NMDA Hyperfunction in Autism

[dopamimetic]

Just found this very interesting paper, not only contains a graph that indeed appears to confirm one of the more "strange" theories I developed in the past years but also other things around it. Indicates that autism spectrum disorders and psychosis are the opposite ends of NMDA receptor dysfunction/dysbalance, finally, while earlier papers always only covered the normal to psychosis part of the picture which confused me somewhat as my own experiences did not fit in this.

Also it's not just me, I know a (unfortunately just one) friend with confirmed Asperger's diagnosis and her experiences are much the same as mine. Just she tolerates DXM much better and chose it as her DOC while I tried my way through the arylcyclohexylamines and memantine, the latter being imho a very underrated substance that, together with venlafaxine, improves my condition by so much..

Sigma receptor isn't mentioned in the study but I would suggest from my "data" that agonism is good and antagonism (sertraline, haloperidol etc) is bad. Yay, even my old kynurenic acid is there. Agmatine is no surprise, but might it make an effective treatment?? Never thought about trying that. Had sarcosine but after horrible experiences with even low dosages of the hyped racetams (granted, not exactly the same, but made me vary about going pro-NMDA) I only tried little of it without any noticeable results. [shortly afterwards, my ex flushed all my chems]

Yeah, what do you think? Could NMDA antagonists, especially memantine in higher dosages (20-50mg) possibly combined with an antidepressant*, make a considerable anti-autistic medicine? It would fit with my impression that they are two-phasic, first improvement, then worsening again and psychotomimesis.. it always confused me that ketamine etc. are described as being psychotomimetic in healthy volunteers at low dosages etc..

* memantine alone didn't cut it for me, got depressed and anxious after the initial stimulation faded away. venlafaxine alone didn't either, it helps but there's always something missing. together it's the best aid I known, besides that ominous 4,4'-dimethylaminorex of which I'd almost bet it'd show some NMDA antagonism too.

How does this fit with earlier theories, like too much endorphines and GABAergic inhibition? I know that NMDA antagonism is associated with less inhibition (check) and lowered tolerance to opioids (?? - yeah, even memenatine is strong enough to get me off 200mg morphine.. seems oppositing but morphine != endorphines and oppositing to almost everybody, opioids can be heavily psychotomimetic for me too).

 

[polymath]

3 days ago I noticed that my reaction time when playing video games (CoD Warzone) was surprisingly good after taking less than 100 mg of DXM. Even a treshold amount of Asperger's, such as what I have, makes one react slowly to unexpected situations. It could also have been just a random occurrence, but there's this publication about NMDA blockers reversing reaction time impairment by antipsychotics:

Amelioration of some neuroleptic-induced deficits by the... : Behavioural Pharmacology

release it within 1 sec of a light cue in order to obtain food reward. Chlorpromazine reduced the overall number of lever presses, caused an early cessation of responding, slowed lever release in response to an external cue, and increased the time taken to reach the food hopper after a correct...

journals.lww.com

Anything more than 60-100 mg of DXM would most likely just impair performance even more, regardless of PCP users being known to fight unusually hard when arrested.

 

[dopamimetic]

Yeah, I loved low (these plateaus never really matched with my experiences, now I know why) doses of DXM too ever since I more or less accidentally took one in my adolescence.. just makes one to live so much more in the moment, a feeling I had missed even without knowing it..

 

[thegreenhand]

Although the dopamine hypothesis of schizophrenia is quite contentious, it would provide additional support for this idea.

Motor deficits have often been observed in children with autism or aspergers which could be likened to the tardive dyskinesia seen in those treated with antipsychotic drugs. Decreased dopamine activity could be at least in part responsible for the motor deficits seen in both groups

 

[polymath]

Yeah, I loved low (these plateaus never really matched with my experiences, now I know why) doses of DXM too ever since I more or less accidentally took one in my adolescence.. just makes one to live so much more in the moment, a feeling I had missed even without knowing it..

A low dose of DXM seems to be much better at potentiating opiates than anything over 100 mg. That's why I took some 3 days ago with codeine. They could also interfere with each others metabolic CYP2D6 conversion, which could partially explain this.

 

[sekio]

DXM is a pretty strong NRI and SRI so that may contribute to analgesic effects too. (c.f. tapentadol, tramadol)

 

[S.J.B.]

Wait, autism is the opposite of psychosis? I can't imagine this is anywhere near a mainstream position. Other data suggest that autism seems to be a risk factor for psychosis.

 

[thegreenhand]

Wait, autism is the opposite of psychosis? I can't imagine this is anywhere near a mainstream position. Other data suggest that autism seems to be a risk factor for psychosis.

