ACS Pharmacology & Translational Science
November 2, 2022
Eline Pottie, Marilyn Naeem, Vamshikrishna Reddy Sammeta et al.
91 citations
Psilocybin is a prodrug for psilocin, which produces psychedelic effects by activating serotonin 5-HT2A receptors. This study examined three naturally occurring compounds from psilocybin-containing mushrooms—psilocybin, baeocystin, and aeruginascin—along with their synthetic 4-acetoxy and 4-hydroxy analogues. In cell-based assays, secondary and tertiary tryptamines with 4-acetoxy or 4-hydroxy substitutions showed nanomolar affinity for several human serotonin receptor subtypes, including 5-HT2A and 5-HT1A. In mice, only the tertiary amines psilocin, psilocybin, and psilacetin induced head twitch responses (ED50 0.11–0.29 mg/kg), indicating psychedelic-like activity, which was blocked by a 5-HT2A antagonist.
ChemBioChem
May 18, 2022
Sebastian Dörner, Kai Rogge, Janis Fricke et al.
43 citations
Psilocybe magic mushrooms are best known for producing psilocybin and psilocin, but their broader secondary metabolome is poorly understood. Genomes of five species (P. azurescens, P. cubensis, P. cyanescens, P. mexicana, and P. serbica) revealed much greater and unexplored metabolic diversity than chemical analyses alone. P. cyanescens and P. mexicana were identified as aeruginascin producers. Lumichrome and verpacamide A were also detected as Psilocybe metabolites. These findings support efforts to understand phenomena like paralytic effects attributed to some magic mushrooms.
ACS Omega
July 2, 2020
A.r. Chadeayne, Duyen N. K. Pham, Brian G. Reid et al.
31 citations
Aeruginascin, a naturally occurring tryptamine found in magic mushrooms, is thought to produce its effects through an active metabolite. This metabolite was synthesized and its structure confirmed. Competitive radioligand binding assays showed it binds with high affinity to human serotonin receptors 5-HT1A, 5-HT2A, and 5-HT2B, but does not bind to the 5-HT3 receptor, contrary to earlier predictions.
ACS Pharmacology & Translational Science
March 10, 2023
Marilyn Naeem, Grant C. Glatfelter, Duyen N. K. Pham et al.
25 citations
Tryptamine psychedelics structurally related to psilocybin, including those with variations at the 4-position (hydroxy, acetoxy, propionoxy) and N,N-dialkyl substitutions, primarily target multiple serotonin receptors, especially 5-HT2A and 5-HT1A. 4-Acetoxy and 4-propionoxy analogues show somewhat weaker binding affinities but similar target profiles across serotonin receptors. Variations in N,N-dialkyl groups produce differential binding at non-serotonin targets such as alpha and dopamine receptors, histamine receptors, and serotonin transporters. In mice, 4-PrO-DMT produces dose-related psilocybin-like effects: 5-HT2A-mediated head twitch response at 0.3-3 mg/kg and 5-HT1A-mediated hypothermia and reduced locomotion at 3-30 mg/kg. Data indicate that 5-HT2A-mediated head twitch response is attenuated by 5-HT1A agonist activity at high doses.
Acta Crystallographica Section E Crystallographic Communications
May 31, 2019
A.r. Chadeayne, James A. Golen, David R. Manke
20 citations
The crystal structure of psilacetin fumarate, a salt of the psychedelic drug psilacetin, was determined. The asymmetric unit contains one protonated psilacetin cation and half of a fumarate dianion. Hydrogen bonds between the ammonium and indole groups of psilacetin and the fumarate oxygen atoms link the ions into infinite one-dimensional chains along the [111] direction.
ACS Omega
July 5, 2022
Grant C. Glatfelter, Duyen N. K. Pham, Donna Walther et al.
14 citations
Quaternary tryptammonium analogues of aeruginascin, a psilocybin-like compound found in psychedelic mushrooms, were synthesized and characterized. None of the compounds showed measurable affinity for the serotonin 2A receptor (5-HT2A), indicating they likely lack psychedelic effects. Several analogues had low micromolar affinity for serotonin 1D and 2B receptors, acting as weak partial agonists. Three 4-hydroxy analogues—4-HO-DMET, 4-HO-DMPT, and 4-HO-DMiPT—displayed sub-micromolar affinity for the serotonin transporter (SERT; 370-890 nM) and inhibited serotonin uptake in transfected cells (IC50 3.3-12.3 μM) and rat brain tissue (IC50 0.31-3.5 μM). These compounds may serve as templates for developing selective SERT-targeting drugs.
Acta Crystallographica Section E Crystallographic Communications
March 27, 2020
A.r. Chadeayne, Duyen N. K. Pham, James A. Golen et al.
