DXM may protect against MDMA-induced brains lesions -Study in non-human primates

[DotChem]

why they use ketamine to anesthesize the animals before drug administration (see paper)??. Isnt ketamine and/or its metabolites potentially interfere with the effect of ecstasy?? or the metabolism of DXM? but it looks convincing the protective effet of DXM on ecstasy induce neurotoxity

Effects of dextromethorphan on MDMA-induced serotonergic aberration in the brains of non-human primates using [123I]-ADAM/SPECT; Ma et al. Sci Rep. 2016; 6: 38695. Published online 2016 Dec 12. doi: 10.1038/srep38695
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5150522/

ABSTRACT: 3,4-Methylenedioxymethamphetamine (MDMA), a common recreational drug, is known to cause serotonergic neurotoxicity in the brain. Dextromethorphan (DM) is a widely used antitussive reported to exert anti-inflammatory effect in vivo. In this study, we examined the long-term effect of MDMA on the primate serotonergic system and the protective property of DM against MDMA-induced serotonergic abnormality using single photon emission computed tomography (SPECT). Nine monkeys (Macaca cyclopis) were divided into three groups, namely control, MDMA and co-treatment (MDMA/DM). [¹²³I]-ADAM was used as the radioligand for serotonin transporters (SERT) in SPECT scans. SERT levels of the brain were evaluated and presented as the uptake ratios (URs) of [¹²³I]-ADAM in several regions of interest of the brain including midbrain, thalamus and striatum. We found that the URs of [¹²³I]-ADAM were significantly lower in the brains of MDMA than control group, indicating lower brain SERT levels in the MDMA-treated monkeys. This MDMA-induced decrease in brain SERT levels could persist for over four years. However, the loss of brain SERT levels was not observed in co-treatment group. These results suggest that DM may exert a protective effect against MDMA-induced serotonergic toxicity in the brains of the non-human primate.

 

[serotonin2A]

why they use ketamine to anesthesize the animals before drug administration (see paper)??. Isnt ketamine and/or its metabolites potentially interfere with the effect of ecstasy?? or the metabolism of DXM? but it looks convincing the protective effet of DXM on ecstasy induce neurotoxity

I think the ketamine was only administered for the imaging study.

 

[Cotcha Yankinov]

So they're saying that administration of an SRI with MDMA prevented loss of SERT? I guess I'm not understanding why that is interesting unless they are ascribing the protective effects to other actions of DXM/DXM metabolites... Its been noted for example that NMDA antagonism can prevent some of the effects of MDMA on parvalbumin expressing interneurons.

 

[DotChem]

^^ I see: it seems ketamine as anesthesic is not the best choice in that particular case since NMDA antagonists like DXM or more selective NMDA anatgonist MK801 were shown to protect against neurotoxicity induced by stims (at least with Methamphetamine: MK-801 and dextromethorphan block microglial activation and protect against methamphetamine-induced neurotoxicity )

So they're saying that administration of an SRI with MDMA prevented loss of SERT? I guess I'm not understanding why that is interesting unless they are ascribing the protective effects to other actions of DXM/DXM metabolites... Its been noted for example that NMDA antagonism can prevent some of the effects of MDMA on parvalbumin expressing interneurons.

I don't think their rationale on using DXM was based on its SRI acvitity but rather as NMDA antagonist since NMDA antagonist like MK801 were shown to protect against METH induced neurotoxicity (cf above ref).

Keeping in mind that their aim is rather clinical seeking to answer the following question: does taking small, non-dissociative doses of NMDA antagonist before (or following) MDMA consumption help prevent neuronal injury induced by MDMA or similar serotonergic stims? It would be interesting if the effect still apparent AFTER MDMA administration because according to their study the damage (MDMA induced downregulation of SERTs) persist for up to 4 years following consumption. In other words it would be interesting for the sake of harm reduction if that would be the case..(taking small dose(s) of DM following stims to prevent long term neurotoxicity)... more studies may be needed I guess.

 

[Cotcha Yankinov]

I see.

