No, that combo is safe.
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N&PD Moderators: Skorpio | someguyontheinternet
NMDA antagonists for tolerance, a collection of the evidence and anecdotal reports
- Thread starter MeDieViL
- Start date
No, that combo is safe.
MagickalKat777
Bluelight Crew
Couldn't this be explained by DXM's nonselective serotonin reuptake inhibition effects though? I don't think the amount of time that DXM inhibits serotonin reuptake has been established but I've known people who (stupidly) take dextromethorphan before rolling to increase the effects of the roll exponentially.
Well my own personal strategy to get more serotonine was like popping 5 extra pills with 120mg MDMA at once, i abused the hell out of MDMA, think doing that twice a week, my receptors COMPLETELY downregulated, if DXM increases serotonine enough to return the magic then a couple extra pills should have done too.
Ive started DXM today, i take around 100ml GBL a week, i ran out of memantine, my response to GBL changed to either sedation with barely any euphoria or brainzaps, restarted dex today, barely feel a thing, effects are greatly diminished because of my last binge without memantine, lets see how this works, this is my first time using DXM like this.
Oh niceness, I started reading about this very recently for two reasons:
1) NMDA receptors are fascinating and I'd love to research them in the future.
2) I started taking amphetamine sulfate orally, am planning to keep doing so for the next decade and am worried that tolerance is going to keep increasing. Since I started taking Magnesium citrate 3 weeks ago sensitivity hasn't been changing it seems (~1g per day dissolved in water, a ridiculous amount of actual Mg considering the size of that ligand).
I was considering to switch to DXM HBr 30mg per day for a few weeks and see if tolerance can actually be decreased that way.
I hope I'll have found out more once I have time to browse through those links.
Thank you!
Edit: Most excellent post MeDieViL, thank you very much!! I'll order some DXM right now! They only cost 2.48€ per 20caps here in Germany, that's nothing really even if it turns out I need 60mg per day! I'll still be at less than 10 Euros per month...
How did this regime work for you mate?
Cheers
MagickalKat777
Bluelight Crew
I've found DXM to work better than memantine in my trials and IMO, the shorter half life of DXM is a GOOD thing because any adverse events would be over with rather quickly whereas they could be prolonged with memantine for some time.
i just read this whole thread as i am interested in the possibility of treating protracted benzo withdrawals with this method. should i just start taking dxm every day and see what happens? i have ketamine also, although in limited supply.
Yeah it seems alot more potent for this, i wish there was a non serotogenic version of DXM.
Seems to work fine, tolerance has levelled out, I'm at a slightly lower amp dose than I was when I started, while before that tolerance was constantly increasing. I'm taking 30-60mg DXM 1-3times per week so far, along with my amp dose and a fat dose of Magnesium (eyeballed).
The following is an article from 2001, so it's not really up-to-date, but still offers some help in understanding the mechanism of nmda-antagonists antidepressant effects and possibly their tolerance decreasing effects as well.
In short: There are 3 genes that are highly expressed (suggesting they contribute to the developement of those neurons) in developing neurons of the newborn's brain. These genes are downregulated by NMDA receptor activity!
While two of these 3 genes were unknown when this was published, the third seems to be the equivalent to a gene found in yeast, that is responsible for inducing the G0 phase of cells. G0 is the phase were cells will not devide themselves any further.
It still doesn't make sense to me, but this sure is helpful.
On another note: Ethanol use seems to have an upregulating influence on NR2b gene transcription. An epigenetic mechanism is suggested here.
Booze->More NMDA 2b receptors
Btw looking at how I've developed a form of tolerance to some drugs, specifically dissociatives and psychedelics, these were much more persistant, less quickly reversible than say pot tolerance. Epigenetic mechanisms?
The epigenetic mechanisms referred to are, you've probably guessed it, methylation and demethylation of CpG sites in the regulatory areas of the mentioned gene. (Methylation of C5 in Cytosine; CpG=Cytidine+phosphate+Guanosin, one of the sequences in our dna/rna; Regions that enhance or silence expression of a gene are usually very rich in these CG-sequences and methylation of Cytosine in position 5 is thought to block these enhancing or silencing function by preventing the responsible specific transcription activators to bind to them).
And indeed it could be shown that booze induced demethylation of these areas, thereby enabling increased occupation of these DNA-binding sites and in consequence increased transcription of the NR2b gen, leading to higher density of NMDA 2b receptors.
Here's the publication:
I think this one is free. For the other one feel free to write me.
http://tinyurl.com/mightbefreedontknow
Ok here it comes. This is some heavy shit. Today we learnt about cytosine methylation of cytosine in CG-rich areas responsible for enhancing gene-transcription. I immediately (in thought) came up with the hypothesis that NMDA-antagonists might interfer with methylation through some unknown route. I head home, google a bit, post above post, come out a bit more knowledgable but still unsatisfied with an unquenched thirst for deeper understanding of the mechanics.
