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DXM as a novel antidepressant

As I don't have a better dissociative at hand now, I thought of taking a low dose of dextromethorphan to help myself with a setback of benzodiazepine withdrawal. I must say that a single 30mg dose helped me with cloudy mind and significantly increased my mood. I could be over-sensitive now though after quitting clonazepam half a year ago, but I used to take DXM when I was a kid (it was actually the first drug that I got addicted to) and I never found doses above 450mg to be pleasant.

I think there's a lot to be done here. I've been always fascinated with DXM's pharmacology, but I somehow forgot about it when I got dependent on opioids for years. DXM's main metabolite DXO isn't really well researched, a few days ago I was looking for some affinities and surprisingly I couldn't find precise information. Moreover, there are so many ways in which DXM and DXO could be modified structurally making it more selective for NMDA receptors. DXM's affinity towards SERT is definitely too high relatively to its affinities at other sites and that makes it feel so dirty.
 
My intuition would have been that more selective NMDA antagonists have reduced incidence of side-effects, but my comparative experiences with ketamine, mxe, and 3-meo-pcp haven't confirmed such. Still hate how DXM feels though.

ebola
 
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I have to imagine a lot of DXM's messiness comes not only from the antinicotinic element, but also interactions with serotonin/norepinephrine reuptake transport as well as ion channel/membrane fuckery. Really, it's just a messy drug, pharmacologically speaking, and the fact that it metabolises into three or four active compounds (DXO, nor-DXM, etc) in a nonlinear fashion complicates things too. Maybe there's some sort of dopamine receptor agonism involved too.

More selective agents for NMDAr seem to reduce the incidence of twitchiness, immobilization, slurred speech, etc. and make the mental effects and hallucinogenic mind warp very prominent. So in that aspect, 3-MEO-PCP > MXE > ketamine for an antidepressant. As a recreational drug it's almost the other way around though. However, if you're a dissociative user, you'll probably like any or all of them, depending on what you can get your hands on the most of.

3-MeO-PCE or its propyl analog are probably real winners too, for that reason. A little less lipophilic so they should be nicer pharmacokinetically speaking. I thiunk the 3-MeO substitution makes elimination a lot easier than plain PCP though, even if it doesn't effect the logP. Sort of like diazepam/lorazepam/temazepam and their comparative kinetics.

In fact, given the lipophilicity of them, PCP is similar to diazepam in terms of tissue redistribution and all that. I wonder if maybe arylcylohexylamines interact with any steroid receptors too? They sure seem greasy and bulky enough to do so.

Further investigations and intensive screening of the arylcylohexylamine class would be very intriguing, I think. Promising drugs for antidepressants in a controlled setting.
 
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I posted somewhere that the reason why DXM feels so dirty is its high affinity to SERT, much more higher than DXO's affinity to NMDA receptors. So by the time you get fairly dissociated, you will have been flooded with a lot of serotonin making you nauseous (but I'm also wondering if that serotonin could likely prevent NMDA neurotoxicity activating 5-HT2A receptors). However, for an antidepressant effect you don't really need a very high dose of a dissociative, thus the accompanying serotonin releasing/SERT blocking effect could be a benefit (completely unnecessary though, the antidepressant effect of dissociatives is almost instant). After a few days of DXM use one would probably feel completely worn out just as with mephedrone and similar serotonin releasers, I know I had to stop taking even that low dose of DXM, because it was clearing all my serotonin. It shouldn't be hard to modify DXM/DXO to make the parent drug less potent at SERT with the metabolite having an even higher afinity at NMDA receptors.
 
I experimented with it a few times in and around the first plateau and it definitely had anti-depressant qualities. I thought it could even be a club drug due to the strong dopamine and serotonin feel. I tried it once in a club setting, and it didn't prove ideal. The nausea ruined any potential it may have had.
 
I'm wondering if the dopamine effect is there per se or it's rather caused indirectly as a result of NMDA antagonism. It's not really much pronounced, but I noticed that if I get only a bit dissociated, then I want more and it's just like with any dissociative in this respect. DXM definitely doesn't have the compulsiveness of stimulants and dissociation seems a natural way of dealing with stuff objectively for me. I mean, I don't have to take a dissociative to attempt dissociation to figure something out. DXM used to have a great afterglow for me, I could suddenly think clearly then, focus on one thought, and be confident (honestly, it feels a bit like people describe their first cycle on testosterone), but I think it's all more caused by sigma agonism and the possibility of new ideas after you regain proper neurotransmission rather than some direct dopamine effects.
 
sekio said:
More selective agents for NMDAr seem to reduce the incidence of twitchiness, immobilization, slurred speech, etc. and make the mental effects and hallucinogenic mind warp very prominent. So in that aspect, 3-MEO-PCP > MXE > ketamine for an antidepressant.
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I'm not following you here, are you ranking them based on strength of side effects?


