NMDA antagonists and synaptic plasticity??

[sleepysaint]

I hope this isn't a repost, I searched and only found a few references here for what I'm asking.
I have a question regarding NMDA receptors and synaptic plasticity/Ca2+ ion channels. It seems that the NMDA receptors' role in synaptic plasticity/long term potentiation is pretty well known. I'm not very knowledgeable about neurobiology compared to some of you folks but from what I have surmised, the Ca2+ channels are crucial for the formation and reinforcement of new neural pathways.

I used to be a fairly heavy dextromethorphan user (I've taken it somewhere around 150 times recreationally). I have never tried ketamine, phencyclidine, or any other dissociatives. During the periods when I used it most heavily (2-6 times weekly for a period of several months) I believe I experienced some lasting general cognitive deficits, especially dealing with memory loss. However, at the time, I was regretably not too concerned with it. Luckily, after I ceased use for a long while the effects seemed to dissipate, and I don't feel like I have injured myself in any way. Recently, when I've taken DXM again, I don't notice any cognitive issues lasting beyond the next day after use. However, I am highly curious on this subject.

Could heavy or continual use of NMDA antagonists, such as ketamine, or DXM, have temporary or permanent effects on neuroplasticity, due to blocking Ca2+ channels? Also, could this mechanism partially explain the short-term memory loss encountered by many during dissociation?

 

[theWorldWithin]

I am not knowledgeable to answer what mechanisms cause these effects but NMDA antagonists absolutely can effect plasticity and impair cognitive function. Just look at any ket head or wet head for a stunning example.

 

[pofacedhoe]

doesn't DXM use affect serotonin quite significantly? well cognitive deficits and short term memory problems are seen in people abusing MDMA another heavy serotonin effect drug

 

[inverse_agonist]

The study of the long-term effects of NMDA antagonists is pretty much an entire subdiscipline within neuroscience. The gist of it is that the state produced by NMDA antagonists has some features in common with schizophrenia, and longer-term exposure to NMDA antagonists causes some cognitive problems that seem to depend on prefrontal cortex and its dopamine input. Schizophrenia seems related to excessive dopamine in the basal ganglia (think amphetamine psychosis) and insufficient dopamine in prefrontal cortex. NMDA antagonists have a similar effect on cortical and subcortical dopamine systems. Some effects of NMDA antagonists are reversible with antipsychotics, so the "PCP model of schizophrenia" has been widely used. Prefrontal cortex-dependent "executive function" has received a lot of attention in the study of pretty much all mental disorders, recently.

The first paper linked below finds changes in the levels of D1 receptors in human ketamine users that match what's found in both animals and schizophrenic patients. Their subjects were high-functioning people without obvious cognitive impairments stemming from their ketamine use. The other paper is an overview of what NMDA antagonists have to do with schizophrenia and cognitive deficits. Both should be available without needing a university subscription.

Altered prefrontal dopaminergic function in chronic recreational ketamine users.
Am J Psychiatry. 2005 Dec;162(12):2352-9.

http://www.ncbi.nlm.nih.gov/pubmed/16330601

The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia.
Neuropsychopharmacology. 1999 Mar;20(3):201-25.

http://www.ncbi.nlm.nih.gov/pubmed/10063482

 

[seep]

Could heavy or continual use of NMDA antagonists, such as ketamine, or DXM, have temporary or permanent effects on neuroplasticity, due to blocking Ca2+ channels? Also, could this mechanism partially explain the short-term memory loss encountered by many during dissociation?

I don't know if this is recreationally relevant, but the diamandoids seem to have a good profile. Memantine, at the very least. It suppresses the glutamatergic system, but not so much as to render it inoperable.

Plus, it's such a beautiful molecule. There are proposals for diamantane and triamantane variants.

You may also want to look at this thread.

 

[Jamshyd]

I can only give subjective feedback here:

My use of Ketamine (heavy at a couple of occasions) was used to change myself into a slightly better person, and it worked. There is definitely some 'rewiring" going on there, and I cannot stress how transformative said experiences can be - on a biological level.

