Molecular and Medical Aspects of Psychedelics
Round 1
Reviewer 1 Report
Comments and Suggestions for Authors
The authors very exactly examine the effects of psychodelcis Psylocybine and ketamine in animals and humans. The mention the combination of neurons with 5-HT2A receptors and NMDA receptors. The neurotransmitters dopamine, serotonin, GABA and glutamate are incluced in this review. This context is also important in the schizophrenia research. This is a very important review, perhaps it might be possible to mention the context between psylocybine, a 5-HT2A agonist and ketamine, an NMDA receptor antagonist in schizophrenia. The formal aspects of a review, the English language and the list of references are very correct. There are few grammatical mistakes in the text.
I recommend a minor revision.
Comments on the Quality of English Language
The authors very exactly examine the effects of psychodelcis Psylocybine and ketamine in animals and humans. The mention the combination of neurons with 5-HT2A receptors and NMDA receptors. The neurotransmitters dopamine, serotonin, GABA and glutamate are incluced in this review. This context is also important in the schizophrenia research. This is a very important review, perhaps it might be possible to mention the context between psylocybine, a 5-HT2A agonist and ketamine, an NMDA receptor antagonist in schizophrenia. The formal aspects of a review, the English language and the list of references are very correct. There are few grammatical mistakes in the text.
I recommend a minor revision.
Author Response
he authors very exactly examine the effects of psychodelcis Psylocybine and ketamine in animals and humans. The mention the combination of neurons with 5-HT2A receptors and NMDA receptors. The neurotransmitters dopamine, serotonin, GABA and glutamate are incluced in this review. This context is also important in the schizophrenia research. This is a very important review, perhaps it might be possible to mention the context between psylocybine, a 5-HT2A agonist and ketamine, an NMDA receptor antagonist in schizophrenia. The formal aspects of a review, the English language and the list of references are very correct. There are few grammatical mistakes in the text.
RE: Thank you for a revision. Schizophrenia counts as one of the very important aspects of psychedelics action regarding their impact on 5-HT2A receptors and psychotic effects they induce. This issue was discussed in section 5.8.The therapeutic potential of psychedelics (page 12, line 544-552).
Reviewer 2 Report
Comments and Suggestions for AuthorsThe present work devoted an actual topic of use psychedelics for medicinal treatments. The review was carried out carefully and a large number of literary sources were processed, all literary references correspond to the content of the work. Thus, the authors perform detailed analysis of very new psychedelics, namely NBOMe series, in the comparison with good known psychoactive drugs such as ketamine and psylocibin. I think that these data will be useful for researchers in different fields of medicine. However, I would like to mark some critical points, which need to be clarified to better understanding of review content.
· First of all, the title of this review is very general, since only one NBOMe class, included two substances, class is discussed together with more two substances (psilocybin and ketamine). In this regard, I believe that NBOMes should be mentioned in the title of this manuscript.
· In introduction, it is also necessary to specifically indicate which specific psychedelics will be the focus of this review and provide the rationale for this choice in relation to psilocybin and ketamine.
· To previous point, it is quite clear the choice of psilocybin, good studied psychedelic, for this research as a reference drug. I would like to ask the authors to clarify their choice of ketamine in part «6. Ketamine» on page 7, since it is undoubtedly psychoactive substance, but it is very relative psychedelic, because of ketamine is generally dissociative anesthetic, that also used for treatment of depression.
· Part «4. NBOMes» in page 3, in the last sentence, it is more correctly used «N-(2-methoxy)benzyl group» instead of «N-benzyl group».
· For the conclusion, is it worth mentioning that new psychoactive NBOMes have increased activity, but potential effectivity of these substances for the medicinal treatment is ambiguous or low in comparison with psilocybin?
Finally, I would like to recommend this manuscript for publication after minor revision.
Author Response
The present work devoted an actual topic of use psychedelics for medicinal treatments. The review was carried out carefully and a large number of literary sources were processed, all literary references correspond to the content of the work. Thus, the authors perform detailed analysis of very new psychedelics, namely NBOMe series, in the comparison with good known psychoactive drugs such as ketamine and psylocibin. I think that these data will be useful for researchers in different fields of medicine. However, I would like to mark some critical points, which need to be clarified to better understanding of review content.