However, I'm not convinced that the adverse effects associated with MDMA anecdotally (A "long term comedown") are because of serotonin neurotoxicity (and I'm assuming that the observed SERT loss in this study is not hypo-expression mediated by epigenetics but rather a marker of nerve terminal loss). So in other words, while its interesting that DXM may be protective against serotonin neurotoxicity, I'm not sure that that will help humans very much if human's adverse effects aren't due to serotonin neurotoxicity. I'm certainly open to the idea that the adverse effects are related to serotonin degeneration though.

Symptoms like HPPD, depersonalization/derealization, anxiety, depression/anhedonia, and insomnia may have some causes that are not related to actual degeneration of serotonin nerve terminals, but the few people who do have persistent brain zaps have always made me wonder. Then again, people can have chronic brain zaps after SSRI withdrawal (rarely) and I wouldn't assume that they are suffering from serotonin neurotoxicity, maybe just LTD from an acute deficit of serotonin signaling. Hard to say.

Anyways, if substituted amphetamine related adverse effects are not due to serotonin nerve terminal loss, I wouldn't be surprised if DXM a couple hours into a trip (where SSRIs can still be protective) might actually be a bad idea. I'm not sure of the dosages of DXM we're talking about here, but dissociation, insomnia/stimulation when someone should be sleeping and recovering from their trip may be no good. If we are guessing the benefit is from NMDA antagonism, I don't think we'll be able to get NMDA antagonism without NRI in the case of DXM/DXO.

 

[serotonin2A]

^^ I see: it seems ketamine as anesthesic is not the best choice in that particular case since NMDA antagonists like DXM or more selective NMDA anatgonist MK801 were shown to protect against neurotoxicity induced by stims (at least with Methamphetamine: MK-801 and dextromethorphan block microglial activation and protect against methamphetamine-induced neurotoxicity )

The use of ketamine as an anesthetic would not confound the results of this study. Although NMDA-R antagonists can protect against neurotoxic insults, NMDA-R antagonists do not reverse neurotoxicity that has already occurred . For there to be an interaction, ketamine would have to be administered while the neurotoxic insult is taking place, not weeks after it.

 

[aced126]

I see.

However, I'm not convinced that the adverse effects associated with MDMA anecdotally (A "long term comedown") are because of serotonin neurotoxicity (and I'm assuming that the observed SERT loss in this study is not hypo-expression mediated by epigenetics but rather a marker of nerve terminal loss). So in other words, while its interesting that DXM may be protective against serotonin neurotoxicity, I'm not sure that that will help humans very much if human's adverse effects aren't due to serotonin neurotoxicity. I'm certainly open to the idea that the adverse effects are related to serotonin degeneration though.

Symptoms like HPPD, depersonalization/derealization, anxiety, depression/anhedonia, and insomnia may have some causes that are not related to actual degeneration of serotonin nerve terminals, but the few people who do have persistent brain zaps have always made me wonder. Then again, people can have chronic brain zaps after SSRI withdrawal (rarely) and I wouldn't assume that they are suffering from serotonin neurotoxicity, maybe just LTD from an acute deficit of serotonin signaling. Hard to say.

Anyways, if substituted amphetamine related adverse effects are not due to serotonin nerve terminal loss, I wouldn't be surprised if DXM a couple hours into a trip (where SSRIs can still be protective) might actually be a bad idea. I'm not sure of the dosages of DXM we're talking about here, but dissociation, insomnia/stimulation when someone should be sleeping and recovering from their trip may be no good. If we are guessing the benefit is from NMDA antagonism, I don't think we'll be able to get NMDA antagonism without NRI in the case of DXM/DXO.

I would've thought that the small proportion of people suffering extreme depression from MDMA for months after heavy abuse could have stemmed from 5HT neurotoxicity.

