NADPH Oxidase - Overlooked Key Player for Tolerance, Stress-related Mental Disorders?

[dopamimetic]

NADPH oxidase mediates depressive behavior induced by chronic stress in mice.

Stress is a potent risk factor for depression, yet the underlying mechanism is not clearly understood. In the present study, we explored the mechanism of development and maintenance of depression in a stress-induced animal model. Mice restrained for 2 h daily for 14 d showed distinct depressive behavior, and the altered behavior persisted for >3 months in the absence of intervention. Acute restraint induced a surge of oxidative stress in the brain, and stress-induced oxidative stress progressively increased with repetition of stress. In vitro, the stress hormone glucocorticoid generated superoxide via upregulation of NADPH oxidase. Consistently, repeated restraints increased the expression of the key subunits of NADPH oxidase, p47phox and p67phox, in the brain. Moreover, stressed brains markedly upregulated the expression of p47phox to weak restress evoked in the poststress period, and this molecular response was reminiscent of amplified ROS surge to restress. Pharmacological inhibition of NADPH oxidase by apocynin during the stress or poststress period completely blocked depressive behavior. Consistently, heterozygous p47phox knock-out mice (p47phox(+/-)) or molecular inhibition of p47phox with Lenti shRNA-p47phox in the hippocampus suppressed depressive behavior. These results suggest that repeated stress promotes depressive behavior through the upregulation of NADPH oxidase and the resultant metabolic oxidative stress, and that the inhibition of NADPH oxidase provides beneficial antidepression effects.

Involvement of NOX1/NADPH Oxidase in Morphine-Induced Analgesia and Tolerance

The involvement of reactive oxygen species (ROS) in morphine-induced analgesia and tolerance has been suggested, yet how and where ROS take part in these processes remains largely unknown. Here, we report a novel role for the superoxide-generating enzyme NOX1/NADPH oxidase in the regulation of analgesia and acute analgesic tolerance. In mice lacking Nox1 (Nox1−/Y), the magnitude of the analgesia induced by morphine was significantly augmented. More importantly, analgesic tolerance induced by repeated administration of morphine was significantly suppressed compared with that in the littermates, wild-type Nox1+/Y. In a membrane fraction obtained from the dorsal spinal cord, no difference was observed in morphine-induced [35S]GTPγS-binding between the genotypes, whereas morphine-stimulated GTPase activity was significantly attenuated in Nox1−/Y. At 2 h after morphine administration, a significant decline in [35S]GTPγS-binding was observed in Nox1+/Y but not in Nox1−/Y. No difference in the maximal binding and affinity of [3H]DAMGO was observed between the genotypes, but the translocation of protein kinase C isoforms to the membrane fraction following morphine administration was almost completely abolished in Nox1−/Y. Finally, the phosphorylation of RGS9-2 and formation of a complex by Gαi2/RGS9-2 with 14-3-3 found in morphine-treated Nox1+/Y were significantly suppressed in Nox1−/Y. Together, these results suggest that NOX1/NADPH oxidase attenuates the pharmacological effects of opioids by regulating GTPase activity and the phosphorylation of RGS9-2 by protein kinase C. NOX1/NADPH oxidase may thus be a novel target for the development of adjuvant therapy to retain the beneficial effects of morphine.

--

NOX has several homologs, including NOX2 implicated in neurodegenerative and psychiatric disorders (Sorce and Krause, 2009). NOX2 was also reported to take part in the development of neuropathic pain induced by nerve injury (Kim et al., 2010). NOX1 is not well understood, and although its role in some organs is being elucidated (Matsuno et al., 2005, Cui et al., 2011), its function in the nervous system is still unclear. Previously, we demonstrated the involvement of NOX1 in hyperalgesia using mice lacking the Nox1 gene (...)

(Free full text!)

Could explain somewhat why the NMDA antagonism approach to prevent tolerance development (to stimulants, opioids) did not work as expected for many, or at least eventually one begins to become tolerant to the NMDA antagonist itself. While it is disputed (afaik) whether the NMDA receptors do up regulate to a relevant degree at all with low-to-moderate antagonism, there undoubtedly is the phenomenon of dissociative tolerance.