First of all, the title of this review is very general, since only one NBOMe class, included two substances, class is discussed together with more two substances (psilocybin and ketamine). In this regard, I believe that NBOMes should be mentioned in the title of this manuscript.
RE: Thank you for your revision. Below please find my response to your comments.
RE: “the title of this review is very general” – Our work constitutes a the part of special MDPI issue "Molecular Advances in Psychiatric Therapies" and the title of article proposed by Guest Editor “Molecular and Medical Aspects of Psychedelics” cannot be changed.
In introduction, it is also necessary to specifically indicate which specific psychedelics will be the focus of this review and provide the rationale for this choice in relation to psilocybin and ketamine.
RE: “In introduction it is also necessary to specifically indicate which specific psychedelics will be the focus of this review and provide the rationale for this choice in relation to psilocybin and ketamine” – we have specified which psychedelics are the subject of our work towards the end of “Introduction”(page 2 lines 47-48). Furthermore, we have decided that sections regarding ketamine which is a dissociative anesthetic while not being a serotonergic psychedelic (although used in treatment of depression) will be omitted in the present article. I think that it added clarity of the review.
Part «4. NBOMes» in page 3, in the last sentence, it is more correctly used «N-(2-methoxy)benzyl group» instead of «N-benzyl group».
RE: "it is more correctly used «N-(2-methoxy)benzyl group» instead of «N-benzyl group» - you are absolutely right, the sentence was corrected (Chapter 4 page 4 line 135).
For the conclusion, is it worth mentioning that new psychoactive NBOMes have increased activity, but potential effectivity of these substances for the medicinal treatment is ambiguous or low in comparison with psilocybin?
RE: "potential effectivity of these substances for the medicinal treatment is ambiguous or low in comparison with psilocybin?" - the respective comment is given in section 4.2, line 196-198 and chapter 6. line 556-557
Reviewer 3 Report
Comments and Suggestions for AuthorsDear Authors,
I am sorry to say that I think your work lacks concreteness. Reading the title, one would expect a section where you talk specifically about the molecular mechanisms of psychedelics and another where you talk about medical use. However, while these ideas can be glimpsed in the text, they are unclear. The abstract and objective say "current state or preclinical research", so it should be indicated in the title. But then in the conclusion it is not mentioned and is intended to be extended to medical (human) use. Another example would be that you only say that Ketamine has an effect on the mTOR pathway, but then in the conclusion you indicate "mechanistically, psychedelic changes in neuronal structure activating mTOR signalling".
Sometimes there are repetitions, e.g. page 1 line 34 and page 2 line 61. In this respect, you should name the chemical name the first time the term mescaline is used. Page 3 line 104 and page 7 line 333, PFC prefrontal cortex, not frontal cortex, and then on page 8 line 401 FCX. Page 6 line 271 and page 10 line 490. The use of FST to determine depression-like behaviour is also discussed in this article https://doi.org/10.1016/j.psyneuen.2015.08.028
The abstract only talks about the change in neurotransmission in rats without mentioning the mouse and does not even mention what happens in humans. I think you should make a decision about what you want to say. Either you describe the preclinical experiments in rodents, or all preclinical experiments in all species, or the experiments in human clinics, or all at once, but we have to know in the text which phase each result is from.
In general, the text is difficult to follow because there is a lack of tables or graphs to help understand your message. In a review, you are expected to explain previous work in a way that makes it easier for the reader to know what has been done on a topic so far. Your text is a concatenation of past results, and in the end, we don't really know what the general framework of psychedelics is.
The text cannot be published in this way and I am sorry to give it a reject. I suggest a possible order in the belief that it may help you in the rewriting of your work.
Introduction: introduce the history and classification of psychedelics. Add a table or something graphic with the classification.
Mechanism of action: explain the mechanism of action and compare the two. Make a table of doses per animal, for example.
Action by brain areas: so that you can then link this to the behavioural effects. Describe the differences between the different psychedelics.
General conclusion and future perspective.
Best regards,
Author Response
Dear Authors,
I am sorry to say that I think your work lacks concreteness. Reading the title, one would expect a section where you talk specifically about the molecular mechanisms of psychedelics and another where you talk about medical use. However, while these ideas can be glimpsed in the text, they are unclear. The abstract and objective say "current state or preclinical research", so it should be indicated in the title. But then in the conclusion it is not mentioned and is intended to be extended to medical (human) use. Another example would be that you only say that Ketamine has an effect on the mTOR pathway, but then in the conclusion you indicate "mechanistically, psychedelic changes in neuronal structure activating mTOR signalling".