 

[Cotcha Yankinov]

I've suspected some people are suffering from 5-HT neurotoxicity or degeneration of other cells (although I dare not say it to them) but the weird thing is that a lot of people over in the MDMA recovery and support thread have their chronic adverse effects from practically a one-off use, and some people have reported having the same exact side effects (depersonalization/anhedonia/anxiety/HPPD) after a bad LSD trip for some time, and then they later went on to develop a full blown LTC after ecstasy. There is also depersonalization from weed too. So I'm really confused on what is causing the symptoms in different cases...

I might just be in denial, but I wonder if some of the overlap between MDMA/LSD/weed adverse effects is due to commonality in effects on parvalbumin expressing neurons (ie epigenetic modification of their GAD67 expression), and the effects just manifest differently because of the various drugs altering neurotransmission/neurophysiology in different ways.

I'm starting to lean towards 5-HT neurotoxicity may be happening and is relevant in some of the heavy users though, but the issue is that I'm not really ever seeing data that has focused on the adverse effects (LTC) sufferers, who may be a bit different than people who have abused chronically.

 

[serotonin2A]

I've suspected some people are suffering from 5-HT neurotoxicity or degeneration of other cells (although I dare not say it to them) but the weird thing is that a lot of people over in the MDMA recovery and support thread have their chronic adverse effects from practically a one-off use, and some people have reported having the same exact side effects (depersonalization/anhedonia/anxiety/HPPD) after a bad LSD trip for some time, and then they later went on to develop a full blown LTC after ecstasy. There is also depersonalization from weed too. So I'm really confused on what is causing the symptoms in different cases...

I might just be in denial, but I wonder if some of the overlap between MDMA/LSD/weed adverse effects is due to commonality in effects on parvalbumin expressing neurons (ie epigenetic modification of their GAD67 expression), and the effects just manifest differently because of the various drugs altering neurotransmission/neurophysiology in different ways.

I'm starting to lean towards 5-HT neurotoxicity may be happening and is relevant in some of the heavy users though, but the issue is that I'm not really ever seeing data that has focused on the adverse effects (LTC) sufferers, who may be a bit different than people who have abused chronically.

There is absolutely no evidence that hallucinogens damage GABAergic neurons or have effects on PV expression. The HPPD symptoms can occur in people who have never taken hallucinogens.

 

[Cotcha Yankinov]

There is absolutely no evidence that hallucinogens damage GABAergic neurons or have effects on PV expression. The HPPD symptoms can occur in people who have never taken hallucinogens.

I'm confused.

I have looked a bit for studies on the effects of psychedelics on PV interneurons and not been able to find anything, but judging by the way you speak, there have been checks for psychedelic effects on expression of PV/GAD67 in different species. I've read some on the effect of MDMA on PV interneurons, which appears to involve activation of 5-HT2A/C -> COX-2 -> glutamate release (with NMDA receptors also playing some role).

Is MDMA causing enough depolarization -> calcium influx through NMDA that the findings aren't relevant to traditional psychedelics? Could differences in 5-HT vs. psychedelic activation of 5-HT2 play a role? Effects related to neurotoxicity (activation of microglia)? Essentially that MDMA mediated activation of 5-HT2 is necessary but not sufficient to induce changes in PV interneurons..

I guess I'm not convinced that psychedelics have zero potential to have an effect on PV interneurons in some humans. I'm under the impression that people with mental illness like schizophrenia/bipolar already have issues with PV interneurons (epigenetic alteration of the expression of GAD67). I don't mean to start a fire that's difficult to put out (I understand the burden of proof is on me), but it just seems like psychedelics could alter epigenetic expression of GAD67 in a vulnerable human.


I understand that drug naïve people do get HPPD symptoms, but I don't know if that is a good argument for psychedelics not having an effect on PV interneurons. It seems like various drugs along with endogenous brain activity/genes could lead to epigenetic changes, with certain genes (schizophrenia/bipolar) increasing the likelihood of developing issues with PV interneurons.

One scenario would be that because ie schizophrenia is polygenic, if you have many "schizophrenia genes" you stand a chance of developing fully apparent HPPD symptoms, while if you only have a couple genes and symptomatically display just some visual snow, a psychedelic could unleash fully symptomatic HPPD.

