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DXM as a novel antidepressant

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zenistry

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Its been known for awhile that NMDA antagonism is a novel approach to antidepressants
Med Hypotheses. 2011 Feb 28. [Epub ahead of print]
Dextromethorphan as a potential rapid-acting antidepressant.
Lauterbach EC.

Department of Psychiatry and Behavioral Sciences, Mercer University School of Medicine, 1550 College Street, Macon, GA 31201, United States; Department of Internal Medicine, Neurology Section, Mercer University School of Medicine, 1550 College Street, Macon, GA 31201, United States.
Abstract
Dextromethorphan shares pharmacological properties in common with antidepressants and, in particular, ketamine, a drug with demonstrated rapid-acting antidepressant activity. Pharmacodynamic similarities include actions on NMDA, μ opiate, sigma-1, calcium channel, serotonin transporter, and muscarinic sites. Additional unique properties potentially contributory to an antidepressant effect include actions at ß, alpha-2, and serotonin1b/d receptors. It is therefore, hypothesized that dextromethorphan may have antidepressant efficacy in bipolar, unipolar, major depression, psychotic, and treatment-resistant depressive disorders, and may display rapid-onset of antidepressant response. An antidepressant response may be associated with a positive family history of alcoholism, prediction of ketamine response, increased AMPA-to-NMDA receptor activity ratio, antidepressant properties in animal models of depression, reward system activation, enhanced erythrocyte magnesium concentration, and correlation with frontal μ receptor binding potential. Clinical trials of dextromethorphan in depressive disorders, especially treatment-resistant depression, now seem warranted.



I was the original poster in this thread http://www.bluelight.org/vb/threads/545504-DXM-noticeably-improved-my-intelligence

and have begun trialing 60mg extended release to combat my depression/hypomania. The results last time showed noticeable antidepressant effects withno long term benefit upon cessation. No side effects were noted. I was wondering if anybody else has been using it for this purpose. I am currently on 75mg venlefaxine now, but there have been no side effects at these dosages.
 
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Combining DXM and another SNRI drug is probably not too wise. Risk of hypertensive crisis/serotonin syndrome, hard to correctly dose both drugs because they inhibit each other's metabolism, etc.

I wouldn't be suprised if you could substitute DXM for venlafaxine though, especially if you're on a low dose. They are pretty similar in terms of pharmacology. (both are SNRI drugs which are mostly SSRI at low dose and SNRI at higher doses)
 
DXO probably contributes to DXM's antidepressant effects though, and that one's pretty strong at NMDA. Still probably not wise to combine the two for the reasons sekio mentioned.
 
^^

I disagree. I don't believe NMDA antagonism has anything to do with antidepression. The reason I say that is due to the fact that Ketamine's antidepressant effects are entirely mediated by AMPAergic activity.
 
Ketamine don't bind to AMPA receptors though. Its downstream effects may indeed increase AMPA receptor mediated signalling but it's damn well established that it binds to and blocks NMDAr as its primary mode of action.
 
I have been proceeding with caution while on the venlefaxine. My personal opinion is that serotonin syndrome at these doses is not a risk. I've read of recreational users surviving their monster doses. I have never experienced a hint of serotonin syndrome (serious disorder, with a little overblown scare propaganda, ha)

I don't feel there is enough evidence that low serotonin levels are the main cause of depression. DXM provides a wide strange of binding affinities that could target novel methods of antidepressant treatment.

Unfortunately depression is not uniform, and I hope they continue researching novel methods of depression treatment. Ssri/snri have been the sole focus for too long.
 
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^^ that is very interesting. I like how they reference exploring the deeper cns effects from smaller dosages. I don't think recreational doses have this potential to help long term cognition though.
 
sekio said:
Ketamine don't bind to AMPA receptors though. Its downstream effects may indeed increase AMPA receptor mediated signalling but it's damn well established that it binds to and blocks NMDAr as its primary mode of action.
Click to expand...

However, when Ketamine was administered with an AMPA antagonist (not sure if this study was on mice, apes, or humans), it totally blocked the antidepressant effects of Ketamine. I don't know what study this is from, I don't know who exactly said it, but I read all that information on this forum and the post was made by either you, ebola, endotropic, or maybe... bronson? Either way, they did cite a source in their post.
 
