Review Reports - Psilocybin in Older Adults: Therapeutic Opportunities in Inflammation-Driven Disorders of Aging—From Depression to Neurodegeneration

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In this manuscript, Jóźwiak-Bębenista and colleagues review the therapeutic potential of psilocybin in older adults, with a focus on inflammation-driven neuropsychiatric and neurodegenerative disorders of aging. The Authors present a broad overview of psilocybin's pharmacokinetics, mechanisms of action, clinical applications, and safety profile in the geriatric population. The topic is timely and of considerable scientific and clinical interest given the growing burden of depression and neurodegeneration in aging societies. Despite these findings would be of general interest to this field of research, some major and minor points need to be addressed.

Major points

Throughout the manuscript, psilocybin/psilocin is inconsistently described as a "5-HT2A receptor agonist" (Abstract, Introduction) while Table 1 correctly refers to it as a "partial, biased agonist at 5-HT2A." This inconsistency is pharmacologically significant and must be resolved. Psilocin is a partial agonist at 5-HT2A, and its biased agonism preferential engagement of the Gq/PLC pathway over β-arrestin is considered central to its distinct psychedelic and therapeutic profile relative to endogenous serotonin. Importantly, recent in vitro evidence suggests that classical psychedelics may in fact be partial, relatively unbiased agonists at 5-HT2A, with their key distinguishing feature versus non-psychedelic 5-HT2A ligands residing in higher signaling efficacy rather than pathway selectivity per se (PMID: 26841800; PMID: 36795823). The Authors must harmonize the terminology across the Abstract, body text, and Table 1, and provide a dedicated mechanistic discussion of partial vs. full agonism and functional selectivity (biased agonism), including its therapeutic relevance in the geriatric context.
Table 1 ("Mechanisms of action of psilocybin/psilocin and their relevance to aging") contains no bibliographic references for any of the listed mechanisms (e.g., BDNF/TrkB engagement, NF-κB inhibition, DMN reorganization, kynurenine pathway modulation). In a peer-reviewed review article, every mechanistic claim in a table must be traceable to a primary source. The Authors must add appropriate and specific citations to each row of Table 1.

The manuscript does not discuss sex differences in the response to psilocybin, despite growing preclinical and emerging clinical evidence that biological sex is a significant modulator of serotonergic psychedelic effects. This is a major omission, particularly in a geriatric context where sex-related differences in neuropsychiatric disorders including depression, anxiety, and neurodegenerative conditions are well documented both clinically and at the molecular level. Preclinical studies demonstrate that 5-HT2A receptor expression is regulated by estrogens and varies with the estrous cycle phase, with sex-specific differences in behavioral responses to psychedelics (e.g., head twitch response, conditioned reward behavior). The Authors have to discuss for example that sex-dimorphic patterns of vulnerability and resilience to stress, with distinct molecular signatures in hippocampal neuroplasticity and oxidative stress pathways, have been consistently reported in preclinical models of depression across both sexes (PMID: 36532726) A very recent study demonstrates that psilocybin reduces conditioned opioid reward in male but not female mice via 5-HT2A receptor activation in the frontal cortex–nucleus accumbens circuit, with sex-specific differences in genomic enhancer activity (PMID: 41266307). The Authors must add a dedicated subsection on sex differences in psilocybin response, discussing: (a) sex-related differences in 5-HT2A receptor density and hormonal regulation across the lifespan and in aging; (b) preclinical evidence for sex-dimorphic behavioral and molecular responses to psilocybin; (c) implications for the design of age- and sex-stratified clinical trials, given that women remain often underrepresented in psychedelic research despite showing distinct patterns of neuropsychiatric vulnerability.

