Drug development faces a forecasting problem, not a measurement problem. In the same way that temperature, pressure, and humidity readings have been collected for centuries, it wasn’t until we developed models and computational power that accurate weather forecasting became possible.
Similarly, in drug development, we’ve long had access to extensive pre-clinical data and measurement tools. However, without predictive models to interpret this data, we will continue to struggle to forecast a drug’s safety and effectiveness in humans.
Interesting coincidence that for the last several decades, the rate of success of a drug advancing from a phase 1 clinical trial to approval is about 10%, which was just about how good we were at forecasting tomorrow’s weather between 1900-1950.
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.
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.
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.
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.
Similarly, in drug development, we’ve long had access to extensive pre-clinical data and measurement tools. However, without predictive models to interpret this data, we will continue to struggle to forecast a drug’s safety and effectiveness in humans.
Interesting coincidence that for the last several decades, the rate of success of a drug advancing from a phase 1 clinical trial to approval is about 10%, which was just about how good we were at forecasting tomorrow’s weather between 1900-1950.