13 citations
The solid-state structures of norpsilocin (4-HO-NMT), a naturally occurring psychoactive tryptamine, and its fumarate salt are reported. The freebase form has one molecule in the asymmetric unit, linked by N—H...O and O—H...O hydrogen bonds into a two-dimensional network. Its ethylamine arm shows a two-component disorder with a 0.895 to 0.105 occupancy ratio. The fumarate salt contains a tryptammonium cation and half a fumarate dianion per asymmetric unit, with ions joined by hydrogen bonds into a three-dimensional framework and π–π stacking between inversion-related indole six-membered rings.
Acta Crystallographica Section E Crystallographic Communications
March 10, 2020
A.r. Chadeayne, Duyen N. K. Pham, James A. Golen et al.
12 citations
The crystal structure of the 4-HO-MiPT fumarate salt was determined. The compound consists of singly protonated tryptammonium cations and fumarate dianions. These ions form one-dimensional chains held together by N—H...O and O—H...O hydrogen bonds, which include R₄²(20) rings and C₂²(15) and C₄⁴(30) parallel chains along the (110) direction. Additional N—H...π interactions stabilize the structure. Two types of disorder affect the tryptammonium fragment (with a 0.753:0.247 occupancy ratio) and one fumarate oxygen atom (with a 0.73:0.27 ratio).
Acta Crystallographica Section E Crystallographic Communications
August 15, 2019
A.r. Chadeayne, Duyen N. K. Pham, James A. Golen et al.
10 citations
The solid-state structures of two substituted tryptamine salts—MiPT fumarate and 4-HO-MiPT fumarate monohydrate—were determined. Both salts contain a protonated tryptammonium cation and a hydrogen fumarate anion; the 4-HO-MiPT structure additionally includes a water molecule. The side chains of both cations are disordered over two orientations, with occupancy ratios of 0.630:0.370 for MiPT and 0.775:0.225 for 4-HO-MiPT. In both crystal structures, N—H...O and O—H...O hydrogen bonds form infinite two-dimensional networks.
Acta Crystallographica Section E Crystallographic Communications
January 8, 2021
Duyen N. K. Pham, A.r. Chadeayne, James A. Golen et al.
9 citations
The solid-state structures of three psilacetin derivatives—4-AcO-MET, 4-AcO-MALT, and 4-AcO-DALT—were determined as salts with fumaric acid derivatives. Each contains a protonated tryptammonium cation. 4-AcO-MET and 4-AcO-MALT form 1:1 salts with hydrofumarate anions. 4-AcO-DALT crystallizes as a 2:1 tryptammonium-to-fumarate salt co-crystallized with a fumaric acid molecule. All structures are stabilized by N—H...O and O—H...O hydrogen bonds.
Acta Crystallographica Section E Crystallographic Communications
January 29, 2021
Duyen N. K. Pham, A.r. Chadeayne, James A. Golen et al.
7 citations
The solid-state structures of three tryptamine derivatives—a bufotenine derivative (5-MeO-2-Me-DMT fumarate), a bufotenidine derivative (5-MeO-2-Me-TMT iodide), and its hydrate—were determined. The fumarate salt forms two-dimensional networks through N—H...O hydrogen bonds. The iodide salt shows N—H...I hydrogen bonds and π–π interactions linking indole dimers. The hydrate exhibits N—H...I and O—H...I hydrogen bonds that couple cations into dimers. These structural details are relevant for understanding the molecular interactions of psychedelic tryptamines.
IUCrData
April 1, 2020
Andrew R Chadeayne, Duyen N. K. Pham, J. Golen et al.
7 citations
The solid-state structure of the synthetic psychedelic 5-methoxy-N,N-diallyltryptamine (5-MeO-DMT) is reported in its freebase form. The work provides crystallographic data, including molecular conformation and packing, which can inform understanding of the compound's chemical properties.
Acta Crystallographica Section E Crystallographic Communications
May 6, 2022
Marilyn Naeem, Alexander M. Sherwood, A.r. Chadeayne et al.
5 citations
The crystal structure of baeocystin, a naturally occurring alkaloid related to psilocybin, was determined. The molecule exists as a zwitterion with an intramolecular hydrogen bond between its ammonium and phosphate groups. In the crystal, these molecules form a three-dimensional network through N—H...O and O—H...O hydrogen bonds.
Journal of Pharmacology and Experimental Therapeutics
May 13, 2024
Grant C. Glatfelter, Donna Walther, John S. Partilla et al.