And this dissociative tolerance could be mediated by upregulated NOX, leading through a cascade of mechanisms amongst other nasty effects also to a generally higher amount of glutamatergic neurotransmission (and thus higher doses of NMDA antagonists required for the same effects, as well as a general shift in effects because the other glutamate receptors are affected too- this includes partially positive reactions like the Ketamine-mediated rapid antidepressant effect, as well as negative ones ranging from excitatory rebound up to psychosis - and/or 'dissociative addiction').

Maybe the oxidative stress itself can lead to production of quinolinic acid - and things will escalate.

Now we have a readily available NOX inhibitor: dextromethorphan. Indeed it seems not only to exhibit qualitatively unique anxiolytic, antidepressant and especially stress-alleviating effects, but also lowers tolerance to NMDA antagonists and potentiates the anti-tolerance effects of e.g. memantine as proven by many anecdotal reports and myself - with DXM dosages used that are too low to act on NMDA etc. to a significant degree.

Apocynin is a vanillin-related compound that would be free of DXM's other effects and side effects. Unfortunately it's not available as a medicine yet, but it certainly needs to be further explored.

(As a side theory - since dopamine gets partially metabolized to homovanillic acid - which is structurally similar to apocynin - could it be that elevated dopamine levels will cause a downstream decrease of NADPH oxidase, and low DA levels potentially the opposite - leading to a novel explanation for the beneficial effects psychostimulants exhibit for e.g. ADHD even after one becomes used / tolerant to the acute effects? Besides the interesting fact that the 'non-stimulant' atomoxetine indeed is a NMDA antagonist in clinically relevant dosages- which probably mediates a good part of it's benefits.)

And we have that weird bupropion with it's insignificant NDRI properties, that looks like a somewhat locked-down cathinone that from time to time counters even parallel administered psychostimulants and indeed it modulates glutamate. In rats, it inhibits glutamate release. But rats also self-administer bupropion much more than humans, speculated due to differing metabolism.. now it depends if this inhibition is caused by the bupropion itself or dependent on the metabolism. (By accident I've discovered that DXM is able to 'unlock' bupropion, which now finally makes sense - with just 50mg of time-released DXM being enough to get powerful cathinone-like stimulation out of 150mg bupropion SR - but only when used chronically, not acutely. The CYP inhibition probably contributes to that, but I'd bet it's about NOX & glutamate, maybe as well as the SSRI effect from DXM, eventually leading to a triple reuptake inhibitor)

Just wild guessing, but it's somewhat intriguing to me

--

The NADPH oxidase NOX2 controls glutamate release: a novel mechanism involved in psychosis-like ketamine responses.
Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase.

--

Edit: Last but not least, what negative / potentially dangerous effects could inhibiting the NOX have (acutely and chronically)? I highly guess that, as usual, there's nothing without a catch and these superoxides are necessary for something like immune response ...

 

[dopamimetic]

Apocynin is actually contained in the Himalayan herb Kutki (Picrorhiza kurroa), but maybe only in the roots while they usually only sell / use the leaves (?) have to research more. I need such a Kutki plant!

 

[rabidrick]

Hmm... I have no clue if it is a significant part; it's so damn ubiquitous it would probably be very hard to differentiate it from all the noise.

Isn't DXM a NMDA antagonist, itself? So you can't become tolerant to it? That seems odd.

Looking at the structure of Apocynin, it is propylvanillin which you can find from fragrance chemical suppliers. Ethylvanillin is more common and is really close.

 

[dopamimetic]

Thanks for your reply!

The NMDA antagonist tolerance thing is really confusing. It seems that there is no direct tolerance development like to e.g. dopaminergics or opioids, but the brain reacts by upregulating that NADPH oxidase, maybe through interleukin–6, eventually resulting in more glutamate through some downstream cascade effects. This might be the mechanism behind dissociative tolerance, 'addiction' etc. up to psychotic and manic reactions to things like MXE or Ketamine. But it also mediates the rapid acting antidepressant effects for some.

Now DXM is unique in that it inhibits the NADPH oxidase. With high dosages this gets probably overpowered and one can and will become tolerant to the other effects of DXM. But it indeed has a weird, unique non-linear tolerance line. And in low doses it potentiates other dissociatives, abolishes the after effects and tolerance!

Will write more later, am from mobile now..