The manuscript does not address the peripheral effects of psilocybin, particularly its interactions with the gut-brain axis and the intestinal serotonergic system. This is a major omission given that approximately 90–95% of the body's serotonin is produced by enterochromaffin cells in the gastrointestinal tract, and that psilocin is partly generated during first-pass GI metabolism of psilocybin.. Furthermore, the bidirectional interaction between psychedelic therapy and the microbiota-gut-brain axis has been reviewed in depth, suggesting that the gut microbiome may modulate both the preparatory and integration phases of psychedelic therapy (PMID: 36605409). Psilocin may also activate serotonergic receptors in the enteric nervous system and modulate vagal afferent signaling, potentially contributing to central neuroplasticity effects. In older adults, gut dysbiosis is prevalent and fuels inflammaging through increased intestinal permeability and systemic translocation of microbial metabolites. The Authors should add a dedicated section on the peripheral effects of psilocybin, covering intestinal serotonergic signaling, gut microbiota modulation, and the potential role of the gut-brain axis in mediating long-term antidepressant effects, particularly in the aging context.

Section 5.4 addresses the effectiveness of psilocybin in older adults but remains insufficient given the stated scope of the review. The Authors acknowledge that only 1.4% of participants in psychedelic trials since 1965 were aged 65 or older, yet the available evidence is treated superficially. The prospective observational cohort study by Kettner and colleagues arguably the most clinically relevant reference in this section is cited without critical analysis (PMID: 38849218). The finding that older adults reported lower intensity of classical psychedelic experiences (ego dissolution, mystical states) yet achieved comparable improvements in well-being compared to younger controls has important neurobiological and therapeutic implications including age-related reductions in cortical 5-HT2A receptor density and altered DMN responsiveness — that are not discussed. The Authors should expand this section to include a critical appraisal of each available dataset.

The current structure of the manuscript places the Pharmacokinetics section (Section 5.3) after the Clinical Applications section (Sections 5.1–5.2), which disrupts the logical flow of the review. Pharmacokinetic properties including the prodrug conversion of psilocybin to psilocin, the phase II glucuronidation profile, the short elimination half-life, and the minimal CYP450 involvement are fundamental to understanding both the mechanism of action and the clinical rationale for use in older adults. This information should precede, not follow, the discussion of mechanism of action and clinical evidence. The Authors must restructure the manuscript so that the Pharmacokinetics section appears before the Mechanism of Action section, in accordance with standard review article conventions in pharmacology.

The final section of the manuscript is titled "Summary" and consists of a recapitulation of content already presented in the body text, without adding critical synthesis or directional conclusions. This is not appropriate for a peer-reviewed review article. The Authors must rename this section "Conclusions" and rewrite it to include: (a) a critical synthesis, not a summary, integrating the reviewed evidence into an argued position; (b) explicit identification of the major knowledge gaps highlighted by this review (sex differences, peripheral effects, underrepresentation of older adults in clinical trials); (c) concrete and prioritized recommendations for future research; (d) clinical and regulatory implications for the use of psilocybin in geriatric neuropsychiatry.

Minor points

Table 2 (Adverse Effects) lists bibliographic references only as a block at the end of the table rather than associating them with individual rows. The Authors should attribute references to specific adverse event categories for traceability.

The nomenclature of the 5-HT2A receptor is inconsistent throughout the manuscript. In some sections (e.g., p. 4) the receptor is referred to as "5-HTA" instead of "5-HT2A." The Authors must standardize receptor nomenclature throughout the text.

The manuscript lacks a discussion of potential pharmacokinetic and pharmacodynamic interactions between psilocybin and medications commonly prescribed in older adults beyond SSRIs and MAOIs for example, anticoagulants, antihypertensives, acetylcholinesterase inhibitors, and statins. This is particularly relevant given the polypharmacy burden emphasized throughout the manuscript.

Several statements throughout the text are presented without supporting references. The Authors should conduct a thorough check of the manuscript and add appropriate primary citations where missing.

The English language should be carefully revised throughout the manuscript to improve clarity and precision in several sections.

Author Response

Reviewer 1

Thank you very much for the reviewer comments. We have carefully considered all of your remarks and addressed each point in detail. Our responses are provided below, together with the corresponding revisions made in the manuscript (highlighted in yellow).

