Dextromethorphan as a potential rapid-acting antidepressant.

[MeDieViL]

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.

So it may not only be a wonderdrug for tolerance, there is ENORMOUS potential in nmda antagonists, this stuff, tolerance, ketamine for depression and so forth.

 

[sekio]

I always thought that DXM would make a good antidepressant. It's like a super SNRI.

 

[MeDieViL]

I always thought that DXM would make a good antidepressant. It's like a super SNRI.

It appears to be quite safe too:

Neurologist. 2007 Sep;13(5):272-93.
Dextromethorphan as a potential neuroprotective agent with unique mechanisms of action.
Werling LL, Lauterbach EC, Calef U.

The Institute for Biomedical Sciences, The George Washington University Medical Center, Washington, DC, USA.
Abstract
BACKGROUND: Dextromethorphan (DM) is a widely-used antitussive. DM's complex central nervous system (CNS) pharmacology became of interest when it was discovered to be neuroprotective due to its low-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonism.

REVIEW SUMMARY: Mounting preclinical evidence has proven that DM has important neuroprotective properties in various CNS injury models, including focal and global ischemia, seizure, and traumatic brain injury paradigms. Many of these protective actions seem functionally related to its inhibitory effects on glutamate-induced neurotoxicity via NMDA receptor antagonist, sigma-1 receptor agonist, and voltage-gated calcium channel antagonist actions. DM's protection of dopamine neurons in parkinsonian models may be due to inhibition of neurodegenerative inflammatory responses. Clinical findings are limited, with preliminary evidence indicating that DM protects against neuronal damage. Negative findings seem to relate to attainment of inadequate DM brain concentrations. Small studies have shown some promise for treatment of perioperative brain injury, amyotrophic lateral sclerosis, and symptoms of methotrexate neurotoxicity. DM safety/tolerability trials in stroke, neurosurgery, and amyotrophic lateral sclerosis patients demonstrated a favorable safety profile. DM's limited clinical benefit is proposed to be associated with its rapid metabolism to dextrorphan, which restricts its central bioavailability and therapeutic utility. Systemic concentrations of DM can be increased via coadministration of low-dose quinidine (Q), which reversibly inhibits its first-pass elimination. Potential drug interactions with DM/Q are discussed.

CONCLUSIONS: Given the compelling preclinical evidence for neuroprotective properties of DM, initial clinical neuroprotective findings, and clinical demonstrations that the DM/Q combination is well tolerated, this strategy may hold promise for the treatment of various acute and degenerative neurologic disorders.

Neurotoxicology. 2007 Jul;28(4):813-8. Epub 2007 Apr 6.
Oral administration of dextromethorphan does not produce neuronal vacuolation in the rat brain.
Carliss RD, Radovsky A, Chengelis CP, O'Neill TP, Shuey DL.

University of South Alabama, Mobile, AL 36604, USA. [email protected]
Abstract
Dextromethorphan is a widely used antitussive agent, also showing increased recreational abuse. Dextromethorphan and its metabolite dextrorphan are non-competitive antagonists at the N-methyl-d-aspartate (NMDA) receptor ion channel. Single doses of some NMDA receptor antagonists produce neuropathologic changes in neurons of the retrosplenial/posterior cingulate cortices (RS/PC), characterized by vacuolation or neurodegeneration. To determine whether dextromethorphan produces these characteristic lesions, dextromethorphan was administered orally either as a single dose of 120mg/kg to female rats, or daily for 30 days at doses of 5-400 mg/(kg day) to male rats and 5-120mg/(kg day) to female rats. Brains were examined microscopically for evidence of neuronal vacuolation (4-6h postdose) and neurodegeneration ( approximately 24 or 48h postdose). Administration of dextromethorphan at 120mg/(kg day) in females, and at > or =150mg/(kg day) in males produced marked behavioral changes, indicative of neurologic effects. Mortality occurred at the highest doses administered. There were no detectable neuropathologic changes following single or repeated oral administration of dextromethorphan at any dose. Administration of MK-801 (9mg/kg) produced both cytoplasmic vacuolation and neuronal degeneration in neurons of the RS/PC cortex. Thus characteristic neuropathologic changes found with more potent NMDA receptor antagonists do not occur following single or repeated oral administration of dextromethorphan.

 

[kmatrixg]

This is very off-topic, but before DXM made me sick to my stomach (even gel caps) I remember in my early opiate-addiction days, being able to switch on and off between this and low-dose opiates. I am fresh off Buprenorphine and am looking into the use of KOR agonist substances to curb my cravings for full-agonist opiates. I am going to purchase some gel caps (ew .) tomorrow to test their effects. I'm at the point where I will do anything to avoid going back to my old lifestyle.

