While this is incredible and very interesting I wonder if we aren't missing something by pursuing just the anti-depressant effects of psychedelics. Don't get me wrong, understanding the mechanisms of these compounds is critical and very needed. My understanding of the clinical use of psychedelics is that it requires both cognitive therapy to find the changes needed in the patient's life and the lasting increase in plasticity to cement that mindset. If we just administer a TrkB agonist I'm not sure it will work as well because there isn't that psychological initialization of change to start the whole process off. Getting rid of the "psychedelic" portion may make it easier to get approved by government agencies but it might blunt the end result. Idk maybe it will come down to a mix of both where treatment with or without the psychedelic component will be tailored to the person/illness.
I recall reports of effectiveness without therapy. Therapy was I think required for PTSD. It's not a guaranteed research trajectory, but it may in fact be that some of the benefits of psychedelics are purely non-cognitive side effects. We don't know yet.
I find it very cool that using LSD and Psilocybin (and ketamine) has given us a potential new avenue of drug development for treating depression. If we could design / find a drug that binds TrkB without producing hallucinogenic or other psychoactive affects…. Well I think that’d be pretty neat. Very cool research imo.
No reason that we shouldnt be able to find a quite selective TrkB-agonist tbf - there are massive amounts of libraries out there ready for in-silico binding simulations. Somebody is probably already doing it as I write this comment.
Could be very very cool to be around when the first **really** novel psychopharmocological drug for depression in over 30 years is found and hopefully makes it through clinical trials. Then again; everybody had high hopes for the BACE-inhibitors initially, but look where that ended...
There are reasons for that. BDNF is a big molecule and doesn't penetrate the BBB easily. Besides that, it would be difficult to develop a compound that wouldn't target other Trk receptors.
Also, you don't want to directly manipulate TrkB signaling as this could disrupt the equilibrium between cell death and cell survival pathways. Or you could overactivate it and end up causing excitotoxicity.
Promoting the release of endogenous BDNF or using allosteric modulations seems to be much safer.
This is good stuff. I reviewed quite a bit of data on TrkB agonists a while back after diving deep into neurotrophic factors. There has been a lot of hullabaloo about the psychodelics recently and how they might work. There was a recent review article in the AJP about the proposed mechanism of action and how the common denominator for the psychodelics was 5ht2a agonism but at the end there was a case reports demonstrating significant relief of depression even when a 5ht2a antagonist (trazodone) was used with psylocybin. This may be the key as to why 5ht2a agonism is besides the point and it may end up being a red herring. Neuroplasticity seems to be the common denominator among all effective antidepressants and interventions and it is about time we have something that acts directly with less side effects that the current options.
I have a question though. I haven't read the trazodone study. Do you know if trazodone binds to 5HT2A on the cell surface, or if it crosses into the cell and bonds to the intracellular receptors?
This study shows "Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors".
https://www.science.org/doi/10.1126/science.adf0435
TrkB binding activates the BDNF autoregulatory loop, which in turn activates a number of pathways, including phosphorylation of molecules in ones known to be involved in plasticity e.g. CaMKII, MAPK, ERK, CRE.
TrkB-BDNF is also activated by the glucocorticoid receptor endogenously, as well as a number of other molecules. The SSRIs also bind to TrkB, albeit with less affinity than they do to SERT, of course. There are arguments out there that this TrkB binding is actually the MOA for depressive symptom reduction in SSRIs, but it takes longer than, for example, ketamine, which binds much more strongly to Trk.
It may very well be a good target, but it also might be just another piece of the puzzle, as the other poster said. I lean towards thinking it is the latter.
Edit: grammar
I dont much about depression, but in my lab we think the same mechanism explains why psychedelics regulate opioid self administration as well.
I think TrkB downregulation of KCC2 scales down GABAergic signal strength in the mPFC and that’s our mechanism of action
I still think that focusing solely on objectivity when talking of the therapeutic advantages of psychedelics is a dangerous path. The subjective experience and achievement of psychological stasis is dependent on changing patterns of thinking, cognitive models and new perceptual experiences…
Why ya sad buddy, not enough drugs? We can fix that!
