Psychedelics: A New Drug Candidate for Treating Mental Illness

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 25 September 2025 | Viewed by 1182

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CNRS, CBM, Équipe NEURRIT, UPR 4301, EPSM Georges DAUMEZON GHT, 45 1 route de Chanteau, 45400 Fleury les Aubrais, France
Interests: psychedelic; mental health; pharmacology; drugs during pregnancy and breastfeeding

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Institut de Chimie Organique et Analytique (ICOA), Université d’Orléans, UMR-CNRS 7311, BP 6759, Rue de Chartres, 45067 Orléans, France
Interests: organic synthesis; hemi-synthesis; green chemistry; sustainable solvents and processes; therapeutic molecules
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Special Issue Information

Dear Colleagues,

Psychedelics play a fundamental role in traditional, shamanic medicine, particularly in South American countries such as Peru and Colombia. They are once again being used in the development of medicines for mental health in the treatment of depression or anxiety in severe alcohol use disorders.

With the need to develop new drugs that are effective, safe, and have an acceptable risk–benefit balance, we have recently seen renewed interest in psychedelic research from both the scientific and pharmaceutical communities. “Magic" mushrooms contain natural psychedelics such as psilocybin and psilocin. Furthermore, compared with natural molecules, laboratories can synthesize the psychedelics essential for rational drug design.

This Special Issue, entitled "Psychedelics: A New Drug Candidate for Treating Mental Illness", aims to bring together both original articles and comprehensive reviews of research into psychedelics, including natural products of mycological origin, and focuses on their role in the shamanic history of South American countries, several millennia BC. Topics of interest for this Special Issue include pharmacokinetics of psilocybin and its active form, psilocin; hepatic and intestinal enzymatic interactions that may give rise to active psilocybin metabolites; preclinical studies in mice and the impact of psychedelics on neuronal growth; current human clinical trials and the proven effects of psilocybin on relapse prevention in the maintenance of alcohol abstinence; and possibilities of producing a stable, easy-to-absorb psilocybin to maximize pharmacokinetic parameters and limit drug interactions with other alcohol dependence medications.

Dr. Raphaël Serreau
Prof. Dr. Sabine Berteina-Raboin
Guest Editors

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Keywords

  • psychedelics drugs
  • psilocybin
  • psilocin
  • pharmacokinetic
  • pharmacodynamic
  • new drug candidate
  • mental diseases

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Published Papers (2 papers)

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Research

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17 pages, 1906 KiB  
Article
Effects of Psilocin and Psilocybin on Human 5-HT4 Serotonin and H2 Histamine Receptors in Perfused Hearts of Transgenic Mice
by Pauline Braekow, Joachim Neumann, Uwe Kirchhefer and Ulrich Gergs
Pharmaceuticals 2025, 18(7), 1009; https://doi.org/10.3390/ph18071009 - 6 Jul 2025
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Abstract
Background/Objectives: Hallucinogenic substances such as psilocybin, psilocin, ergometrine, ergotamine, and lysergic acid diethylamide (LSD) have been demonstrated to enhance the force of contraction (FOC), in part due to the phosphorylation of phospholamban in human atrial preparations via 5-HT4 serotonin receptors and/or [...] Read more.
Background/Objectives: Hallucinogenic substances such as psilocybin, psilocin, ergometrine, ergotamine, and lysergic acid diethylamide (LSD) have been demonstrated to enhance the force of contraction (FOC), in part due to the phosphorylation of phospholamban in human atrial preparations via 5-HT4 serotonin receptors and/or H2 histamine receptors. However, whether psilocybin or psilocin acts at isolated mammalian ventricular preparations and whether they increase protein phosphorylation in the mammalian ventricle remains to be elucidated. Methods: To this end, the FOC and phospholamban phosphorylation in isolated perfused hearts from transgenic mice with cardiomyocyte-specific overexpression of either human 5-HT4 receptors (5-HT4-TG) or human H2 receptors (H2-TG) and their wild-type littermates (WT) were examined. Furthermore, the ergot alkaloids ergometrine, ergotamine, and LSD were used as references. Results: Psilocybin and psilocin enhanced the FOC to 137% and to 152%, respectively, and elevated the phospholamban phosphorylation in isolated perfused hearts from 5-HT4-TG. In H2-TG hearts, psilocybin and psilocin increased the FOC to a much lesser extent but had no effect on the phospholamban phosphorylation. In contrast, LSD increased the FOC and phosphorylation state of phospholamban in isolated hearts of both 5-HT4-TG and H2-TG. On the other hand, ergometrine and ergotamine increased the FOC only in H2-TG. Ergometrine increased the phosphorylation state of phospholamban in perfused hearts from H2-TG, but not from 5-HT4-TG. Ergotamine failed to increase the phospholamban phosphorylation in both H2-TG and 5-HT4-TG. Psilocybin, psilocin, ergotamine, ergometrine, and LSD were unable to increase FOC and phospholamban phosphorylation in perfused hearts from WT. Conclusions: The increase in the phosphorylation state of phospholamban could provide a partial explanation for the positive inotropic effects and the relaxant effects of not only psilocybin and psilocin but also ergometrine and LSD in the isolated hearts of the animals used in this study. Full article
(This article belongs to the Special Issue Psychedelics: A New Drug Candidate for Treating Mental Illness)
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Review

