73 replies to this topic

[jack black]

It appears that in the mGluR/5HT2A heteromer, binding to the 5HT2A receptor decreases affinity of glutamate for mGluR 2, which is responsible for glutamate release as well as GABA release at the presynaptic terminal (PMID: 20055706). 

 

i actually knew about it and posted about it above. I just occurred to me that blocking mGluR2 contributes to NMDA-mediated excitotoxicity in the acute phase of psychodelic use. Maybe this is why some susceptible individuals can be harmed? On the other hand, if micro-dosing (chronic phase) works by down-regulating the 5HT2a, how about the mGluR2 part?  would that work by increasing mGluR2 signal and be anti-excitotoxicity?

 

BTW, the issue i observed with micro-dosing, the research animal indicated dysphoria and irritability on the days without a micro-dose. I tried the every other day and every 3rd day schedules. Maybe I should try every day dosing to avoid that?

[gamesguru]

Maybe I should try every day dosing to avoid that?

 

Yeah mate good thinking, I mean what could possibly go wrong?

 

And if anything one would expect the NMDA toxicity during the withdrawal, not acute, phase.  I just don't know about all that research on mGluR2... those particular receptors really swing both ways if you know what I mean.

Neuropsychopharmacology. 1998 Jan;18(1):57-62.

Serotonergic agents that activate 5HT2A receptors prevent NMDA antagonist neurotoxicity.

Farber NB¹, Hanslick J, Kirby C, McWilliams L, Olney JW.

Author information

Abstract

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

[jaiho]

how does weeks = long-term???

 

i was taking them more often than i would recommend and had 6 months of a kind of afterglow, where i wasn't really in a bad mood despite a shitty life situation.  once that wore off, my mood also became shitty.  but even 6 months is not long-term.  it's like jerking off with pine needles, an interesting experience sure, but not something you would probably do again unless you had to.  especially once you have a bad trip, you want to go back there but make it easier on yourself this time, and unfortunately there isn't any way to guarantee that... the treadmill, magnesium and ginkgo may not last 6 months after you quit, but they also won't put you in a waking nightmare half the time

 

so jack yes i'm right, and the downside mentioned by jaiho is a huge one.  not to mention the fact that it only improves your mood not your motivation, basically it's like prozac, makes you content with a shitty situation without motivating you to change it.. proceed with caution

 

That bad trip must have taught you something you didn't want to know.

The psilocybin experience is fascinating and certainly not like masturbating with pine needles.

 

Psilocybin is far more likely to show you what you dont want to see, that your lifestyle or current outlook is contributing to your problems, while Prozac will numb you to your experiences and make you content to exist rather than to live and seek new experiences.

 

Long term is weeks, when it comes to a drug's effects leave your system within 12 hours. 

 

I think it all comes down to the default mode network, Meditation has similar effects on the brain as psychedelics, and if you regularly meditate & consume psychedelics, you'll be far more present & be able to enjoy life.

[gamesguru]

you can learn a lot of things without ever ingesting psychedelics, look at Bertrand Russell, Orsen Welles among others.  Pine needles in the sense of a mix of pleasure and pain, reward and punishment.  That's how I felt about the psychedelic experiene.  And probably the white pine needles, not red (the ones the native Americans used to make bedding out of)

 

if psilocybin shows me all my problems, why hasn't fixing them been made any easier?  If anything, abusing psychedelics has zapped my mental clarity and motivation, leaving me holding a sort of empty stick.  My mind was all dressed up with no where to run

 

we'll agree to disagree that two weeks is "medium-term".  these studies with terminal patients make it sound like the effects last years, decades, well practically as long as a terminal patient would care... a year a decade, now that is long-term.

 

and you rattled that last sentence off like you should meditate and trip out at equal frequencies, like twice a week?  in reality i would elect for daily meditations but no more than monthly trips.  but of course you know much more than me, with all those great experiences you have under your belt and i have not under mine

Edited by gamesguru, 11 April 2017 - 12:23 PM.

[jack black]

 

Maybe I should try every day dosing to avoid that?