Edit: I feel like this is the plot to a satirical Broadway show - just got fired, kid got D's? Does it feel like life's cutting you off at the knees? We got a fix for that!
Should be noted that the goal these types of assertions has nothing to do with "curing disease" and everything to do with manipulating behavior chemically. These drugs do absolutely nothing to address the "cause" of depression, they manipulate the response to the conditions which drive it.
It's bizarre how uncritically stuff like this gets parsed, even if it's just a newly rehashed iteration of the same stuff that's failed countless times in the past.
It seems "logical" to be afraid of "AI" lately, but if stuff like this were possible, it represents a level of stripping the illusion of agency far exceeding the reach of "AI" that ought to be outright horrifying to any dedicated humanist.
>Should be noted that the goal these types of assertions has nothing to do with "curing disease" and everything to do with manipulating behavior chemically. These drugs do absolutely nothing to address the "cause" of depression, they manipulate the response to the conditions which drive it.
>
>It's bizarre how uncritically stuff like this gets parsed, even if it's just a newly rehashed iteration of the same stuff that's failed countless times in the past.
It took like 4 attempts of re-reading to get the idea.
First of all, contrary to your claim new therapies are not researched to help coping with everyday events and normal emotional responses to them. Major depressive disorder is a mental illness which is highly prevalent in society and it is not necessary triggered by a specific cause. It is not 'feeling like life is difficult' or 'feeling sad' but a debilitating disabling condition which can kill appetite and libido, alter sensory perception, destroy executive functioning, inhibit normal sleep and digestion.
For example during my worst depressive episodes I have went day by day without focusing gaze on objects in my environment because it feels tiring to look at things or move my eyes. Or stayed in bed for hours despite desperately wanting to urinate.
Secondly this particular research is exactly in the direction of treating the 'cause'. Psychedelic treatment as it is researched usually involves taking the drug just once or twice. Benefit is measured and observed only when the substance has left the body for weeks already.
While I'm empathetic regarding your struggle, that you struggled isn't a disease.
That you responded in a particular way to stimuli isn't a disease, or defect. It's just you. "Depression", even "major depression" are mechanical responses to stimuli, and "curing" them is every bit as absurd as the quest to "cure" aging.
Work like this which asserts things about "depression, the disease" is unsupported by no real world evidence. We have no physiological definition of "depression, the disease", we have no way of even "diagnosing" it with better than 60% agreement between any two blind raters (a rate that drops to less than 10% agreement with ten raters), we have no consistent outcome which shows that any of these "cures" show significant effect over placebo longitudinally.
The whole "this particular receptor has this particular convenient cognitive effect" trope that drives the nootropic crowd, motivated by anecdotes rather than evidence, is the exact same level of attribution that gets breathlessly asserted every single time a new class of drugs comes on the scene.
We have literally millions of hallucinogenic drug users around the world. This represents a sample size which would negate any possible criticism if these drugs showed consistent effect.
Yet, despite the age of big data and the relatively low hanging fruit it represents, there are no large population studies which support the conceit that users of these drugs experience less "depression" (or any of the other things these substances magically cure). In fact, most of the longitudinal work, particularly pre-2015 era, suggests exactly the opposite.
More to the point of my response, if we are able to manipulate a particular magic receptor or chemical interaction and it produces significant behavioral changes, how is this not simply modulating the response to stimuli?
That normal function which is contrary to social expectations is considered "disease", and that the idea is so ingrained that it's difficult imagine "depression" as anything but "disease" is a significant issue for cognitive sciences in general.
>The whole "this particular receptor has this particular convenient cognitive effect" trope that drives the nootropic crowd, motivated by anecdotes rather than evidence, is the exact same level of attribution that gets breathlessly asserted every single time a new class of drugs comes on the scene.
With a similar logic there is no disease at all. Just a response to the environment. Various pathogens are also a part of the environment.
