Skin on Drugs: Psychotropic Compounds in Cutaneous Biology

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review covers an interesting and emerging area at the intersection of neuropharmacology and dermatology. The manuscript is broad in scope and generally well organized, particularly in its discussion of neuroimmune signaling and cutaneous pharmacology. I nevertheless think a few sections would benefit from a more cautious and critical framing.
1. The discussion of psilocybin and skin aging in Section 4.2 currently reads somewhat stronger than the available evidence may support. The cited findings are intriguing, but the field remains highly preliminary and largely limited to experimental models from a small number of groups. It would help to more clearly acknowledge that there are currently no human dermatological studies demonstrating anti-aging effects of psilocybin or psilocin. The statement suggesting a potential therapeutic role in aging processes could therefore be toned down slightly.
2. The antidepressant section is generally balanced and appropriately discusses both clinical utility and adverse effects. However, because the review emphasizes potential anti-inflammatory and wound-healing applications, it may still be useful to more explicitly distinguish between evidence derived from topical versus systemic administration. This distinction becomes particularly important when considering safety, tolerability, and translational relevance.
3. Section 4.5 raises important formulation challenges for psychedelics, although the discussion remains relatively general. Since psilocin and related compounds act through serotonergic pathways, even limited systemic absorption after topical administration could potentially become relevant from a safety perspective. A more detailed discussion of strategies to minimize systemic exposure while maintaining local efficacy would strengthen this section.

Author Response

Comments 1: The discussion of psilocybin and skin aging in Section 4.2 currently reads somewhat stronger than the available evidence may support. The cited findings are intriguing, but the field remains highly preliminary and largely limited to experimental models from a small number of groups. It would help to more clearly acknowledge that there are currently no human dermatological studies demonstrating anti-aging effects of psilocybin or psilocin. The statement suggesting a potential therapeutic role in aging processes could therefore be toned down slightly.

Response 1: We thank the reviewer for this important comment. We fully agree that the available evidence regarding the anti-aging effects of psilocybin and psilocin remains preliminary and largely limited to experimental models. To address this point, we have revised Section 4.2 by adding a statement explicitly acknowledging the lack of evidence in human skin. The revised text now clarifies that current findings are restricted to in vitro and animal studies and that no data are available demonstrating efficacy in human dermatological settings. Specifically, we have included the following sentence: “However, there is no evidence that these effects would work in a real environment like human skin. Consequently, more research in this field should be carried out with better representative experimental models and more detailed in vivo assays in animal models.” This modification ensures a more cautious and balanced interpretation of the available data.

 

Comments 2: The antidepressant section is generally balanced and appropriately discusses both clinical utility and adverse effects. However, because the review emphasizes potential anti-inflammatory and wound-healing applications, it may still be useful to more explicitly distinguish between evidence derived from topical versus systemic administration. This distinction becomes particularly important when considering safety, tolerability, and translational relevance.

Response 2:  We thank the reviewer for this valuable suggestion. We fully agree that distinguishing between systemic and topical administration is essential when assessing the translational relevance, safety, and applicability of antidepressant therapies in dermatology. In response, we have revised the manuscript to explicitly clarify the route of administration in key sections of the antidepressant chapter. In particular, we have specified when the reported effects derive from systemic administration in vivo (e.g., intraperitoneal delivery in animal models), as opposed to local or cellular effects observed in in vitro systems. For example, in Section 5.2, we now explicitly state that the immunomodulatory effects reported by Kubera et al. were observed following systemic (intraperitoneal) administration in mice, thereby providing appropriate context for interpreting these findings. In addition, we have included a general statement early in the section highlighting that the observed effects may differ depending on whether antidepressants are administered systemically or applied topically, with important implications for both safety profile and clinical translation.

 

Comments 3: Section 4.5 raises important formulation challenges for psychedelics, although the discussion remains relatively general. Since psilocin and related compounds act through serotonergic pathways, even limited systemic absorption after topical administration could potentially become relevant from a safety perspective. A more detailed discussion of strategies to minimize systemic exposure while maintaining local efficacy would strengthen this section.

Response 3: We thank the reviewer for this insightful comment. We fully agree that the potential for systemic absorption is a critical consideration, particularly given the serotonergic activity of these compounds and the possibility of central nervous system effects. To address this concern, we have revised Section 4.5 by expanding the discussion on the translational limitations and safety considerations associated with psychedelic compounds in dermatology. In the revised manuscript, we now explicitly refer to the use of low, non-psychedelic doses, as illustrated by the recent Phase 1 study by Colognesi et al. (2026), and emphasize that current evidence does not yet support clinical application in human skin. In addition, we have incorporated a specific statement highlighting the need for formulation strategies aimed at minimizing systemic absorption, such as the use of nanocarriers or controlled-release delivery systems, in order to limit potential central nervous system effects associated with serotonergic activation.

Reviewer 2 Report

Comments and Suggestions for Authors

Many keywords were not taken from MeSH. It is better to have a maximum of five keywords taken from MeSH.

Names of all antidepressants should be listed.

All the skin reactions, such as type I, II, III, and IV hypersensitivity reactions, should be discussed.