Major points

Throughout the manuscript, psilocybin/psilocin is inconsistently described as a "5-HT2A receptor agonist" (Abstract, Introduction) while Table 1 correctly refers to it as a "partial, biased agonist at 5-HT2A." This inconsistency is pharmacologically significant and must be resolved. Psilocin is a partial agonist at 5-HT2A, and its biased agonism preferential engagement of the Gq/PLC pathway over β-arrestin is considered central to its distinct psychedelic and therapeutic profile relative to endogenous serotonin. Importantly, recent in vitro evidence suggests that classical psychedelics may in fact be partial, relatively unbiased agonists at 5-HT2A, with their key distinguishing feature versus non-psychedelic 5-HT2A ligands residing in higher signaling efficacy rather than pathway selectivity per se (PMID: 26841800; PMID: 36795823). The Authors must harmonize the terminology across the Abstract, body text, and Table 1, and provide a dedicated mechanistic discussion of partial vs. full agonism and functional selectivity (biased agonism), including its therapeutic relevance in the geriatric context.

Thank you for this insightful comment. In addition to harmonizing terminology throughout the manuscript, we have expanded the mechanistic section to include a dedicated discussion of partial versus full agonism, functional selectivity (biased agonism), and the potential relevance of these pharmacodynamic features in older adults.

Table 1 ("Mechanisms of action of psilocybin/psilocin and their relevance to aging") contains no bibliographic references for any of the listed mechanisms (e.g., BDNF/TrkB engagement, NF-κB inhibition, DMN reorganization, kynurenine pathway modulation). In a peer-reviewed review article, every mechanistic claim in a table must be traceable to a primary source. The Authors must add appropriate and specific citations to each row of Table 1.

Accordingly, Table 1 has been fully revised, and specific bibliographic citations have now been added to each row.

The manuscript does not discuss sex differences in the response to psilocybin, despite growing preclinical and emerging clinical evidence that biological sex is a significant modulator of serotonergic psychedelic effects. This is a major omission, particularly in a geriatric context where sex-related differences in neuropsychiatric disorders including depression, anxiety, and neurodegenerative conditions are well documented both clinically and at the molecular level. Preclinical studies demonstrate that 5-HT2A receptor expression is regulated by estrogens and varies with the estrous cycle phase, with sex-specific differences in behavioral responses to psychedelics (e.g., head twitch response, conditioned reward behavior). The Authors have to discuss for example that sex-dimorphic patterns of vulnerability and resilience to stress, with distinct molecular signatures in hippocampal neuroplasticity and oxidative stress pathways, have been consistently reported in preclinical models of depression across both sexes (PMID: 36532726) A very recent study demonstrates that psilocybin reduces conditioned opioid reward in male but not female mice via 5-HT2A receptor activation in the frontal cortex–nucleus accumbens circuit, with sex-specific differences in genomic enhancer activity (PMID: 41266307). The Authors must add a dedicated subsection on sex differences in psilocybin response, discussing: (a) sex-related differences in 5-HT2A receptor density and hormonal regulation across the lifespan and in aging; (b) preclinical evidence for sex-dimorphic behavioral and molecular responses to psilocybin; (c) implications for the design of age- and sex-stratified clinical trials, given that women remain often underrepresented in psychedelic research despite showing distinct patterns of neuropsychiatric vulnerability.

Thank you for this important comment. We agree that sex differences are highly relevant, particularly in older adults, and that their inclusion improves the overall quality of the manuscript. Accordingly, we have expanded Section 6.3.1 Neurobiological Considerations to include a discussion of sex-related differences in 5-HT₂A signalling, hormonal influences across aging, emerging preclinical evidence for sex-specific responses to psilocybin, and the need for sex-stratified analyses in future clinical trials. Relevant references have been added.

The manuscript does not address the peripheral effects of psilocybin, particularly its interactions with the gut-brain axis and the intestinal serotonergic system. This is a major omission given that approximately 90–95% of the body's serotonin is produced by enterochromaffin cells in the gastrointestinal tract, and that psilocin is partly generated during first-pass GI metabolism of psilocybin.. Furthermore, the bidirectional interaction between psychedelic therapy and the microbiota-gut-brain axis has been reviewed in depth, suggesting that the gut microbiome may modulate both the preparatory and integration phases of psychedelic therapy (PMID: 36605409). Psilocin may also activate serotonergic receptors in the enteric nervous system and modulate vagal afferent signaling, potentially contributing to central neuroplasticity effects. In older adults, gut dysbiosis is prevalent and fuels inflammaging through increased intestinal permeability and systemic translocation of microbial metabolites. The Authors should add a dedicated section on the peripheral effects of psilocybin, covering intestinal serotonergic signaling, gut microbiota modulation, and the potential role of the gut-brain axis in mediating long-term antidepressant effects, particularly in the aging context.

