Review Reports - <i>Passiflora Incarnata L. Herba</i> in the Treatment of Anxiety Symptoms and Insomnia in Children and Adolescents with Feeding and Eating Disorders

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for letting me review the article “Passiflora Incarnata L. Herba in the treatment of anxiety symptoms and insomnia in children and adolescents with Feeding and Eating Disorders.” I have the following comments:

1.First, the study does not include a control group.

2.Second, why focus on the role of Passiflora Incarnata in children and adolescents with Feeding and Eating Disorders? What about its effect in generally anxious children?

3.Third, why was a chi-square test used for analyzing the reduction in symptoms?

Author Response

Dear Editor,

Thank you for your kind attention. We appreciate the thorough feedback that we received. We addressed each comment. Please find below our detailed responses following the guidelines provided.

Referee # 1

- Comment: First, the study does not include a control group.

Reply: Thank you for your observation. We acknowledge the reviewer’s observation regarding the absence of a control group and agree that this represents a limitation in terms of establishing causal inferences. However, we would like to highlight that this study was intentionally designed as a naturalistic, retrospective observational study, with the primary aim of describing real-world clinical practices and treatment outcomes in a specific and under-investigated population children and adolescents with Feeding and Eating Disorders (FEDs) treated with Passiflora incarnata L. Herba. Given the exploratory nature of the research and the ethical and logistical constraints in this clinical population often involving complex multimodal treatment plans and clinical fragility a controlled, randomized design was not feasible at this stage. Instead, our goal was to provide preliminary data on safety, tolerability, and potential efficacy in a real-world setting, which could serve as a basis for future controlled trials. We have now further emphasized this limitation and clarified the rationale in the Discussion section of the manuscript. We also agree that future studies should include randomized controlled designs with matched comparator groups to confirm and expand upon these initial findings.

- Comment: Second, why focus on the role of Passiflora Incarnata in children and adolescents with Feeding and Eating Disorders? What about its effect in generally anxious children?

Reply: We thank the reviewer for this insightful question and we add a phrase regarding the topic in the Discussion section. Our decision to focus specifically on the population of children and adolescents with Feeding and Eating Disorders (FEDs) stems from both clinical and research-based considerations. Firstly, anxiety symptoms and insomnia are highly prevalent and often clinically significant in the context of FEDs, contributing to both symptom severity and treatment resistance. Several studies have underlined that anxiety in patients with FEDs is not only a frequent comorbidity, but often plays a role in the pathogenesis and maintenance of the disorder, particularly in conditions such as Anorexia Nervosa. Therefore, targeting anxiety within this specific population has direct therapeutic relevance. Secondly, the management of anxiety and sleep disturbances in youth with FEDs is complex due to their increased vulnerability to adverse pharmacological effects and frequent polypharmacy. For this reason, there is a growing clinical interest in identifying safe, well-tolerated, and evidence-based alternative interventions. Passiflora incarnata, with its favorable tolerability profile and potential anxiolytic and sedative properties, represents a promising candidate for adjunctive treatment specifically in this fragile population. Thirdly, while studies on Passiflora incarnata in pediatric populations with generalized anxiety do exist, they often lack diagnostic specificity, and to our knowledge, no prior studies have explored its application within the context of FEDs—a population where comorbid anxiety often presents with unique phenomenological and neurobiological characteristics. This gap in the literature warranted our focused investigation. Finally, although our study does not include a control group of generally anxious children without FEDs, our findings may serve as a basis for future comparative studies. Exploring differences in the response profile of Passiflora incarnata between FED-related anxiety and primary anxiety disorders represents an interesting and clinically valuable direction for further research.

- Comment: Third, why was a chi-square test used for analyzing the reduction in symptoms?

Replay:
The chi-square test was applied because the reduction in symptoms was evaluated using the CGI-I scale, which categorized patients into groups (e.g., improvement: CGI-I score 2 or 3, vs. no benefit: CGI-I score 4). Since the outcome was categorical and we aimed to compare the frequency of improvement between groups, the chi-square test was deemed appropriate for this type of analysis. We have now clarified this rationale in the Methods section of the revised manuscript to avoid any confusion. Thank you again for helping us improve the clarity and rigor of our methodology.