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22 pages, 2703 KiB  
Review
Chemical Composition and Biological Activities of Psilocybe Mushrooms: Gaps and Perspectives
by Mateus A. Luz, Hellen V. S. Guedes, Antônio B. M. Bisneto, Raquel A. de Jesus, Taynah P. Galdino, Lucas C. Oliveira, Victor Ignacio Afonso, Marcus Vinícius L. Fook, Antônio G. B. Lima, Suedina M. de L. Silva and Maria C. M. Torres
Pharmaceuticals 2025, 18(7), 989; https://doi.org/10.3390/ph18070989 - 1 Jul 2025
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Abstract
The Psilocybe genus is known for producing tryptamine alkaloids, specifically the compounds psilocybin and psilocin, which have shown antidepressant and anxiolytic potential. The presence of these alkaloids makes Psilocybe mushrooms promising sources of molecules with potential applications in the treatment of mental disorders. [...] Read more.
The Psilocybe genus is known for producing tryptamine alkaloids, specifically the compounds psilocybin and psilocin, which have shown antidepressant and anxiolytic potential. The presence of these alkaloids makes Psilocybe mushrooms promising sources of molecules with potential applications in the treatment of mental disorders. To explore this, a bibliographic study was conducted with the aim of synthesizing published data regarding the biological properties and chemical composition of Psilocybe mushrooms. Searches were performed on indexing platforms, and the articles found were processed using StArt software. These articles were then classified by score and selected based on inclusion and exclusion criteria. This survey yielded a total of 74 articles, and among them, 66 works showed the presence of psilocybin and/or psilocin alkaloids, indicating the psychoactivity of the mushrooms, and 4 works demonstrated the antimicrobial and antioxidant activities of the extract from certain species of the genus. Additionally, 37 chemical compounds were identified across the genus, 23 of which are alkaloids. Data regarding the temporal and chemical stability of these compounds were also observed, which could help optimize the handling of materials that contain indole alkaloids. Therefore, it is evident that species of this genus remain underexplored in terms of chemical diversity; only compounds classified as alkaloids, terpenoids and phenolic compounds were found, and, in total, only 36 compounds in a study range time of 67 years. Furthermore, most studies focused primarily on evaluating the tryptamine alkaloids responsible for the psychoactivity of the mushrooms, without any study focusing on demonstrating the biological activity of isolated compounds against any pathological factor, except for studies relating the whole extract to larvicidal, antimicrobial and antioxidant potential. So, this review provides a general overview of the molecules isolated from the genus and their biological activities and also suggests that researchers working with these mushroom species could focus their efforts on isolating new compounds and evaluating other types of biological activities that can improve the knowledge of mushrooms’ alternative applications. Full article
(This article belongs to the Special Issue Psychedelics: A New Drug Candidate for Treating Mental Illness)
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