Back to uni, back home, gone half insane in the process I google again and come up with this: BÄBÄÄÄM!
Here it goes, so hold on tight.
This reinforces my idea of NMDA antagonists interfering with DNA methylation and also suggests that drug tolerance can manifest through modification of the very essence of life: DNA!
Back to uni, back home, gone half insane in the process I google again and come up with this: BÄBÄÄÄM!
Here it goes, so hold on tight.
And indeed this proved to be true. But not only that, NMDA antagonist MK-801 proved to reverse the methylation of CpG rich regulatory areas for calcineurin genes in the prefrontocortex, meaning the (fear-)memories acquired by the rats could not be maintained after MK-801 had been injected. Lucky rats I say!
This reinforces my idea of NMDA antagonists interfering with DNA methylation and also suggests that drug tolerance can manifest through modification of the very essence of life: DNA!
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MyDoorsAreOpen
Bluelight Crew
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I assume by 'memory', you're interpreting the word as a layman would, to mean recall of thought patterns in the CNS, right? I ask because it has a broader definition to neuroscientists and cellular biologists, and includes such phenomena as conditioned lowered depolarization thresholds in any or all cells. (Which is very relevant to a discussion of NMDA antagonists!)
The problem with your idea is that neurons don't divide, and even more importantly, don't spawn gametes. Your idea would only work if the DNA methylation you mentioned not only involved neurons, but oocytes and spermatocytes as well. Also, the methylated DNA segments would probably code for different proteins in different cells.
That said, I'd be open to the (admittedly controversial) idea that over the millennia, different cultures have selected for and against tolerance to the effects of certain drugs (especially alcohol), due to different survival pressures. But this just involves people who from birth are less (or more) susceptible to the drug's adverse effects having greater opportunities to have children. It wouldn't be affected at the genetic level by an individual's drug-taking behavior in one lifetime. But we're getting way off topic here.
A) No, my understanding of memory represents the broad definition :D
B) Of course it's bullshit. Actually I was the one mentioning today in lecture that the deduction of behaviour possibly being handed down to our children is very far fetched considering there'd have to be a transfer of information (i use the very wide thermodynamic meaning of that word btw ;P) between cell in question and sperm cell or ovum.
Then again, even that is not completely true cause even those cells will be subject to some experience and might adapt through 5-Cytosine methylation as well.
Anyway, thanks for mentioning that our nerve cells don't divide, that was one very useful bit of information. Obviously, I had a hard time demonstrating the character of that last paragraph as it was the case so many times before even when I explicitely marked sentences and posts with the official sign for irony (a vertically mirrored "?"). I oughta delete it altogether lol. It's pretty obvious though that the memory acquired by a large number of neurons is unlikely to be implemented into one single DNA though. Or so I thought. I'm a tad drunkj, excuse me.
Anyway, having read that post and having pointed out all possible errors, you are not the least bit surprised by the idea of NMDA antagonists interfering with memory (again, the broad definition as it should've been perfectly clear already from above post) through demethylation of cytosine in calcineurin transcription enhancing areas?
Fear kept up through our cells' DNA? Not impressed eh?
Cause to me, this is quite astonishing and even the possibility of NMDA antagonists tolerance lowering properties having a common mechanism of action sounds like big fucking news to me. A neuronal reset switch through blockade of NMDA receptors.
I mean if I had any interest in this topic whatsoever, I'd have much better things to do than tearing apart a lame joke that was badly brought across.
EDIT: Lol seeing the lack of impression in you, I'm starting to sense that you only read the last paragraph of my post and decided to delete it altogether. :D
EDIT2: Rereading your post again while trying to find out why you completely ignored the actual posted information and instead selectively tore apart the last bit that contained no relevant information and seeing your mention of "lowered depolarization thresholds" being very important in understanding the effects of nmda antagonists in the same paragraph (this was the same paragraph in which you called me layman btw), then remembering you wrote a paper about it in med school, I finally came to realize what's wrong:
This information is completely new to you and wasn't included in your paper. So you're either rejecting the idea of nmda antagonists triggering a demethylation process of calcineurin gene enhancers cause you really do think it's highly unlikely the case or you're trying to discredit it since it poses a threat to the validity of your own findings! Either way, it's a typical behaviour often seen in academic narcissists, many of those being uni professors spending their time discrediting promising work of actual researchers to sucessfully earn fame among their easily impressed students. ;P Or maybe I'm just being paranoid, you were too lazy to read the whole post and I am overestimating the gravity of the above linked publication.
