3 ms·

While I'm not the biggest fan of companies trying to land grab the psychedelic craze, there are things that would be nice to have, like psychedelics that don't

While I'm not the biggest fan of companies trying to land grab the psychedelic craze, there are things that would be nice to have, like psychedelics that don't activate 5-HT2B (associated strongly with aortic hypertrophy, i.e., your heart valves grow too big) over time. Sure, we haven't necessarily seen a ton of direct linkage to IRL use, yet, AFAIPK, but still it's something that's been strongly shown, and most 5-HT2A psychedelics also activate 5-HT2B. Curious about selectivity against 5-HT3 as well as the nausea can be a problem. Some people wish for non hallucinogenic 5-HT2A activation and that seems like a bizzarely detached from reality pipe dream. Like, sure, maybe it's technically possible, but are you going to find a compound that selective (likely not) and is it actually going to remove all psychomometic effects (lol no, how do you think these things work)? There's always tradeoffs, it's like the weirdly detached desire to "reduce hallucinations" in language models but keep the same level of performance. Like, how do you think it's going to learn? You can't just magically make an unbiased perfect estimator with no variance for some limited capacity and data, your variance must live somewhere and in language models it tends to (generally) live in the higher level correlations between concepts. A good dose of basic mathematics and information theory really could set these fields straight. In any case, some of the future here looks exciting.

engeljohnb 3y ago
> psychedelics that don't activate 5-HT2B (associated strongly with aortic hypertrophy, i.e., your heart valves grow too big) Do you have a source for that? I'm a cardiac sonographer and I've never heard of aortic hypertrophy.
- dkasper 3y ago
  I hadn’t heard of it either but it does seem like there are some studies. https://link.springer.com/chapter/10.1007/978-3-030-55920-5_16 https://link.springer.com/chapter/10.1007/978-3-030-55920-5_... Cardiac valvulopathy is likely not an adverse effect to consider when psychedelics are used occasionally but this may be different for “microdosing” which involves low doses of psychedelics taken daily or multiple times per week.
gavinray 3y ago
> Some people wish for non hallucinogenic 5-HT2A activation and that seems like a bizzarely detached from reality pipe dream. This is actually an area of active research with promising developments, FWIW: https://psychedelichealth.co.uk/2023/06/13/non-hallucinogenic-psilocybin-derivative-clinical-candidate/ https://psychedelichealth.co.uk/2023/06/13/non-hallucinogeni...
- binary132 3y ago
  It's hard for me to understand what is meant by "similar characteristics to psilocybin" without hallucinogenic effects. Is the idea that the hyperreality of the subconscious / inner life would dominate conscious perception, but without the confusing or distressing associated overload of the physical senses, e.g. seeing or hearing things that aren't there? It's almost impossible to imagine the one aspect of the dreamlike state dominating the mind without the disruption of the other, but even if the senses are perfectly unperturbed I would think the unconstrained and disordered psyche alone could be very upsetting or confusing.
  - tbalsam 3y ago
    Yes I think this is it right here. Like, at a micro dose (or slightly above) level it maybe makes sense, but the raw characteristics of how psychedelics work will still be there. Maybe there's some way, who knows, but I don't think we're likely to find out up front, somewhat similar to trying to turn lead into gold just because, as it were (at least as best as I understand. :,(((( )
- tbalsam 3y ago
  Please read in context with the rest of the post! The idea is that it's very hard to raise the entropy of the brain without psychomometic effects as best as I understand, due to some fundamental informational qualities of those processes. It's like looking for a flu medicine and judging it by if makes a fever go down because a fever is an arbitrary human-measurable metric. Has some quality of life impacts but is second player to the actual health impacts of conditions including fever (especially ones with long term impacts) and is extremely superficial. I think that's the idea, maybe you can avoid visual cortex stuff but you can't magically get no psychomometic effects unless somehow the medication is perfectly shooting some kind of entropic gap. I'm sure it's possible but I feel like it's much better as an accidentally discovered thing or a second or third generation medication thing, not a first priority, if that makes sense.
notamy 3y ago
> Curious about selectivity against 5-HT3 as well as the nausea can be a problem. That would be a nice feature aiui; some people I know got into the habit of always taking psychedelics with ondansetron to try to avoid the nausea.
- bbqq 3y ago
  Ginger is often suggested as well, which is another 5ht3 antagonist. I wonder if it's linked to susceptibility to motion sickness, which is known to be genetic, as neither psychedelics nor motion give me nausea at all.
  - tbalsam 3y ago
    Yes, though thankfully ondnanestron has a shockingly good safety profile for a serotonergic antiemetic. That said, reducing that external complexity would be nice. CBD actual has some mild antiemesis properties as well and can be as immediately effective as Zofran if inhaled. I once backpacked with a dab pen and CBD due to having constant nausea, the crystal CBD isolate was easier to source and refill (since it's hemp derived) and the dab pen meant that I got nausea relief in seconds. Unfortunately CBD in ultra high doses can contribute to serotonin syndrome IIUC due to 5-HT1A activation (which is how it exerts anti-emetic effects IIUC/IIRC). So that of course is always a big problem and I think can make polypharmacy with it a bit more difficult (though I am of course not a doctor and this is not medical advice). That said CBD does help w.r.t. some social inhibitions due to autism IIRC and when I was dabbing between 300 mg - 1 g a day I definitely noticed a very calm, warm, low-key "peace" about the world that I very much appreciated. That was very nice indeed. Also, ginger can be nice for oral nausea as IIRC, however it does not cross the gut barrier as well so it takes more (and sometimes the spiciness can be a problem). It also inhibits a bunch of CYP enzymes as well which is something to consider (I guess many things do, but I tend to use it more as an emergency backup of emergency backups when I don't have anything else available to me. Order generally is Zofran -> CBD (200-300 mg sublingual if not urgent) -> Pepto -> Slightly more Pepto+Ginger depending upon urgency/availability. Refilling prescriptions can be a problem due to the overwhelm of autism for me, so I try to dole/parse it out sparing, at least as I am able to. <3 :')))) Happy to answer any questions, sorry this was an autistic infodump, really like this topic here.b<3 :'))))

