Oral psilocybin is rapidly converted to psilocin and shows linear pharmacokinetics over doubling the dose

There is a scientific article which examines how increasing oral doses of psilocybin behave in the body in healthy adults.

In it, we discuss:

The researchers conducted an open-label dose-escalation study in 12 healthy adults. Participants received three oral doses of psilocybin of 0.3, 0.45 and 0.6 mg/kg in a controlled setting, with about a month between sessions. They received 6-8 hours of preparation beforehand, and they were monitored for 24 hours after each session.

The real focus of this paper is not on therapeutic outcomes, but on the pharmacokinetics of psilocybin and especially psilocin, the active metabolite. Blood and urine samples were collected for 24 hours and analysed using a validated LC-MS/MS method, allowing the researchers to determine how quickly the substance was absorbed, converted and excreted.

The results showed that intact psilocybin itself was not detectable in plasma or urine, indicating that it is rapidly converted. It also showed that less than 2 per cent of the total clearance was via renal excretion of intact psilocin. According to the authors, this means that the kidney plays only a minor role in the direct excretion of unaltered psilocin.

In addition, the pharmacokinetics of psilocin appeared linear within this approximately twofold dose range. The mean elimination half-life of psilocin was about 3 hours, with a standard deviation of 1.1 hours. In some participants, the researchers observed a prolonged elimination phase, which they believe may be consistent with hydrolysis of the psilocin glucuronide metabolite.

They also found that variation in psilocin clearance was not well predicted by body weight. Moreover, the authors used their pharmacokinetic parameters to simulate that a fixed oral dose of 25 mg would give approximately similar exposure to 0.3 mg/kg. This is practically relevant because many subsequent studies work with fixed doses rather than weight-based dosing.

Importantly, however, this is a small open-label pharmacokinetic study in healthy volunteers. So the article says little about clinical efficacy, nor directly about how patients with psychiatric disorders or severe organ problems would respond to psilocybin. However, the authors do report that no serious physical or psychological side effects occurred during the study or within 30 days of doses, even at 0.6 mg/kg.

In one sentence, this article shows that oral psilocybin is rapidly converted to psilocin, that psilocin has linear pharmacokinetics within this dose range with a half-life of about 3 hours, and that a fixed dose of 25 mg is roughly equivalent to 0.3 mg/kg in terms of exposure.