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Damn, this is a very interesting topic even if some of this goes a little over my head. Next semester we're getting classes that I think cover the basics of things like this so might as wel read up a little on NMDA receptors and related shit already 
It's definitely a bit over my head as well Solide. As MyDoorsAreOpen has so precisely pointed out in his last post, I'm nothing more than a layman who by chance started studying medicine 3months ago. 7yrs out of school, no biology since 9th grade (last had an F), awful chemistry teacher back then... Not the best situation to work your way into neurophysiology, pharmacology and molecular biology.Damn, this is a very interesting topic even if some of this goes a little over my head. Next semester we're getting classes that I think cover the basics of things like this so might as wel read up a little on NMDA receptors and related shit already
I can tell you though it's nothing that you wouldn't have access to. While the lextures sure helped, they supplied nothing that I couldn't have tought myself through books in these 3 months (mind you, 3/4 of the time was spent dissecting a corpse and reading Clemente's Gray's Anatomy (1985)).
So if you are interested, don't make the same mistakes that I've been continuously making since I was 15 yrs old and assume that the topic is inaccessible. You can easily teach yourself all the basics in notime if you feel attracted to them.
So I'll try to give you a few recommendations how to start:
-Principles of chemistry: Anatomy of the atom; Orbital theory; tendencies is the periodic system; Types of connections between molecules; ph and acid-base reactions, ph buffer solutions; redox-reactions
-Organic chemistry: Features of carbon - apply orbital theory to this and make sure you understand the 3-dimensional character of a carbon atom that forms 4 covalent bonds; Hydrocarbons and the functional groups attached to them; cyclic hydrocarbons; aromatic qualities of cyclic hydrocarbons and heterocyclic molecules; Structure of various organic molecules; types of reactions that hydrocarbons are part of - electrophile subsitution, nucleophile substitution sn1 and sn2, radicalic substitution; repeat types of organic molecules and functional groups and the whole last bit over and over till you got a grip on it.
-Anatomy/Biology: You can skip that for the most part. Might wanna keep a good book for each at hand for whenever questions occur
-Biochem: Get started! A great book I'd recommend: "Lehninger Principles of Biochemistry, Fifth Edition" by Cox (lol) and Nelson; it's huge, don't be scared, the size and detail of the book will only help you opposed to a short book that covers almost all the same things in less detail; the body (un?)fortunately won't become less complex by reading simple literature. I got a link to the 5th ed as pdf so you can check it out before deciding whether you're gonna buy it or not.
I'm sure you'll absolutely love it. Good luck with getting familiar with the whole thing, it's really not as bad as it all sounds. Oh and before I forget, imho the basic principles of thermodynamics are very useful to know. The sooner the better, cause it'll probably take years till you really feel what Gibbs claimed in his days and you can apply that to any process we witness which will help you to a deeper understanding.
Regarding the above list: I can't guarantee for completeness, so anyone should feel free to add things. I also translated everything from German to english, since I'm mostly studying in German some of the things might be translated incorrectly. Just correct me if that's the case, I'll change the post. I'll also try to work on this biochem thread once I feel more secure with the whole topic.
peace
Becareful with psychopharmacology text books, the current ones used in med-school (USA) are antiquated, and while the fundamental information is good, it is simply full of errors, omissions, etc. I recently befriended the director of the NIH, and have expressed to him some of my concerns regarding the frightening lack of psychopharmacology in current US med-school curriculum.
Unfortunately, the easiest, shortest residency, and least competitive specialty is generally speaking, Psychiatry. There is very little competition for this; unless you are at the top of your field, Psychiatrists are paid little, looked down on by many other M.D's/D.O.'s, and are generally not high ranking students. There are some definite exceptions, particularly those who take on multiple specialties, such as neurology etc. The sub-specialties within psychiatry are almost a joke, there are plenty of inept psychiatrists with 4,5 or even 6 sub-specialties (geriatric, forensic, liason, addiction, CAD etc, etc).
I am of the opinion that the standard must be set higher for psychiatrists, perhaps a mandatory PhD in psychopharmacology. Dermatological specialties (a pretty hot specialty right now due to high pay) are far more competitive, and I find most dermatologists - especially those who are also board certified dermatopathologists -know far more about psychopharmacology than the psychiatrists who are prescribing the heavily marketed medications pushed by savy drug-reps. Even more frightening, there has been an explosion in the number of psychiatrists obtaining the DATA waiver to prescribe Buprenorphine for opioid addiction, solely by taking an 8 hour online course. If curious, I will post the questions for the version I took; it is a fucking joke. In the meantime, these clueless psychiatrists are making a killing prescribing these C-III's without fear of provoking the DEA, yet are often by no means specialist in addiction medicine.
