Psilocybin Decelerates Cellular Senescence • Hacker News Board

Re: Psilocybin Decelerates Cellular Senescence

#11

Post by TheToadKnows » Sat, Jul 01, 2023, 12:16 PM UTC

This experimental design is flawed. It's important to remember that orally dosed psilocybin acts as a prodrug for psilocin. It is metabolized into psilocin in the gut before absorbing into circulation. It is psilocin that is primarily responsible for the physiological and psychoactive effects.

Therefore, in vitro (cell culture) studies like this one that only focus on psilocybin and not psilocin are limited in translational value. They fail to accurately mimic the physiological context, where psilocin, not psilocybin, would interact with these cell types. For translational relevance, we need to study the actual bioactive compound (psilocin) in systems that closely replicate human physiology. Thus, in vitro studies with psilocybin provide an inaccurate picture. I would be surprised if this made it through peer review anywhere.

Re: Psilocybin Decelerates Cellular Senescence

#12

Post by amts » Sat, Jul 01, 2023, 12:20 PM UTC

dist-epoch wrote: post #5

As in all things biology, that's not necessarily a good thing, otherwise we would have evolved it already. Surely there are downsides (cancer, ...) > it has been suggested that cellular senescence evolved as a way to prevent the onset and spread of cancer. Somatic cells that have divided many times will have accumulated DNA mutations and would be more susceptible to becoming cancerous if cell division continued. As s…

>>Surely there are downsides (cancer, ...)

Me doesn't quite understand the rationale behind this widely used argument. Ok, senescent cells emerge as a mechanism to ward off cancer. They are basically semi-cancerous cells with an arrested cell division cycle ("zombies"). The goal of cancer therapies is to eliminate cancer cells. So what's wrong with the elimination of senescent cells? (especially if you get new stem cells differentiating into new healthy tissue in place of senescent ones or let the surrounding healthy tissue to proliferate there)

Re: Psilocybin Decelerates Cellular Senescence

#13

Post by dist-epoch » Sat, Jul 01, 2023, 12:24 PM UTC

amts wrote: post #12

dist-epoch wrote: post #5

As in all things biology, that's not necessarily a good thing, otherwise we would have evolved it already. Surely there are downsides (cancer, ...) > it has been suggested that cellular senescence evolved as a way to prevent the onset and spread of cancer. Somatic cells that have divided many times will have accumulated DNA mutations and would be more susceptible to becoming cancerous if cell division continued. As s…

>>Surely there are downsides (cancer, ...) Me doesn't quite understand the rationale behind this widely used argument. Ok, senescent cells emerge as a mechanism to ward off cancer. They are basically semi-cancerous cells with an arrested cell division cycle ("zombies"). The goal of cancer therapies is to eliminate cancer cells. So what's wrong with the elimination of senescent cells? (especially if you get new stem c…

There is nothing wrong with eliminating them. But this study says psylocybin slows down cells becoming senescent, not that it eliminates them. So in fact it makes them live longer.

Re: Psilocybin Decelerates Cellular Senescence

#14

Post by amts » Sat, Jul 01, 2023, 2:27 PM UTC

dist-epoch wrote: post #13

amts wrote: post #12

Earlier quoted context omitted.

>>Surely there are downsides (cancer, ...) Me doesn't quite understand the rationale behind this widely used argument. Ok, senescent cells emerge as a mechanism to ward off cancer. They are basically semi-cancerous cells with an arrested cell division cycle ("zombies"). The goal of cancer therapies is to eliminate cancer cells. So what's wrong with the elimination of senescent cells? (especially if you get new stem c…

There is nothing wrong with eliminating them. But this study says psylocybin slows down cells becoming senescent, not that it eliminates them. So in fact it makes them live longer.

Yep, they show it's not a senolytic, but I'd like to see an experimental human group (preferably with a dopamine transporter allele making them more prone to placebo-like responses) being given psilocybin and told that it is a senolytic.

"Psilocybin treatment led to a dose-dependent decrease in cell cycle arrest markers (p21, p16, and p53) and an increase in markers of DNA replication (phosphorylated-Retinoblastoma protein; pRB) and proliferation (PCNA), as compared to vehicle-treated cells". They don't say it IS carcinogenic. At least this statement favors taking psilocybin after fasting/senolytics/autophagy induction.

"may mediate SIRT1-dependent pathways which impact cellular senescence". So if senescence is delayed by it and during this period SIRTs are activated, it may be anti-cancerous.