I'm still really in the dark about HPPD. The only thing I've really managed to find is Abraham theorizing about effects on PV interneurons like degeneration/alteration of serotonin receptors on PV interneurons, but because MDMA/ketamine apparently alter PV expression, I was wondering if effects on epigenetic expression of GAD67/PV could also be considered as a possible cause of HPPD. Are there other theories?

 

[serotonin2A]

I'm confused.

I have looked a bit for studies on the effects of psychedelics on PV interneurons and not been able to find anything, but judging by the way you speak, there have been checks for psychedelic effects on expression of PV/GAD67 in different species. I've read some on the effect of MDMA on PV interneurons, which appears to involve activation of 5-HT2A/C -> COX-2 -> glutamate release (with NMDA receptors also playing some role).

Is MDMA causing enough depolarization -> calcium influx through NMDA that the findings aren't relevant to traditional psychedelics? Could differences in 5-HT vs. psychedelic activation of 5-HT2 play a role? Effects related to neurotoxicity (activation of microglia)? Essentially that MDMA mediated activation of 5-HT2 is necessary but not sufficient to induce changes in PV interneurons..

I guess I'm not convinced that psychedelics have zero potential to have an effect on PV interneurons in some humans. I'm under the impression that people with mental illness like schizophrenia/bipolar already have issues with PV interneurons (epigenetic alteration of the expression of GAD67). I don't mean to start a fire that's difficult to put out (I understand the burden of proof is on me), but it just seems like psychedelics could alter epigenetic expression of GAD67 in a vulnerable human.


I understand that drug naïve people do get HPPD symptoms, but I don't know if that is a good argument for psychedelics not having an effect on PV interneurons. It seems like various drugs along with endogenous brain activity/genes could lead to epigenetic changes, with certain genes (schizophrenia/bipolar) increasing the likelihood of developing issues with PV interneurons.

One scenario would be that because ie schizophrenia is polygenic, if you have many "schizophrenia genes" you stand a chance of developing fully apparent HPPD symptoms, while if you only have a couple genes and symptomatically display just some visual snow, a psychedelic could unleash fully symptomatic HPPD.

I'm still really in the dark about HPPD. The only thing I've really managed to find is Abraham theorizing about effects on PV interneurons like degeneration/alteration of serotonin receptors on PV interneurons, but because MDMA/ketamine apparently alter PV expression, I was wondering if effects on epigenetic expression of GAD67/PV could also be considered as a possible cause of HPPD. Are there other theories?

Abraham was just grasping for some potential explanation for the disorder -- probably an editor or reviewer wouldn't let him publish without proposing some mechanism for HPPD. But this was all just rank speculation on his part and there is absolutely no evidence that such a mechanism actually occurs in the brain.

Another reason not to dwell on a neurotoxicity explanation is that HPPD seems to be a disorder that is aggravated by psychedelics rather than being caused by them. So it doesn't seem necessary to resort to a pharmacological explanation related to 5-HT2A receptors -- it could simply be that subthreshold HPPD symptoms are aggravated by the intensity of the subjective experience induced by MDMA or psychedelics. Or maybe there is normally higher level cortical feedback that normally suppresses HPPD symptom generation in sensory cortical regions, but psychedelic use destabilizes this regulation, eventually allowing symptoms to emerge?

Another reason that the neurotoxicity explaination doesn't make much sense is that it isn't consistant with the pharmacology of different hallucinogens that cause HPPD. Compared to selective 5-HT2 agonists, nonselective hallucinogens like LSD produce less neuronal excitation due to effects on 5-HT1A, and hence should be less likely to produce HPPD. But that doesn't seem to be the case.

 

[Cotcha Yankinov]

Abraham was just grasping for some potential explanation for the disorder -- probably an editor or reviewer wouldn't let him publish without proposing some mechanism for HPPD. But this was all just rank speculation on his part and there is absolutely no evidence that such a mechanism actually occurs in the brain.