Like I say in almost every other K-related post, I think that Ketamine is humanity's single most valuable pharmaceutical achievement.

 

[seep]

I can only give subjective feedback here:

My use of Ketamine (heavy at a couple of occasions) was used to change myself into a slightly better person, and it worked. There is definitely some 'rewiring" going on there, and I cannot stress how transformative said experiences can be - on a biological level.

Like I say in almost every other K-related post, I think that Ketamine is humanity's single most valuable pharmaceutical achievement.

Curious about whether or not you know if your experience stems from the racemic mix or from a formulation with some degree of optical activity. I've been wondering whether or not R-ketamine (or something with some degree of enantiomeric excess) is available in any sort of venue.

 

[Jamshyd]

^ This has always been a sore thumb in my circles: what is the ratio of S and R? Which one did what?

In any case, it seems that R is more responsible for the anaesthetic effects while S is more psychedelic. This, of course, is a gross generalization.

The Ketamine I found most useful is the stuff I got while in India, which reminded me a lot of the stuff I got in Toronto, and it seems to be an equal mix of the two.

Now, for me, Anaesthesia is an important aspect of Ketamine's entheogenic experience. Think of it the same way as with an isolation tank - the total loss of sensory input can lead to profound states of divine union. But that's a different subject altogether. Yeah, K is very versatile, it is my snake oil.

As for your last question, without going into too much detail, I have come across Ketamine that was purported to be "mostly R". I only had the chance to try it twice and my life was at a very dire state at the time, so I cannot write much home about it. I do not know whether or not this Ketamine is still in circulation, though.

And for the record, I have actually never had a chance to try pure esketamine, so I cannot comment on that, either.

 

[Jamshyd]

By the way, you might find my writeup about medicinal use of K interesting for your plasticity questions..

 

[Jamshyd]

The study of the long-term effects of NMDA antagonists is pretty much an entire subdiscipline within neuroscience. The gist of it is that the state produced by NMDA antagonists has some features in common with schizophrenia, and longer-term exposure to NMDA antagonists causes some cognitive problems that seem to depend on prefrontal cortex and its dopamine input. Schizophrenia seems related to excessive dopamine in the basal ganglia (think amphetamine psychosis) and insufficient dopamine in prefrontal cortex. NMDA antagonists have a similar effect on cortical and subcortical dopamine systems. Some effects of NMDA antagonists are reversible with antipsychotics, so the "PCP model of schizophrenia" has been widely used. Prefrontal cortex-dependent "executive function" has received a lot of attention in the study of pretty much all mental disorders, recently.

The first paper linked below finds changes in the levels of D1 receptors in human ketamine users that match what's found in both animals and schizophrenic patients. Their subjects were high-functioning people without obvious cognitive impairments stemming from their ketamine use. The other paper is an overview of what NMDA antagonists have to do with schizophrenia and cognitive deficits. Both should be available without needing a university subscription.

Altered prefrontal dopaminergic function in chronic recreational ketamine users.
Am J Psychiatry. 2005 Dec;162(12):2352-9.

http://www.ncbi.nlm.nih.gov/pubmed/16330601

The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia.
Neuropsychopharmacology. 1999 Mar;20(3):201-25.

http://www.ncbi.nlm.nih.gov/pubmed/10063482

I take issue with this.

As soon as you even say the word "schizophrenia", you introduce a social-construction that is ultimately based on the morality and authority of so-called "experts" and any kind of "scientific" work ultimately relies on the agreement with these authorities about their subjective idea of mental illness.

I simply refuse to even look at studies that try to come up with a scientific explanation between a chemical reaction and a moral judgement.

 

[seep]

In any case, it seems that R is more responsible for the anaesthetic effects while S is more psychedelic. This, of course, is a gross generalization.

I've usually read it's the other way around. That R is principally hallucinogenic and S principally anesthetic. The priorities (correct me if I'm wrong) in this case would be,

1) The methylamino
2) The ketone branch
3) The chlorophenyl
4) The unsubstituted carbons on the thecyclohexyl

The Ketamine I found most useful is the stuff I got while in India, which reminded me a lot of the stuff I got in Toronto, and it seems to be an equal mix of the two...Now, for me, Anaesthesia is an important aspect of Ketamine's entheogenic experience. Think of it the same way as with an isolation tank - the total loss of sensory input can lead to profound states of divine union.