adder said:
I posted somewhere that the reason why DXM feels so dirty is its high affinity to SERT, much more higher than DXO's affinity to NMDA receptors. So by the time you get fairly dissociated, you will have been flooded with a lot of serotonin making you nauseous (but I'm also wondering if that serotonin could likely prevent NMDA neurotoxicity activating 5-HT2A receptors). However, for an antidepressant effect you don't really need a very high dose of a dissociative, thus the accompanying serotonin releasing/SERT blocking effect could be a benefit (completely unnecessary though, the antidepressant effect of dissociatives is almost instant). After a few days of DXM use one would probably feel completely worn out just as with mephedrone and similar serotonin releasers, I know I had to stop taking even that low dose of DXM, because it was clearing all my serotonin. It shouldn't be hard to modify DXM/DXO to make the parent drug less potent at SERT with the metabolite having an even higher afinity at NMDA receptors.
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Best I can tell DXM is a reuptake inhibitor without releasing properties. It should have more in common with Prozac than Mephedrone in that regard - that is not much impact on the psyche unless taken chronically.
 
Serotonin releasers that I've taken definitely seem to be more "flooding" with serotonin than DXM. Still, with DXM serotonin levels must be getting very high once it kicks in. It's very potent at SERT, yet not as potent as fluoxetine or paroxetine. Its absorption is slow and quite low, but when it kicks in, it feels a bit too powerful to be only an SRI. A 50mg's dose of paroxetine made me nowhere near as nauseous as 150mg's of DXM taken a few months ago, and 60mg's a week ago (one of the first doses) were a bit nauseous, perhaps a bit less than the first 50mg's of paroxetine were. Comparing paroxetine's affinity at SERT (0.08 nM) and DXM's (23 nM), I think that it may be a weak serotonin releaser as well. Also, after the afterglow is gone, which indeed must be SERT inhibition, some minor depression follows even after using it for a few consecutive days. I agree though that it's definitely too bulky to rely on its releasing ability only and be effective. I could be wrong with all of this though. ?

Low and inconsistent absorption, one of the metabolites blocking CYP2D6, and instantly rising tolerance make dosing it linearly impossible. One needs to take one full dose of DXM for best conversion to DXO, redosing will just make the DXM/DXO ratio higher with less dissociation and positive effects, and more side effects. Tolerance also seems to affect low doses like 30mg's a lot. After one week I've found myself taking 60mg's to get a similar effect (with ~24 hours spacer). It's hard to know by how much you need to upper your dose, because if you redose a very low dose like 15mg's, you can be sure, it's mostly lost and metabolised later, and not really having an effect anyway. I guess dissolving pills in propylene glycol or PEG could help a lot to control the dose, which I'm going to try when I have some money to spend on a thing like this. I should lay off DXM for now anyway, after I had cleared my serotonin and it'd stopped making me nauseous (or perhaps 5-HT3 receptors get quite quickly downregulated? ondansetron being an antagonist reverses downregulation caused by cocaine), I found myself taking way too much than I need. NMDA receptors upregulation is an issue too making some benzodiazepine withdrawal side effects actually more apparent after discontinuation (like cloudy mind). But like I said, I started taking too much (not dissociative doses though). I guess that's making yourself a lab rat.
 
dat endo said:
I'm not following you here, are you ranking them based on strength of side effects?
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I'm thinking that sekio was talking about ratio of anti-depressant effects to side-effects (or maybe just undesirable side-effects...who cares if your anti-depressant makes music sound better? :P).

ebola
 
I'm talking about both selectivity for NMDAr and the prevalence of side effects... 3-meo-pcp seems to be mostly mental effects whereas something like DXM will have you robowalking even before the dissociation really gets going.
 
sekio said:
I'm talking about both selectivity for NMDAr and the prevalence of side effects... 3-meo-pcp seems to be mostly mental effects whereas something like DXM will have you robowalking even before the dissociation really gets going.
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I'm not so sure selectivity is what you want for antidepressant effects though. All we know for sure so far is that ketamine has long lasting antidepressant effects. Leading guesses say NMDA receptor - end of story, but some of ketamine's "off-target" activity might actually be essential.
 
I didn't really want to wait for PEG or propylene glycol, so I made soft-boiled eggs and then mixed crushed pills with the yolk. I didn't really feel much, yy tolerance is already high and I took only 75 mg's, but it might really work to have a greater DXO/DXM ratio and there was absolutely no hint of nausea. Honestly, yolk makes the taste less awful, believe me or not. An antidepressant formula could simply be a phase-transfer agent placed with DXM in a capsule to ensure faster and more reliable absorption and thus higher conversion to DXO (well, oral levorphanol is quite effective, only around half weaker than given parenterally, so all we need is just good will just as with ketamine for an antidepressant). I've found some text on it at Dextroverse, I haven't read it all, but this is the same idea.

DXM/DXO works well for depression just as ketamine does in my opinion. I also think that a lot of DXM users actually appreciate DXM's own effects, they're just too strong, but they complement dissociative effects (more colourful CEVs + more euphoria), so making DXO to DXM conversion more efficient could actually lower dependence liability for some people. Proper dissociation doesn't really lie in low doses like 150-300 mg's, one needs to take way more to be immobilized. Given that DXM's affinity to NMDA receptors is ~4,000 nM (I'm a bit tired to give a link, I'll update tomorrow if nobody does) and the effective dose for DXO as a NMDA antagonist is 10 times lower than that for DXM, DXO seems to be quite a potent NMDA antagonist compared to arylcyclohexanamines. All I mean is that it could really be less addictive on its own than ketamine.