 

Yeah mate good thinking, I mean what could possibly go wrong?

 

And if anything one would expect the NMDA toxicity during the withdrawal, not acute, phase.  I just don't know about all that research on mGluR2... those particular receptors really swing both ways if you know what I mean.

Neuropsychopharmacology. 1998 Jan;18(1):57-62.

Serotonergic agents that activate 5HT2A receptors prevent NMDA antagonist neurotoxicity.

Farber NB¹, Hanslick J, Kirby C, McWilliams L, Olney JW.

Author information

Abstract

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

 

 

as for the what possibly could go wrong, how about what possibly could go right?

http://www.longecity...es/#entry745359

 

as for that paper of LSD being anti-excitotoxicity, how are you going to separate the issue of 5HT2aR stimulation vs down-regulation effects as we know these 2 things are connected? I can tell you from my previous experiences that 5HT2aR antagonists have rapid anti-anxiety (anti-excitotoxicity?) effects on myself.

 

Yet, my research animal reported to me that there is a noticeable increase in energy, stimulation, and some anxiety shortly after a micro-dose. If there any transient excitotoxicity associated with psychedelics, i think this might be it.

 

[aperson444]

 

It appears that in the mGluR/5HT2A heteromer, binding to the 5HT2A receptor decreases affinity of glutamate for mGluR 2, which is responsible for glutamate release as well as GABA release at the presynaptic terminal (PMID: 20055706). 

 

i actually knew about it and posted about it above. I just occurred to me that blocking mGluR2 contributes to NMDA-mediated excitotoxicity in the acute phase of psychodelic use. Maybe this is why some susceptible individuals can be harmed? On the other hand, if micro-dosing (chronic phase) works by down-regulating the 5HT2a, how about the mGluR2 part?  would that work by increasing mGluR2 signal and be anti-excitotoxicity?

 

BTW, the issue i observed with micro-dosing, the research animal indicated dysphoria and irritability on the days without a micro-dose. I tried the every other day and every 3rd day schedules. Maybe I should try every day dosing to avoid that?

 

I remember one study involving delta-mu opioid receptor heteromers that found that when delta-opioid receptors were activated and internalized, they "dragged down" the mu-opioid receptors with them (PMID: 17941650). The same effect was seen for the mu agonists on the delta-mu heteromer. Now, the opioid receptor is different from the 5HT2A receptor by quite a good amount, but if heteromers behave in this fashion, it is likely that the 5HT2A-mGluR 2 heteromer behaves this way as well. 

 

It should be noted that mGluR 2 is implicated in cognition and memory-related processes and that activation of the mGluR 2 might impair cognition. So downregulation of mGluR 2 might not be too much of a bad thing (PMID: 20055706). It looks like mGluR 3 has been moreso implicated in the anti-excitotoxic effects of mGluR Group II agonists. The mGluR 2 has actually been implicated in enhancing the excitotoxicity of NMDA such that in mGluR 3 knockout mice, NMDA's excitotoxicity is enhanced by administration of LY379268 (PMID: 17670976). Because the 5HT2A receptor blocks the activity of mGluR 2 when it is found in a heteromer, therefore, the effect should be a net neuroprotective effect if one is considering only the mGluR 2/5HT2A heteromer. 

[jack black]

 

 

It appears that in the mGluR/5HT2A heteromer, binding to the 5HT2A receptor decreases affinity of glutamate for mGluR 2, which is responsible for glutamate release as well as GABA release at the presynaptic terminal (PMID: 20055706). 

 

i actually knew about it and posted about it above. I just occurred to me that blocking mGluR2 contributes to NMDA-mediated excitotoxicity in the acute phase of psychodelic use. Maybe this is why some susceptible individuals can be harmed? On the other hand, if micro-dosing (chronic phase) works by down-regulating the 5HT2a, how about the mGluR2 part?  would that work by increasing mGluR2 signal and be anti-excitotoxicity?

 

BTW, the issue i observed with micro-dosing, the research animal indicated dysphoria and irritability on the days without a micro-dose. I tried the every other day and every 3rd day schedules. Maybe I should try every day dosing to avoid that?

