NMDA Receptor Antagonists, Depression & Methadone

[Gaz_hmmmm]

I've noticed from MXE, Diphenidine and DXM anti-depressant effects that have lasted at least a few days after the drug has worn off.

Can someone please explain why Methadone doesn't seem to have the same effect? Or does it in people who only use it once in a while?

Is it/could it be that there isn't a big enough amount of Dextro-Methadone (The NMDA antagonist, where as Levo is the Mu-Opioid agonist) to cause anti-depressant effects?

 

[hangyourhead]

I've been on MMT (50mg, just increased daily dose to 70mg of liquid 'done) for little over a month now and I am wondering the same thing. NMDA antagonism IMO can do MIRACLES for opioid addictions. Especially my experience with Methoxetamine, it has the therapeutic value of ketamine but higher potency, longer duration, and a unique warm, energy of it's own unique properties. I think 3-MeO-PCP could be right up there as well, just unfortunately have yet to order some.

I plan on using mad benzos- particularly long-duration ie valium or kpins (xanax for panic attacks) alongside arylcyclohexylamines. NDMA antagonism is a critical aspect in terms on opioid tolerance, resetting it, and dissociation for acute, painful WDs. Smoking heavy, sedative indica strains is a given, of course haha.

I'd like to hear somebody who has more knowledge of methadone and it's unique NMDA antagonism so BUMP

 

[Dr Pepper]

Well what makes you think it isn't having any activity?

Also, careful because lots of NMDA antagonism can cause brain damage.

 

[Gaz_hmmmm]

Dr Pepper I think it is having an effect, but maybe differently.

Also Olney's or Onley's Lesions haven't been reported in primates (Just to clarify to the people who have imaginary friend's and think Unintelligent Design is fact, primates includes Humans too!).

 

[sekio]

Both dextro- and laevo-methadone are NMDA antagonists, apparently. But they're not very potent; dextromethorphan is actually not very stong as a NMDA angagonist (its metabolite, dextrorphan, is stronger & responsible for the dissociative fx). Empirical evidence also suggests that methadone isn't anywhere as useful as an antidepressant as ketamine is; it's been used for a long time as an opioid...

Neurosci Lett. 1997 Feb 14;223(1):5-8.
The d- and l-isomers of methadone bind to the non-competitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord.
Gorman AL, Elliott KJ, Inturrisi CE.

Racemic (dl)-methadone has antagonist activity at the N-methyl-D-aspartate (NMDA) receptor. We evaluated dl-methadone, the opioid active (l-) and the opioid inactive (d-) isomers in competition binding assays. dl-Methadone and its d- and l- isomers exhibited low micromolar affinities for the [3H]MK-801-labeled non-competitive site of the NMDA receptor in both rat forebrain and spinal cord synaptic membranes, with Ki values and displacement curves similar to those of dextromethorphan, an established NMDA receptor antagonist. They lacked affinity at the [3H]CGS-19755-labeled competitive site of the NMDA receptor. Therefore, both methadone and its the d- and l- isomers differ from morphine, hydromorphone, and naltrexone in that they have non-competitive antagonist activity at the NMDA receptor. A non-opioid NMDA receptor antagonist, such as d-methadone, may improve the efficacy of morphine by attenuating the development of tolerance.

It is also of note that the dextro-isomer of methadone (aka, S-methadone) is around 3.5x more potent at blocking hERG, a cause of cardiac disturb

QT Prolongation and Arrhythmia Risk in Methadone Maintenance Treatment
CHIRAG R. BARBHAIYA, MD, RANDY M. SEEWALD, MD and SAM HANON, MD, FHRS

Clin Pharmacol Ther. 2007 May;81(5):719-28. Epub 2007 Feb 28.
Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers.
Eap CB, Crettol S, Rougier JS, Schläpfer J, Sintra Grilo L, Déglon JJ, Besson J, Croquette-Krokar M, Carrupt PA, Abriel H.

Methadone inhibits the cardiac potassium channel hERG and can cause a prolonged QT interval. Methadone is chiral but its therapeutic activity is mainly due to (R)-methadone. Whole-cell patch-clamp experiments using cells expressing hERG showed that (S)-methadone blocked the hERG current 3.5-fold more potently than (R)-methadone (IC50s (half-maximal inhibitory concentrations) at 37 degrees C: 2 and 7 microM). [....] This risk could be reduced by the administration of (R)-methadone.

Also consider: not every NMDA antagonist is suitable to work as a rapid antidepressant.