We wish to thank the Reviewer and hope that having revised the paper based on their observations, it will be possible to publish it in your journal.

Sincerely,

Prof. Antonia Parmeggiani

Reviewer 2 Report

Comments and Suggestions for Authors

Suggestions are attached.

Comments for author File: Comments.pdf

Author Response

Dear Editor,

Thank you for your kind attention. We appreciate the thorough feedback that we received. We addressed each comment. Please find below our detailed responses following the guidelines provided.

Referee # 2

- Comment: the article entitled "Passiflora Incarnata L. Herba in the Treatment of Anxiety Symptoms and Insomnia in Children and Adolescents with Feeding and Eating Disorders," authored by La Tempa Angela et al., aims to evaluate the efficacy of Passiflora Incarnata as a treatment for anxiety and insomnia in children and adolescents diagnosed with Feeding and Eating Disorders (FEDs). The study investigates its use as an adjunct therapy to conventional psychopharmacological treatments. Please consider the following suggestions: There are some abbreviations in the abstract; please write the full names when first mentioned

Reply: as suggested the full names were written.

- Comment: Why does the author choose a retrospective observational study for this research? Wouldn't it narrow the potential to build an association between variables

Reply: We thank the reviewer for this important observation.
We chose a retrospective observational design because our primary aim was to evaluate real-world data regarding the use of Passiflora Incarnata in clinical practice, rather than to establish causal relationships. A retrospective approach allowed us to explore patterns of use and preliminary associations in a naturalistic setting, providing initial insights that could inform the design of future, more rigorous prospective studies. We fully acknowledge that retrospective studies have inherent limitations, particularly regarding the ability to control for confounding factors and to establish causal inferences. These limitations have now been more clearly discussed in the revised version of the manuscript, and we have emphasized the need for future prospective and randomized studies to further investigate the associations observed. Thank you again for this valuable feedback.

- Comment: The study provides valuable data on Passiflora Incarnata's efficacy; however, including additional data from other regions or studies on phytotherapy in FEDs could strengthen the contextual relevance of the findings.

Reply: Thank you for your insightful comment, we add a phrase in the Discussion. We fully agree that incorporating additional data from other regions or complementary studies on phytotherapy in Feeding and Eating Disorders (FEDs) would enhance the generalizability and contextual relevance of our findings. While our study represents a pioneering step in investigating the use of Passiflora Incarnata L. Herba in a pediatric FED population within a specific Italian clinical setting, we acknowledge the importance of cross-regional data to account for potential cultural, dietary, and healthcare system-related variables that may influence treatment outcomes. Future research should indeed aim to include multicenter or multinational samples, and comparative analyses with other herbal compounds could further substantiate the role of phytotherapy as an adjunctive intervention in this field. This would allow for a more comprehensive evaluation of both efficacy and safety profiles across diverse clinical contexts.

- Comment: The data sources and inclusion-exclusion criteria are well described and supported, providing a precise understanding of the research.

Replay: Thanks for the comment.

- Comment: What was the rationale for selecting the Regional Center for FEDs as the study site? Was it due to patient volume, regional prevalence of eating disorders, or other factors? Please specify.

Reply: Thank you for your observation we add some data in the section Materials and methods. The selection of the Regional Center for Feeding and Eating Disorders (FEDs) as the study site was based on several key factors. Primarily, this Center represents a third-level specialized referral facility with a high volume of pediatric and adolescent FED cases (more than 500 patients are followed in one year), ensuring a sufficient and diverse clinical population for observational research. Additionally, it serves as a regional hub for the diagnosis and treatment of complex FEDs, covering a broad geographical area and receiving referrals from multiple local health units. This positioning allows for the inclusion of a heterogeneous patient sample in terms of clinical severity, comorbidities, and treatment histories. The Center's established protocols for the assessment and management of FEDs, as well as its integrated multidisciplinary team—including child neuropsychiatrists, psychologists, and dietitians—further supported its selection as an optimal setting for investigating the use of Passiflora Incarnata L. Herba within routine clinical practice.

