Collective inteligence in action: lets find how to reverse/reset NMDAs tolerance

[Cotcha Yankinov]

I would take care to distinguish between schizophrenia and schizophrenia like symptoms induced by NMDA antagonists - I think you would find differences between schizophrenics and humans exposed to NMDA antagonists long term.

Schizophrenia has some morpological basis such as pyramidal neurons being oriented in the wrong direction or enlarged ventricles and such - so if your concern is NMDA antagonists inducing schizophrenia, I wouldn't worry too much. They can certainly cause psychosis though, and ketamine has effects on developing GABA interneurons, possibly due to "suppression of a trophic function of glutamate". How much this applies to the adult brain is something I would love to know.

 

[serotonin2A]

There are some other sounding papers though:

Repeated application of ketamine to rats induces changes in the hippocampal expression of parvalbumin, neuronal nitric oxide synthase and cFOS similar to those found in human schizophrenia.

Yes, that is true, but that those effects are not necessarily what causes schizophrenia. There is a general consensus that the root cause of schizophrenia is probably excessive pruning of synapses. This reduces connectivity between neurons, which ends up causing many higher-level functions to breakdown. Hence these findings:

http://www.nature.com/nature/journal/v530/n7589/full/nature16549.html

Note that the genetic association found in that study probably isn't THE cause of schizophrenia -- the presence of C4 gene structural varieties only increased the risk of schizophrenia by 1.3x. By contrast, studies looking at identical twins have found that if one twin has schizophrenia then there is a 50% change that that other twin will also develop the disorder. But it does support the view that problems with synaptic pruning are likely to be a causative factor in schizophrenia.

 

[dude_87]

Bumps in hope someone has an answer, or at least a theory that can be test

I've read a user report that black pepper extract (piperine) can reverse DXM tolerance. I wonder if this would also work for ketamine? Edit: I should at that the user theorizes that it lowers DXM tolerance by reducing the production of the CYP3A4 enzyme in the liver. He proposes that this allows more DXM to enter the brain before being broken down by CYP3A4. Interestingly, if this theory is correct and piperine works as a potentiator/tolerance reducer, this would mean that the permanent/semi-permanent changes caused by DXM (and likely other NMDA antagonist dissociatives) are actually changes to the liver rather than the brain.

This theory makes sense to me when I consider that in my sober state, I feel completely fine and not like I have suffered any permanent alteration to my brain, yet on K or DXM I feel almost no subjective effects. I would imagine that if ketamine has permanently affected my NMDA receptors (or some other part of my brain), I would feel it when sober.

I'm taking a 13 week break from K, but I intend to try piperine once my break is over and I'll report back. With that being said, are there any risks I should consider before testing this theory? I usually take ketamine with MDMA. Could piperine, or CYP3A4 enzyme inhibition, be dangerous when combined with MDMA or Ketamine?

 

[serotonin2A]

This theory makes sense to me when I consider that in my sober state, I feel completely fine and not like I have suffered any permanent alteration to my brain, yet on K or DXM I feel almost no subjective effects. I would imagine that if ketamine has permanently affected my NMDA receptors (or some other part of my brain), I would feel it when sober.

You probably wouldn't notice any change unless you were significantly impaired. People with extensive brain damage due to stroke or other infractions sometimes don't recognize they have deficits. For example: https://en.wikipedia.org/wiki/Hemispatial_neglect

 

[dude_87]

Did some more research. In this thread, the last user to post theorizes that AMPAkines could possibly reset ketamine tolerance. Any thoughts on this theory?

 

[Cotcha Yankinov]

- the presence of C4 gene structural varieties only increased the risk of schizophrenia by 1.3x. By contrast, studies looking at identical twins have found that if one twin has schizophrenia then there is a 50% change that that other twin will also develop the disorder.

Have there been any attempts to isolate the interaction that such genes have with the in utero environment upon schizophrenia risk?

Maybe having a particular gene increases the risk of developing schizophrenia by 1.3x on average, but there is much higher risk of developing schizophrenia when that C4 variation is combined with in pre-natal stress/inflammation.

The twins would share this in utero environment and also by definition have an abnormal in utero environment. Maybe there is a gene-environment interaction at play here that causes i.e. C4 to appear more commonplace in the normal population because those people didn't have the particular womb conditions necessary for C4 to appreciable contribute to schizophrenia development.

This could cause C4 to be under-represented as a contributor to schizophrenia (hypothetically speaking).

 

[serotonin2A]

Have there been any attempts to isolate the interaction that such genes have with the in utero environment upon schizophrenia risk?