Sorry about the psychiatry rant, I just find it to a festering sore in our medical system. Fortunately, I made the scramble into a ACGME-accredited school; I was originally planning on simply getting the M.D., but at this stage, I might as well get the D.O. in anesthesiology (perioperative medicine), although the residency and fellowship commitments are steep. In my area, it is easy for a good anesthesiologist to make 45-50k a month for "comparatively" less time than other D.O's. Obviously, when you add on to that a pain management practice, the numbers increase significantly. Still, anyway you look at it, it is quite a bit a work, and not nearly as lucrative as finance (my actual "bread and butter")..........I've let this medicine get out of control, but I must say, I have a knack for anesthesia, but i've had extensive veterinary practice since the age of 17!
Sorry for the rant, going on 50 hours without sleep.......
Unfortunately, the easiest, shortest residency, and least competitive specialty is generally speaking, Psychiatry. There is very little competition for this; unless you are at the top of your field, Psychiatrists are paid little, looked down on by many other M.D's/D.O.'s, and are generally not high ranking students. There are some definite exceptions, particularly those who take on multiple specialties, such as neurology etc. The sub-specialties within psychiatry are almost a joke, there are plenty of inept psychiatrists with 4,5 or even 6 sub-specialties (geriatric, forensic, liason, addiction, CAD etc, etc).
I am of the opinion that the standard must be set higher for psychiatrists, perhaps a mandatory PhD in psychopharmacology. Dermatological specialties (a pretty hot specialty right now due to high pay) are far more competitive, and I find most dermatologists - especially those who are also board certified dermatopathologists -know far more about psychopharmacology than the psychiatrists who are prescribing the heavily marketed medications pushed by savy drug-reps. Even more frightening, there has been an explosion in the number of psychiatrists obtaining the DATA waiver to prescribe Buprenorphine for opioid addiction, solely by taking an 8 hour online course. If curious, I will post the questions for the version I took; it is a fucking joke. In the meantime, these clueless psychiatrists are making a killing prescribing these C-III's without fear of provoking the DEA, yet are often by no means specialist in addiction medicine.
Sorry about the psychiatry rant, I just find it to a festering sore in our medical system. Fortunately, I made the scramble into a ACGME-accredited school; I was originally planning on simply getting the M.D., but at this stage, I might as well get the D.O. in anesthesiology (perioperative medicine), although the residency and fellowship commitments are steep. In my area, it is easy for a good anesthesiologist to make 45-50k a month for "comparatively" less time than other D.O's. Obviously, when you add on to that a pain management practice, the numbers increase significantly. Still, anyway you look at it, it is quite a bit a work, and not nearly as lucrative as finance (my actual "bread and butter")..........I've let this medicine get out of control, but I must say, I have a knack for anesthesia, but i've had extensive veterinary practice since the age of 17!
Sorry for the rant, going on 50 hours without sleep.......
Amphetamine ftw eh?
Hey man, thanks for the reccomendations and effort! Tho I feel I should've been a little more clear :D
I'm studying pharmaceutical sciences (second year now) and by 'basics of things like this' I implied the basics of pharmacological stuff. I've already passed principles of chemistry and organic chemistry and some basic biochemistry courses. Next semester i'm having courses such as 'medicinal chemistry' which are more geared towards pharmacology specifically.
I've looked through that pdf and it looks like a good, not to complex book, but most of it looked pretty familiar (in fact, I saw a couple of things which I'm studying right now for an exam tomorrow
)Also, to be contributing a little to this topic: I'm prescribed Ritalin and the last few weeks my tolerance has gone up quite a bit. I've been supplementing with magnesium a little, but tomorrow I'm going to add a little bit of DXM everyday and see how that affects tolerance.
MyDoorsAreOpen
Bluelight Crew
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- Aug 20, 2003
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True. We only got a whirlwind tour of it in my first 2 years. I've learned more about psychopharmacology from BL than I did in med school, no fooling.
negrogesic said:
This problem is largely a part of the underfunding and neglect of mental health services in the US. Also, when you've got a patient base that's largely unemployable (and therefore poor), unpleasant to deal with, and that society stigmatizes, it shouldn't be any wonder that the bar gets lowered for attracting people to this line of work. I'm not anti-psychiatry at all. I think that the legally sanctioned use of most drugs and treatments that target the mind warrant the oversight of a well-trained physician, who understands the human body and how these tools affect it. But I agree with you that psychiatry needs to put the 'physic' back in 'physician' -- a good psychiatrist should know their pharmacology better than a pharmacist, and ought to be on their toes with the physiology of the entire body. (Because the things they prescribe don't just affect the brain!)