somewhen at 2a.m. as usual, brushed teeth and put some calm music on. Again, seemed to fell asleep very quickly and into a deep, refreshing sleep. I usually dream in the morning hours around 5-7a.m. and the dreams tend to become surreal and strange with time, eventually waking me up with some hints of anxiety.. this would the have been the time to either take some benzodiazepine or a bump of MXE (which is equally anxiolytic for me, but not as sedating and I really fear the long-lasting horrific physical addiction GABAergics can bring with, so I usually go with the dissociatives)..

Not this morning. I woke up fully awake, but refreshed, no more morning anxiety or borderline-panic - remembering parts of dreams, finally 'real' dreams and not nightmares any more ... confident, motivated, ... Continued to take 30mg HBr at morning, at noon and later then the evening one. This is the recommended dosage schedule for cough, some with serious chronic bronchitis etc. go even higher. I don't take any CYP inhibiting meds currently.
Fascinating result: Anxiety is abolished by maybe 75%. Inner tension maybe by 50%. Headache completely gone through the day. I had no urge at all to take either MXE or IPPD (from the latter I took a tiny bit in the afternoon to keep me motivated, but that was <5mg, together with 125mg of emoxypine)

From time to time I'm feeling a bit sick, a common side effect from DXM probably due to its 5-HT activity.. this will pass. It seems to synergize pretty well with the memantine (currently trying to cut the dosage down as well, 25mg today) ... would be soo nice to have a legal, established, pharmaceutical way to recreate the MXE antidepressant effect ... and this even safer and without the rebound!!

The amount of DXM I'm using is probably too low to do anything serious beyond mild SSRI action and said NADPH oxidase inhibition. Maybe very mild sigma-1 activation. So it really boils down to the NADPH oxidase!

--

I really need to get this apocynin vanilloid related NADPH oxidase inhibitor, and I'm really interested in the 2'-OxO-PCE (pleeease kids, just find it disturbing or dysphoric, whatever, and forget about it, please.. it should be relatively forgiving in terms of overdose etc. as ACH dissociatives tend to be, but someone always manages to kill him/herself with the unlikeliest substance available-sigh) which should arrive these days. Pure dextrorphan would be nice too, to allow some fine tuning ...

--

I'm definitely out of the (hypo)mania now, but I'm not depressed either (so please don't worry when I need a bit more time to write / respond..). I'm just here. Calm, positive, open-minded. A bit tired from all the intense stuff and some unbelievable stories I've experienced in my private life, but all in all pretty confident and hopeful. Could this OTC cough suppressant I've stumbled into as a teenage of 17 years or so.. really be the solution I've been desperately looking for!?
It even seems to have an established safety profile now for long term use, they think about giving it to people with Parkinson's and all sorts of degenerative diseases ... as well as the DXM/quinidine combo (Nuedexta) for Pseudobulbar Affect <-- something I really need to look into, maybe this could also be about the NADPH oxidase inhibiting effect & thus combining with quinidine would allow for smaller, longer lasting doses and maybe less side effects from the DXO metabolite... (but I'm not sure yet whether I like the dissociation or not.. from time to time certainly, yes, it has a true therapeutic quality to it.. but it's nothing to be on all the time, even though this would bring relief for some of the hyper-sensible / possibly OCD people..)

 

[dopamimetic]

An extension of hypotheses regarding rapid-acting, treatment-refractory, and conventional antidepressant activity of dextromethorphan and dextrorphan.

It was previously hypothesized that dextromethorphan (DM) and dextrorphan (DX) may possess antidepressant properties, including rapid and conventional onsets of action and utility in treatment-refractory depression, based on pharmacodynamic similarities to ketamine. These similarities included sigma-1 (σ(1)) agonist and NMDA antagonist properties, calcium channel blockade, muscarinic binding, serotonin transporter (5HTT) inhibition, and μ receptor potentiation. Here, six specific hypotheses are developed in light of additional mechanisms and evidence. Comparable potencies to ketamine for DM and DX are detailed for σ(1) (DX>DM>ketamine), NMDA PCP site (DX>ketamine>DM), and muscarinic (DX>ketamine>>>>DM) receptors, 5HTT (DM>DX≫ketamine), and NMDA antagonist potentiation of μ receptor stimulation (DM>ketamine). Rapid acting antidepressant properties of DM include NMDA high-affinity site, NMDR-2A, and functional NMDR-2B receptor antagonism, σ(1) stimulation, putative mTOR activation (by σ(1) stimulation, μ potentiation, and 5HTT inhibition), putative AMPA receptor trafficking (by mTOR activation, PCP antagonism, σ(1) stimulation, μ potentiation, and 5HTT inhibition), and dendritogenesis, spinogenesis, synaptogenesis, and neuronal survival by NMDA antagonism and σ(1) and mTOR signaling. Those for dextrorphan include NMDA high-affinity site and NMDR-2A antagonism, σ(1) stimulation, putative mTOR activation (by σ(1) stimulation and ß adrenoreceptor stimulation), putative AMPA receptor trafficking (by mTOR activation, PCP antagonism, σ(1) stimulation, ß stimulation, and μ antagonism), and dendritogenesis, spinogenesis, synaptogenesis, and neuronal survival by NMDA antagonism and σ(1) and mTOR signaling. Conventional antidepressant properties for dextromethorphan and dextrorphan include 5HTT and norepinephrine transporter inhibition, σ(1) stimulation, NMDA and PCP antagonism, and possible serotonin 5HT1b/d receptor stimulation. Additional properties for dextromethorphan include possible presynaptic α(2) adrenoreceptor antagonism or postsynaptic α(2) stimulation and, for dextrorphan, ß stimulation and possible muscarinic and μ antagonism. Treatment-refractory depression properties include increased serotonin and norepinephrine availability, PCP, NMDR-2B, presynaptic alpha-2 antagonism, and the multiplicity of other antidepressant receptor mechanisms.

This stuff is real and exciting. It's making me pretty tired at the moment, but in a comfortable way, I guess from the over excitation being normalized now ... very relaxed and finally (nearly) no more anxiety & hopelessness ... !!!
I've felt / 'knew' all this so much earlier, years ago, but I did not trust my feelings and I and others convinced me that it was just drug delusions and I was on the way to becoming addicted.. the myth that DXM is an opiate is still around amongst some medical staff, pharmacists etc. It's feeling so much better knowing the science now and seeing that low-to-moderate dosed DXM even seems to have a really well established long-term safety profile.

Remarkable that dextrorphan actually antagonizes the mu opioid receptor! (While DXM potentiates it, which might make a net plus though - and it would explain that story out of the DXM FAQ of some guy tripping hard on high doses who eventually got opioid withdrawal with and without dosing...)

But can anyone clarify what they mean with this PCP receptor? I know they named the binding sites after the ligands sometimes, so they had PCP1, PCP2 etc.. but here we have NMDA and even subunits with exact description, and then again a PCP receptor. Is this what White suggested, dopamine reuptake inhibition either directly the DAT or by an indirect mechanism? Or what?

Thanks

 

[dopamimetic]

Oh dear, please read through the thread and the references I've posted (probably we don't have all there, but if you're interested look here). DXM has actually been proposed as a rapid-acting powerful antidepressant for refractory and/or therapy resistant depression. We don't speak about full-on dosages, the range is above the cough dosage (but not much) and below of what's used recreationally. It's also used for a condition called pseudo bulbar affect and is FDA approved for this (Nuedexta).

That said, for me it didn't work. DXM has some dark sides to it that the unfortunately prohibited arylcyclohexylamines lack, despite all papers and theories.

(And for cough it doesn't do fuck. Am having a heavy cold right now.)