I don't think they are arguing that autism and psychosis are exact polar opposites. Rather that when looking at neurotransmitter disfunction, one can observe that some neurotransmitters may have irregularities in opposite directions.

I think the paper may be extrapolating a bit too far imo. For example they say that high empathy caused my MDMA can lead to psychosis which I do not see as being very truthful.

 

[Wilson Wilson]

I've used ketamine to medicate anxiety and depression successfully, but I didn't notice any effect on autism.

Thing with trying to have an "anti-autistic medicine" is it just... doesn't work like that. If you are an aspie you grew up a certain way, adopted certain behaviours and thought patterns all your life, and all this is now part of you as an individual. It's tied in with your personality. You cannot expect to take a pill and change your entire personality.

MDMA and psychedelics can certainly aid in introspection which in turn can help you make realisations applicable to your daily life. They're great for that kind of stuff. But they won't "cure" autism.

I am also highly sceptical about MDMA treating low empathy. I mean it technically does for the duration of the roll sure. But it goes away again straight after. Also MDMA is still a very "fake" feeling experience for the autistic brain, as it is for anyone, because your brain is just being flooded with silly levels of serotonin.

I honestly find good old weed is the best thing to keep my head level without the risk of addiction etc you get from opiates or benzos. It helps especially well with sensory issues. Kids screaming usually drive me mad, but if I'm stoned I don't even notice 'em.

I have another autistic friend who does happen to like both DXM and ketamine though, but she's into all kinds of drugs so I don't think that means anything.

P.S. Why the fuck would I wanna cure Aspergers? We live in a world where programmers can get paid six figures and some of the top billionaires in the world probably have it (certainly they show traits, do you think Elon Musk and Mark Zuckerberg are NTs?). This is our fucking time.

 

[polymath]

Thing with trying to have an "anti-autistic medicine" is it just... doesn't work like that. If you are an aspie you grew up a certain way, adopted certain behaviours and thought patterns all your life, and all this is now part of you as an individual. It's tied in with your personality. You cannot expect to take a pill and change your entire personality.

P.S. Why the fuck would I wanna cure Aspergers? We live in a world where programmers can get paid six figures and some of the top billionaires in the world probably have it (certainly they show traits, do you think Elon Musk and Mark Zuckerberg are NTs?). This is our fucking time.

I think people with autistic disorders can learn new behavior patterns at an age when most other people are too old to change their habits. Even my dad has become a much less difficult person after 65.

Mild autism-like symptoms can make some people good programmers, scientists, artists and so on. But sometimes you see someone with difficult enough AS that they only have to say a few words aloud and you already know they've almost surely failed practically everything in their life. Even something that would make them just a little bit more social would have a large effect on their standard of life.

 

[Wilson Wilson]

I think people with autistic disorders can learn new behavior patterns at an age when most other people are too old to change their habits. Even my dad has become a much less difficult person after 65.

Mild autism-like symptoms can make some people good programmers, scientists, artists and so on. But sometimes you see someone with difficult enough AS that they only have to say a few words aloud and you already know they've almost surely failed practically everything in their life. Even something that would make them just a little bit more social would have a large effect on their standard of life.

We can and do adapt to social norms by necessity, but this is a stressful thing to do day in day out. Our base instincts and abnormal brain function don't really change, rather we learn we need to project a false persona to the world or we cannot get ahead. As soon as we're behind closed doors we revert right back to our weirdo selves.

I'm not speaking only about myself here as this is very commonly documented behaviour, it's known as "autistic masking" or just "masking" if you wanna look it up.

As you can imagine faking your whole personality is a burden. It does become second nature to us because we have to practice it all the time. But it's not something we want to do and it is something we do on the conscious level of our brain as a learned behaviour. To use a computer analogy, the firmware is the same, but the software gets tweaked so it acts a bit different.

You are correct about lower functioning autistic people but Aspergers is by definition a subset of high functioning autism. In fact the diagnosis of AS does not exist in the DSM 5 it's just high functioning autism spectrum now. In order to get a diagnosis of AS you also had to have an IQ test and score at least 100 (average). So people with AS are not low functioning or mentally retarded or anything like that. A lot have above average IQ. Most are just weird and awkward with intense interests and most adapt to society (even if it is stressful to do so). I've also seen data showing most people with AS have relationships, most commonly with others on the spectrum, which is nice and makes sense. You want someone you can take your mask off around (percocet... molly percocets).

