Psilocybin vs. Psilocin

In Brief:

• Psilocybin is not bioactive in humans, meaning on its own it has no hallucinogenic effect. In the human body, it converts into a related compound called psilocin, which is responsible for the hallucinogenic effects associated with magic mushrooms
• Both psilocybin and psilocin are found in magic mushrooms
• Because it’s very challenging to make stable synthetic psilocin, almost all research has been done with synthetic psilocybin, even though there are a number of potential benefits of administering psilocin directly such as faster onset time, lower side effects, and more consistent dosing
• Filament Health has developed proprietary technology to produce formulations of stable psilocin and stable psilocybin from magic mushrooms and has recently received authorization from US FDA to administer them in human trials
  
  

Psilocybin, the commonly-known primary ingredient in magic mushrooms, is widely believed to be the leading candidate for a revolution in mental health care. However, psilocybin in fact owes its notoriety to a much lesser-known but far more important compound called psilocin. This is because psilocybin itself is not bioactive, meaning it has no biological activity. It must first be converted into psilocin through a process called dephosphorylation. Psilocin is the compound which mimics the structure of serotonin and thus is an agonist of several 5HT receptors. This agonism is responsible for the hallucinogenic effects, as well as the therapeutic possibilities causing much excitement. In pharmacology a substance which converts into the active substance in this way is called a prodrug. Psilocybin is a prodrug to the drug psilocin.

Because both psilocybin and psilocin are present in magic mushrooms, a logical question arises: Wouldn’t it be more logical to administer psilocin directly? At Filament Health, we believe the answer to this question is a firm yes. But before we get into the reasons why, let’s get into the reasons why psilocybin has become more commonplace in the industry and the public eye alike.

Psilocybin and psilocin were first identified by Albert Hoffman in 1957. Because he was a pharmaceutical chemist and an expert in chemical synthesis, he was able to invent a method to create them synthetically in his lab which obviated the need to grow and extract mushrooms. However, the psilocin created synthetically through his method is unstable,. To overcome this instability it was, and is, necessary to add a phosphate protecting-group which is also what turns psilocin into psilocybin. In fact, the addition of the phosphate group is the opposite of what happens during the dephosphorylation process mentioned above and in essence transforms the active psilocin into the inactive (but stable) psilocybin. It isn’t for any pharmacological reason but rather because of the relative stability of synthetic psilocybin vs the instability of psilocin, and also because chemical synthesis has become the standard way to produce these compounds, that psilocin has fallen by the wayside. Clinicaltrials.gov currently lists 67 studies with psilocybin as an intervention versus none with psilocin.

At Filament, we approach things a little differently. All the compounds we produce are extracted from natural sources. When we first started developing magic mushroom extracts, we identified both psilocybin and psilocin in the mushrooms, as well as in the resulting extracts. We decided that it would be very useful to have two versions of this extract, with each containing a high level of psilocybin and psilocin respectively. We developed innovative technology for controlling the relative amount of each that could be produced during the extraction process. We also designed our processes mindful of the potentially unstable nature of psilocin to ensure it would not degrade.

Through all of this hard work we were able to produce our three leading botanical drug candidates: PEX010, PEX020, and PEX030. PEX010 is a standardized 25 mg dose of natural psilocybin designed to provide the standard clinical dose. PEX020 and PEX030 however, are standardized doses of natural psilocin delivered orally and sublingually. They are stable by virtue of our unique, natural process.

We recently received FDA approval to administer these study drugs into a phase 1 clinical trial. This approval is significant because it is the first such approval for natural psilocybin. In addition, it is the first such approval for the direct administration of psilocin. Dr. Josh Woolley, the trial’s Principal Investigator, said “We are excited to directly compare the effects of psilocybin and psilocin in healthy individuals. This research can help us determine if psilocin has advantages over psilocybin as a potential therapeutic drug”

The direct administration of psilocin brings a number exciting potential benefits which we will study in this trial:

1. Faster Onset/Shorter Duration: Since there is no need to wait for the dephosphorylation process to occur the psilocin may act more quickly than psilocybin.
2. More Consistent Dose: Due to the differences in metabolism, some people may experience quicker or more complete conversion to psilocin from psilocybin, leading to a variable experience. By removing the need for metabolism by administering psilocin directly, we can potentially remove this variability.
3. Lower Gastrointestinal (GI) Side Effects: It’s possible that the GI side effects commonly associated with psilocybin are caused by the enzyme phosphatase which is also primarily responsible for the dephosphorylation process. By removing the dephosphorylation, it’s possible that the GI side effects will be mitigated. This may be further compounded by the sublingual delivery of psilocin.
4. Improved Delivery Methods: Because the enzyme which converts psilocybin into psilocin is primarily active in first-pass metabolism, it’s best to deliver psilocybin orally so that it can reach the enzyme and be converted in the gut. However, since no such conversion is necessary for psilocin it is a much better candidate to deliver through noningestive methods such as sublingually or transdermally. These alternative delivery methods may themselves bring further benefits such as faster onset time or the ability to implement extended release technology. In addition, some patients (especially those in end-of-life distress) have trouble swallowing capsules and stand to benefit from a sublingual dose.
   
   

You may hear of companies focused on creating synthetic analogues of ‘classical’ psychedelics like psilocin which are purported to potentially bring similar kinds of benefits. But if these benefits can be had without creating entirely new molecules, isn’t a more logical first step to study the natural molecules that already exist and have a long history of being consumed by humans? This is one of the core tenets of Filament, that it is much more useful to study compounds that are already known, but lack clinical data, rather than to pursue entirely new compounds simply because they are patentable.

• Horita A. Some biochemical studies on psilocybin and psilocin. J Neuropsychiatr. 1963 Apr;4:270-3. PMID: 13954906.
• Hofmann, A., Heim, R., Brack, A. et al. Psilocybin, ein psychotroper Wirkstoff aus dem mexikanischen RauschpilzPsilocybe mexicana Heim. Experientia 14, 107–109 (1958). https://doi.org/10.1007/BF02159243
• Lenz, C et al. Injury-Triggered Blueing Reactions of Psilocybe ″Magic″ Mushrooms. Angew. Chem., Int. Ed. 2020, 59, 1450−1454
• Kargbo R.B.; Sherwood, A. Direct Phosphorylation of Psilocin Enables Optimized cGMP Kilogram-Scale Manufacture of Psilocybin ACS Omega 2020 5 (27), 16959-16966 DOI: 10.1021/acsomega.0c02387
• All controlled activities such as extraction are carried out by Filament’s wholly-owned subsidiary Psilo Scientific Ltd.
• Garcia-Romeu A, Barrett FS, Carbonaro TM, Johnson MW, Griffiths RR. Optimal dosing for psilocybin pharmacotherapy: Considering weight-adjusted and fixed dosing approaches. J Psychopharmacol. 2021 Apr;35(4):353-361. doi: 10.1177/0269881121991822. Epub 2021 Feb 20. PMID: 33611977; PMCID: PMC8056712.

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