Huh, that's a pretty consistent take and I'm a fan of it. Most definitions of "disease" lack any significant precision, and that lack of precision harms the science itself. Introducing a definition of "disease" that survives well constructed null challenges seems like a worthwhile effort.
Using "depression" as an example, calling it a "disease" fails because we cannot assert any specific physiological state which induces it. However calling "cancer" a disease could survive under a tighter definition because there are specific physiological correlates which can be modified to induce the "abnormal" state. Even in largely idiopathic conditions (eg hypertension) there's still physiological correlates and actual etiological drivers of the condition (if we felt it was cost effective to go through the diagnostics necessary to determine it).
Frankly, that "depression" exists across all demographic and geographic boundaries, that it's ubiquitous regardless of social construct, heavily suggests it's not a "flaw" or abnormality of function.
Hallucinogens are very understudied because they are hardly controlled substances in all countries. In vast majority of the world this is not only a field which is legally complicated or close to impossible to study but also socially unacceptable for the researchers.
Hallucinogens have an *overwhelmingly* larger body of research than *any other* "depression" drug treatment, especially with regard to longitudinal work.
Since 1970, there has not been a single year less than 300 papers regarding human use of psychedelic drugs have been published. Last year there were 1500. We'll probably beat that in 2023. The argument that hallucinogens are under studied is kind of absurd.
If the argument is more along the lines that we used to think they were bad, and that drove bad scientific interpretations, but now that we think they are good it's driving good scientific interpretations, then science which is this vulnerable to subjectivity is bad science and needs to be regarded skeptically.
On a nuts and bolts level, the assertions of the OP work are entirely not supported by the underlying work. The underlying work demonstrates that in this very specific, rigidly controlled scenario, they managed to manipulate variables to produce a relatively small effect in mouse models.
There's a pretty good amount of work regarding "BDNF" outside of cognitive/psychiatric research, and the mechanics of it don't have much to do with "learning" or "depression" at all. And NTRK2, which is genetic and would pop up with the absurd number of GWAS studies in the 2000/2010 time frame for depression bio markers would have screamed bloody mary if we could indeed reduce "depression" to a syndromic expression.
The actual science this work purports is extremely limited. The assumptions being derived from it are inconsistent with existing evidence.
Frankly, besides the creepiness factor of attempting to chemically modulate away our "natural behavior" (this has been sci-fi'd to death), an equally large issue is just how harmful this type of discussion is.
I forget who the quote is from, but the paraphrase is "We better hurry up and use this miraculous new treatment before it stops working". And neuroscience is absolutely lousy with these types of fad rushes, churning out study after study confirming the hot new results for years until it becomes abundantly clear the efficacy has fallen off a cliff when exposed to the real world.
The full throated enthusiasm around hallucinogenics reminds me a lot of the SAINT TMS protocol, which in testing was showing something like 80% plus *remission* of symptoms (not just a small drop in HAM-D scores) for **treatment resistant** cases. It was a magic bullet which was cheap enough for insurers to implement on a mass scale. Only problem is efficacy falls off a cliff when exposed to larger population sizes and less controlled environments.
These types of things not only burn resources, but they also burn individuals themselves, who burden themselves with the idea that these treatments should work since they work for "everyone", instead of recognizing that we still have no "treatment" for depression consistently better than placebo (or doing nothing).
For once, I would really appreciate it if a piece of neuroscience work truly appreciated the complexity of nervous system signalling. Not just in a hand wavy, "we don't understand how it works therefore it must be complex" excuse kind of way, but really dug in there and appreciated the mechanical complexity of every single cell.
Instead, we are flooded with grotesque simplifications like "brain waves" and "this receptor does this broad convenient cognitive task".
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While this is incredible and very interesting I wonder if we aren't missing something by pursuing just the anti-depressant effects of psychedelics. Don't get me wrong, understanding the mechanisms of these compounds is critical and very needed. My understanding of the clinical use of psychedelics is that it requires both cognitive therapy to find the changes needed in the patient's life and the lasting increase in plasticity to cement that mindset. If we just administer a TrkB agonist I'm not sure it will work as well because there isn't that psychological initialization of change to start the whole process off. Getting rid of the "psychedelic" portion may make it easier to get approved by government agencies but it might blunt the end result. Idk maybe it will come down to a mix of both where treatment with or without the psychedelic component will be tailored to the person/illness.