 

[MyExcuse]

Dopamimetic, what dose of DXM?

 

[dopamimetic]

It's active at real therapeutic dosages, one capsule (22mg) 3x per day or so.. The dosage is not that relevant for it to inhibit NADPH oxidase (NOX) as it seems to be fairly potent at this & it's certainly independent from the recreational effects. Unfortunately there are no numbers yet afaik about the potency and strength of DXM at inhibiting the NOX, so we don't know whether it's able to fully or only partially inhibit it, competitive or not and reversible / irreversible. Concerning the latter, I'd say it's reversible.

Constant low plasma levels are crucial for it to work properly - that's why they co-administer the CYP2D6 inhibiting cimetidine when used as Nuedexta for emotional lability.

Also DXM is somewhat bi-phasic (or even tri-phasic, as one more metabolite, 3-hydroxymorphinan, was shown to be active too- it inhibits glutamate release, is anticonvulsant and neuroprotective!). Now it gets metabolised over at least two CYP enzymes that have varying activity in different individuals and depending on the DXM regimen as well as other medication and even food (grapefruit juice for example!), smoking etc. they get partially inhibited too, leading to altered levels and ratios of the metabolites to the main component.

So we have DXM that is mainly a SSRI (SNRI and σ1 agonist at higher dosages) and NOX inhibitor. Then we have DXO that's a noncompetitive NMDA and Glycine antagonist, σ1 & σ2 agonist, L-type voltage-gated calcium channel blocker, κ-agonist and μ-antagonist as well as α3β4, α4β2, and α7 nACh antagonist. Unfortunately no Ki numbers for DXO as far as I know, at least not openly accessible :/

And finally 3-HM that also blocks presynaptic voltage-dependent calcium channels and protein kinase C. (Remember that NMDAr´s are kind of Ca channel doormen, so Ca channel blockers affect NMDAr´s but not always the other way round, Ca channels are even much more abundant throughout our brain and body)

This makes DXM a really complicated and non-linear compound. For tolerance reduction, mostly the NOX inhibition of DXM itself is relevant because this is unique and very possibly alleviates tolerance development as well as psychotomimetic adverse effects from dissociatives. In regards to tolerance reduction to opioids or dopaminergics, you'll want a synergy between NOX inhibition and NMDA antagonism, so a balanced ratio between DXM and DXO or - maybe with less side effects - DXM and memantine.

Problem I see is that DXM gets metabolised into DXO. So the NOX inhibition wears off before the DXO leaves the system, resulting in a brief surge of glutamate afterwards - which could well explain the feeling many DXM users experienced and have described in reports that it feels 'toxic' or 'psychotic' etc. (besides the direct 5-HT activity which, over activation of e.g. 5-HT2a, is psychedelic itself) - while DXM indeed might be a somewhat safe dissociative, possibly safer than ketamine (in the low-moderate dosages, when going higher the 5-HT can lead to temporal lobe seizures[1] and hyperthermia). But one would need to take 1-2 additional capsules on the end of the trip, to alleviate the rebound glutamate. This could also well be combined, just use low dose DXM along with other dissociatives like MXE etc. and you'll probably get a smoother experience.

[1] TLS - wikipedia - especially the link to religiosity and this can induce / progress to psychotic episodes that last longer than the actual pharmacological activity, as well as unexplainable feelings of jamais-vu / deja-vu / sadness etc. I highly suspect this to be a major mechanism for MXE and DXM (maybe even LSD / serotonergic psychedelic) related black-outs, mystical experiences and psychosis. The exact mechanisms aren't established yet, but since ketamine is much less prone to this (ketamine psychosis seems to be due to NOX and glutamate and is more a thing of chronic use that doesn't occur acutely in most people - K is used as an anaesthetic with few complications after all[2]) and since both MXE and DXM are powerful serotonergics, it's obvious to think of a serotonergic (5-HT2A?) mediated mechanism for me. Also this part of White's DXM FAQ is quite interesting here.