- Comment: Could the authors elaborate on how the findings are expected to benefit healthcare professionals, caregivers, and policymakers in incorporating Passiflora Incarnata into treatment regimens for FED patients?

Reply: We added in the text: ...”This phytotherapeutic option demonstrated excellent tolerability, with no reported adverse effects or drug interactions. Therefore, it may represent a valuable choice for clinicians in cases where symptoms are mildly expressed or when caregivers are hesitant about conventional pharmacological treatments. Moreover, its favorable safety profile and the encouraging preliminary results observed in this study should encourage further controlled trials exploring phytotherapy-based strategies, especially in vulnerable populations such as children and adolescents with FEDs. However, the variability in treatment response across different FED subtypes highlights the need for additional research to optimize therapeutic approaches. Future studies should focus on larger, well-designed clinical trials to confirm these findings and to refine dosing protocols and potential combination strategies aimed at maximizing clinical benefit”.

- Comment: The author could further elaborate on the mechanism through which Passiflora Incarnata exerts its effects, providing a more detailed discussion on its pharmacological action and potential interactions with other treatments.

Reply: We added in the text: ...”Reflecting on potential interactions with other medications, some studies have reported that Passiflora incarnata L. Herba may interact with central nervous system (CNS) depressants—such as benzodiazepines, sedatives, and alcohol—potentially enhancing sedative effects and increasing the risk of drowsiness and somnolence[13].”

- Comment: The author should consider adding more details on potential factors influencing the variability in response to passiflora Incarnata across different FED diagnosis, including symptom severity, comorbidities, and treatment duration

Reply: We added in the text: ...”In conclusion, the variability in response to Passiflora incarnata L. Herba observed across different FED diagnoses may be influenced by several clinical factors. First, symptom severity—particularly the intensity and chronicity of anxiety or insomnia—may play a key role in determining the efficacy of the intervention. Patients with more severe or persistent symptoms may require longer treatment periods or higher doses to achieve significant improvements. Second, the presence of psychiatric comorbidities could interfere with treatment outcomes by introducing additional layers of clinical complexity. Finally, treatment duration and adherence may also influence the degree of improvement observed. Since herbal remedies often have a more gradual onset of action compared to conventional medications, longer treatment courses might be necessary to observe their full therapeutic potential”.

- comment: The conclusion effectively summarizes the findings with the research question. However, it would be beneficial to specify and elaborate on potential directions for future research.

Reply: We add in the Conclusion section potential directions for future research. …”Future research may explore several promising directions. One potential avenue involves examining the synergistic effects of Passiflora incarnata when combined with other herbal treatments in the management of anxiety, sleep disturbances, and mood disorders. Another important direction could be the investigation of the potential benefits of integrating Passiflora incarnata with FBT, CBT or other psychological interventions to enhance therapeutic outcomes in anxiety and stress-related conditions. Finally, comparative studies assessing the clinical effectiveness of Passiflora incarnata versus established anxiolytics, such as benzodiazepines or selective serotonin reuptake inhibitors (SSRIs), could provide another valuable insight into its role as a complementary or alternative treatment option for anxiety and depression”.

- Comment: Justify the dosage used in this study: Incarnata was used at a dose of 200 mg of dry extract.

Reply: The requirement of medicinal use for at least 30 years (15 years within the Community) according to Directive 2004/24/EC as amended is considered fulfilled for the following herbal preparations: a) Comminuted herbal substance b) Powdered herbal substance c) Liquid extract (DER 1:8) extraction solvent ethanol 25% V/V d) Liquid extract (DER 1:8) extraction solvent ethanol 45% V/V e) Liquid extract (DER 1:3.6) extraction solvent ethanol 60% V/V f) Liquid extract (DER 1:1) extraction solvent ethanol 25% V/V g) Liquid extract (DER 1:1) extraction solvent ethanol 70% V/V h) Liquid extract (DER 1:3.8-4.3) extraction solvent ethanol 54% m/m, glycerine 4% m/m, water 60%. The recommended daily dosage for Liquid extract (DER 1:3.6) extraction solvent ethanol 60% V/V, based on official monographs such as those from the EMA (European Medicines Agency) and ESCOP (European Scientific Cooperative on Phytotherapy), is 0.5 – 1 ml, up to 3 times per day. A single dose of 0.5 – 1 ml corresponds to approximately 139 – 278 mg of dry estract. The maximum daily dosage (up to 3 times per day) corresponds to approximately 417 – 834 mg of dry extract.