SwampFox56 said:
However, when Ketamine was administered with an AMPA antagonist (not sure if this study was on mice, apes, or humans), it totally blocked the antidepressant effects of Ketamine. I don't know what study this is from, I don't know who exactly said it, but I read all that information on this forum and the post was made by either you, ebola, endotropic, or maybe... bronson? Either way, they did cite a source in their post.
Click to expand...

I remember the paper you're referring to (I don't have it in front of me right now) but they argued that the NMDA antagonist effect caused an upregulation of AMPA receptors leading to the antidepressant effect. NMDA antagonism was still the mechanism of action, the AMPA upregulation was a downstream effect.

Another study showed that 5-HT depletion also eliminated the antidepressant effect, that doesn't mean NMDA or AMPA for that matter aren't important. An antidepressant effect is always going to be a many step process with multiple signaling molecules and receptors involved. With Ketamine the NMDA antagonism just kicks off that chain of events.
 
It would be helpful to know if selective NMDA antagonist also exhibit anti-depressant effects. I know at least two people who have taken low-dose dissociatives for anti-depressant purposes and found compounds like DXM, MXE and 3-MeO-PCP to be effective (but of course not necessarily appropriate / safe / responsible on the long term) over ketamine, while it doesn't prove anything I find it suspicious... it seems to me like the role of monoamine reuptake inhibition effects should be excluded to get more clarity on the topic. At least, when the goal is to understand better what's going on and isolate the effect to perhaps in the future be treated more selectively.
 
Solipsis said:
It would be helpful to know if selective NMDA antagonist also exhibit anti-depressant effects.
Click to expand...

The problem is that currently there are no selective NMDA antagonists.
Even MK-801 isn't selective.
 
Solipsis said:
Perhaps when looking at the commonly used dissociative drugs, but what about ones labeled selective in this list:
http://www.tocris.com/pharmacologicalBrowser.php?ItemId=4919&Type=Antagonists#.U535UihRa5c

Wrong binding site? All of them?
Click to expand...

It doesn't mean much that they are labeled selective, MK-801 was also considered to be selective for a long time.

I would like to see these "selective" NMDA antagonists tested against the high-affinity state of the d2 receptor.
 
Update

Only thing I can say do far is that I feel a little bit more even, with a little sociability increase.

I wonder if the dampened neuronal firing can level out some bipolar tendencies. Extrapolating further, maybe a little dissociation from the sensory input can help oneself be slightly more of a fly on the wall to their own life experiences. I will update with more ramblings when I notice more.
 
(1) Read this quoted review's abstract (interesting paper imo)

(2) Read this wikipedia section summary:

A Cochrane Collaboration review on amphetamine and methamphetamine dependence and abuse indicates that the current evidence on effective treatments is extremely limited.[73] The review indicated that fluoxetine[note 8] and imipramine[note 9] have some limited benefits in treating abuse and addiction, but concluded, "no treatment has been demonstrated to be effective for the treatment of amphetamine dependence and abuse."[73] A corroborating review indicated that amphetamine dependence is mediated through increased activation of dopamine receptors and co-localized NMDA receptors in the mesolimbic pathway.[74] This review also noted that magnesium ions, which inhibit NMDA receptor calcium channels, and serotonin have inhibitory effects on NMDA receptors.[74] It also suggested that, based upon animal testing, pathological amphetamine use significantly reduces the level of intracellular magnesium throughout the brain.[74] Supplemental magnesium,[note 10] like fluoxetine treatment, has been shown to reduce self-administration in both humans and lab animals.[73][74]

(3) Draw fairly straightforward conclusion about NMDA receptor channel inhibitors (or receptor antagonists - same idea, just different mechanisms to shut down an LGIC signaling cascade) as antidepressants
(Hint: they are)
 
^ Nothing you posted discusses depression or antidepressant effects, how are you making that connection?
 
endotropic said:
^ Nothing you posted discusses depression or antidepressant effects, how are you making that connection?
Click to expand...

This is talking about rewarding effects/sensation arising from channel blockade in the mesolimbic pathway/nucleus accumbens. It's more general than addiction because neither 5-HT nor magnesium produce an immediate effect on ΔFosB there.

Worth noting that dopamine and glutamate are cotransmitters in that pathway/brain structure. DA neurons have AMPA and NMDA receptors along with DA receptors in the postsynaptic density there.

The most direct support for an antidepressant effect from the magnesium paper is the statement that it reduces the intensity of symptoms in the withdrawal syndrome. Depression/dysphoria and fatigue are how withdrawal presents (sometimes hypersomnia/hypherphagia/etc too).
 
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