[2] But dissociative anaesthesia can trigger psychosis in susceptible individuals, I know of someone who was paranoid before, but after a surgery seemingly involving dissociative anaesthesia (from her subjective description of the experience) it escalated with her thinking of a chip had been implanted in her head etc.. leading to diagnosis of chronic schizophrenia, treatment with neuroleptics etc- that did not really work (as it doesn't in about 50% the cases or so, if you ask me) but eventually she responded quite well to psychostimulants- they had severe adverse effects and dosage escalation, also as usual, so she had to cease use. But it makes all perfect sense now thinking of the dopamine-homovanillic acid-NOX inhibiting link & that she probably has an underlying genetic fragile glutamate system, possibly emotional hyper sensibility too.

(Anyone knows the Ki values of ketamine for the sigma receptors compared to MXE / DXM / PCP? And how about dizocilpine, which seems to be somewhat well studied?)

--

Maybe even the good old N-acetyl cysteine (NAC/ACC) has some similar effect in high dosages, it's being researched for use against various mental disorders (free full text) - amazing!

--

rabidrick, thanks for the link to propylvanillin, I'll certainly look further into this. Could be nothing, but it could also make a huge change to dissociative tolerance / side effects etc.! But maybe this isn't even necessary if the NAC thing works as they propose.

The use of NAC in restoring GSH levels is well established. Glutathione is the primary endogenous antioxidant. Glutathione neutralizes reactive oxygen and nitrogen species from the cell through both direct and indirect scavenging. As the most abundant and ubiquitous antioxidant, it is responsible for maintaining the oxidative balance in the cell. This occurs through both direct removal of reactive species through the formation and breakdown of adducts and is also catalyzed by glutathione peroxidase (GPx) in a nicotinamide adenine dinucleotide phosphate (NADPH)–dependent reaction.

So NAC does somewhat the same as an NADPH oxidase inhibitor but over a different pathway!

--

Edit: This all even leads me to speculate about whether the mechanism behind these infamous Olney's lesions that have limited the use of NMDA antagonists as neuroprotectives for quite some time, as well as the chronic neurotoxicity of Ketamine that has recently been observed in humans, is related to the oxidative stress and could be avoided with all this new evidence!

--

- Oxidative stress in psychiatric disorders: evidence base and therapeutic implications.
- Schizophrenia susceptibility genes converge on interlinked pathways related to glutamatergic transmission and long-term potentiation, oxidative stress and oligodendrocyte viability.

 

[dopamimetic]

I can't believe it, but all this stuff is fucking incredibly true and working ... I'm experiencing it right now.. so long forgotten clarity and pure emotions of being finally at home and calm, awake and open to the world at the same time ... somewhat like being an innocent child again ... no more head- and body aches, no more anxiety, fear, hopelessness, isolation, whatever ... it's just plainly incredible. That hi-definition vision people sometimes experience from nootropics - just recognising so much more details like all the leaves on a tree, houses on the horizon and all that ... but with no stress at all.. and my sense of smell seems to heal too, it was severely impacted for years (something that quite a few depressed people seem to experience) ... the neurogenesis is possible and real

What I'm currently taking:
Dextromethorphan 22mg 4x/day
Memantine 30mg/day
N-acetylcysteine 800mg 3-4x/day
Clonidine 50mcg when required (for sleep usually)
and some vitamins & magnesium bisglycinate, don't know how relevant they are.

It even seems that some physical symptoms like my chronically clammy hands and diarrhoea begin to get better now ... but I'm also feeling pretty lonely at the moment because I know that I can't talk about all this with anyone, not even thinking of the professionals who are trying to get me into drug detox etc ... thankfully I have a very open-minded doctor who is seriously interested in my findings and all that, and I really hope things will come out good but it's so complicated ...

 

[dopamimetic]

Yeah, it continues it's pretty impressing to have this clarity of mind and easy access to all these partially forgotten memories in a somewhat calm, positive but not hypomanic state ... also I've just measured my blood pressure & pulse and realised that the pulse is down to 75, when I've had tachycardia since I can remember with 80-85 being my usual resting BPM and I've been taking metoprolol every now and then in the last time, but no need for it any more currently ... let's see maybe I can even go off the clonidine!?

Also fell asleep very easy yesterday, sleep was deep and without disturbing dreams.. woke up after 8 hours or so fully refreshed and awake, just like it was before I became depressed and all that.. but I forgot much about that time..

Low-dose dextromethorphan, a NADPH oxidase inhibitor, reduces blood pressure and enhances vascular protection in experimental hypertension.