Hmmm... Well that is good to know that it was just uninformed speculation as far as degeneration of PV expressing interneurons induced by psychedelics, but I should clarify that I never thought that particular neurotoxicity explanation made sense in light of details about the remittance of HPPD after different medications and under different circumstances.

But when you say "There is absolutely no evidence that such a mechanism actually occurs in the brain", I assume you are referring to degeneration of PV interneurons by use of psychedelics rather than just alteration of expression of GAD67/PV? I'm only aware of the studies on MDMA and PV interneurons (showing decreased GAD67/PV expression) and have heard you speak of PV expression being altered by ketamine - does zero of that have a chance of transferring over to classical psychedelic use in a vulnerable human who already has issues with GAD67/PV expression in PV interneurons? I suppose whether or not that can occur and whether or not that causes HPPD are two different subjects.

Another reason not to dwell on a neurotoxicity explanation is that HPPD seems to be a disorder that is aggravated by psychedelics rather than being caused by them. So it doesn't seem necessary to resort to a pharmacological explanation related to 5-HT2A receptors -- it could simply be that subthreshold HPPD symptoms are aggravated by the intensity of the subjective experience induced by MDMA or psychedelics. Or maybe there is normally higher level cortical feedback that normally suppresses HPPD symptom generation in sensory cortical regions, but psychedelic use destabilizes this regulation, eventually allowing symptoms to emerge?

In regards to "So it doesn't seem necessary to resort to a pharmacological explanation related to 5-HT2A receptors -- it could simply be that subthreshold HPPD symptoms are aggravated by the intensity of the subjective experience induced by MDMA or psychedelics", I'm really confused.

My first thought is that the only reason the subjective experience would matter is if the subjective experience is influencing, for lack of a better word, "Newtonian" biology, and I'm convinced that consciousness does indeed affect biology, but I'm confused because the psychedelic is causing a change in biology and then consciousness.. In other words, if someone is saying that a "psychological" reaction to the subjective experience is at play in HPPD or depersonalization, then I don't know how that psychological reaction could be separated from 5-HT2A (or whatever receptor) activation and downstream alterations in neurophysiology (the psychological reaction will be affected by psychedelic activation of whatever receptors, therefore those receptors are still of interest even if they are distant to the cause of developing HPPD).

When you say "HPPD seems to be a disorder that is aggravated by psychedelics rather than being caused by them. So it doesn't seem necessary to resort to a pharmacological explanation related to 5-HT2A receptors" do you just mean that we need not resort to an explanation that is very close to ie 5-HT2A, and that the causes could be very far downstream and have to do with alteration of the entire brain network seen with psychedelics?

Another reason that the neurotoxicity explaination doesn't make much sense is that it isn't consistant with the pharmacology of different hallucinogens that cause HPPD. Compared to selective 5-HT2 agonists, nonselective hallucinogens like LSD produce less neuronal excitation due to effects on 5-HT1A, and hence should be less likely to produce HPPD. But that doesn't seem to be the case.

Just to clarify again I'm not in the neurotoxicity camp, but I'm essentially saying that there could be many different pharmacological pathways to get to above-threshold HPPD symptoms, and there must be many different pathways by which you could get to GAD67/PV hypoexpression in PV interneurons. Now, not to say that I'm not currently being swayed away from HPPD being due to issues with GAD67/PV, but I'm sure we could come up with reasons why LSD might tend to cause more issues with HPPD without completely abandoning the GAD67/PV theory, for example LSD D2 activation contributing to altering epigenetics during the late phase of the trip.

http://link.springer.com/article/10.1007/s00702-003-0826-8 "Decreases in the 67 kDa isoenzyme of brain glutamic acid decarboxylase (GAD₆₇) expression have been consistently found in patients with bipolar disorder and schizophrenia. In animals GAD₆₇ expression is diminished by chronic, but not acute stimulation of dopamine D₂ receptors and by short-term blockade of NMDA receptors."