Some would say the same of the masochism seen in many ascetic cults.

There has to be somebody, somewhere, seeking out the most synergistic mixture of the enantiomers. In a controlled setting, I mean. It's not impossible that equi-racemic is best.

 

[inverse_agonist]

Sigh....Your opinion that ketamine is a "valuable achievement" is also a "construction." A pile of ketamine is just a pile of ketamine. It has no value or meaning except through the way we conceptualize it. By the same principle, I could take issue with your use of the term "entheogen," since religion is a social construction based on the morality and authority of so-called "religious leaders." I simply refuse to even look at writings that try to link such interesting chemicals to religious social control.

The perspective of "mainstream neuroscience" is relevant to the original question, seeing as the question was about neuroplasticity. Alterations in the expression of dopamine-related proteins is relevant, as such plasticity might be expected to impact memory, which is what the question was about. In passing, I'll also link a paper discussing a possible role of NMDA receptors in keeping information in working memory, independent of its role in longer-term changes:

http://www.nature.com/neuro/journal/v1/n4/abs/nn0898_273.html

Anyway, noting a resemblance between NMDA antagonist effects and psychosis/cognitive impairment is as fair as noting a resemblance between those effects and mystical states. It's an interesting resemblance. Does a decrease in sensory processing caused by ketamine resemble the alterations in sensory processing during meditation? Which of PCP's effects are caused by norepinephrine and which aren't? Nobody "owns" the right to ask questions about psychedelics.

You have to agree that there are sets of behaviors that tend to go together in subsets of people. Are those behaviors always caused by the same brain processes? Are these behaviors associated with major changes in a small number of genes, or minor changes in many genes? Those questions are interesting to some of us, whether or not you call it "schizophrenia." Some people hear voices and others don't. Why?

Science is based on authority much less than a lot of human endeavors. Nobody took James Watson seriously when he decided to speculate publicly about the genetic inferiority of black people, and he got the Nobel Prize for figuring out the structure of DNA. The best thing you can do for your career is to disprove some sort of conventional wisdom or major theory incorrect. The reasoning behind scientific conclusions is totally transparent. "Here is what I did. Here is what happened. Here is what I think it means." Suppose the DSM V comes out and schizophrenia is completely reconceptualized. Would this render all previous research into schizophrenia irrelevant, or simply mean it must be reinterpreted? Prior to the discovery of the CB1 receptor, we had an inaccurate theory of THC's mechanism of action. Does that invalidate every study of cannabis performed before the 1980s?

"The universe is wider than our views of it."--Henry David Thoreau

 

[Repulse]

Now, I don't know too much fancy philosophic language, nor wanna take the discussion in that direction -- I do not believe that was what #0 wished for. But I am however an biologist, and know a bit about Ketamine, DXM and PCP. These are NMDA antagonists, that during their action in the human brain, release a significant amount of dopamine. Reading this in line with heavy DXM use (or Ketamine, could be either) led me to believe that your temporary cognitive disability or disfunction (whichever fits your experience) was caused partly by a dopamine depletion. Dopamine is a central compound in terms of cognitivity, as it works as a transmitter for the neurons in the brain. Especially in movement of extremities (fine-cognitive skills) it plays a significant role.

I do not know wether or not the synaptic plasticity was also a problem.
As for now - avoid heavy use, as you might experience it again.

regards,

 

[seep]

Not to take any sides, but DSM has the following exclusion for any diagnosis of schizophrenia:

E. Substance/general medical condition exclusion: The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition.

As a side note, DSM-V will be dead at the gate unless it's subjected to unrestricted peer review before publication.

 

[Jamshyd]

Sigh....Your opinion that ketamine is a "valuable achievement" is also a "construction." A pile of ketamine is just a pile of ketamine. It has no value or meaning except through the way we conceptualize it. By the same principle, I could take issue with your use of the term "entheogen," since religion is a social construction based on the morality and authority of so-called "religious leaders." I simply refuse to even look at writings that try to link such interesting chemicals to religious social control.