 

[thegreenhand]

MDMA is actually believed to reopen the "critical period" of social learning and can lead to synaptic changes. https://www.sciencedirect.com/science/article/pii/S0278584617308655

It's not as simple as "flooding the brain with serotonin". Obviously that is a major mechanism of its action but one also has to consider what effect this has on the psyche when in a therapy session. The paper I linked describes a possible psychological mechanism. Past memories from one's critical period of social learning that are associated with distressful emotions are accessed under the influence of MDMA and with a trained therapist those memories could be reassociated with the positive emotions one is feeling right then. Not saying that is completely true but I think it's a bit cynical to say that MDMA can't have lasting positive impacts on one's level of empathy when we have plenty of evidence that it does

 

[Wilson Wilson]

MDMA is actually believed to reopen the "critical period" of social learning and can lead to synaptic changes. https://www.sciencedirect.com/science/article/pii/S0278584617308655

It's not as simple as "flooding the brain with serotonin". Obviously that is a major mechanism of its action but one also has to consider what effect this has on the psyche when in a therapy session. The paper I linked describes a possible psychological mechanism. Past memories from one's critical period of social learning that are associated with distressful emotions are accessed under the influence of MDMA and with a trained therapist those memories could be reassociated with the positive emotions one is feeling right then. Not saying that is completely true but I think it's a bit cynical to say that MDMA can't have lasting positive impacts on one's level of empathy when we have plenty of evidence that it does

Yes within the context of psychedelic therapy it can be a powerful thing for sure. I can also believe it reduces social anxiety and therefore improves social ability - this is one of the things MAPS was (is?) studying it for, specifically social anxiety in adults with autism. Psychedelic experiences have helped me deal with all sorts of things, autism included. I'm an advocate of that.

That's not what the image in the OP seemed to be saying though, unless perhaps I'm reading it too literally (heh).

However in any case, I believe that claims about any drug or combination of drugs "curing" autism can be taken with a huge pinch of salt. They can help treat some of the symptoms, as MDMA does, but there is no cure for what is fundamentally differing brain function. I don't think an aspie with improved social skills is suddenly an NT, nor would any psychiatrist.

It's the same with any neurological or mental disorder. You cannot "cure" clinical depression, you can treat some of the symptoms to improve quality of life, but nothing is cured.

 

[thegreenhand]

Yes within the context of psychedelic therapy it can be a powerful thing for sure. I can also believe it reduces social anxiety and therefore improves social ability - this is one of the things MAPS was (is?) studying it for, specifically social anxiety in adults with autism. Psychedelic experiences have helped me deal with all sorts of things, autism included. I'm an advocate of that.

That's not what the image in the OP seemed to be saying though, unless perhaps I'm reading it too literally (heh).

However in any case, I believe that claims about any drug or combination of drugs "curing" autism can be taken with a huge pinch of salt. They can help treat some of the symptoms, as MDMA does, but there is no cure for what is fundamentally differing brain function. I don't think an aspie with improved social skills is suddenly an NT, nor would any psychiatrist.

It's the same with any neurological or mental disorder. You cannot "cure" clinical depression, you can treat some of the symptoms to improve quality of life, but nothing is cured.

I agree, I think that image is VASTLY oversimplifying many things.

This is quite off topic from the original topic of NMDA hyperfunction and lends itself perhaps more to philosophical discussion (sorry if this isnt allowed Sekio) but I think the idea of a "normally functioning brain" or a "chemically balanced brain" is absolute BS. Sure some people may vary more from the average but I'm not a fan of the medical idea that someone's brain function needs to be corrected and put back into line. I think that using tools like therapy and reasonable pharmaceutical treatment to help one find how they function best as THEMSELVES is key. Not trying to conform everyone to some arbitrary standard outlined in the DSM.

 

[Wilson Wilson]

I agree, I think that image is VASTLY oversimplifying many things.

This is quite off topic from the original topic of NMDA hyperfunction and lends itself perhaps more to philosophical discussion (sorry if this isnt allowed Sekio) but I think the idea of a "normally functioning brain" or a "chemically balanced brain" is absolute BS. Sure some people may vary more from the average but I'm not a fan of the medical idea that someone's brain function needs to be corrected and put back into line. I think that using tools like therapy and reasonable pharmaceutical treatment to help one find how they function best as THEMSELVES is key. Not trying to conform everyone to some arbitrary standard outlined in the DSM.

I couldn't agree more. So much of society is extremely arbitrary to me. I ask for reasons about why I need to do XYZ. In most cases society answers back "because that's how it is, it's tradition, it's culture, it's normal." Okay but why? Silence.

This is also why I use psychoactive substances as tools. I think of it like hacking my brain. When I'm smart about it and do it right, it works well. I don't really care if society wants to call me a criminal for doing something that helps me. What because the socially acceptable poison, alcohol, is better?

Going way off topic here I know. Sorry OP. Still on topic regarding autism though to be fair because this is effectively how most of us see things. The world is presented to us, we try to make sense of it, we ask for reasons why we do certain things or don't do others, never get proper answers and are told we're the crazy ones.