I don't mean to complicate the subject, but the other thing I feel I should add in here is the seemingly enormous co-morbidity between depersonalization and HPPD, I have seen this talked about in the literature and have heard endless anecdotal reports of this co-morbidity over in the MDMA recovery thread. But it seems to me that something could cause both HPPD and depersonalization at the same time, rather than it be the case that depersonalization is just a fallout of HPPD.

Or maybe there is normally higher level cortical feedback that normally suppresses HPPD symptom generation in sensory cortical regions, but psychedelic use destabilizes this regulation, eventually allowing symptoms to emerge

Is this a sort of hebbian theory of HPPD in the sense that an acute alteration of neurophysiology can be somewhat maintained by neuroplasticity? So a psychedelic causes ie visual patterns by inhibiting this cortical regulation of sensory cortex, and then the pattern/manner of the neurophysiology that gives rise to those visual patterns can be sustained via strengthening of those synapses and weakening of the ones you're not using during that time?

The last thing I'll add is that dysfunction of the regulation of sensory cortices and epigenetic issues with GAD67/PV in PV interneurons don't seem to me to be incompatible theories of HPPD.

I hope I'm not seeming argumentative or anything, I'm just fascinated by HPPD but not content with the deficit of research, although it is such a rare disorder.

 

[serotonin2A]

Hmmm... Well that is good to know that it was just uninformed speculation as far as degeneration of PV expressing interneurons induced by psychedelics, but I should clarify that I never thought that particular neurotoxicity explanation made sense in light of details about the remittance of HPPD after different medications and under different circumstances.

But when you say "There is absolutely no evidence that such a mechanism actually occurs in the brain", I assume you are referring to degeneration of PV interneurons by use of psychedelics rather than just alteration of expression of GAD67/PV? I'm only aware of the studies on MDMA and PV interneurons (showing decreased GAD67/PV expression) and have heard you speak of PV expression being altered by ketamine - does zero of that have a chance of transferring over to classical psychedelic use in a vulnerable human who already has issues with GAD67/PV expression in PV interneurons? I suppose whether or not that can occur and whether or not that causes HPPD are two different subjects.



In regards to "So it doesn't seem necessary to resort to a pharmacological explanation related to 5-HT2A receptors -- it could simply be that subthreshold HPPD symptoms are aggravated by the intensity of the subjective experience induced by MDMA or psychedelics", I'm really confused.

My first thought is that the only reason the subjective experience would matter is if the subjective experience is influencing, for lack of a better word, "Newtonian" biology, and I'm convinced that consciousness does indeed affect biology, but I'm confused because the psychedelic is causing a change in biology and then consciousness.. In other words, if someone is saying that a "psychological" reaction to the subjective experience is at play in HPPD or depersonalization, then I don't know how that psychological reaction could be separated from 5-HT2A (or whatever receptor) activation and downstream alterations in neurophysiology (the psychological reaction will be affected by psychedelic activation of whatever receptors, therefore those receptors are still of interest even if they are distant to the cause of developing HPPD).

When you say "HPPD seems to be a disorder that is aggravated by psychedelics rather than being caused by them. So it doesn't seem necessary to resort to a pharmacological explanation related to 5-HT2A receptors" do you just mean that we need not resort to an explanation that is very close to ie 5-HT2A, and that the causes could be very far downstream and have to do with alteration of the entire brain network seen with psychedelics?



Just to clarify again I'm not in the neurotoxicity camp, but I'm essentially saying that there could be many different pharmacological pathways to get to above-threshold HPPD symptoms, and there must be many different pathways by which you could get to GAD67/PV hypoexpression in PV interneurons. Now, not to say that I'm not currently being swayed away from HPPD being due to issues with GAD67/PV, but I'm sure we could come up with reasons why LSD might tend to cause more issues with HPPD without completely abandoning the GAD67/PV theory, for example LSD D2 activation contributing to altering epigenetics during the late phase of the trip.

http://link.springer.com/article/10.1007/s00702-003-0826-8 "Decreases in the 67 kDa isoenzyme of brain glutamic acid decarboxylase (GAD₆₇) expression have been consistently found in patients with bipolar disorder and schizophrenia. In animals GAD₆₇ expression is diminished by chronic, but not acute stimulation of dopamine D₂ receptors and by short-term blockade of NMDA receptors."

