Efficient Acyloxymethylation of Psilocin and Other Tryptamines Yielding ACOM Prodrugs for Psychedelic-Assisted Therapy.
Judith Stirn, Christian D. Klein
Archiv der Pharmazie July 1, 2025 DOI: 10.1002/ardp.70022 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro study Peer reviewed |
|---|---|
| Topics | Psilocybin Psychedelic-assisted therapy |
| Keywords | Acom prodrug Psychedelic‐assisted therapy Therapeutic outcomes Psychedelic tryptamines Adjustable release rates Optimized administration Buccal/sublingual delivery Novel method Tailoring |
| Key points | A novel synthetic route enables chemoselective ACOM prodrug formation for tryptamines, with adjustable plasma bioactivation rates but rapid saliva breakdown precluding buccal or sublingual use. |
Abstract
Acyloxymethyl (ACOM) derivatives of tryptamines such as the psychedelic drug psilocin and the anti-migraine drug sumatriptan bear potential as prodrugs. Previous synthetic approaches suffer from insufficient chemoselectivity between the desired functionalization of the phenolic (psilocin) or sulfonamide (sumatriptan) groups versus other reactive groups in the parent drugs. We report a novel synthetic route toward ACOM prodrugs of tryptamines via the chemoselective installation of a carbamate protecting group at the indole nitrogen by means of a Heller-Sarpong reagent and final deprotection under extremely mild conditions. This enables delicate transformations such as the O-acyloxymethylation of psilocin or the N2-acyloxymethylation of sumatriptan. Several novel O-ACOM ethers of hydroxytryptamines were obtained and evaluated in vitro for their potential as novel prodrugs for psychedelic therapy. The rate of bioactivation in human plasma may be adjusted to rapid (t1/2 240 min) kinetics by varying the acyl residue in the ACOM promoiety. Irrespective of the acyl residue, short half-lives in human saliva will likely preclude the sublingual or buccal application of ACOM ether prodrugs of hydroxytryptamines, while other routes such as peroral, transdermal, nasal, or intravenous administration may be pursued.
Comparable studies
Other preclinical and animal studies on psilocybin and psychedelic-assisted therapy, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin prevents reinstatement of alcohol seeking by disrupting the reconsolidation of alcohol-related memories. Male and female Marchigian Sardinian alcohol-preferring (msP) rats | 2023 | Preclinical experimental study | |
| A Proposal to Study the Safety and Efficacy of Psilocybe cubensis in Preclinical and Clinical Studies as a Therapeutic Alternative for Major Depressive Disorder Healthy adults and patients with major depressive disorder | 2023 | Research project design with preclinical and clinical experimental components | |
| Synergistic behavioral and neuroplastic effects of psilocybin-NMDAR modulator administration ICR male mice | 2025 | Observational study |