RE: Thank you for your all comments. The whole work was reconstructed and was divided into following chapters:
The first 3 chapters are more general and represent short history of psychedelics and the main focus of the work (1. Introduction), pharmacological profile of psychedelics and substances representing their groups (2. Classification of psychedelics) and the role of 5-HT2A receptor as a molecular target in the mechanism of psychedelics’ action (3.The mechanism of action of psychedelics). The next two main chapters are devoted of NBOMes as a one class of serotonergic psychedelics belonging to phenethylamine class (Chapter 4) and Psilocybin representing indoleamine class (Chapter 5). The main chapters (4 and 5) are divided into subsections showing in a more specific way the properties of NBOMe class and indoleamine class as these both classes of psychedelics have distinct pharmacology. Therefore, presenting direct comparisons between of behavioral, neurochemical and neurotoxic effects of NBOMes and psilocybin is not possible. We think that this way we could describe effects of both groups more clearly. I’d like to emphasize that knowledge on the impact of psychedelics on neurotransmitter release in the brain is very sparse in the current literature and by collecting data showing how changes in neurotransmitters translate onto behavioral response is a main premise of the article.
The last section of Chapter 5 is devoted to therapeutic effects of psilocybin as NBOMe drugs toxicity excludes this group of substances from medical use. There are many detailed review articles in the literature presenting clinical studies. Therefore, we only accentuated the most important trends in clinical pharmacology of psychedelics.
The last chapter 6 (Conclusions and future questions) shortly summarises main ideas presented in the review and what are the future questions to be resolved.
Sometimes there are repetitions, e.g. page 1 line 34 and page 2 line 61. In this respect, you should name the chemical name the first time the term mescaline is used. Page 3 line 104 and page 7 line 333, PFC prefrontal cortex, not frontal cortex, and then on page 8 line 401 FCX. Page 6 line 271 and page 10 line 490. The use of FST to determine depression-like behaviour is also discussed in this article https://doi.org/10.1016/j.psyneuen.2015.08.028
RE: The chemical name of mescaline was missing in the first mentioning of this substance (corrected, along with all abbreviations in the text). Thank you for the link to article discussing FST.
The abstract only talks about the change in neurotransmission in rats without mentioning the mouse and does not even mention what happens in humans. I think you should make a decision about what you want to say. Either you describe the preclinical experiments in rodents, or all preclinical experiments in all species, or the experiments in human clinics, or all at once, but we have to know in the text which phase each result is from.
RE: the limit of words in abstract (250 words) does not allow us to include all the detailed data discussed in the review. As mentioned above, we directed our attention to neurotransmission and how changes in neurotransmitters translate into behavioral effects of psychedelics – as this data is sparse. The results of studies performed on rats and mice are discussed in the main body of the text.
In general, the text is difficult to follow because there is a lack of tables or graphs to help understand your message. In a review, you are expected to explain previous work in a way that makes it easier for the reader to know what has been done on a topic so far. Your text is a concatenation of past results, and in the end, we don't really know what the general framework of psychedelics is.
RE: The tables and graphs illustrating underlying mechanism of psychedelics action is included in the respective sections of the text. I hope that this helps in understanding of the complicated subject of psychedelics impact on the brain.
The text cannot be published in this way and I am sorry to give it a reject. I suggest a possible order in the belief that it may help you in the rewriting of your work.
Introduction: introduce the history and classification of psychedelics. Add a table or something graphic with the classification.
Mechanism of action: explain the mechanism of action and compare the two. Make a table of doses per animal, for example.
Action by brain areas: so that you can then link this to the behavioural effects. Describe the differences between the different psychedelics.
General conclusion and future perspective.
Best regards,
RE: As explained above, the manuscript was reorganized and hopefully in its present form it is easier to follow by the reader.
Round 2
Reviewer 3 Report
Comments and Suggestions for AuthorsDear Authors,
After the modifications made, I think you have made the work more focused and coherent. The tables and illustrations make it easier to read. Little more to contribute.
Best regards,