We use 200 mg of dry extract (obtained using ethanol 60% V/V as the extraction solvent), 1-2 tablets for day, as recommended by the guidelines - European Medicines Agency (EMA). Community herbal monograph on Passiflora incarnata L., herba. Reference number: EMEA/HMPC/111180/2007).

- Comment: Are there any reported side effects? Please discuss.

Reply: As reported in the sections Introduction, Results and Conclusions, Passiflora incarnata is generally considered safe when used appropriately, At the time of the HMPC assessment, no side effects had been reported with these medicines.

We wish to thank the Reviewer and hope that having revised the paper based on their observations, it will be possible to publish it in your journal.

Sincerely, Prof. Antonia Parmeggiani

Reviewer 3 Report

Comments and Suggestions for Authors

see attached file

Comments for author File: Comments.pdf

Author Response

Dear Editor,

Thank you for your kind attention. We appreciate the thorough feedback that we received. We addressed each comment. Please find below our detailed responses following the guidelines provided.

Referee # 3

- Comment: As stated by the authors, the aim of this study is to explore the use of Passiflora incarnata L. Herba in conjunction with traditional psycho-pharmacological therapies to reduce the co-administration of traditional drugs. However, the study is only an attempt to describe a sample of patients observed at the study Center in 2020-2023. Unfortunately, such a description and the calculations performed, firstly, provide little new understanding of the use of Passiflora Incarnata L. Herba in children and adolescents with FEDs co-occurring with anxiety and insomnia. Secondly, the goal of the study is not achieved since the manuscript does not answer the question of whether the use of Passiflora Incarnata L. allows to reduce the co-administration of traditional drugs.

Reply: The aim of the study has been reformulated as suggested: “The aim of this study is to explore the use of Passiflora incarnata L. Herba, administered as tablets (each containing 200 mg of dry extract, an equivalent dose of 700–1000 mg of Passionflower extract obtained using ethanol 60% V/V as the extraction solvent), in conjunction with traditional psychopharmacological therapies, in children and adolescents with FEDs co-occurring with anxiety and insomnia”.

- Comment: The conclusions in the article are apparently based on an analysis of previously made medical records. This approach is acceptable in principle, although it has a number of limitations. Indeed, as the authors admit (lines 228-231) "The sample size is relatively small". At the same time, there is confusion with the sample size. The authors stated that the sample included 94 patients, but the effectiveness of taking the herbal preparation was determined only in 64 patients. It is hardly possible to judge any expediency of using Passiflora Incarnata if we include in the calculations patients who were not assessed in terms of the effectiveness of treatment. Mentioning some "naturalistic nature" of the study cannot replace the missing data for 30 patients. The calculations in the text (lines 135-148) are mathematically unclear. Why does 34 patients equal 27.2%? 34 should equal 53% of 64 patients, or 36% of 94 patients, which is incorrect for the above reason. The calculation of patients with no benefit gives 47%, not 31.9%, since only 64 patients can be taken into account here. Then, in lines 141-142, 90 patients are described: "The first group included 67 patients (72.0%) who used Passiflora Incarnata for anxiety symptoms, while the second group comprised 23 patients (24.7%) who used Passiflora Incarnata for insomnia." Where are the other 4 patients? The examples given show that the authors have chosen a methodological approach to calculations that is not adequate to the task at hand. It is strongly recommended that adjustments be made to the analysis of the collected material.

