17 replies to this topic

[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.

Toxicology data:

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. rcarliss@usouthal.edu
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.

For those that are on SSRI's:

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.

[Valor5]

I think I read somewhere that dextromethorphan has a negative effect on white matter but I will have to post latter since I have to go.

[nupi]

I certainly never recognized any AD activity from DXM - neither at therapeutic or supertherapeutic doses (I would not recommend the latter). It's a half decent cough suppressant but I still stay away from it when I can. Besides, Codeine feels better

[Valor5]

Well I may be wrong. From skimming some journal abstracts it appears that dxm is rather good in many situations. So I will have to keep exploring.

[nupi]

You could obviously also just try it (I would really suggest not to exceed therapeutic doses though)... Seeing that it supposedly is rapid acting, you should know quickly.

Just make sure you get a pure DXM form without Acetoaminophen or other crap...

[YOLF]

I agree. While it's no longer classified as a cough suppressant, I think we've lost track of it's actual purpose... make the coughs hurt less so you can cough more and get rid of the stuff your body is trying to eject. Definitely my favorite, but it's hard to get. The amphetamine cough syrup seems to make you a little bit stronger and more energetic, I guess that's good too? Opium Speed cough syrup with a little prednisone even better?

I certainly never recognized any AD activity from DXM - neither at therapeutic or supertherapeutic doses (I would not recommend the latter). It's a half decent cough suppressant but I still stay away from it when I can. Besides, Codeine feels better

[renfr]

DXM can cause permanent brain damage and even cause actual lesions, look up for Olney's lesions.

[lifebuddy]

It doesn't cause Olney's lesions. That was a single paper that has since been discredited.

[cargocultist]

I'm a little late to the game but DXM certainly helps with my treatment resistant depression although I haven't tried it long term. It had a strange effect on me. Sometimes it would clear my mind and sometimes it would make me sluggish or even dizzy, particularly during exercise. I believe this may be do to the hyperthermic effect of DXM

Nicotine is perhaps more interesting in that it can buffer calcium via the mechanism of calbinding*. About 5% of people with depression have antibodies against the NMDA-receptor and the percentage is much higher for schizophrenics. NMDA antibodies decrease NMDA receptors perhaps causing more Ca2+ to linger in the intracellular medium perhaps overloading the remaining NMDA receptors and their neurons in a vicious cycle. Interestingly, nicotine is heavily used by schizophrenics to relieve symptoms and calbindin attenuation may be the mechanism of action. Furthermore, there is pretty strong evidence that nicotine protects against developing Parkinson's disease in which excitotoxicity is heavily implicated.

So although DXM is neuroprotective in the short run, chronic use may cause more damage by causing more Ca2+ to linger in the intracellular medium causing a rebound effect. I simply do not know enough to say this for sure but I would be careful with DXM. Perhaps homeostasis takes care of the excess Ca2+ ions by dumping them from the cerebrospinal fluid but whether this happens fast enough I have no idea. Maybe the net effect of low dose DXM is possitive even long term. People with PD use it long term so it may be safe and effective.

Since taking nicotine I am again able to drink alcohol and I wasn't able to drink it at all without feeling ill for a couple of years. Whether this is due to calbindin attenuation or perhaps inhibition of IL-17 or IL-23, interleukins that play a role in the blood brain barrier, or via some other mechanism I don't know. I do know that I have a problem with IL-17 because I have nail psoriasis and it gets better with nicotine, which reduces th-17/IL-17 activity, both of which which are targets for new drugs developed for psoriasis and other autoimmune diseases.

Here's the study showing the opposing effect of alcohol and nicotine on calbindin in the hippocampus.
Opposing effects of ethanol and nicotine on hippocampal calbindin-D28k expression:

http://www.ncbi.nlm....pubmed/14615005

Maybe nicotine can prevent some of the damage associated with heavy drinking. Some table salt certainly is better than nothing.