Thank you for this important comment. We agree that peripheral mechanisms, particularly those involving the microbiota–gut–brain axis and intestinal serotonergic signalling, are relevant to psilocybin response in older adults. We integrated this topic into Section 6.3.1 Neurobiological Considerations. We now discuss age-related gut dysbiosis, inflammaging, gastrointestinal first-pass metabolism of psilocybin, and the potential role of the gut microbiome in modulating different phases of psychedelic therapy, citing the suggested review and additional relevant literature.

Section 5.4 addresses the effectiveness of psilocybin in older adults but remains insufficient given the stated scope of the review. The Authors acknowledge that only 1.4% of participants in psychedelic trials since 1965 were aged 65 or older, yet the available evidence is treated superficially. The prospective observational cohort study by Kettner and colleagues arguably the most clinically relevant reference in this section is cited without critical analysis (PMID: 38849218). The finding that older adults reported lower intensity of classical psychedelic experiences (ego dissolution, mystical states) yet achieved comparable improvements in well-being compared to younger controls has important neurobiological and therapeutic implications including age-related reductions in cortical 5-HT2A receptor density and altered DMN responsiveness — that are not discussed. The Authors should expand this section to include a critical appraisal of each available dataset.

Thank you for this valuable observation. We have expanded this section accordingly and now discuss potential neurobiological explanations for the reduced intensity of acute psychedelic experiences in older adults, including age-related reductions in cortical 5-HT₂A receptor density and altered DMN responsiveness, while noting preserved improvements in well-being. We have also added a more critical appraisal of the available dataset and its limitations.

The current structure of the manuscript places the Pharmacokinetics section (Section 5.3) after the Clinical Applications section (Sections 5.1–5.2), which disrupts the logical flow of the review. Pharmacokinetic properties including the prodrug conversion of psilocybin to psilocin, the phase II glucuronidation profile, the short elimination half-life, and the minimal CYP450 involvement are fundamental to understanding both the mechanism of action and the clinical rationale for use in older adults. This information should precede, not follow, the discussion of mechanism of action and clinical evidence. The Authors must restructure the manuscript so that the Pharmacokinetics section appears before the Mechanism of Action section, in accordance with standard review article conventions in pharmacology.

We have restructured the manuscript so that the Pharmacokinetics section now appears before these sections, in line with the Reviewer's suggestion.

The final section of the manuscript is titled "Summary" and consists of a recapitulation of content already presented in the body text, without adding critical synthesis or directional conclusions. This is not appropriate for a peer-reviewed review article. The Authors must rename this section "Conclusions" and rewrite it to include: (a) a critical synthesis, not a summary, integrating the reviewed evidence into an argued position; (b) explicit identification of the major knowledge gaps highlighted by this review (sex differences, peripheral effects, underrepresentation of older adults in clinical trials); (c) concrete and prioritized recommendations for future research; (d) clinical and regulatory implications for the use of psilocybin in geriatric neuropsychiatry.

Thank you for this important comment. We agree that the final section required stronger synthesis. Accordingly, we have renamed it Conclusions and revised it to critically integrate the reviewed evidence, highlight key knowledge gaps, outline future research priorities, and discuss clinical and regulatory implications for psilocybin use in geriatric neuropsychiatry.

Minor points

Table 2 (Adverse Effects) lists bibliographic references only as a block at the end of the table rather than associating them with individual rows. The Authors should attribute references to specific adverse event categories for traceability.

We have revised Table 2 so that references are now linked to the specific adverse event categories within individual rows, thereby improving traceability and clarity.

The nomenclature of the 5-HT2A receptor is inconsistent throughout the manuscript. In some sections (e.g., p. 4) the receptor is referred to as "5-HTA" instead of "5-HT2A." The Authors must standardize receptor nomenclature throughout the text.

Receptor nomenclature has now been carefully standardized throughout the manuscript.