 

[kmatrixg]

Also, in my drug experimental years, I would reach 3rd plateau a few times a month - and from what I recall, the only side effects I would have were lack of dreams and sometimes a social awkwardness the few days after, probably due to it's dissociative effects and enjoying dark enclosed areas.

 

[MeDieViL]

Your saying low doses upset your stomach or recreational doses?

 

[MeDieViL]

For those that are thinking about SSRI augmentation:

Dextromethorphan-induced serotonin syndrome.
Schwartz AR, Pizon AF, Brooks DE.

University of Pittsburgh, Division of Medical Toxicology, UPMC Presbyterian, Pittsburgh, Pennsylvania 15213, USA.
Abstract
INTRODUCTION: The ability of dextromethorphan to potentiate serotonin levels and lead to serotonin syndrome is well known but few case reports are published. The lack of published cases suggests therapeutic doses of these drugs are not enough to cause serotonin syndrome. We present two cases of serotonin syndrome associated with supra-therapeutic doses of dextromethorphan and therapeutic levels of a selective serotonin reuptake inhibitors (SSRI).

CASE SERIES: In case one, serum drug levels from admission revealed a dextromethorphan level of 950 ng/mL (normal < 5), escitalopram of 23 ng/mL (normal < 200), chlorpheniramine of 430 ng/mL (normal < 20) and undetectable levels of aripiprazole and benztropine. In case two, serum drug levels from admission revealed a dextromethorphan level of 2820 ng/mL, sertraline of 12.5 ng/mL (normal < 200), and caffeine of 1.4 microg/mL (normal < or = 9 microg/mL).

DISCUSSION: To our knowledge, these are the first cases to use serum levels of dextromethorphan and a SSRI to confirm dextromethorphan-induced serotonin syndrome.

CONCLUSION: Our cases suggest supra-therapeutic dextromethorphan doses with a therapeutic amount of a SSRI are required for serotonin syndrome. More work is needed to answer this question more completely.

 

[kmatrixg]

Your saying low doses upset your stomach or recreational doses?

It was more a psychological effect than a physical one... Because I used to choke down about 40 gelcaps for a normal robo-trip, the feeling of that rock in my stomach really turned me off after awhile. Now, everytime I think about those caps, take those caps or see those caps, I get a little nauseous.

I would like to add that I took 60mg of DXM about 45 mins ago (in day-quil form, which I realize is not recommended) and the effects of the low dose have overwhelmed the cravings for right now. I have no idea what to expect in the long term. These cravings were intense post-bupe kick cravings and even more intense that I had during my opiate addiction.

I also read some of your opiate tolerance thread involving NMDA agonists and came across many corroborating stories of the similar instances where DXM was used in the submission of withdrawal effects, which gives me hope that this experiment will help suppress the cravings.

I still have yet to find any log where it was used solely for cravings in recovery, instead of being used as a substitute in the instance one didn't have their fix.

 

[MeDieViL]

With overwhelmed you mean your cravings have been abolished? Can you reply in my pharmaceuticals for addiction thread please so we can discuss this further there.

 

[MeDieViL]

Bump, would like to see more experiences with regards to DXM as an antidepressant.

 

[j0nblaze]

depressed?

i dont know what that means... i think i am always depressed.. but i continue, dont complain and most of the time i think it doesnt affect how i relate to people or choices i make and can still enjoy things. i started taking dexidrine for a energy to help me work more. i definetly wouldnt say i am depressed now.. would you.. is not wanting to do a shitty job for shitty money unreasonable.. some of us adapt to this world we live in, some of us already belong, and some of us dont. what do you do?
i know dxm and dexi..

 

[MyDoorsAreOpen]

This study makes me very happy. A highly underappreciated psychoactive compound, this one, so long as it's used very judiciously.

With a few more pieces of literature like this to back me up, I may feel safe trying 60mg DXM per day, plus or minus L-theanine and diphenhydramine, on otherwise healthy very depressed patients of mine who are on few to no other drugs.

The thing that would make me wince about prescribing any more than the highest Treatment Guidelines ™ antitussive dose of DXM is the extensive drug-drug interaction. In warning patients, I'd probably have to put it in the same league as MAOIs and TCAs, in terms of the respect the list of banned drugs and foods (white grapefruit juice) commands. I'd only offer it to people whom I could count on to not go around putting random things in their bodies and brains, either for fun or for minor aches and pains.

But how long could this kind of therapy continue? Anecdotal reports say that recreational doses of DXM have diminishing returns, and tolerance appears to be permanent. Does tolerance develop to all the effects? For therapy, I could give a flipping flapjack about the dissociation, but I wouldn't want the DA receptor upregulation to peter out.