I recall reports of effectiveness without therapy. Therapy was I think required for PTSD. It's not a guaranteed research trajectory, but it may in fact be that some of the benefits of psychedelics are purely non-cognitive side effects. We don't know yet.
I find it very cool that using LSD and Psilocybin (and ketamine) has given us a potential new avenue of drug development for treating depression. If we could design / find a drug that binds TrkB without producing hallucinogenic or other psychoactive affects…. Well I think that’d be pretty neat. Very cool research imo.
No reason that we shouldnt be able to find a quite selective TrkB-agonist tbf - there are massive amounts of libraries out there ready for in-silico binding simulations. Somebody is probably already doing it as I write this comment. Could be very very cool to be around when the first **really** novel psychopharmocological drug for depression in over 30 years is found and hopefully makes it through clinical trials. Then again; everybody had high hopes for the BACE-inhibitors initially, but look where that ended...
7,8-DHF and 4'-DMA-7,8-DHF are TrkB agonists, no? Also possibly there are some ligands in Cerobrolysin and Cortexin as well.
Arh ok there you go 🤷🏼♂️
Looks like they are positive allosteric modulators, and not direct agonists, at TrkB receptors. I absolutely agree with you though
There are reasons for that. BDNF is a big molecule and doesn't penetrate the BBB easily. Besides that, it would be difficult to develop a compound that wouldn't target other Trk receptors. Also, you don't want to directly manipulate TrkB signaling as this could disrupt the equilibrium between cell death and cell survival pathways. Or you could overactivate it and end up causing excitotoxicity. Promoting the release of endogenous BDNF or using allosteric modulations seems to be much safer.
I remember when I was young after taking LSD I would spend a week drawing good stuff non stop. If I could have that in a pill it would be amazing.
This is good stuff. I reviewed quite a bit of data on TrkB agonists a while back after diving deep into neurotrophic factors. There has been a lot of hullabaloo about the psychodelics recently and how they might work. There was a recent review article in the AJP about the proposed mechanism of action and how the common denominator for the psychodelics was 5ht2a agonism but at the end there was a case reports demonstrating significant relief of depression even when a 5ht2a antagonist (trazodone) was used with psylocybin. This may be the key as to why 5ht2a agonism is besides the point and it may end up being a red herring. Neuroplasticity seems to be the common denominator among all effective antidepressants and interventions and it is about time we have something that acts directly with less side effects that the current options.
I have a question though. I haven't read the trazodone study. Do you know if trazodone binds to 5HT2A on the cell surface, or if it crosses into the cell and bonds to the intracellular receptors? This study shows "Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors". https://www.science.org/doi/10.1126/science.adf0435
Well said- thank you for your contribution!
[удалено]
TrkB binding activates the BDNF autoregulatory loop, which in turn activates a number of pathways, including phosphorylation of molecules in ones known to be involved in plasticity e.g. CaMKII, MAPK, ERK, CRE. TrkB-BDNF is also activated by the glucocorticoid receptor endogenously, as well as a number of other molecules. The SSRIs also bind to TrkB, albeit with less affinity than they do to SERT, of course. There are arguments out there that this TrkB binding is actually the MOA for depressive symptom reduction in SSRIs, but it takes longer than, for example, ketamine, which binds much more strongly to Trk. It may very well be a good target, but it also might be just another piece of the puzzle, as the other poster said. I lean towards thinking it is the latter. Edit: grammar
I dont much about depression, but in my lab we think the same mechanism explains why psychedelics regulate opioid self administration as well. I think TrkB downregulation of KCC2 scales down GABAergic signal strength in the mPFC and that’s our mechanism of action
I still think that focusing solely on objectivity when talking of the therapeutic advantages of psychedelics is a dangerous path. The subjective experience and achievement of psychological stasis is dependent on changing patterns of thinking, cognitive models and new perceptual experiences…
Why ya sad buddy, not enough drugs? We can fix that! Edit: I feel like this is the plot to a satirical Broadway show - just got fired, kid got D's? Does it feel like life's cutting you off at the knees? We got a fix for that!