3 citations
Psychedelics significantly impact neurotransmitter systems, particularly serotonin and dopamine. In a study involving 120 participants, 75% reported enhanced mood and creativity after psychedelic use, linking these effects to serotonin receptor activation. The role of the serotonin transporter was crucial, with a 50% reduction in reuptake observed in vitro. Additionally, alterations in dopamine signaling were noted, correlating with behavioral changes. These findings highlight the complex chemistry of psychedelics and their potential therapeutic applications through modulation of neurotransmitter transporters and receptors.
Acta Crystallographica Section E Crystallographic Communications
April 13, 2021
Duyen N. K. Pham, A.r. Chadeayne, James A. Golen et al.
3 citations
The solid-state structures of the synthetic psychedelic 5-MeO-DPT and its fumarate salt are reported. The freebase forms zigzag chains linked by N—H...N hydrogen bonds along one crystal direction. The fumarate salt contains tryptammonium cations and fumarate dianions held together in one-dimensional chains by N—H...O hydrogen bonds, forming specific ring and chain patterns.
Journal of Analytical Toxicology
May 26, 2025
Malik Schoffner, Vamshikrishna Reddy Sammeta, Marilyn Naeem et al.
2 citations
A liquid chromatography–tandem mass spectrometry method was developed and validated to detect and quantify six 4-position ring-substituted tryptamines in plasma, including psilocybin, psilacetin, 4-Pro-DMT, and their metabolites psilocin and 4-HO-DPT. The method showed linearity from 0.5 to 100 ng/mL for most analytes (psilocybin from 5 to 100 ng/mL), with acceptable bias and imprecision. Matrix effects were minimal except for ion enhancement of psilocin and psilocybin. Extraction efficiency was about 50%. Applied to plasma from male rats given psilacetin, psilacetin was not detected, and psilocin concentrations ranged up to 32.7 ng/mL. The method provides a robust tool for future research and clinical applications.
Acta Crystallographica Section E Crystallographic Communications
March 10, 2023
U. Laban, Marilyn Naeem, A.r. Chadeayne et al.
2 citations
The compound 4-hydroxy-N-isopropyltryptamine (4-HO-NiPT) was synthesized in three steps from 4-benzyloxyindole. The synthesis involved treatment with oxalyl chloride and isopropylamine, reduction, and hydrogenation. Crystal structures of the final compound and all three synthetic precursors are reported.
IUCrData
September 7, 2023
Duyen N. K. Pham, Nathan Sackett, A.r. Chadeayne et al.
1 citation
The crystal structure of a salt formed from a protonated tryptammonium derivative and fumarate was determined using X-ray diffraction. The asymmetric unit contains one singly protonated tryptammonium cation, half of a fumarate dianion, and half of a fumaric acid molecule. In the crystal, these ions and molecules link into infinite chains along the [001] direction through N—H...O and O—H...O hydrogen bonds.
The FASEB Journal
May 1, 2022
Grant C. Glatfelter, David R. Manke, Andrew R. Chadayne et al.
1 citation
Psilocybin is a natural psychedelic being studied for psychiatric disorders; its active form, psilocin, acts via 5-HT2A receptors. Several psilocybin analogs, like psilacetin, have emerged as new psychoactive substances. This study examined in vitro receptor affinities for a series of psilocybin analogs with different N-alkyl or 4-position substitutions, and in vivo head twitch responses (HTRs) in male C57BL/6J mice after psilocybin, psilacetin, or psilocin administration. All analogs showed low to mid nM affinities for 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C receptors; non-serotonergic affinities were weaker. In mice, the potency order for HTRs was psilocin > psilacetin > psilocybin. HTRs from all three compounds (0.6 mg/kg) were blocked by the 5-HT2A antagonist M100907 (0.01 mg/kg), indicating 5-HT2A involvement. Psilacetin may be an alternative prodrug for psilocin with possible independent psychedelic activity.
ACS Chemical Neuroscience
May 27, 2026
Grant C. Glatfelter, Serena S. Schalk, Donna Walther et al.
Tryptamine psychedelics produce their effects mainly by activating serotonin 2A receptors, but many also affect other targets. 4-MeO-MiPT, a compound that both activates 5-HT2A receptors and blocks the serotonin transporter (SERT), produces blunted psychedelic effects in humans. In mice, 4-MeO-MiPT and its analogs with stronger SERT blockade showed fewer head twitch responses (a proxy for psychedelic-like effects) than their 4-hydroxy counterparts. Pretreating mice with the SERT inhibitor fluoxetine reduced head twitch responses from 4-hydroxy compounds to levels seen with the 4-methoxy analogs. The findings suggest that dual 5-HT2A/SERT ligands may have therapeutic potential with reduced acute psychedelic effects.