 

I remember one study involving delta-mu opioid receptor heteromers that found that when delta-opioid receptors were activated and internalized, they "dragged down" the mu-opioid receptors with them (PMID: 17941650). The same effect was seen for the mu agonists on the delta-mu heteromer. Now, the opioid receptor is different from the 5HT2A receptor by quite a good amount, but if heteromers behave in this fashion, it is likely that the 5HT2A-mGluR 2 heteromer behaves this way as well. 

 

It should be noted that mGluR 2 is implicated in cognition and memory-related processes and that activation of the mGluR 2 might impair cognition. So downregulation of mGluR 2 might not be too much of a bad thing (PMID: 20055706). It looks like mGluR 3 has been moreso implicated in the anti-excitotoxic effects of mGluR Group II agonists. The mGluR 2 has actually been implicated in enhancing the excitotoxicity of NMDA such that in mGluR 3 knockout mice, NMDA's excitotoxicity is enhanced by administration of LY379268 (PMID: 17670976). Because the 5HT2A receptor blocks the activity of mGluR 2 when it is found in a heteromer, therefore, the effect should be a net neuroprotective effect if one is considering only the mGluR 2/5HT2A heteromer. 

 

 

Thanks! This really helps me understand it better. In the later stages of experiments I may want to combine psychedelics with memantine to see if any difference.

 

[Omega 3 Snake Oil]

i actually knew about it and posted about it above. I just occurred to me that blocking mGluR2 contributes to NMDA-mediated excitotoxicity in the acute phase of psychodelic use. Maybe this is why some susceptible individuals can be harmed? On the other hand, if micro-dosing (chronic phase) works by down-regulating the 5HT2a, how about the mGluR2 part?  would that work by increasing mGluR2 signal and be anti-excitotoxicity?

 

BTW, the issue i observed with micro-dosing, the research animal indicated dysphoria and irritability on the days without a micro-dose. I tried the every other day and every 3rd day schedules. Maybe I should try every day dosing to avoid that?

 

 

Yeah mate good thinking, I mean what could possibly go wrong?

 

And if anything one would expect the NMDA toxicity during the withdrawal, not acute, phase.  I just don't know about all that research on mGluR2... those particular receptors really swing both ways if you know what I mean.

I tried my first microdose of psilocybin last night and got some interesting results. 

I only took around 60-70mg. After about an hour I felt slightly euphoric/happy, but no big deal. I thought about taking another dose before bed but decided against it since insomnia and central apnea are a big problem for me. 

Today I feel awful. Everything feels fuzzy and it hurts to be out of bed. Note my pre-existing condition: neurological Lyme for several years, mold toxicity and suspected copper toxicity. I've reacted badly to many typically safe substances (serious neurological problems, worsened neuropathy and dysautonomia). 

One thing I've put together is that I have a big problem with glutamate toxicity/GABA balance. Zopiclone only works when I pair it with 300mg pharmaGABA, and if I eat/drink anything high in glutamate I get tremors/fasiculations, plus complete insomnia. Also, a single tiny 5mg dose of NSI-189 caused severe dysautonomia (worsened by consuming calcium) that lasted around 18 months. I seem to have methylation issues as well, bad methylation genes.

So, yeah, it seems a microdose actually didn't help me at all. I read somewhere that psilo. affects blood flow to the thalamus, which I've long suspected is a problem area for me (sensory processing has been an issue since I first got Lyme, and has only worsened over the years).  

[gamesguru]

I tried my first microdose of psilocybin last night and got some interesting results. 

I only took around 60-70mg. After about an hour I felt slightly euphoric/happy, but no big deal. I thought about taking another dose before bed but decided against it since insomnia and central apnea are a big problem for me. 

Today I feel awful. Everything feels fuzzy and it hurts to be out of bed. Note my pre-existing condition: neurological Lyme for several years, mold toxicity and suspected copper toxicity. I've reacted badly to many typically safe substances (serious neurological problems, worsened neuropathy and dysautonomia). 