I don't mean to complicate the subject, but the other thing I feel I should add in here is the seemingly enormous co-morbidity between depersonalization and HPPD, I have seen this talked about in the literature and have heard endless anecdotal reports of this co-morbidity over in the MDMA recovery thread. But it seems to me that something could cause both HPPD and depersonalization at the same time, rather than it be the case that depersonalization is just a fallout of HPPD.




Is this a sort of hebbian theory of HPPD in the sense that an acute alteration of neurophysiology can be somewhat maintained by neuroplasticity? So a psychedelic causes ie visual patterns by inhibiting this cortical regulation of sensory cortex, and then the pattern/manner of the neurophysiology that gives rise to those visual patterns can be sustained via strengthening of those synapses and weakening of the ones you're not using during that time?

The last thing I'll add is that dysfunction of the regulation of sensory cortices and epigenetic issues with GAD67/PV in PV interneurons don't seem to me to be incompatible theories of HPPD.

I hope I'm not seeming argumentative or anything, I'm just fascinated by HPPD but not content with the deficit of research, although it is such a rare disorder.

Hi CY, the interneurons in hippocampus are completely different than neocortical interneurons in terms of function and connectivity. Hippocampal interneurons are uniquely sensitive to excitation and you can't generalize what is known about those cells to interneurons in visual cortex or visual association areas.

When I was talking about hallucinogen effects on interneurons, I am talking about neocortex, because that is where the abnormalities are undoubtedly occuring (based on functional considerations).

Studies of genetics in patient populations are not relevant because the patients don't have HPPD. You cited studies of bipolar patients, but that illness is not typically associated with HPPD symptoms. The only studies that would be relevant are studies in HPPD patients.

I think what I posted about potentially not needing to resort to a direct pharmacological explaination was probably confusing. What I meant is that the disorder could be a direct effect of 5-HT2A receptor-induced excitation of neurons, or alternatively it could be way downstream at the network level. Large scale alterations of how visual cortical regions are functionally interconnected (including oscillatory changes that would alter how information propagates up to higher level regions and back down to lower regions) could certainly result in HPPD symptoms. It makes sense that HPPD is not a direct consequence of 5-HT2A activation, because if it was then many more people would be expected to get HPPD.

The fact that certain medications can relieve HPPD symptoms strongly indicates that cellular damage or cellular loss of function is not involved. If the cells were no longer functional, then it would be much more difficult to resolve HPPD symptoms. Neocortical GABAergic interneurons are not passive mediators of inhibition, but rather active circuit elements that regulate the specific pattern of pyramidal cell excitation. Additionally (and more importantly), although we tend to think of GABAergic interneurons like resistors in an electrical circuit, they actually function more like filters and oscillators. So if GABAergic interneuron dysfunction was responsible for HPPD, then just giving patients a benzodiazepine wouldn't be sufficient to relieve the symptoms (much like benzodiazepines are not specific treatments for schizophrenia).

I wasn't really referring to Hebbian learning. There are other ways for network functions to change. Networks can be bistable or there may be multiple states of stability, and it is possible for network function to undergo a state change. This is sort of how metals (crystals) can undergo phase changes when heated. Visual cortex might be able to exist in multiple functional processing states, one of which we think of as normal and another corresponding to HPPD symptoms. In succeptible individuals, exciting cortex may cause the processing state to change to HPPD. Hence, why dampening excitation with benzodiazepines flips the processing state back to normal. Hebbian learning isn't required for something like that to occur.

 

[Cotcha Yankinov]

Thank you very much for the enlightenment.

Large scale alterations of how visual cortical regions are functionally interconnected (including oscillatory changes that would alter how information propagates up to higher level regions and back down to lower regions) could certainly result in HPPD symptoms.