Maybe having a particular gene increases the risk of developing schizophrenia by 1.3x on average, but there is much higher risk of developing schizophrenia when that C4 variation is combined with in pre-natal stress/inflammation.

The twins would share this in utero environment and also by definition have an abnormal in utero environment. Maybe there is a gene-environment interaction at play here that causes i.e. C4 to appear more commonplace in the normal population because those people didn't have the particular womb conditions necessary for C4 to appreciable contribute to schizophrenia development.

This could cause C4 to be under-represented as a contributor to schizophrenia (hypothetically speaking).

If the in utero environment is capable of increasing schizophrenia risk to such a great extent then it is hard to believe that some identical twins don't develop schizophrenia. The fact that twins have a 50% risk indicates that events that occur later in life play an important role in the pathogenesis of schizophrenia.

 

[Solipsis]

I have personally wondered whether the inability to hole anymore on ketamine due to tolerance comes from not just the NMDA antagonism but also hyperpolarization channels which (in conjuction with acute NMDA antagonism) appear to be responsible for that hypnotic holing effect relatively unique to only some dissociatives in the first place.
Furthermore, with chronic dissociative use/abuse, do other glutamatergic pathways form that create some sort of alternative routing that just become your baseline pathways and from then on keep being part of your development - creating some permatolerance?

Theoretically that would mean it would take knowing which pathways those are and doing the reverse to try and have it focus mostly on NMDAR again? I think what nootropics do can offer some illustration, but I don't understand well enough to try and theorize some more.
Or might there be other ways to have another drug take on those hyperpolarizing channels - I think I checked but there doesn't seem to be a lot out there, let alone something with reasonable safety.

Even with identical twins I think it's possible one of them gets a lot of stress from something, like inequal distribution of nutrients and development... isn't it possible to gestate in the wrong side of the hood? Possibly that's enough for some epigenetic difference.

By the way I thought you said parthenogenesis of schizophrenia which would certainly make a lot of sense for Jesus.

 

[serotonin2A]

Even with identical twins I think it's possible one of them gets a lot of stress from something, like inequal distribution of nutrients and development... isn't it possible to gestate in the wrong side of the hood? Possibly that's enough for some epigenetic difference.

It is not unusual for there to be differences in nutrient status when multiple fetuses develop simultaneously. However, a difference large enough to stress one fetus to the point that they develop schizophrenia later in life would lead to obvious physical changes (there are physical signs when one fetus is dominent and the other is deprived of nutrients).

 

[Solipsis]

Personally I don't dare to presume I know what is enough for epigenetic variation but you might be right.

 

[serotonin2A]

Personally I don't dare to presume I know what is enough for epigenetic variation but you might be right.

They have found large epigenetic effects in babies born during famine or war, so in utero environment can definitely markedly alter the genome. But the reason we know that is because it is possible to study the genome to detect such changes (in addition to studing the physiology of the babies). It is possible that there are other types of more subtle epigenetic modifications that remain undiscovered.

But here we are talking about a very specific situation brought up by CY, based on a gene that normally has only a weak influence on schizophrenia (contrast the 1.3-fold increase in succeptibility with the much higher incidence when an identical twin has schizophrenia). The influence of the in utero environment on the function of that gene would have to be immense, but yet leave no physiological or epigenetic trace that is so far detectable. I think the situation proposed would require a much greater genetic risk factor than just 1.3x

 

[Cotcha Yankinov]

A little thought experiment to better outline the scenario I proposed in relation to gene-environment interactions - lets say that a polygenic disease like schizophrenia has 1000 possible susceptibility genes.

The average person may have 10 of these genes. A schizotypal/mild schizophrenic individual may have 25-50. A schizophrenic may average around 100. Now lets say that stress in utero magnifies the effect of these genes by 2x. This would mean that a person who would've likely only ended up schizotypal (with their 50 genes) may end up a schizophrenic with in utero stress.

Now I'm completely unaware of how researchers arrive at their 1.3x risk for C4 genes, but I'm curious if they have attempted to account for a possible distorting effect that gene-environment interactions may have on that gene's contribution to schizophrenia (rather than just controlling for post-natal stress/socio economic factors etc). This is to say that the gene may not be an incredible risk factor by itself, but in the presence of in utero stress, it could be an important contributor to schizophrenic biology.

One possibility is that if a particular gene only increases risk of schizophrenia under the conditions of in-utero stress, it could still be fairly well represented in all the controls who have the gene but didn't have the stress. This would lead to the appearance that i.e. C4 contributes less to schizophrenic biology than it actually does, just because its not that much more common in schizophrenics.