The perspective of "mainstream neuroscience" is relevant to the original question, seeing as the question was about neuroplasticity. Alterations in the expression of dopamine-related proteins is relevant, as such plasticity might be expected to impact memory, which is what the question was about. In passing, I'll also link a paper discussing a possible role of NMDA receptors in keeping information in working memory, independent of its role in longer-term changes:

http://www.nature.com/neuro/journal/v1/n4/abs/nn0898_273.html

Anyway, noting a resemblance between NMDA antagonist effects and psychosis/cognitive impairment is as fair as noting a resemblance between those effects and mystical states. It's an interesting resemblance. Does a decrease in sensory processing caused by ketamine resemble the alterations in sensory processing during meditation? Which of PCP's effects are caused by norepinephrine and which aren't? Nobody "owns" the right to ask questions about psychedelics.

You have to agree that there are sets of behaviors that tend to go together in subsets of people. Are those behaviors always caused by the same brain processes? Are these behaviors associated with major changes in a small number of genes, or minor changes in many genes? Those questions are interesting to some of us, whether or not you call it "schizophrenia." Some people hear voices and others don't. Why?

Science is based on authority much less than a lot of human endeavors. Nobody took James Watson seriously when he decided to speculate publicly about the genetic inferiority of black people, and he got the Nobel Prize for figuring out the structure of DNA. The best thing you can do for your career is to disprove some sort of conventional wisdom or major theory incorrect. The reasoning behind scientific conclusions is totally transparent. "Here is what I did. Here is what happened. Here is what I think it means." Suppose the DSM V comes out and schizophrenia is completely reconceptualized. Would this render all previous research into schizophrenia irrelevant, or simply mean it must be reinterpreted? Prior to the discovery of the CB1 receptor, we had an inaccurate theory of THC's mechanism of action. Does that invalidate every study of cannabis performed before the 1980s?

"The universe is wider than our views of it."--Henry David Thoreau

Uuuuuum, aren't you forgetting an itty bitty tiny detail?

I presented my views as a post on an internet forum, not as scientific research! This makes your entire post irrelevant. Yes of course all my descriptions are value-judgments and constructions. But I am not writing a scientific paper.

And by the way, I never implied that science is "based on authority". In fact, my point of view is that science can be used to legitimize authority. That said, this is all I'm saying about science, because I discussed it to death in another thread.

 

[Jamshyd]

Now, I don't know too much fancy philosophic language, nor wanna take the discussion in that direction -- I do not believe that was what #0 wished for. But I am however an biologist, and know a bit about Ketamine, DXM and PCP. These are NMDA antagonists, that during their action in the human brain, release a significant amount of dopamine. Reading this in line with heavy DXM use (or Ketamine, could be either) led me to believe that your temporary cognitive disability or disfunction (whichever fits your experience) was caused partly by a dopamine depletion. Dopamine is a central compound in terms of cognitivity, as it works as a transmitter for the neurons in the brain. Especially in movement of extremities (fine-cognitive skills) it plays a significant role.

I do not know wether or not the synaptic plasticity was also a problem.
As for now - avoid heavy use, as you might experience it again.

regards,

Bromocryptine is dopaminergic, and so is Amphetamine. They have almost nothing in common behaviour-wise. When will people stop trying to find all answers to life's questions in a single molecule? Not criticizing you - I am criticizing the very outdated "dopamine hypothesis".

 

[sleepysaint]

And by the way, I never implied that science is "based on authority".

You did say that " 'scientific' work ultimately relies on the agreement with these authorities about their subjective idea of mental illness". But we're just posting on an internet forum, so we can define things in whatever way we please, regardless of any authorities on the matter .