Reply: thank you for your careful reading and constructive comments. You are right in pointing out the inconsistencies in the numbers reported. We have carefully reviewed the data according to the provided indications, and made the necessary corrections to ensure that the figures now accurately reflect the sample analyzed. We agree that clarity in the presentation of patient numbers and percentages is essential, especially when drawing conclusions regarding treatment effectiveness. The revised version, mentioned below, includes corrected calculations and a clearer explanation of the sample composition: “Specifically, 34 patients (53,1% of the sample with data on treatment outcomes) reported benefit from the intake, obtaining a score of 2 (n=23, 39,1%) or 3 (n=11, 17,2%); 30 patients (46,8%) reported no benefit, obtaining a score of 4. No clinical worsening or side effects were recorded. To better characterize the population reporting benefit, the sample was divided into two groups based on target symptoms. The first group included 71 patients (75,5%) who used Passiflora Incarnata for anxiety symptoms, while the second group comprised 27 patients (28,7%) who used Passiflora Incarnata L. Herba for insomnia (4 patients used Passiflora Incarnata L. Herba to target both anxiety and insomnia symptoms). In the first group, 24 patients (33%) reported improvement in symptoms, obtaining a CGI-I score of 2 or 3, while 21 patients (29%) reported no benefit (CGI-I: 4). No significant difference was found from this analysis (X2=6.592; p=0,086). In the second group, 10 patients (37%) reported improvement in symptoms, obtaining a score of 2 on CGI-I, while 120 patients (44%) reported no benefit (CGI-I: 4). This difference was statistically significant (X2=10.872; p=0,012)”. Furthermore, we better clarify in the conclusions that “The size of the group with data in terms of effectiveness is relatively small (n=64), and the study lacks a control group, which limits the generalizability and causal inferences of our results”.

- Comment: Abstract: - Methods need to be described more specifically; - SSRIs need to be fully specified.

Reply: Methods were described more specifically: ...”Methods: this is an observational and retrospective study that includes patients assessed in a third-level Italian Regional Centre for Feeding and Eating Disorders in Children and Adolescents between 01/01/2020 and 31/12/2023. Eligible patients had a confirmed diagnosis of a FED, along with either an anxiety or a sleep disorder. During follow up, the clinical efficacy of Passiflora Incarnata L. Herba was assessed using the Clinical Global Impression – Improvement scale (CGI-I). Comparative analyses were conducted stratifying the sample, based on the target symptoms (sleep disorders/insomnia and anxiety), FED subtype, and whether polytherapy was used”.

SSRIs were fully specified as suggested: ”selective serotonin reuptake inhibitors (SSRIs).

- comment: Line 32: (Hornberger et al., 2021) should be transformed into an ordinal reference.

Replay: (Hornberger et al., 2021) was transformed into an ordinal reference.

- Comment: Line 80: What does "naturalistic" mean?

Reply: Naturalistic observation is a qualitative research method where you record the behaviors of your research subjects in real world settings. You avoid interfering with or influencing any variables in a naturalistic observation.

- Comment: Line 88: The manufacturer of the tablets should be indicated. It is obvious that the molecular composition of the plant extract is extremely variable and depends on many factors.

Reply: as suggested we have added in the text the manufacturer of the tablets: ...”each containing 200 mg of dry extract, an equivalent dose of 700 – 1000 mg of Passionflower extract obtained using ethanol 60% V/V as the extraction solvent”.

- Comment: Lines 112-114: The text should be removed.

Reply: the text has been removed as suggested.

- Comment: Lines 120-121: It is not clear what the phrase "(equivalent to 700 mg-1000 mg)" means.

Reply: It means that each coated tablet contains 200 mg of dry extract, corresponding at 700 mg – 1000 mg of fresh plant. This means the extract is standardized to be equivalent to that amount of whole plant, ensuring consistent levels of active compounds.

- Comment: Line 136 the phrase “reporting by patients” is confusing since the Clinical Global impression (CGI-I) scale evaluates the clinician’s view of the patient’s condition

Reply: We have added in the text: ...”the benefit of Passiflora incarnata L. Herba was assessed using the CGI-I, based on the clinician’s evaluation. The assessment was informed by the clinical interview and the mental state examination conducted during follow-up appointments.

- Comment: Lines 180-181: Please provide more information on the "... complexity pathophysiology of anxiety in FEDS"...