engeljohnb 3y ago

> psychedelics that don't activate 5-HT2B (associated strongly with aortic hypertrophy, i.e., your heart valves grow too big) Do you have a source for that? I'm a cardiac sonographer and I've never heard of aortic hypertrophy.

dkasper 3y ago
I hadn’t heard of it either but it does seem like there are some studies. https://link.springer.com/chapter/10.1007/978-3-030-55920-5_16 https://link.springer.com/chapter/10.1007/978-3-030-55920-5_... Cardiac valvulopathy is likely not an adverse effect to consider when psychedelics are used occasionally but this may be different for “microdosing” which involves low doses of psychedelics taken daily or multiple times per week.

gavinray 3y ago

> Some people wish for non hallucinogenic 5-HT2A activation and that seems like a bizzarely detached from reality pipe dream. This is actually an area of active research with promising developments, FWIW: https://psychedelichealth.co.uk/2023/06/13/non-hallucinogenic-psilocybin-derivative-clinical-candidate/ https://psychedelichealth.co.uk/2023/06/13/non-hallucinogeni...

binary132 3y ago
It's hard for me to understand what is meant by "similar characteristics to psilocybin" without hallucinogenic effects. Is the idea that the hyperreality of the subconscious / inner life would dominate conscious perception, but without the confusing or distressing associated overload of the physical senses, e.g. seeing or hearing things that aren't there? It's almost impossible to imagine the one aspect of the dreamlike state dominating the mind without the disruption of the other, but even if the senses are perfectly unperturbed I would think the unconstrained and disordered psyche alone could be very upsetting or confusing.
- tbalsam 3y ago
  Yes I think this is it right here. Like, at a micro dose (or slightly above) level it maybe makes sense, but the raw characteristics of how psychedelics work will still be there. Maybe there's some way, who knows, but I don't think we're likely to find out up front, somewhat similar to trying to turn lead into gold just because, as it were (at least as best as I understand. :,(((( )
tbalsam 3y ago
Please read in context with the rest of the post! The idea is that it's very hard to raise the entropy of the brain without psychomometic effects as best as I understand, due to some fundamental informational qualities of those processes. It's like looking for a flu medicine and judging it by if makes a fever go down because a fever is an arbitrary human-measurable metric. Has some quality of life impacts but is second player to the actual health impacts of conditions including fever (especially ones with long term impacts) and is extremely superficial. I think that's the idea, maybe you can avoid visual cortex stuff but you can't magically get no psychomometic effects unless somehow the medication is perfectly shooting some kind of entropic gap. I'm sure it's possible but I feel like it's much better as an accidentally discovered thing or a second or third generation medication thing, not a first priority, if that makes sense.

notamy 3y ago

> Curious about selectivity against 5-HT3 as well as the nausea can be a problem. That would be a nice feature aiui; some people I know got into the habit of always taking psychedelics with ondansetron to try to avoid the nausea.

bbqq 3y ago
Ginger is often suggested as well, which is another 5ht3 antagonist. I wonder if it's linked to susceptibility to motion sickness, which is known to be genetic, as neither psychedelics nor motion give me nausea at all.
- tbalsam 3y ago
  Yes, though thankfully ondnanestron has a shockingly good safety profile for a serotonergic antiemetic. That said, reducing that external complexity would be nice. CBD actual has some mild antiemesis properties as well and can be as immediately effective as Zofran if inhaled. I once backpacked with a dab pen and CBD due to having constant nausea, the crystal CBD isolate was easier to source and refill (since it's hemp derived) and the dab pen meant that I got nausea relief in seconds. Unfortunately CBD in ultra high doses can contribute to serotonin syndrome IIUC due to 5-HT1A activation (which is how it exerts anti-emetic effects IIUC/IIRC). So that of course is always a big problem and I think can make polypharmacy with it a bit more difficult (though I am of course not a doctor and this is not medical advice). That said CBD does help w.r.t. some social inhibitions due to autism IIRC and when I was dabbing between 300 mg - 1 g a day I definitely noticed a very calm, warm, low-key "peace" about the world that I very much appreciated. That was very nice indeed. Also, ginger can be nice for oral nausea as IIRC, however it does not cross the gut barrier as well so it takes more (and sometimes the spiciness can be a problem). It also inhibits a bunch of CYP enzymes as well which is something to consider (I guess many things do, but I tend to use it more as an emergency backup of emergency backups when I don't have anything else available to me. Order generally is Zofran -> CBD (200-300 mg sublingual if not urgent) -> Pepto -> Slightly more Pepto+Ginger depending upon urgency/availability. Refilling prescriptions can be a problem due to the overwhelm of autism for me, so I try to dole/parse it out sparing, at least as I am able to. <3 :')))) Happy to answer any questions, sorry this was an autistic infodump, really like this topic here.b<3 :'))))