Schizophrenia isn't a fuzzy concept to me. It's a group of pretty well-defined symptoms (I'm fine with DSM-IV's definition) that are linked at least somewhat to dopamine activity. Some may find the dopamine hypothesis to be flawed, but I would find it hard to believe that dopamine isn't at least indirectly implicated with schizophrenia. Anyway, I had a good idea of what was meant when inverse_agonist originally mentioned schizophrenia in relation to the NMDA receptors so I don't see the need to quibble over words.
Don't both bromocriptine and amphetamine cause psychosis-like symptoms at high doses due to their dopamine activity?

By the way, I found your thread on your ketamine therapy method interesting. Although I am too concerned about my own issues with addiction/self-control to seek ketamine out, and I've never been diagnosed with bipolar disorder or clinical depression (I wouldn't listen to them if they did diagnose me with those ). I certainly got similar effects to what you described when I first started using low doses of DXM. Considering how much its effects have changed for me, I doubt I could get the same thing from it. I practically never feel like using DXM these days at any dose. Certainly though, there is already some formal research supporting the idea that ketamine could help those with depressive disorders.

 

[The Monkey Mantra]

I've read a few studies showing excitotoxicity from NMDA antagonists; it's based on the inhibitory activity on an inhibitory system, causing downstream excitotoxicity. What this means is, at low doses, NMDA antagonists can be neuroprotective, which is the speculated mechanism of its anti-Alzheimers' activity, but in high doses, they cause the downstream excitotoxicity, which is what they blame for the brain damage and schizophrenic effects.

Basically, the excitotoxicity is there - we think. What the effects of it are, however, are mere speculation:

Deutsch, Stephen I.; Rosse, Richard B.; Schwartz, Barbara L.; Mastropaolo, John. "A Revised Excitotoxic Hypothesis of Schizophrenia: Therapeutic Implications", Clinical Neuropharmacology:
January/February 2001 - Volume 24 - Issue 1 - pp 43-49

NSFW:

Abstract: A revision of an excitotoxic hypothesis of schizophrenia is summarized. The hypothesis suggests that in, at least, a subtype of patients with schizophrenia, progressive excitotoxic neuronal cell death in hippocampal and cortical areas occurs via disinhibition of glutamatergic projections to these areas. Patients who have excitotoxic damage would be expected to have poor outcomes characterized, perhaps, by anatomic evidence of progressive neurodegeneration, pronounced negative symptoms and cognitive deficits, and profound psychosocial deterioration. Disinhibited glutamatergic activity could result from inhibition of N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission and a consequent failure to stimulate inhibitory gamma-aminobutyric acid (GABA)-ergic interneurons, and/or anatomic degeneration of inhibitory GABAergic interneurons. The result of these hypothesized mechanisms is excessive stimulation of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate class of glutamate receptor complexes. In turn, this excessive stimulation of AMPA/kainate receptors could lead to disruption of ionic gradients, depletion of energy reserves expended in an attempt to restore and maintain the ionic disequilibrium across neuronal membranes, generation of reactive oxygen species, and cell death from apoptotic and other mechanisms. The postulated existence of disinhibited glutamatergic neurotransmission and the subsequent cascade of excitotoxic events resulting from NMDA receptor hypofunction (NRH), anatomic degeneration of inhibitory GABAergic interneurons, or a combination of the two has suggested a diverse variety of experimental therapeutic interventions for schizophrenia. These interventions include facilitation of NMDA receptor-mediated neurotransmission, potentiation of GABAergic neurotransmission, antagonism of AMPA/kainate receptors, and quenching of locally generated reactive oxygen species. In fact, several of these approaches have already been pursued or are proposed as part of a systematic clinical investigation of the revised excitotoxic hypothesis of schizophrenia.