This is largely the reason I enjoyed reading Nietzsche. Finally here is someone, very well respected at that, who is willing to question traditions and norms and ask why should we follow them instead of thinking for ourselves? Resonates with me a lot.

Anyway I don't wanna derail the thread. If you wanna continue this discussion feel free to PM though

 

[polymath]

I couldn't agree more. So much of society is extremely arbitrary to me. I ask for reasons about why I need to do XYZ. In most cases society answers back "because that's how it is, it's tradition, it's culture, it's normal." Okay but why? Silence.

Yeah, it's a bit like in the 1950s when they tied the left hand of left-handed schoolchildren to the back of the chair and then called them idiots for writing total mess. I think the ideation behind that goes like "If we allow kids to be different in one sense, are we also giving a permission to steal, fight and use drugs, too?". But in a state of total anarchy, people with any kind of deviations would be in an even worse position.

With climate change, epidemic diseases and other things threatening our lifestyle, you'd expect society to use everyone's special talents without discrimination, but unfortunately this still doesn't happen that well.

 

[dopamimetic]

Well, I know too little about all the scientific details to really say something about the matter, and is why I always come up with some more or less abstruse theories that interestingly tend to fit with the papers from time to time (or I happen just to find these ones I like, really dunno).. I agree that it's an oversimplification.

Yet about the NMDA pathway they might indeed be right, for part of the affected population. As said, I and a good friend respond exact like on the image to dissociatives and others. Just posted it as it's something probably many would and have disagreed to instantly without being able to come up with any other satisfying theory or explaination.

Question though. In many papers dissos are mentioned as psychotomimetic, as acute model psychosis, PCP is used to induce schizophreniac disorder in animals etc. Is it really this? That "healthy" individuals immediately get positive symptoms when taking a decent dose of a disso? Because for some it is definitely not. They become more functional and subjectively even sober up on them, as long as you don't push the dosage too far, then it's true psychosis.. the same people too never are able to reach the state known as "k-hole", which would support something weird about NMDA.

 

[thegreenhand]

I am skeptical of a drug being labeled “psychotomimetic” for the simple fact that drug induced psychosis can occur from many substances (amphetamines, dissos, psychedelics, alcohol I’d even say) given the right dosage. So I would agree that dissos consistently being labeled psychotomimetic is not the full picture.

I would like to see more research on how dissociatices affect those with autism beyond just anecdotes -though yours are much appreciated - as I’m sure one would see distinct differences from the general population

 

[sekio]

I always thought autism was somewhat like being overdosed on LSD or other 5-HT2a agonists. Your senses are just blasting at 120% "volume" across the board, your mind is racing, and socializing goes wacky really quick.

Dissociatives are not good mimics of true schizophrenia either. Well, at least for me. There's flat affect, strange speech patterns, nonlinear thought, but nothing as far as command hallucinations, delusions, feeling of persecution/threat, etc. The one time I did OD on 3-MeO-PCP, the doctors were leaning more towards an initial diagnosis of stroke rather than intoxication/schizophrenia. (After someone tipped them off that it was PCP, then they decided to use Haldol - because PCP = excited schizophrenic delerium ALWAYS - plus restraints. Guess what, none of that helped at all, just made me more scrambled, scared, and confused.)

I'm not diagnosed as such but I'm sure I could be classified as high functioning autistic or Assburgers (sorry)... still like my hallucinogens. And dissociatives. They are kind of polar opposites though: LSD makes the senses amplified, PCP/ketamine makes the senses nullified. I actually prefer dissociatives somewhat just because they provide a sense of serenity and a "mind open to the sky". The combination of the two is interesting too. I remember torching a Narcotics Anonynmous handbook on a grill while on PCP+LSD. Very symbolic, made me feel happy.

 

[Flynnal]

I supposedly have AS. When I was 18, and going out to a party with my stepsisters, cousins, sisters, etc, I had a couple of beers to get started, and my sisters told me that I acted normal for the first time in my life. Normal.

Was it the NMDAR antagonism that caused this semblance of "normality" in my AS brain? I would never know, as I've done alcohol later on, and yes, it certainly made life a whole lot easier to deal with, but I decided I wasn't going down the alcoholic path where I'd be drinking escalating doses of this poison just to feel or seemingly act normal.

Then I saw dissociatives like ketamine, memantine, methoxetamine, and wanted to try them out, especially the memantine. But the doctor indicated that he wasn't comfortable putting me on memantine because of the nasty side effects for many people who are taking it. Not sure what a safe dose of memantine is, but I've done DXM 30mg and it made me feel a little weird.