Networks can be bistable or there may be multiple states of stability, and it is possible for network function to undergo a state change. This is sort of how metals (crystals) can undergo phase changes when heated. Visual cortex might be able to exist in multiple functional processing states, one of which we think of as normal and another corresponding to HPPD symptoms. In succeptible individuals, exciting cortex may cause the processing state to change to HPPD. Hence, why dampening excitation with benzodiazepines flips the processing state back to normal. Hebbian learning isn't required for something like that to occur.

Interesting...

I have read depersonalization may involve issues of communication between the cortices. Considering the co-morbidity between HPPD and depersonalization, do you think that this could be taken as some evidence for a component of network-wide communication issues in HPPD?

Are there any particular regions (mPFC/LGN/V1?) or rhythmic connection between structures/regions that you would be interested in examining if given the opportunity to study HPPD patients?

I recall a recent finding that there were distinct depressive patient subtypes that could be classified by their resting state network. Do you think that any one of the genetics or environmental factors that predispose one to alterations in neural oscillations (ie mPFC-amygdala theta rhythms in S allele carriers) could be a risk factor for developing HPPD?

In the case of mPFC-amygdala theta rhythms in 5-HTT KO or hypoexpression models, it was found that the oscillation could even change direction apparently, supposedly because of hyperexcitability of PFC neurons.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3144906/
"Social defeat changes the directionality between LA and mPFC in 5-HTT wild-type mice, indicated by the “permanent” leading role of the mPFC, presumably due to “uncontrolled” hyperexcitability of PFC neurons (see discussion above).

-- socially defeated wild-types and/or a loss of 5-HTT functionality may modulate the directionality between LA and mPFC towards mPFC leads LA."

So if we suppose that loss of 5-HTT function can contribute to altered rhythmicity apparently theorized to be due to hyper-excitability of the PFC, then maybe short allele carriers and MDMA users are more vulnerable to developing HPPD if HPPD is an issue caused by an acute excitability of the cortex. That is not to say that HPPD in its ultimate form is plainly excitability of the cortex, but rather acute excitability of the cortex is a possible cause of network alterations that leads to HPPD, and people with 5-HTT hypofunction tend to have more excitable cortex.


RE: the patient whose HPPD remitted rapidly on Lamotrigine - I suppose this could be then thought to be due to the anti-epileptic effect of lamotrigine, both ion channel blockade and HDACi effects (Rather than HDACi reversing epigenetic alteration of GAD67), ultimately stabilizing network activity, but I'm a bit confused on whether or not there may be differences in acute vs. chronic HPPD in the sense that maybe there are neuroplastic adaptations in long-standing HPPD that do make it more difficult to treat.

I would like to think that the circuits involved are somewhat "hardwired" (I have heard the visual cortex doesn't tend to undergo much neuroplastic change or undergo change like that is seen in other regions with drugs of abuse) but is it a possibility that there is a neuroplastic component that maintains the theorized altered network function when HPPD is long-standing? It seems like that scenario would put HPPD in the category of schizophrenia as far as time is of the essence when treating it...

Whereas the notion over in the recovery threads and such is essentially "Go it as long as you can natural and medication free" for HPPD/depersonalization.

Thanks for the discussion and any thoughts.

 

[DotChem]

while its interesting that DXM may be protective against serotonin neurotoxicity, I'm not sure that that will help humans very much if human's adverse effects aren't due to serotonin neurotoxicity...

Why not? As far as brain chemistry I don't think there is much difference between "humans" and "monkeys" in so far as the effect of a drug on its target receptor(s) is concerned. Macaque monkeys are pretty much as close as is get to humans. Now, they may not have (or rather they may not be able to describe) any subjective experience they may be having while tripping but the same neurons will certainly get activated and/or inhibited as in "humans" by the drug. So macaques may well be "seeing "GOD" on DMT or Salvia just because they can't tell their buddies or write their experience on erowid or BL doesnt mean they didn't have that same experience as "humans".. but who knows?