[Darryl]

I experimented with DXM recreationally some years ago, and definitely think it has potential as a short-acting antidepressant (perhaps for acute treatment of the suicidal). Unfortunately, the doses at which DXM markedly improves mood are close to those at which it impairs memory formation. Moreover, there's serious withdrawal symptoms in mood with extended use (days to weeks), which brings potential for addiction.

There was an interesting discussion of neuroprotective effects of DXM in this review:

Koppula, Sushruta, et al. "Reactive oxygen species and inhibitors of inflammatory enzymes, NADPH oxidase, and iNOS in experimental models of Parkinson’s disease." Mediators of inflammation 2012 (2012).

Dextromethorphan (DXM) is neuroprotective through inhibition of microglial activation and NADPH oxidase activation. Earlier reports reveal that DXM protects dopaminergic neurons against inflammation-mediated degeneration induced by LPS, through inhibition of superoxide radicals. Furthermore, Li et al. reported that femto- (10⁻¹³ and 10⁻¹⁴M) and micromolar (10⁻⁵ to 10⁻⁷M) concentrations of DXM (both pre- and posttreatment) showed equal efficacy in protecting LPS-induced dopaminergic neuron death in midbrain neuron-glia cultures. These studies indicated that the neuroprotective effect elicited by femtomolar concentrations of DXM is mediated through the inhibition of LPS-induced proinflammatory mediators, especially superoxide. In another study, DXM was reported to elicit neuroprotective effects in the MPTP-intoxicated PD model in mice. DXM significantly reduced the MPTP-induced production of both extracellular superoxide free radicals and intracellular ROS in both in vitro and in vivo experiments.

Recently, Ramanathan et al. revealed that DXM increased superoxide dismutase (SOD) and catalase, reduced thiobarbituric acid reactive substances in the hippocampal and striatal regions of monosodium glutamate-induced neurodegeneration in rats, and improved neuroprotection based on its antioxidant properties. Another recent report also indicated that increased ROS production in activated BV-2 microglial cells by LPS was associated with increased expression of NADPH oxidase (NOX)-2, a subunit component of NADPH oxidase and DXM significantly suppressed the upregulation of NOX-2 as well as subsequent ROS production in activated BV-2 cells. In light of this, DXM may form the potential therapeutic strategy for the treatment of PD.

I haven't read the discussed primary research yet, but protective activity at femtomolar concentrations and inhibition of NADPH oxidase (arguably a bigger source for reactive species than mitochondria) definitely got my attention:

Liu, Yuxin, et al. "Dextromethorphan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation."Journal of Pharmacology and Experimental Therapeutics 305.1 (2003): 212-218.
Li, Guorong, et al. "Protective effect of dextromethorphan against endotoxic shock in mice." Biochemical pharmacology 69.2 (2005): 233-240.
Zhang, W. E. I., et al. "Neuroprotective effect of dextromethorphan in the MPTP Parkinson’s disease model: role of NADPH oxidase." The FASEB journal 18.3 (2004): 589-591.
Ramanathan, M., et al. "Neuroprotective evaluation of standardized extract of Centella asciatica in monosodium glutamate treated rats." Indian journal of experimental biology 45.5 (2007): 425.
Huo, Yingqian, et al. "Dexamethasone inhibits the Nox-dependent ROS production via suppression of MKP-1-dependent MAPK pathways in activated microglia." BMC neuroscience 12.1 (2011): 49.

Edited by Darryl, 22 November 2013 - 05:25 AM.

[cargocultist]

@Darryl

It's a very interesting article that I read too recently. I wonder if a superoxide dismutase (SOD) supplement or maybe even NAC and other antioxidants could have a similar effect. Have you researched this?

[Darryl]

@ cargocultist: neither SOD or NAC appear to interact with NADPH oxidase. Other supplements that appear to inhibit this enzyme are the Chinese arthritis herbal sinomenine, phycocyanobilin (1% of dry spirulina), and perhaps resveratrol and epigallocatechin (though the later two may just be downregulating NADPH oxidase expression via Nrf2 activation and NF-kB inhibition).