One thing I've put together is that I have a big problem with glutamate toxicity/GABA balance. Zopiclone only works when I pair it with 300mg pharmaGABA, and if I eat/drink anything high in glutamate I get tremors/fasiculations, plus complete insomnia. Also, a single tiny 5mg dose of NSI-189 caused severe dysautonomia (worsened by consuming calcium) that lasted around 18 months. I seem to have methylation issues as well, bad methylation genes.

So, yeah, it seems a microdose actually didn't help me at all. I read somewhere that psilo. affects blood flow to the thalamus, which I've long suspected is a problem area for me (sensory processing has been an issue since I first got Lyme, and has only worsened over the years).  

 

If you mean 0.07 g of mushroom material, then a lot of it is probably placebo.  Sounds like you just need to get a few dietary things in line, and the lack of sleep caught up with you.  Magnesium powder may be a good place to start.  There was a Lyme thread elsewhere, curating some interesting results

[Omega 3 Snake Oil]

If you mean 0.07 g of mushroom material, then a lot of it is probably placebo.  Sounds like you just need to get a few dietary things in line, and the lack of sleep caught up with you.  Magnesium powder may be a good place to start.  There was a Lyme thread elsewhere, curating some interesting results

Yeah, may have been. I've been microdosing 200mg every third day or so, combined with 150mg niacin and 3g Lion's Mane (i.e. Paul Stamets protocol) and I definitely feel something from that. More focus, less anxiety and I think it may even be helping my neuropathy.

[gamesguru]

Yeah, may have been. I've been microdosing 200mg every third day or so, combined with 150mg niacin and 3g Lion's Mane (i.e. Paul Stamets protocol) and I definitely feel something from that. More focus, less anxiety and I think it may even be helping my neuropathy.

 

That is not really a micro-dose, depending on the strength a quarter gram is more than threshold.  In order to meet the qualifications of a "micro-dose", I am suggesting an intake of no more than 50% of a threshold dose.

 

And by this point I should make it clear how I have rather strong opinions against the micro-dosing movement.  With psychedelic trips short of mega-dosing: intensity matters more than frequency, and frequency harms more than intensity.

 

In the flagship 2016 study, a relief of end-of-life anxiety in terminal patients was not observed on the lower dose.  Lower doses are unlikely to provide any therapeutic breakthroughs; and however frequently repeated, they are only the more likely to foreshadow an approaching mental breakdown than to provide any genuine self-furtherance.  Compare that with the years' lasting benefit of a single large dose, and you begin to see the other side of the coin

[Keizo]

Shrooms have some toxicity. They cause vomiting in high doses. The pure psychedelics don't do that.

Really? I very much doubt that based on personal experience with some psychedelic drugs (Ketamine, 4-ho-met (aka metocin i.e. a psilocin analogue) and a few others). All of them have caused vomiting at some point or another for me. I never tried psilocybin mushrooms tho, I could see how that'd be even worse in that regard.

 

Personally I'm not a fan of tryptamines. I think it makes a lot of sense that Ketamine has been approved for treatment resistant depression by the FDA (and probably will be approved for all kinds of things) whereas other psychedelics haven't been approved for anything AFAIK. Ketamine because it's such an easy-going substance as far as subjective effects has the potential for mass-marketing, whereas things like psilocin tends to cause anxiety more often. And if the way you get the most benefit from LSD or psilocin would be from the weird experiences rather than a under-the surface (neuronal growth etc) kind of thing, then that makes it even more impractical to market. 

Edited by Keizo, 13 January 2020 - 11:58 AM.

[poonja]

One other factor is the cardio toxicity of both tryptamine and lysergamides as they bind to 5ht2b receptors and can cause valvular disease.

[Aeon]

I know that in recent years there is quite a lot of research about the potential health benefits of psychedelics, including Psilocybin mushrooms, in a suitable use.

 

I am quite interested to know if there is research about the effect of a controlled use of Psilocybin mushrooms on life expectancy or at least long term general health, as I could not find research specifically on that.