EDIT: The affinities for DXM and DXO at NMDA receptors (source):
DXM: 7253 ± 302 nM
DXO: 906 ± 77 nM
 
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Another update to my trials:

I have since switched to the delsym brand (dxm polistirex) in order to maintain a more steady blood level of dxm. I dose a total of roughly 60-100 mg divided into 3-4 doses.

I'm finding the experience to be surprisingly more beneficial than I had originally hoped. The antidepressant effects are fairly rapid upon ingestion. The novel quality I notice about it is how completely natural it feels. I'm by no means euphoric, but I'm just much more content/happy along with a more level head during stressful situations. Kind of like an "everything's going to work out" optimistic feeling.

I would never consider the feeling a "high", unless you count not being severely depressed anymore as a high! The feeling of content is, again, extremely natural and sober feeling; unlike the drooling euphoria "content" feelings that opiates give that could impair good judgement.

My occasional states of unwanted hypomania, and states of depression-induced apathy have almost completely gone away.

As an added bonus, my prescription Adderall tolerance has halted, if not slightly reversed. Opiates while on thi dosing protocol are ridiculously potentiated. Initially that specific combination felt a little "dirty" with the dxm overpowering the high. After about 3 weeks of dosing dxm continuously, dxm no longer overpowered the high, but instead it greatly potentiated it (extreme itchy, euphoria etc). As fairly opiate tolerant occasional user (80mg hydrocodone for a buzz), this has been an amazing side effect.

The dissociative effects of dxm has slightly decreased over time, but oddly (and wonderfully!) The potentiating effects, and antidepressant effects have increased over time. I would love to hear any theories as to the pharmacology of what is making this happen.

SO... I'm only seeing good things from this medicine as a general life enhancer. I will keep updating as I continue.
 
Another update:

I've since quit my venlefaxine, and have been taking the dxm off and on.

I can say with certainty that no other drug can help cope with those "what is the point in anything?" Lethargic depressing thoughts like dxm. My prescribed alprazolam can sort of "dumb me down", the venlefaxine wasn't doing anything, and clonidine only helps with panicky feelings.

I feel that the nmda antagonism really helps curb dark thoughts, and makes me feel genuinely happy. I would be interested in knowing how the sigma agonizing actions (along with all other dxm pharmacology) is playing its part in the acute antidepressant effects that I feel.

Regardless of thread popularity, I will still post updates when I can. Hopefully others can benefit from this novel (also OTC) antidepressant.
 
Having used DXM for this purpose before and it indeed has a strong antidepressant action that feels different than what SSRIs did. I can confirm this "natural" thing too, but at the same time the substance has a dirty, "plastic-like" synthetic side and a bunch of side effects. And at least there must be something different to the way DXM blocks the SERT, but I suspect some minor releasing properties. Maybe Venlafaxine/Tramadol have the most (bit of) similarity. DXM is a bitch to get off when taking it chronically but it is less intense and shorter lasting than any SSRI or SNRI. More of a stimulant come down with a hint of 5-HT compared to the full blown brain zap withdrawal syndrome.

Huge drawback is that, at least for me, DXM and stimulants is a no-go. Maybe cause of its strong NET affinity, but don't know really. After some weeks of 100-150mg combined with 18mg Concerta (methylphenidate ER) my heart began to burn. Slightly and more intense eventually to the point I went to see a doctor. EKG was normal, they suspected I had some stomach issue but they found nothing and it gradually went away upon cessation. Even more than a year ago, when taking more than 75mg of DXM, I do get this feeling again even without stimulants at all. Some stims (like 3-MMC even in low dose, while 4,4'-DMMC did not curiously) also trigger this. And the tiniest bit of a beta blocker brings me some weird feeling in my heart.

Angina pectoris / pulmonary hypertension - I have no idea. Just that dark feeling in the back of my mind that I've done some damage to my only heart I will ever have.

Maybe taking a bit of clonidine together with the DXM could help, or - if I were right with that - a selective 5-HT2B antagonist. Unfortunately I don't think such one is available for prescription yet.

Would love to try pure dextrorphan by the way.
 
DXM is the best SNRI at the pharmacy imo.
It doesn't help my depression that much, but it does have an affect on me and my mood, and it also makes cannabis more effective which is good with my tolerance

Haven't had any in around half a year. I may give it another go.
 
Memantine is a somewhat selective NMDA antagonist compared to Ketamine and DXM. Also it feels equipotent to Ketamine, but it has a very long half-life (60-100 hours).
 
Memantine is a somewhat selective NMDA antagonist compared to Ketamine and DXM.
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Memantine isn't remotely selective (indeed, its primary mechanism might not involve the nmda-complex at all), and it interacts with the complex in a way distinct from ketamine, etc. (memantine binds at the magnesium site, but with higher efficacy).

ebola
 
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