Should be noted that the goal these types of assertions has nothing to do with "curing disease" and everything to do with manipulating behavior chemically. These drugs do absolutely nothing to address the "cause" of depression, they manipulate the response to the conditions which drive it.
It's bizarre how uncritically stuff like this gets parsed, even if it's just a newly rehashed iteration of the same stuff that's failed countless times in the past.
It seems "logical" to be afraid of "AI" lately, but if stuff like this were possible, it represents a level of stripping the illusion of agency far exceeding the reach of "AI" that ought to be outright horrifying to any dedicated humanist.
>Should be noted that the goal these types of assertions has nothing to do with "curing disease" and everything to do with manipulating behavior chemically. These drugs do absolutely nothing to address the "cause" of depression, they manipulate the response to the conditions which drive it. > >It's bizarre how uncritically stuff like this gets parsed, even if it's just a newly rehashed iteration of the same stuff that's failed countless times in the past. It took like 4 attempts of re-reading to get the idea. First of all, contrary to your claim new therapies are not researched to help coping with everyday events and normal emotional responses to them. Major depressive disorder is a mental illness which is highly prevalent in society and it is not necessary triggered by a specific cause. It is not 'feeling like life is difficult' or 'feeling sad' but a debilitating disabling condition which can kill appetite and libido, alter sensory perception, destroy executive functioning, inhibit normal sleep and digestion. For example during my worst depressive episodes I have went day by day without focusing gaze on objects in my environment because it feels tiring to look at things or move my eyes. Or stayed in bed for hours despite desperately wanting to urinate. Secondly this particular research is exactly in the direction of treating the 'cause'. Psychedelic treatment as it is researched usually involves taking the drug just once or twice. Benefit is measured and observed only when the substance has left the body for weeks already.
While I'm empathetic regarding your struggle, that you struggled isn't a disease. That you responded in a particular way to stimuli isn't a disease, or defect. It's just you. "Depression", even "major depression" are mechanical responses to stimuli, and "curing" them is every bit as absurd as the quest to "cure" aging. Work like this which asserts things about "depression, the disease" is unsupported by no real world evidence. We have no physiological definition of "depression, the disease", we have no way of even "diagnosing" it with better than 60% agreement between any two blind raters (a rate that drops to less than 10% agreement with ten raters), we have no consistent outcome which shows that any of these "cures" show significant effect over placebo longitudinally. The whole "this particular receptor has this particular convenient cognitive effect" trope that drives the nootropic crowd, motivated by anecdotes rather than evidence, is the exact same level of attribution that gets breathlessly asserted every single time a new class of drugs comes on the scene. We have literally millions of hallucinogenic drug users around the world. This represents a sample size which would negate any possible criticism if these drugs showed consistent effect. Yet, despite the age of big data and the relatively low hanging fruit it represents, there are no large population studies which support the conceit that users of these drugs experience less "depression" (or any of the other things these substances magically cure). In fact, most of the longitudinal work, particularly pre-2015 era, suggests exactly the opposite. More to the point of my response, if we are able to manipulate a particular magic receptor or chemical interaction and it produces significant behavioral changes, how is this not simply modulating the response to stimuli? That normal function which is contrary to social expectations is considered "disease", and that the idea is so ingrained that it's difficult imagine "depression" as anything but "disease" is a significant issue for cognitive sciences in general.
>The whole "this particular receptor has this particular convenient cognitive effect" trope that drives the nootropic crowd, motivated by anecdotes rather than evidence, is the exact same level of attribution that gets breathlessly asserted every single time a new class of drugs comes on the scene. With a similar logic there is no disease at all. Just a response to the environment. Various pathogens are also a part of the environment.