The manuscript lacks a discussion of potential pharmacokinetic and pharmacodynamic interactions between psilocybin and medications commonly prescribed in older adults beyond SSRIs and MAOIs for example, anticoagulants, antihypertensives, acetylcholinesterase inhibitors, and statins. This is particularly relevant given the polypharmacy burden emphasized throughout the manuscript.

Thank you for this important comment. We have expanded the manuscript to address potential pharmacokinetic and pharmacodynamic considerations relevant to polypharmacy in older adults. We also emphasize that psilocin is metabolized predominantly via phase II glucuronidation, with limited CYP450 involvement, which may reduce the likelihood of multiple metabolic drug–drug interactions compared with many medications commonly prescribed in this population. In addition, psilocybin is typically administered intermittently rather than chronically, which may further limit cumulative interaction burden.

Several statements throughout the text are presented without supporting references. The Authors should conduct a thorough check of the manuscript and add appropriate primary citations where missing.

We have carefully reviewed the manuscript and added appropriate supporting references where needed.

The English language should be carefully revised throughout the manuscript to improve clarity and precision in several sections.

The manuscript has undergone careful language revision to improve clarity, readability, and precision throughout.

Reviewer 2 Report

Comments and Suggestions for Authors

This review article titled "Psilocybin in older adults: therapeutic opportunities in inflammation-driven disorders of aging—from depression to neurodegeneration" is mechanistically rich and clinically relevant, particularly given the increasing burden of neuropsychiatric and neurodegenerative diseases in older populations. Currently the manuscript needs minor revision before acceptance to IJMS. So authors need to address the following comments.

1. While the manuscript presents psilocybin as anti-inflammatory, the human evidence remains limited and inconsistent. Most findings are from healthy volunteers or preclinical models, and cytokine data (IL-6, CRP) are variable and context dependent. So, clearly distinguish preclinical evidence, human experimental data, and clinical patient data (pre -clinical and clinical). I suggest presenting them in the form of tables.

2. Although safety is discussed, the manuscript underestimates geriatric-specific risks, such as cardiovascular instability, cognitive vulnerability, delirium risk, and drug interactions in polypharmacy. I suggest expanding discussion on frailty and physiological reserve, exclusion bias in trials, and real-world vs. controlled settings.

3. Figure 1 can be enhanced and can give a bigger picture. Even reduce the dense text too.

4. One more figure, as figure 3, focusing solely on the neurotherapeutic potential of Psilocybin

Author Response

Reviewer 2

Thank you very much for these positive, thoughtful, and constructive comments. We sincerely appreciate your favorable evaluation of our manuscript and your recognition of its clinical relevance and mechanistic scope. We have carefully considered all of your suggestions and have revised the manuscript accordingly. Our point-by-point responses are provided below, together with the corresponding changes introduced in the revised version of the manuscript (highlighted in yellow).

While the manuscript presents psilocybin as anti-inflammatory, the human evidence remains limited and inconsistent. Most findings are from healthy volunteers or preclinical models, and cytokine data (IL-6, CRP) are variable and context dependent. So, clearly distinguish preclinical evidence, human experimental data, and clinical patient data (pre -clinical and clinical). I suggest presenting them in the form of tables.

Thank you very much for this important suggestion. We have revised the relevant section to more clearly distinguish preclinical evidence, experimental human data, and clinical patient data regarding the anti-inflammatory effects of psilocybin. In addition, a new summary table (Table 2) has been added to present the available evidence in a structured form.

Although safety is discussed, the manuscript underestimates geriatric-specific risks, such as cardiovascular instability, cognitive vulnerability, delirium risk, and drug interactions in polypharmacy. I suggest expanding discussion on frailty and physiological reserve, exclusion bias in trials, and real-world vs. controlled settings.

We have revised Sections 6.3 and 7 to further strengthen the discussion of geriatric-specific safety considerations and age-related clinical factors relevant to psilocybin use in older adults, in line with the Reviewer’s suggestion.

Figure 1 can be enhanced and can give a bigger picture. Even reduce the dense text too.

Figure 1 has been revised to improve visual clarity.

One more figure, as figure 3, focusing solely on the neurotherapeutic potential of Psilocybin

A new Figure 3 has been added, focusing specifically on the neurotherapeutic potential of psilocybin.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The Authors have addressed all the points I raised.