This is just one paper, and you'd do well to check out the references in the paper before making your own conclusions. As an aside, 5-HT2a agonists appear to BLOCK this neurotoxicity:

Nuri B Farber MD, Jennifer Hanslick BS, Charity Kirby BS, Laurie McWilliams BA and John W Olney MD, "Serotonergic Agents That Activate 5HT2A Receptors Prevent NMDA Antagonist Neurotoxicity". Neuropsychopharmacology (1998) 18 57-62.10.1038/sj.npp.1395108

NSFW:

Abstracthencyclidine, ketamine, and other agents that block NMDA glutamate receptors trigger a schizophrenia-like psychosis in humans and induce pathomorphological changes in cerebrocortical neurons in rat brain. Accumulating evidence suggests that a complex network disturbance involving multiple transmitter receptor systems is responsible for the neuronal injury, and it is proposed that a similar network disturbance is responsible for the psychotomimetic effects of NMDA antagonists, and might also be involved in the pathophysiology of schizophrenia. In the present study we present evidence that serotonergic agents possessing 5HT2A agonist activity prevent NMDA antagonist neurotoxicity in rat brain. It is proposed that 5HT2A agonists may also prevent the psychotomimetic effects of NMDA antagonists. Among the 5HT2A agonists examined and found to be neuroprotective are LSD and related hallucinogens. The apparent contradiction in proposing that these agents might have antipsychotic properties is resolved by evidence linking their hallucinogenic activity to agonist action at 5HT2C receptors, whereas antipsychotic activity would be attributable to agonist action at 5HT2A receptors.

Look at the last name on the list ;-) Correct me if I'm wrong, but that's usually the supervisor/research manager's spot, right?

As always, this is research in progress, and it's all waaaay more complicated than we currently understand. NMDA research is a hot, hot topic, so look for lots more progress and papers on the horizon.

 

[fireball]

I've read a few studies showing excitotoxicity from NMDA antagonists; it's based on the inhibitory activity on an inhibitory system, causing downstream excitotoxicity. What this means is, at low doses, NMDA antagonists can be neuroprotective, which is the speculated mechanism of its anti-Alzheimers' activity, but in high doses, they cause the downstream excitotoxicity, which is what they blame for the brain damage and schizophrenic effects.

Basically, the excitotoxicity is there - we think. What the effects of it are, however, are mere speculation:

What is the evidence for this downstream excitoxity and where is it supposed to be occuring? what inhibitory system are you talking about?

Im struggling to get how higher concentrations of an open channel blocker make much of a difference. Considering the fast off rate kinetics of memantine means that when the channel closes its removed from the pore regardless of concentration. This of course would not be the case for a competitive antagonist.

Also for OP:

The NMDA receptor is calcium permeable. Yes blocking it will affect LTP which is thought to be the first stage in memory formation. See alcohol for further examples of this. Id guess that any interference here would be short term, and any long term effects would have much more complicated causes as how memories are actually formed is very much still an open question.

 

[MyDoorsAreOpen]

Schizophrenia is an unsolved puzzle. It's a fairly consistent set of changes, without a clear underlying reason for that exact group of symptoms to occur together. There's not only dopamine overload from the limbic system to the PFC, but also a sharp downturn in glutamatergic signaling from the cortex back to the basal ganglia, and probably a bunch more effects.

None of the the 6 core symptoms of schizophrenia are unique to this disorder. You can even find several of them together in a few other mental problems that are distinctly different from schizophrenia. For example, it's not at all uncommon for bipolar people to have episodes of psychosis, especially during the heights of manic episodes. If someone presents to a doctor with clear psychosis, after making sure the person doesn't have a brain tumor or a bunch o' chemical fun in there, the first thing to try on them is a mood stabilizer, not an antipsychotic. Many times if the depression and mania go away, so does the psychosis. And their diagnosis is written up as bipolar, not schizophrenic.

I would say high dose and long duration amphetamine use has SOME effects in common with schizophrenia. I would also say NMDA antagonists that are psychotropic (not all of them are) have SOME effects in common with schizophrenia, including some of the same ones as amps. But there is no way we yet know of to manipulate the brain, with chemical, physical, or thought-induced means, to produce all the core symptoms of schizophrenia, no more no less, in any given person.

Schizophrenia is just so intriguing because it raises profound questions of just how much we can ever know the inner life of any other sentient being. It's also a diagnosis with a terrible stigma, that should never be given lightly. Probably because people don't like facing this profound question.

If there were a drug I could take that would make me a whirlwind tour of schizophrenia, I would try it. I'd want to know exactly how patients with it felt.