Just hope I don't develop tolerance to the DXM now by some other even more weird mechanism ... we'll see

--

Anyone able to access this publication?
Concerns about dextromethorphan as a potential rapid-acting antidepressant. Not even an abstract is publicly available

--

Strange thing is that I'm slightly hyper in some moments, now that the dissociation has worn off (and/or DXM is just less pronounced in this, as I've finally run out of MXE some days ago) and especially I'm experiencing some sort of cravings ... while I was depressed, I've been nearly immune to addiction or drug-seeking behaviour. Of course the physical side was there sometimes as well as the obvious comedowns, rebounds etc. but usually I took them as signs to stop and had no problem to do so.. but now, as I'm feeling normal and positive, and maybe my brain is going to act more like in the average non-depressed human, I seem to become susceptible to cravings as well.. this is something I've experienced with DXM and the related antidepressant / mood-lifting effect several years ago and then I eventually struggled with drinking, but I didn't realise the mechanisms really.. also it might be one reason for the (relatively rare) cases of DXM dose escalation and addiction?

It's nothing I can't control and passes quickly when I focus on something else, so it's not serious maybe because I'm not that new to psychoactive use in general, but it's funny and well.. a bit annoying. I'm craving for dopamine, despite that I'm pretty happy. I'm wanting to do some ketamine or MXE or drink some wine ...

Also this might well be a factor that has limited the use of strong antidepressant agents in psychiatry because it would need some serious counselling etc. when one's used to being depressed for years and then suddenly feels normal, it's not easy to stay in control... this can easily be misinterpreted as hypomania or delusional thinking or whatever by outside persons (as well as by oneself) ...

 

[dopamimetic]

Concerns about dextromethorphan as a potential rapid-acting antidepressant
We read with great interest the study by Lauterbach [1] in which the author proposed an insightful hypothesis that dextromethorphan has the potential to be a fast-acting antidepressant. We appreciate the hypothesis proposed, and would like to add few predictions relevant to this article.
First, the author proposed that further researches are needed to test the rapid-onset of antidepressant effect within days after dextromethorphan administration. However, several lines of evidence have demonstrated ketamine exerting antidepressant with- in hours after medication [2], and the fast-acting activity within days are not the predominate characteristic of NMDA receptor antagonist. So we assumed that it is appropriate to validate the rapid-onset of antidepressant effect of dextromethorphan within hours.
Second, a pivotal prediction, we concentrated, whereas the author neglected. Conventional antidepressants are intended to exert their therapeutic effects, which are mainly attributed to the increase of intrasynaptic monoamine transmitter via inhibiting monoaminergic transporters. A preclinical study has shown that ketamine inhibits the expression of monoamine transporters in cultured human embryonic kidney 293 cells [3]. Based on this point, the inhibition of monoamine transporters is probably one of the mechanisms for ketamine exerting antidepressant effect. Accordingly, a prediction is needed to verify the inhibition effect of dextromethorphan on monoamine transporters.
Third, an excellent job reported in Science recently has shown that the up-regulated mammalian target of rapamycin (mTOR) in rat prefrontal cortex mediates the ketamine-induced fast-acting antidepressant effect [4]. Consequently, as the same as ketamine, an NMDA antagonist, we presumed that dextromethorphan may elicit fast-onset antidepressant effect via activating the pivotal signal mTOR.
References
[1] Lauterbach EC. Dextromethorphan as a potential rapid-acting antidepressant. Med Hypotheses 2011.
[2] Machado-Vieira R, Salvadore G, Diazgranados N, et al. Ketamine and the next generation of antidepressants with a rapid onset of action. Pharmacol Ther 2009;123:143–50.
[3] Nishimura M, Sato K, Okada T, et al. Ketamine inhibits monoamine transporters
expressed in human embryonic kidney 293 cells. Anesthesiology 1998;88:768–74.
[4] Li N, Lee B, Liu RJ, et al. MTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010;329:959–64.
Zhiqiang Zhou Jing Wu Chun Yang Department of Anesthesiology

Nothing really new, but sci-hub rules!