The genetic predisposition in certain individuals may be important. Please discuss these facts.

An important condition, i.e., Stevens-Johnson Syndrome, was not discussed. We encounter this condition quite frequently. Please discuss this condition.

Discuss lithium, valproate, and clozapine.

Discuss any options to use artificial intelligence to counter the side effects.

How can patient education be helpful?

A table may be incorporated in the manuscript.

Please include the latest references from 2025 and 2026.

Author Response

Comments 1: Many keywords were not taken from MeSH. It is better to have a maximum of five keywords taken from MeSH.

Response 1: We thank the reviewer for this suggestion. The keywords have been revised to align with MeSH terminology and reduced to a maximum of five, as recommended. The updated keywords better reflect the main topics of the manuscript while improving indexing and discoverability.

 

Comments 2: Names of all antidepressants should be listed.

Response 2: We thank the reviewer for this comment. The manuscript has been revised to provide a clearer description of the main classes of antidepressants and representative compounds relevant to dermatological applications, including SSRIs (e.g., fluoxetine, sertraline, paroxetine) and tricyclic antidepressants (e.g., doxepin, amitriptyline, imipramine, desipramine). These modifications improve the clarity of the section while maintaining the scope of the review.

 

Comments 3: All the skin reactions, such as type I, II, III, and IV hypersensitivity reactions, should be discussed.

Response 3: We thank the reviewer for this valuable suggestion. The manuscript has been revised to provide a more comprehensive framework for understanding cutaneous adverse reactions to psychotropic drugs. Specifically, we have included a statement indicating that these reactions may involve different immunological mechanisms, including type I–IV hypersensitivity responses. In addition, we have clarified that contact hypersensitivity (CHS) models represent a form of type IV delayed hypersensitivity reaction. These additions improve the immunological context of the manuscript and better reflect the diversity of skin reactions associated with psychotropic compounds.

 

Comments 4: The genetic predisposition in certain individuals may be important. Please discuss these facts.

Response 4: We thank the reviewer for this important comment. The manuscript has been revised to highlight that interindividual variability, including genetic predisposition, may influence susceptibility to cutaneous adverse drug reactions. In particular, pharmacogenetic factors such as specific HLA alleles have been associated with an increased risk of severe cutaneous adverse reactions. These additions provide a more comprehensive perspective on the variability of skin responses to psychotropic compounds.

 

Comments 5: An important condition, i.e., Stevens-Johnson Syndrome, was not discussed. We encounter this condition quite frequently. Please discuss this condition.

Response 5: We thank the reviewer for highlighting this important condition. The manuscript has been revised to include a concise discussion of Stevens–Johnson syndrome and toxic epidermal necrolysis within the safety section. Specifically, we now describe their clinical presentation, severity as life-threatening cutaneous adverse reactions, and their association with drug exposure.

 

Comments 6: Discuss lithium, valproate, and clozapine.

Response 6: We thank the reviewer for this valuable suggestion. In response, we have incorporated a new section (Section 6) dedicated to antipsychotic compounds, where lithium and valproate are discussed in detail in relation to their cutaneous effects. In addition, we have now included clozapine and its associated cutaneous adverse reactions. These additions improve the completeness of the manuscript and broaden the discussion of psychotropic drugs relevant to dermatology.

 

Comments 7: Discuss any options to use artificial intelligence to counter the side effects.

Response 7: We thank the reviewer for this insightful suggestion. The manuscript has been revised to acknowledge the emerging role of artificial intelligence in dermatology. Specifically, we highlight its application in the analysis of clinical and imaging data, as well as its potential to predict adverse drug reactions and support personalized therapeutic decision making. 

 

Comments 8: How can patient education be helpful?

Response 8: We thank the reviewer for highlighting this important aspect. A statement has been added to the manuscript to emphasize the role of patient education in improving treatment adherence and enabling early recognition of cutaneous adverse reactions, which may contribute to reducing their severity and improving clinical outcomes.

 

Comments 9: A table may be incorporated in the manuscript.

Response 9: We thank the reviewer for this suggestion. In response, an additional table has been incorporated to provide a clinically oriented summary of the main dermatological applications, potential benefits, and safety considerations of psychotropic compounds. This table complements the molecular overview provided in Table 1 and enhances the translational value of the manuscript.

 

Comments 10: Please include the latest references from 2025 and 2026

Response 10: We thank the reviewer for this suggestion. The manuscript has been updated to include recent references from 2025 and 2026 across multiple sections. Also, recent clinical and translational studies on cannabinoids and updated evidence regarding the safety profile of antidepressants have been incorporated to ensure that the review reflects the most current developments in the field.

Reviewer 3 Report

Comments and Suggestions for Authors

Dear Authors!

I have read your manuscript entitled Skin on Drugs: Psychotropic Compounds in Cutaneous Biology. It is an interesting review describing anti-inflammatory, antipruritic and anti- aging properties of different psychotropic compounds. Numerous references were studied and cited. Nevertheless, some major revisions are needed to make the manuscript suitable for publishing. I will give my comments and suggestions below.

On page 2, in Table 1 several abbreviations are used without explanations. You either add explanations under the Table 1 as legend or add a sentence that all abbreviations are written after the Conclusions on page 24.