It seems like you could interpret the twin studies multiple ways. They either have the same causal genes, causal environment, or some combination. There may not necessarily be great epigenetic evidence, it could just be something like increased pre-natal stress leads to altered activity dependent neuroplasticity (that i.e C4 potentiates) which there should be morpological/histological evidence of but I don't know about epigenetic evidence.

Although I'm totally for the idea that schizophrenia is very polygenic.

 

[serotonin2A]

Now I'm completely unaware of how researchers arrive at their 1.3x risk for C4 genes, but I'm curious if they have attempted to account for a possible distorting effect that gene-environment interactions may have on that gene's contribution to schizophrenia (rather than just controlling for post-natal stress/socio economic factors etc).

They are calculating how much the odds ratio of getting schizophrenia increases when the gene is present. So the 1.3x figure probably includes some individuals with interacting effects.

However, take a look at this page: http://www.schizophrenia.com/hypo.php

Having a relative with schizophrenia increases the odds ratio 9x. That is a much greater effect than 1.3x. That is what makes me think that the gene we are talking about here cannot be the exclusive genetic component. Even with the possibility of in utero and postnatal interactions, this gene does not reproduce the level of risk that other genetic factors are known to contribute.

 

[Cotcha Yankinov]

Interesting..

I'm in total agreement that schizophrenia is polygenic and that it is a bio-psychosocial disease, but I guess part of what I'm trying to ask is:

How much of a synergistic effect is there between the susceptibility genes and environmental risk factors, or is it more additive than synergystic?


Also, just to play devil's advocate, it seems to me that by definition having a family member with schizophrenia means that you are probably going to have a more stressful life - so if you have a 9x higher risk of developing schizophrenia if you have such a family member, I'm not sure how much of that we can be sure to chalk up to genes.

For example, the schizophrenic family member could have even been stressing the mother when she was pregnant (Control for that using other stressed mothers as we may)

Even if that schizophrenic family member isn't actively around the mother during pregnancy or hadn't had contact with her previously, surely some aspects of her life were affected by having had a schizophrenic family member.

 

[serotonin2A]

How much of a synergistic effect is there between the susceptibility genes and environmental risk factors, or is it more additive than synergystic?

No one understands the illness at the level that would be necessary to give a clear answer to that question.

Also, just to play devil's advocate, it seems to me that by definition having a family member with schizophrenia means that you are probably going to have a more stressful life - so if you have a 9x higher risk of developing schizophrenia if you have such a family member, I'm not sure how much of that we can be sure to chalk up to genes.

Not necessarily...it depends on several factors. Having a cousin or an uncle with schizophrenia would not necessarily be much of a stressor. Furthermore, it is possible to study these interactions in people who were adopted and therefore not in contact with their relatives.

 

[Cotcha Yankinov]

Having a cousin or an uncle with schizophrenia would not necessarily be much of a stressor.

I understand there may be particular situations where we can control for the schizophrenic familiar member as having had an effect on the family via their behavior and such, but I guess I don't see there being a complete barrier between ie a cousin/uncle and the patient at hand.

For example, a schizophrenic uncle may have increased the stress that their sibling (who gave birth to the relevant offspring or raised it) experienced during adolescence. The uncle could have also increased the stress of their own parents, who birthed/raised the sibling who would go on to have another schizophrenic offspring. It just seems like its hard to perfectly control for the dynamics of having a schizophrenic person in the family (even extended family), in addition to the mildly schizophrenic family members.

Furthermore, it is possible to study these interactions in people who were adopted and therefore not in contact with their relatives.

In terms of kids who were adopted and went on to become schizophrenic, this seems to me to be another unique case that would be hard to control for perfectly. That the child was adopted means something was abnormal about their early family and possibly pre-natal life, and the adoption itself is a stressor.

We could try to control for this with other adopted children that come from non-schizophrenic families, but I'm just not sure how much of this gamut we've actually run quite yet. As I understand it, some of the better studies on the genetics of schizophrenia have only come about recently.

I realize there is extraordinary evidence for schizophrenia being largely genetic, but I'm just splitting hairs over how well we've managed to control for environmental factors thus far.

 

[serotonin2A]

I understand there may be particular situations where we can control for the schizophrenic familiar member as having had an effect on the family via their behavior and such, but I guess I don't see there being a complete barrier between ie a cousin/uncle and the patient at hand.