 

[Cotcha Yankinov]

I'm so confused, what's the connection between NMDA antagonism and mTOR? Or is it something that's not necessarily related to the NMDA antagonism itself but ketamine and DXM both have effects related to mTOR that aren't related to their NMDA antagonism but they are similar compounds hence DXM likely works on mTOR similar to ketamine because they're structurally related? How about memantine? mTOR is very interesting and important but complicated... Wish I understood it better

From wiki - "TOR is implicated in the failure of a 'pruning' mechanism of the excitatory synapses in autism spectrum disorders.[33]"
Hmmmmmmm

 

[Cotcha Yankinov]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223653/#!po=16.1517
Here is a decent study on TOR, talks about the relationship between TOR and glutamate as well.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210466/#!po=4.59941 -"Dysregulated mTORC1-Dependent Translational Control: From Brain Disorders to Psychoactive Drugs"
This study is a bit better, long but the section Psychoactive Drugs is very interesting, TOR activation seems to be responsible for the glutamate related memory problems with THC even. Seems like mTOR is playing a big role in addiction.

"Abstract
In the last decade, a plethora of studies utilizing pharmacological, biochemical, and genetic approaches have shown that precise translational control is required for long-lasting synaptic plasticity and the formation of long-term memory. Moreover, more recent studies indicate that alterations in translational control are a common pathophysiological feature of human neurological disorders, including developmental disorders, neuropsychiatric disorders, and neurodegenerative diseases. Finally, translational control mechanisms are susceptible to modification by psychoactive drugs. Taken together, these findings point to a central role for translational control in the regulation of synaptic function and behavior.

mTOR Signaling Pathway and Translation Initiation
Mammalian target of rapamycin function is regulated by the activity state of several neuronal surface receptors and channels (i.e., TrkB, NMDAR, AMPA, D1R, D2R, mGluRs) and by diverse signaling cascades activated by these receptors, including PDK1, PI3K, Akt, and TSC1/2"

 

[dopamimetic]

That mTOR's certainly fascinating ... but they haven't yet settled even if it should be called 'mechanistic' or 'mammalian' target of rapamycin (or?). Thanks for sharing, some more food for my brain these days (can't avoid to think of torrent download stuff when reading mTOR - I want a pirated downloadable dissociative! Maybe with the evolution of 3D printers we'll finally have something like that once?)

Seems like it's not just everything about NMDA receptors, because blockade of sigma-1 caused a significant decrease in the antidepressant activity of dextromethorphan. Have to research about the potencies of memantine etc. on sigma-1 because DXM is certainly more potent and somewhat uniquely stimulating - a side that memantine unfortunately lacks. But after some time, I seem to adjust quite well to the DXM too and all over these papers it's being said to have a good safety profile.

It's just making me a bit tired physically and energised at the same time, not too uncomfortable and certainly much better than any of the Rx meds I've gone through ... the yawning has stopped and I realise that I'm able to focus much better than usual with next to no effort required, makes Ritalin look like caffeine somewhat (but the focus thing is also a bit weird.. has some hints of creativity from the 5-HT too, definitely distinct to the cold, mechanical NDRI one). Annoying side effect is that everything that messes with NMDA receptors exacerbates tinnitus in my left ear. Does anyone know about the mechanisms behind this and if there's anything one can do against (probably nothing)? I know to have a damaged / scarred eardrum on the left due to a trauma, can be related.

Quite a few people report this and are alarmed too but it seems to be an entirely psychical / 'virtual' symptom that isn't related at all to hearing less or even toxicity. Speculation is that the tinnitus has always been there, much like that visual snow phenomenon and the really appreciable HD vision in general, and I'm just noticing it more. But the snow is much easier to tolerate, it has no colour to it and if I don't look for it, I don't notice it either. But the sound is always there if I'm not distracting myself...

Ketamine-Induced Loss of Phenotype of Fast-Spiking Interneurons Is Mediated by NADPH-Oxidase (full text)

At the highest doses, greater than 4 mg/kg, up to 64% of patients experienced side effects. A majority felt a sense of euphoria.

Oral dextromethorphan doses as high as 36–38 mg/kg per day have been administered to children undergoing cardiac surgery with cardiopulmonary bypass for neuroprotection. (source)

Funny side effect for an antidepressant (many actually have depression and especially suicidal behaviour listed as adverse effects). No, really, it's indicating that we don't have one more mood-blunting agent like these SSRIs but an actual mood-brightener!