Sorry about the potential thread hijack, but low-dose dextromethorphan as a cheap NADPH oxidase inhibitor is really intriguing:

Li, Guorong, et al. "Femtomolar concentrations of dextromethorphan protect mesencephalic dopaminergic neurons from inflammatory damage." The FASEB journal 19.6 (2005): 489-496.
Liu, Shu-Lin, et al. "Dextromethorphan reduces oxidative stress and inhibits atherosclerosis and neointima formation in mice." Cardiovascular research 82.1 (2009): 161-169.
Li, Ming-Han, et al. "Dextromethorphan efficiently increases bactericidal activity, attenuates inflammatory responses, and prevents group A streptococcal sepsis." Antimicrobial agents and chemotherapy 55.3 (2011): 967-973.
Chechneva, Olga V., et al. "Low dose dextromethorphan attenuates moderate experimental autoimmune encephalomyelitis by inhibiting NOX2 and reducing peripheral immune cells infiltration in the spinal cord." Neurobiology of disease44.1 (2011): 63-72.
Wu, Tao-Cheng, et al. "Low-dose dextromethorphan, a NADPH oxidase inhibitor, reduces blood pressure and enhances vascular protection in experimental hypertension." PloS one 7.9 (2012): e46067.

Edited by Darryl, 22 November 2013 - 08:59 PM.

[tolerant]

Has anybody tried it?

[machete234]

I happened to try some of it two days ago and its fantastic if you have thoughts that torture you or if you have phases when you have very low mood.

I took my last 60mg because I had some slight depression and thought about things too much.

30min later all my obsessions were gone and I could enjoy my weekend and that overall feeling stays for a while, circa for a few days.

 

 

DXM can cause permanent brain damage and even cause actual lesions, look up for Olney's lesions.

It wont make you smarter and chronic use probably makes you dumb but it cant be much worse than drinking heavily.

Olney's lesions where never proven in humans or primates.

 

 

I experimented with DXM recreationally some years ago, and definitely think it has potential as a short-acting antidepressant (perhaps for acute treatment of the suicidal). Unfortunately, the doses at which DXM markedly improves mood are close to those at which it impairs memory formation. Moreover, there's serious withdrawal symptoms in mood with extended use (days to weeks), which brings potential for addiction.

 

Strange: My dose was far from a recreational one and it got rid of all obsessions and got me into a calm state without any background noise.

Edited by machete234, 15 June 2014 - 01:14 PM.

[Babychris]

And what about MXE ?

[machete234]

I somehow regret taking the MXE almost all the time it feels so cold, DXM is very warm and its guaranteed 100% clean because its from a pharmacy.

Im talking about low dosages with both of them I keep the tolerance low and I dont want any anti nootropic effects

[DestinedWalnut]

If I'm not mistaken, DXM has similar effects on the body as ketamine and ketamine is supposedly effective as a rapid acting antidepressant.

 

Anecdotally, a friend was sick once and accidentally took both Mucinex containing DXM and a cold medicine containing DXM without realizing. Within 30 minute he felt a strong sense of relaxation and claims that his long-term depression was lifted. I remember his remarking to me, "This is how normal people must feel". This effect was short-lived, maybe 2-3 hours.

 

He took another dose of Muxcinex several hours later. Within 30 minutes he began to hallucinate and his heart rate and body temperate both increased noticeably. The hallucinations lasted 1-2 hours and varied from seeing shapes and colors all the way to believing that my aunt in the other room eating chips was actually a gigantic bug. It was an interesting but terrifying experience that I do not wish to be a part of again.

 

This experiences appear to be consistent with the "first plateau" of DXM (1.5 to 2.5 mg/kg, effects including alertness, euphoria, loss of balance, and slight intoxication), followed by the "second plateau" of DXM (2.5 to 7.5 mg/kg, heavier intoxication, choppy sensory input, a dreamlike state of consciousness, some detachment from outside world, and closed-eye hallucinations) as described on Wikipedia.

Edited by DestinedWalnut, 17 June 2014 - 08:12 PM.

[machete234]

He must have eaten a lot of thats stuff to reach 2nd plateau. My pills had 30mg in them I ate two and my mood changed dramatically.