For example, a schizophrenic uncle may have increased the stress that their sibling (who gave birth to the relevant offspring or raised it) experienced during adolescence. The uncle could have also increased the stress of their own parents, who birthed/raised the sibling who would go on to have another schizophrenic offspring. It just seems like its hard to perfectly control for the dynamics of having a schizophrenic person in the family (even extended family), in addition to the mildly schizophrenic family members.



In terms of kids who were adopted and went on to become schizophrenic, this seems to me to be another unique case that would be hard to control for perfectly. That the child was adopted means something was abnormal about their early family and possibly pre-natal life, and the adoption itself is a stressor.

We could try to control for this with other adopted children that come from non-schizophrenic families, but I'm just not sure how much of this gamut we've actually run quite yet. As I understand it, some of the better studies on the genetics of schizophrenia have only come about recently.

I realize there is extraordinary evidence for schizophrenia being largely genetic, but I'm just splitting hairs over how well we've managed to control for environmental factors thus far.

It isn't necessary, nor is it possible, to control for all these factors. The goal of these studies is to investigate the influence of the gene in the general population. What you are suggesting is to look at the gene in a very very specific subpopulation (e.g., families with no stress). Yes, it can be stressful if you have a family member with schizophrenia. It is also stressful if your parents fight, if you don't have enough money, if you are teased in school, if you ever get sick, or any number of other problems that affect all children.

In terms of studies of adopted children, use of the proper control (for example, children adopted into families with no members who are schizophrenic) solves the problem you raised.

 

[Cotcha Yankinov]

It isn't necessary, nor is it possible, to control for all these factors. The goal of these studies is to investigate the influence of the gene in the general population. What you are suggesting is to look at the gene in a very very specific subpopulation (e.g., families with no stress). Yes, it can be stressful if you have a family member with schizophrenia. It is also stressful if your parents fight, if you don't have enough money, if you are teased in school, if you ever get sick, or any number of other problems that affect all children.

I guess I was misinterpreting the goal of this sort of phase of genetic research. I shouldn't have been looking at it as a study designed to figure out how many resources we (as a society) should designate for modifying the environment of the kids with risk genes vs. developing biological therapies.

There seems to be a lot of people (in the general public/government offices) who think that it's all in the genes - thusly there is no motivation to consider the environmental role and curb the susceptibility contribution coming from that end.

Essentially, I'm curious if environmental factors may play an appreciable role in the majority of schizophrenia cases and the in utero war/famine cases are not just an outlier, or if schizophrenia is moreso predetermined (with the family studies it seems the latter), and allotment of resources to curb adverse childhood experiences in the kids with risk genes and giving them access to CBT would be unfeasible economically (as CBT in schizophrenics doesn't seem to be helpful).


Will prescription guidelines start to outline medications to avoid in those with a particular genetic predisposition? For example, avoiding amphetamine prescriptions in those with schizophrenia risk genes.

 

[serotonin2A]

I guess I was misinterpreting the goal of this sort of phase of genetic research. I shouldn't have been looking at it as a study designed to figure out how many resources we (as a society) should designate for modifying the environment of the kids with risk genes vs. developing biological therapies.

There seems to be a lot of people (in the general public/government offices) who think that it's all in the genes - thusly there is no motivation to consider the environmental role and curb the susceptibility contribution coming from that end.

Essentially, I'm curious if environmental factors may play an appreciable role in the majority of schizophrenia cases and the in utero war/famine cases are not just an outlier, or if schizophrenia is moreso predetermined (with the family studies it seems the latter), and allotment of resources to curb adverse childhood experiences in the kids with risk genes and giving them access to CBT would be unfeasible economically (as CBT in schizophrenics doesn't seem to be helpful).


Will prescription guidelines start to outline medications to avoid in those with a particular genetic predisposition? For example, avoiding amphetamine prescriptions in those with schizophrenia risk genes.

What the psychiatric profession has mainly done is try to determine whether patients are in the prodromal phase, and potentially medicate them to try to stop illness progression. This course of action is somewhat controversial because there isn't an accurate way to really determine if someone is in the prodromal phase unless their symptoms eventually progress to schizophrenia.

Schizophrenia genes set up a program that the environment may or may not execute during adolescence.

 

[Cotcha Yankinov]

Might genome sequencing help determine whether symptoms are prodromes or not?

I feel like genetic testing isn't being utilized quite yet (from my personal experience). Is it just too early for it to really be useful, or is the clinical practice lagging behind the research? Or is it only utilized at the higher qualities of care?