--

By the way, just finally put my little Sundance Research project online. First post with some PDF's about dextromethorphan. (The site isn't trackable to my real person without efforts, but I'll keep backups for sure.) Have yet to think about what I / we could make out of that idea, but it's becoming interesting!

Anyone who's interested in participating is welcome! Sharing information, knowledge, discussion and all that ...

 

[Cotcha Yankinov]

Hey dopa, do you think the anecdotal reports of negative effects after long term DXM abuse might be due to the fact that a human who has been abusing it has been shutting down their NMDA for a really long time? So it might not necessarily be damage as much as it is they weren't "learning" very well throughout their drug use, their plasticity was inhibited along with the NMDA I suppose? I hope that makes sense... If this is the mechanism of the learning/language sort of deficits than I suppose the big key would to be not to use it consecutively for weeks, to give yourself breaks to let plasticity (or whatever is being inhibited) do its job.

There was a bit in one of the studies about ketamine's antidepressant effects being blocked if you inhibit TOR interestingly, there's so many freaking interactions. I can't stop thinking of the onion router either hehehehe.

I suppose there are all the "neuronal visual snow" related effects to explain the tinnitus, in that it might be related to a filtering of noise or increased awareness, but I feel I should suggest here that it could be related to jaw problems, as tinnitus is very classically associated with jaw problems and you might be clenching a bit more than usual. Just thought I'd throw it out there. Though the one sided bit is odd. I've got a lot of tinnitus as well, it gets much worse when I clench or open my jaw personally.

Anyways it seems that TOR might very well be the culprit behind loads and loads of neurodegenerative diseases, I'll have to read more and try to give an overview someday.

ALSO THE WEBSITE IS FANTASTIC!! Toodles!!

 

[dopamimetic]

Hey there!

It's really just speculation based on the science, my research and experiences together with what I've extrapolated from e.g. White's FAQ - but then, yes, it'd be about glutamate disruption that happens beyond a certain threshold (the plasticity is really interesting, when one is new to dissociatives, there is some kind of learning process - the first time you'll have a blank piece of paper, and every time you re-visit, you're adding a chapter. This phenomenon has been well described by others, and I can confirm it's true. But nothing to worry about, things will eventually integrate and the weirdness goes away.) together with the psychedelia-like aspects from the free flowing thoughts and the 5-HT activation, this easily leads to fear, thinking about brain damage and all that. The cognitive impacts seem to be real too, but I don't know really about them, this is a part that never hit me anywhere as strong as others - what leads me to the theory that dissociatives actually normalise my over-active glutamate and that truly appreciable easy cognition and focus on the right low dosages would confirm this. So people with a normal glutamate activity are more prone to cognitive disruptions and post-dissociative problems obviously. But even these aren't brain damage, NMDA antagonism actually prevents excitotoxicity from happening, this is why they gave and give high-dose DXM etc. to children (like with that surgery mentioned in one of the AD related papers) sometimes.

But as the plasticy phenomenon is real, it's probably crucial too to guide the brain into the right direction - just staring at a blank wall, fearing about fears and damage will lead to bad new connections. Doing creative things while dissociated, and if it's only imagining nice landscapes, feeling good etc - will lead to better synapses forming maybe

I'm not completely sure yet, but it really seems like a well-dosed DXM regimen makes a truly good antidepressant. It would certainly be nice to have the tree active substances (DXM, DXO and 3-HM) separate from each other and be able to fine-tune the dosages, but in the end DXM is so much more than one could expect from an old dusty OTC cough suppressant.

--

The jaw topic might really be something, but it's difficult. I know that my left lower wisdom teeth has it's root growing into some nerve channel. This made my dentist fear of pulling it out so it's still in there. If I clench my jaw, the left tinnitus indeed changes the pitch somewhat, yes.. but if anything then the DXM or NMDA antagonism in general is more muscle relaxing than otherwise. No more tension headaches! And memantine has been a muscle relaxant in the end before they re-patented it for Alzheimer's and decided to make another billion shitload of $$$ with it.

Yeah - forgot about the most obvious association of TOR!
I'll look a bit about plugins for my website today and such.. how versed are you in technology / web things? If you're interested, I'll make you an account with full write access.. I can't fill the whole page alone

Toodles!