Novel psilocin prodrugs with altered pharmacological properties as candidate therapies for treatment-resistant anxiety disorders
Bibliographic record
Abstract
Abstract The psychedelic compound psilocybin has shown therapeutic benefit in the treatment of numerous psychiatric diseases. A recent randomized clinical trial conducted at Johns Hopkins Bayview Medical Center demonstrated the efficacy of psilocybin-assisted therapy in the treatment of Major Depressive Disorder (MDD). Similarly, a phase IIb study evaluating psilocybin-assisted therapy for treatment-resistant depression (TRD) presented statistically meaningful and long-term reduction in depressive symptoms. Also, many studies have reported the successful treatment of severe anxiety after a single oral dose of psilocybin, especially in patients struggling with cancer-related distress (CRD). Despite these compelling clinical results, concerns regarding the duration of the psychedelic experience produced by psilocybin pose a significant barrier to its widespread therapeutic application. Psilocybin, derived from magic mushrooms is the naturally occurring prodrug of the neuroactive compound psilocin. When orally administered, exposure to the acidic gastrointestinal (GI) environment together with enzymatic processing by intestinal and hepatic alkaline phosphatase lead to the dephosphorylation of psilocybin producing elevated levels of systemic psilocin. These plasma levels are detectable up to 24 h and produce a psychoactive episode lasting as long as 6 h post-ingestion. In order to positively modify the kinetics of the acute psychedelic response, we have engineered a library of novel prodrug derivatives (NPDs) of psilocin, introducing a diversity of alternative metabolically cleavable moieties modified at the 4-carbon position of the core indole ring. This library consists of twenty-eight unique compounds represented by nine distinct prodrug classes. Each molecule was screened in vitro for metabolic stability using isolated human serum, and human cellular fractions derived from liver and intestinal tissues. This screen revealed fifteen prodrugs that produced measurable levels of psilocin in vitro , with ester and thiocarbonate-based prodrug derivatives significantly represented. These fifteen NPDs were further evaluated for pharmacokinetic (PK) profiles in mice, assessing plasma levels of both residual prodrug and resultant psilocin. PK results confirmed the efficiency of ester and thiocarbonate-based prodrug metabolism upon oral and intravenous administration, achieving levels reduced, albeit comparable to levels of psilocybin-derived psilocin. Of note, almost all NPDs tested maintained reduced overall exposure of psilocin relative to psilocybin, with no measurable levels detected at 24 h post-dose. Finally, all NPDs were screened for CNS bioavailability in healthy mice using the Head Twitch Response (HTR), a behavioural biomarker of 5-HT 2A receptor stimulation and an established proxy for psychoactive potential. Interestingly, five NPDs produced peak HTR that approached or exceeded levels induced by an equivalent dose of psilocybin. Among these bioactive prodrugs, an ester-based and thiocarbonate-based molecule produced long-term anxiolytic benefit in chronically stressed mice evaluated in the marble burying psychiatric model. Overall, this screening campaign identified novel candidate prodrugs of psilocin with altered metabolic profiles and reduced pharmacological exposure, potentially attenuating the duration of the psychedelic response. These molecules still maintained the long-term psychiatric and physiological benefits characteristic of psilocybin therapy. Additionally, these modified parameters also offer the opportunity for altered routes of administration bypassing conventional oral dosing.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".