Re: Psilocybin Decelerates Cellular Senescence

#15

Post by amts » Sat, Jul 01, 2023, 2:37 PM UTC

TheToadKnows wrote: post #11

This experimental design is flawed. It's important to remember that orally dosed psilocybin acts as a prodrug for psilocin. It is metabolized into psilocin in the gut before absorbing into circulation. It is psilocin that is primarily responsible for the physiological and psychoactive effects. Therefore, in vitro (cell culture) studies like this one that only focus on psilocybin and not psilocin are limited in transl…

Seems like psilocin is dephosphorylated psilocybin. But the main working indole structure with the side chain is preserved. So for a cell to get an extra phosphate rich in energy while producing psilocin for the host should be a bonus.

The general rationale seems rather feasible, given the application of the SSRI antidepressant fluvoxamine [1] to reduce severity of COIVD infection, as James Kirkland on STEM talk from the link below mentioned that senescence also may be induced by infections.

[1] https://www.thelancet.com/journals/lanwpc/article/PIIS2666-6...

Re: Psilocybin Decelerates Cellular Senescence

#16

Post by TheToadKnows » Sat, Jul 01, 2023, 3:10 PM UTC

amts wrote: post #15

TheToadKnows wrote: post #11

This experimental design is flawed. It's important to remember that orally dosed psilocybin acts as a prodrug for psilocin. It is metabolized into psilocin in the gut before absorbing into circulation. It is psilocin that is primarily responsible for the physiological and psychoactive effects. Therefore, in vitro (cell culture) studies like this one that only focus on psilocybin and not psilocin are limited in transl…

Seems like psilocin is dephosphorylated psilocybin. But the main working indole structure with the side chain is preserved. So for a cell to get an extra phosphate rich in energy while producing psilocin for the host should be a bonus. The general rationale seems rather feasible, given the application of the SSRI antidepressant fluvoxamine [1] to reduce severity of COIVD infection, as James Kirkland on STEM talk from…

Indeed, you're correct in stating that psilocin is dephosphorylated psilocybin, and the core indole structure with the side chain is preserved. However, my point is that psilocybin would never make it to most cells in the body. I suggest researching the known pharmacokinetics of psilocybin to better understand the nuances here.

In terms of physical properties, psilocin and psilocybin differ significantly due to this transformation. These differences have meaningful consequences at the receptor level, which is where the physiological and psychoactive effects are primarily mediated. The key concern is how the resultant psilocin molecule interacts with cellular receptors and proteins, which almost certainly differs from psilocybin's interactions.

This distinction is quite similar to drug design concepts, where seemingly minor modifications to structure can drastically alter a drug's efficacy and interactions. The difference between a phosphate group (as in psilocybin) and a hydroxyl group (as in psilocin) may appear subtle, but in pharmacological terms, this can easily distinguish between an active and inactive compound.

Re: Psilocybin Decelerates Cellular Senescence

#17

Post by dist-epoch » Sat, Jul 01, 2023, 4:22 PM UTC

amts wrote: post #14

dist-epoch wrote: post #13

Earlier quoted context omitted.

There is nothing wrong with eliminating them. But this study says psylocybin slows down cells becoming senescent, not that it eliminates them. So in fact it makes them live longer.

Yep, they show it's not a senolytic, but I'd like to see an experimental human group (preferably with a dopamine transporter allele making them more prone to placebo-like responses) being given psilocybin and told that it is a senolytic. "Psilocybin treatment led to a dose-dependent decrease in cell cycle arrest markers (p21, p16, and p53) and an increase in markers of DNA replication (phosphorylated-Retinoblastoma p…

Anti-oxidants prevent cell damage caused by reactive oxygen. People thought that's a good thing. But it turns out that can actually promote cancer, because cells expect to be damaged in time, and kill themselves when that happens, and anti-oxidants mess with this mechanism.

> Some of the largest clinical trials, in fact, had to be aborted because the patients receiving antioxidants had a higher incidence of cancer than patients who did not receive them.

https://www.cancer.gov/news-events/cancer-currents-blog/2015...

Preventing cellular senescence sounds like the same kind of thing, messing with an existing mechanism put in place to prevent cancer.

Re: Psilocybin Decelerates Cellular Senescence

#18

Post by amts » Sat, Jul 01, 2023, 5:11 PM UTC

TheToadKnows wrote: post #16

amts wrote: post #15

Earlier quoted context omitted.

Seems like psilocin is dephosphorylated psilocybin. But the main working indole structure with the side chain is preserved. So for a cell to get an extra phosphate rich in energy while producing psilocin for the host should be a bonus. The general rationale seems rather feasible, given the application of the SSRI antidepressant fluvoxamine [1] to reduce severity of COIVD infection, as James Kirkland on STEM talk from…

Indeed, you're correct in stating that psilocin is dephosphorylated psilocybin, and the core indole structure with the side chain is preserved. However, my point is that psilocybin would never make it to most cells in the body. I suggest researching the known pharmacokinetics of psilocybin to better understand the nuances here. In terms of physical properties, psilocin and psilocybin differ significantly due to this…

Do you mean that it is the OH group on psilocin that binds with the receptor? There probably are many other compounds with an OH group and another backbone, and they are not supposed to bind with 5HT2a.