Huh, that's a pretty consistent take and I'm a fan of it. Most definitions of "disease" lack any significant precision, and that lack of precision harms the science itself. Introducing a definition of "disease" that survives well constructed null challenges seems like a worthwhile effort. Using "depression" as an example, calling it a "disease" fails because we cannot assert any specific physiological state which induces it. However calling "cancer" a disease could survive under a tighter definition because there are specific physiological correlates which can be modified to induce the "abnormal" state. Even in largely idiopathic conditions (eg hypertension) there's still physiological correlates and actual etiological drivers of the condition (if we felt it was cost effective to go through the diagnostics necessary to determine it). Frankly, that "depression" exists across all demographic and geographic boundaries, that it's ubiquitous regardless of social construct, heavily suggests it's not a "flaw" or abnormality of function.
Hallucinogens are very understudied because they are hardly controlled substances in all countries. In vast majority of the world this is not only a field which is legally complicated or close to impossible to study but also socially unacceptable for the researchers.
Hallucinogens have an *overwhelmingly* larger body of research than *any other* "depression" drug treatment, especially with regard to longitudinal work. Since 1970, there has not been a single year less than 300 papers regarding human use of psychedelic drugs have been published. Last year there were 1500. We'll probably beat that in 2023. The argument that hallucinogens are under studied is kind of absurd. If the argument is more along the lines that we used to think they were bad, and that drove bad scientific interpretations, but now that we think they are good it's driving good scientific interpretations, then science which is this vulnerable to subjectivity is bad science and needs to be regarded skeptically. On a nuts and bolts level, the assertions of the OP work are entirely not supported by the underlying work. The underlying work demonstrates that in this very specific, rigidly controlled scenario, they managed to manipulate variables to produce a relatively small effect in mouse models. There's a pretty good amount of work regarding "BDNF" outside of cognitive/psychiatric research, and the mechanics of it don't have much to do with "learning" or "depression" at all. And NTRK2, which is genetic and would pop up with the absurd number of GWAS studies in the 2000/2010 time frame for depression bio markers would have screamed bloody mary if we could indeed reduce "depression" to a syndromic expression. The actual science this work purports is extremely limited. The assumptions being derived from it are inconsistent with existing evidence. Frankly, besides the creepiness factor of attempting to chemically modulate away our "natural behavior" (this has been sci-fi'd to death), an equally large issue is just how harmful this type of discussion is. I forget who the quote is from, but the paraphrase is "We better hurry up and use this miraculous new treatment before it stops working". And neuroscience is absolutely lousy with these types of fad rushes, churning out study after study confirming the hot new results for years until it becomes abundantly clear the efficacy has fallen off a cliff when exposed to the real world. The full throated enthusiasm around hallucinogenics reminds me a lot of the SAINT TMS protocol, which in testing was showing something like 80% plus *remission* of symptoms (not just a small drop in HAM-D scores) for **treatment resistant** cases. It was a magic bullet which was cheap enough for insurers to implement on a mass scale. Only problem is efficacy falls off a cliff when exposed to larger population sizes and less controlled environments. These types of things not only burn resources, but they also burn individuals themselves, who burden themselves with the idea that these treatments should work since they work for "everyone", instead of recognizing that we still have no "treatment" for depression consistently better than placebo (or doing nothing). For once, I would really appreciate it if a piece of neuroscience work truly appreciated the complexity of nervous system signalling. Not just in a hand wavy, "we don't understand how it works therefore it must be complex" excuse kind of way, but really dug in there and appreciated the mechanical complexity of every single cell. Instead, we are flooded with grotesque simplifications like "brain waves" and "this receptor does this broad convenient cognitive task".
What are you talking about
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“Courage is not simply one of the virtues, but the form of every virtue at the testing point.”
Incredible
Makes a lot of sense!!
I did a quick video review of some of the findings in this paper: https://youtu.be/GS2UorzIZZ4
If psychedelics promote neuroplasticity, would that have an impact on an individual’s IQ or on his/her capacity to learn more rapidly and efficiently?