On page 3 there is a short paragraph starting with “This section may be divided etc.” It has no meaning in the manuscript, so delete it please.

In figure 1 the scale bar is 10 µm, but the photo is taken at low magnification, so the bar is at least 100 µm. Please check and correct that. In figure 3 add “bar” in the legend. In some legends of the Figures the word bar is used, on others scale bare. Please use the same term in all legends of microscopic slides.

The major revision is needed in the chapters 3.2.1 and 3.2.2 and 3.2.3 In these chapters several authors are cited, but none of them is listed in the References. For example, Sanogiovanni et al, Miller et al, Ramot et al., Ruhl et al.. At the end of paragraph only references 27-20 are named, which were not written by those authors. This continues in the next paragraph (Correia-Sa et al, Styrczewska et al., Antezana et al., Zheng et al., Klein et al., Wohlman et al., etc). In chapter 3.2.3 you wrote about the research of Maida et al. (page 11, line 436) but the citation at the end is of several articles (24, 28-30 line 443), none of which is written by Maida. This must be corrected; all used literature must be written in the Reference chapter!

Some abbreviations are not explained, for example LPS.

In the References add names and surnames of the authors of 116^th reference (K,C; M,M; M,K?).

And finally, “in vitro” and “in vivo” should be written in italic style (on pages 11, 12, 13,16, 17, 20 and 21).

Author Response

Comments 1: On page 2, in Table 1 several abbreviations are used without explanations. You either add explanations under the Table 1 as legend or add a sentence that all abbreviations are written after the Conclusions on page 24.

Response 1: We thank the reviewer for highlighting this issue. We have revised Table 1 to ensure that all abbreviations are clearly defined. A sentence has been added specifying that all abbreviations are listed in the dedicated Abbreviations section at the end of the manuscript.

 

 

Comments 2: On page 3 there is a short paragraph starting with “This section may be divided etc.” It has no meaning in the manuscript, so delete it please.

Response 2: We thank the reviewer for pointing this out. The paragraph referred to (“This section may be divided…”) corresponds to placeholder text from the IJMS template and does not have scientific relevance within the manuscript. This text has now been removed in the revised version.

 

Comments 3: In figure 1 the scale bar is 10 µm, but the photo is taken at low magnification, so the bar is at least 100 µm. Please check and correct that. In figure 3 add “bar” in the legend. In some legends of the Figures the word bar is used, on others scale bare. Please use the same term in all legends of microscopic slides.

Response 3:  We thank the reviewer for this important observation. We have carefully revised all figure legends to ensure consistency and accuracy.

• The scale bar in Figure 1 has been corrected to reflect the appropriate magnification.
• The term “scale bar” is now used consistently throughout all figure legends.
• In Figure 3, the word “bar” has been added to the legend where required.

 

 

Comments 4: The major revision is needed in the chapters 3.2.1 and 3.2.2 and 3.2.3 In these chapters several authors are cited, but none of them is listed in the References. For example, Sanogiovanni et al, Miller et al, Ramot et al., Ruhl et al.. At the end of paragraph only references 27-20 are named, which were not written by those authors. This continues in the next paragraph (Correia-Sa et al, Styrczewska et al., Antezana et al., Zheng et al., Klein et al., Wohlman et al., etc). In chapter 3.2.3 you wrote about the research of Maida et al. (page 11, line 436) but the citation at the end is of several articles (24, 28-30 line 443), none of which is written by Maida. This must be corrected; all used literature must be written in the Reference chapter!

Response 4:  We thank the reviewer for identifying this important issue. We fully agree that accurate citation of the literature is essential. In the original version of the manuscript, some studies mentioned in Sections 3.2.1–3.2.3 were not correctly matched with their corresponding references. This has now been thoroughly corrected.

Specifically:

• All cited studies (e.g., Sangiovanni et al., Miller et al., Ramot et al., Rühl et al., Correia‑Sá et al., Styrczewska et al., Antezana et al., Zheng et al., Klein et al., Wohlman et al., Maida et al.) have now been properly linked to their corresponding references.
• Missing references have been added to the Reference list where necessary.
• Incorrect or mismatched citation numbers have been corrected throughout the affected sections.

 

 

Comments 5: Some abbreviations are not explained, for example LPS.

Response 5: We thank the reviewer for noting this. Abbreviations have been added to the corresponding section.

 

Comments 6: In the References add names and surnames of the authors of 116^th reference (K,C; M,M; M,K?).

Response 6: We thank the reviewer for identifying this error. The full names and surnames of the authors in reference 116 have now been corrected in accordance with the journal format.

 

 

Comments 7: And finally, “in vitro” and “in vivo” should be written in italic style (on pages 11, 12, 13,16, 17, 20 and 21).

Response 7: We thank the reviewer for this observation. All instances of in vitro, in vivo and ex vivo have been revised and formatted in italic style throughout the manuscript.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors addressed all queries in the revised version.

Reviewer 3 Report

Comments and Suggestions for Authors

Dear Authors!

I have no further comments. In my opinion your corrections significantly improved the text which is now ready for publication.

Kind regards!