Reply: We have provided more information in the text: ...”This discrepancy could be attributed to the complexity and the underlined subtype of anxiety in FEDs. This discrepancy could be attributed to the complexity and the underlying subtypes of anxiety in FEDs. In fact, comorbid anxiety symptoms in this population may have varying impacts on the pathophysiology of FEDs. In some cases, higher levels of anxiety may lead to the adoption of dysfunctional emotion regulation strategies, such as disordered eating behaviors (e.g., binge eating). In other situations, anxiety may be more closely related to social issues. For instance, low self-esteem, combined with a negative self-perception and body dissatisfaction, may represent risk factors for the development of a FED or for aggravating the clinical picture”.

- Comment: Line 181: Why do the authors consider the dose used here to be "low", whereas in the Methods it is stated as "high" (line 88)?

Reply:“Furthermore, another relevant aspect to consider when interpreting the results is the standard dosage of Passiflora incarnata L. Herba used in our study. This observation suggests that clinicians might reflect on the potential benefits of using adjusted doses, or consider combining Passiflora incarnata L. Herba with other interventions to enhance its clinical efficacy”

We wish to thank the Reviewer and hope that having revised the paper based on their observations, it will be possible to publish it in your journal.

Sincerely, Prof. Antonia Parmeggiani

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

No more comments.

Author Response

Dear reviewer,

Thank you for your kind attention. We appreciate the thorough feedback that we received.

Reviewer 3 Report

Comments and Suggestions for Authors

As a result of the corrections made, I can agree with the authors that the study "suggests that
Passiflora incarnata L. Herba may offer a beneficial adjunctive treatment for anxiety and sleep
disturbances in patients with FEDs."
The findings that 1) Passiflora incarnata L. intake at a dose of 200–400 mg per day causes
improvement in an average of 53% of patients with FEDs and 2) 33% and 37% of patients with
FEDs who used Passiflora Incarnata for anxiety and insomnia disturbances, respectively, reported
improvement in symptoms should be included in the conclusion to increase the scientific
significance of the manuscript.
Line 29-30: Please rewrite the conclusion in the Abstract.
Line 95: Please remove the term "naturalistic," as it has no scientific meaning in the context of the
article.
Line 169: Check number 120 (?)
As stated in the author's answer to the comment, "Reply: the text has been removed as suggested,"
the material in question (lines 112-114 in the previous version of the manuscript or lines 130-
132 in the current version) was left in place. Why?
Also, the question of which manufacturer's tablets were used is not answered. It is strongly
recommended to provide the required information.

Author Response

Dear Editor,

Thank you for your kind attention. We appreciate the thorough feedback that we received. We addressed each comment. Please find below our detailed responses following the guidelines provided.

Comment: As a result of the corrections made, I can agree with the authors that the study "suggests that Passiflora incarnata L. Herba may offer a beneficial adjunctive treatment for anxiety and sleep disturbances in patients with FEDs." The findings that 1) Passiflora incarnata L. intake at a dose of 200–400 mg per day causes improvement in an average of 53% of patients with FEDs and 2) 33% and 37% of patients with FEDs who used Passiflora Incarnata for anxiety and insomnia disturbances, respectively, reported improvement in symptoms should be included in the conclusion to increase the scientific significance of the manuscript.

Reply: We included the improvement reported in the conclusion.

Comment: Line 29-30: Please rewrite the conclusion in the Abstract.

Reply: We provided to rewrite the conclusion in the Abstract as suggested.

Comment: Line 95: Please remove the term "naturalistic," as it has no scientific meaning in the context of the article.

Reply: We have removed the term “naturalistic” in line 95.

Comment: Line 169: Check number 120 (?)

Reply: The correct number is 12, we removed the 0.

Comment: As stated in the author's answer to the comment, "Reply: the text has been removed as suggested," the material in question (lines 112-114 in the previous version of the manuscript or lines 130-132 in the current version) was left in place. Why?

Reply: We apologize for not having removed the sentence as required. We have removed this sentence in the latest version.

Comment: Also, the question of which manufacturer's tablets were used is not answered. It is strongly recommended to provide the required information.

Reply: Were used coated tablets of Passiflora Incarnata L., each one contains 200 mg of dry extract of Passiflora Incarnata L., herba equivalent to 700-1000 mg of Passiflora.

We wish to thank also for this review and we hope that now it will be possible to publish our paper in your journal.

Sincerely,

Prof. Antonia Parmeggiani