The OH group is ~0.62% of the whole molecule, so there are way more molecule positions in space in which the OH group will be facing away from the receptor, so the active compound will not react.

Re: Psilocybin Decelerates Cellular Senescence

#19

Post by TheToadKnows » Sat, Jul 01, 2023, 5:36 PM UTC

amts wrote: post #18

TheToadKnows wrote: post #16

Earlier quoted context omitted.

Indeed, you're correct in stating that psilocin is dephosphorylated psilocybin, and the core indole structure with the side chain is preserved. However, my point is that psilocybin would never make it to most cells in the body. I suggest researching the known pharmacokinetics of psilocybin to better understand the nuances here. In terms of physical properties, psilocin and psilocybin differ significantly due to this…

Do you mean that it is the OH group on psilocin that binds with the receptor? There probably are many other compounds with an OH group and another backbone, and they are not supposed to bind with 5HT2a. The OH group is ~0.62% of the whole molecule, so there are way more molecule positions in space in which the OH group will be facing away from the receptor, so the active compound will not react.

I honestly cannot tell if you are trolling now, but I'll oblige one last time. In good faith, I think you might be oversimplifying the situation a bit. The binding of psilocin (or any other ligand) to its receptor is not just about the presence or absence of a particular functional group such as the OH group. The entire structure and dynamics of the molecule, including its overall conformation and the spatial orientation of its functional groups all play crucial roles in how it interacts with the receptor.

In the case of psilocin, the 4-hydroxyl group does not act alone, but is rather a part of the larger molecule. Apart from it's induction effects with the indole ring, this group has been shown to form a very unique intramolecular hydrogen bond with the distal amine that significantly influences the overall conformation of the drug, and this in turn affects how the drug binds to and activates the receptor. Remarkably, this intramolecular hydrogen bond is largely responsible for many of the unique pharmacological and physical properties of psilocin.

( https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002... )

Moreover, receptors like 5HT2A do not interact with their ligands in a one-size-fits-all manner. Rather, they have unique, intricate 'lock-and-key' or 'induced-fit' relationships with each ligand, where the spatial orientation of every atom matters. Hence, just because a molecule has an OH group doesn't automatically qualify it to bind with the 5HT2A receptor; it needs to have the right molecular structure and conformation.

Lastly, while the OH group constitutes a small percentage of the overall molecule, its position and the way it influences the conformation of the psilocin molecule cannot be overlooked. Drug-receptor interactions are not solely dictated by the size or quantity of a particular group, but by the precise alignment of these molecular features. This is the reason even minute changes in the structure of a drug can dramatically alter its pharmacological activity.

Re: Psilocybin Decelerates Cellular Senescence

#20

Post by amts » Sat, Jul 01, 2023, 6:24 PM UTC

TheToadKnows wrote: post #19

amts wrote: post #18

Earlier quoted context omitted.

Do you mean that it is the OH group on psilocin that binds with the receptor? There probably are many other compounds with an OH group and another backbone, and they are not supposed to bind with 5HT2a. The OH group is ~0.62% of the whole molecule, so there are way more molecule positions in space in which the OH group will be facing away from the receptor, so the active compound will not react.

I honestly cannot tell if you are trolling now, but I'll oblige one last time. In good faith, I think you might be oversimplifying the situation a bit. The binding of psilocin (or any other ligand) to its receptor is not just about the presence or absence of a particular functional group such as the OH group. The entire structure and dynamics of the molecule, including its overall conformation and the spatial orienta…

I'm not trolling, this probably is some effect of the psychoactives' field itself and thinking about it.

I am researching the topic about how signalling molecules find their intra- and extracellular targets amongst multiple potential "distractions" along their way. What you describe as 'lock-and-key' or 'induced-fit' relationship is established only at the direct contact of a ligand with the receptor. While the ligand in vivo if not injected locally first needs to move fast through vast distances (relative to its size) until it reaches the receptor. It seems that it is just accepted for granted, as if the ligand "knew" where the receptor is.

Your link and explanation are very informative, it seems like this intramolecular hydrogen bond completes a "virtual" third heterocycle in the whole molecule. While senolytic quercetin, for example, also has 3 benzene rings.

There's a doctor in my contacts who weighs heavily on heterocycles due to the delocalized electron they contain.