Ethics of Psychedelic Use in Psychiatry and Beyond—Drawing upon Legal, Social and Clinical Challenges

Round 1

Reviewer 1 Report

- Line 28: 'Current' works better instead of 'Present'

- Line 29: citation should be (Johnson et al., 2017) [not (Matthew W. John- 29 son et al., 2017)]

- Line 28-20: "Current preliminary data on psychedelics use supports physiological safety and low risk of dependence or misuse abuse (Johnson et al., 2017). Although clinical trials have yet to demonstrate robust evidence for efficacy, their use is slowly being introduced into clinical practice."

- Line 33: citation is incorrectly formatted [of Veterans Affairs et al., 2017]

- Line 31-33: Please rephrase for clarity. I understand that you're saying but the wording is confusing and a bit convoluted. For example, what do you mean by 'alternative mechanisms of action' ? Many articles argue that psychedelics (serotonergic, GABAergic, and NMDA-inhibiting) work in similar ways to conventional antidepressants, hence justifying their medicalization. 

- Line 37-38: "Large clinical trials such as STAR*D and 37 I-SPOT have published data on patients who do not respond..." --> beyond the typos here, this sentence and the paragraph make little sense in the way it is written and needs to be rewritten for clarity.  

- The author(s) continually use the plural 'psychedelics' when it should be referred to in the singular.

- Line 72: I've never heard of 5-MeO-DMT referred to as an empathogen or dissociative. It is usually classed in the 'classic psychedelics' due to its 5HT receptor agonism. 

- Line 79-80: why are you suddenly defining psychedelics as naturally occurring agents when you previously discuss synthetics (LSD, ketamine, MDMA, synthetic 5-MeO-DMT)? Also, to call Native American and Indigenous Amazonian peoples 'rapidly vanishing' is denigrating. Yes, they are threatened on many fronts, but they survive and in some cases thrive. 

- To be blunt, the first part of this paragraph on page 3 reads as if it were put through google translate. The sentences do not flow together and the content seems disjointed. Further, you do not define what kinds of ethics you are discussing - bioethics, medical ethics, philosophical ethics? In the following paragraph it seems you are referring to bioethics/medical ethics. 

- line 106: what were the inclusion/exclusion criteria?

- Results: I'm confused, first you say that you filtered out grey literature and non peer-review, then you say you included perspectives, opinion pieces, essays, and reports. 

- McMillan 2021 is an essay, not a review; Marcus 2022 is a research article,  not a review; Langlitz et al 2021 is a peer-reviewed article; I don't know your criteria for labelling all your articles, but these are just a small sample of the errors you made in organizing your results.

- Line 171: yes, there should be consent and profit sharing, but the issue of bioprospecting in the first place is highly contested and considered inappropriate. 

173-174: I have no idea what you talking about here. Clearly something was discussed in the articles you reference, but you did not explain this at all here. 

- You cite McMillan A LOT, despite there being many other authors to cite here. 

- Most psychedelics come from natural origin? what about the thousands of research chemicals constantly being invented

- I don't really know what to say about this discussion and conclusion section. You have a lot of important content here, but the writing needs to be heavily edited, the topics seem to jump around from sentence-to-sentence, and conclusions are drawn from studies without sufficient explanation for why the reader should accept this as fact. 

- I recommend you find someone with strong English-language writing and editing skills to help you get this publication into appropriate form. 

- The authors conducted a very interesting study and I appreciate their perspectives, and  I do believe that this could be an important contribution to the field. For that reason I suggest that they have the opportunity to make major revisions and resubmit.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

The contribution aims to address the ethical issues related to the current new interest in psychedelics in health care. It therefore examines a very present issue that in fact raises important ethical questions. It does so by choosing an appropriate tool, a systematic integrative review, which focuses on recent studies from the last five years. The intention, consistent with the chosen instrument, is to be able to provide ethical indications for the clinical use of psychedelics.

 

– The review aims to investigate ethical aspects. In fact, it also examines clinical, social and legal aspects which, while interesting, stray somewhat from the focus stated in the title. Therefore, it would be useful to better justify their inclusion within the ethical perspective.

– Table 5, which is intended to summarise the "Ethical challenges to introduce psychedelics" actually contains aspects that do not have an ethical value, but rather a clinical one. It would be worthwhile to also formulate these points by declining them from an ethical perspective.

— In the PRISMA flow-diagram explaining the study selection process presented in Figure 1, the "not research articles" are first of all excluded. Then, however, among the "articles included in the final review" there are other types of articles besides research articles: this thus appears to be an inconsistency, which needs to be reconsidered.

– The fact of having chosen a broad entry in the subject (without circumscribing geographically, nor distinguishing by study design, nor limiting to clinical use or research), led to consider a large number of studies, on which the final selection had to be made. It would therefore be advantageous to make more explicit the selection criteria that lead to choosing, from the 1897 selected, the 42 articles included in the final review, a corpus that remains very varied within itself.

– The bibliography contains some mistakes in the references (e.g. no. 73) and in the links (e.g. no. 73, no. 101), which must be corrected.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

This is an interesting and ambitious article that has the potential to make a significant contribution. However, it still needs to be amended, in some instances restructured, and it would benefit from a clearer anaylsis of its results in terms of the review question.
Below are suggested amendments and comments: 

Methods section

Inclusion and exclusion criteria: It is important to include these to clarify the selection process.

Consideration of quality or quality assessment: this is an important emission. The quality of publications and the process of check should be presented and explained.

l.129: Data extraction date range is incomplete – between 11/11/2022...

What does ‘heterogeneous studies’ mean? Details should be given in this section.

A justification of qualitative approach should come earlier in the section and not just a few sentences at the end of the ‘data extraction’ paragraph.

Data extraction (p.5) – why is thematic the best approach?

l. 135: does this refer to the identification of themes? Did the author adopt a deductive approach and what were the themes? It would be good to have further elaboration on these in this section.

 

Results (p.6)

Grey literature: justification as to why this has been left out. Current research tends to include grey literature so it would be good to know the rationale behind leaving it out of this review.

The description of the selection process doesn’t match the PRISMA flow chart. For instance, 16255 articles were excluded, according to the chart, for not being research articles, which makes the reader think that this is an exclusion criteria. However, several non-research publications seem to be included in the final list (opinion, reviews etc.). This needs to be corrected.

 

General

l.79: Not all psychedelics are naturally occurring. LSD is synthetic, for example. And not all of them are part of native American cultures. 

l.161 – ‘the use of psychedelics raises’ ALL types of use?

The abstract and introduction propose to explore and address the deontological ethics of clinical psychedelics use. However, this is not discussed in the article. It would be good to see why the author has chosen this particular approach in ethics and how it frames the discussion of the results.

The discussion identifies some interesting themes but it’s mostly descriptive and just enumerates the themes without linking or analysing them. It would improve if it was framed in relation to the review questions. Suggestions and guidance based on the discussion should be in this section too, instead of the conclusion.

 

Spelling and typographical errors

The paper needs proofreading. Some errors are listed below.

 l. 30 – ‘its’ to ‘is’

l 67: ‘addition’ to ‘addiction’

l.68: ‘by both molecules’ to ‘by either molecule’.

l.44 –‘the altered state of consciousness’

l.38 – ‘have published patients’

l40-45: Not clear what it means that ‘methodological issues (…) were relevant for positive results’ – which positive results? The paragraph before is discussing rates of failure of conventional treatments.

l.77: ‘due to the notorious relevance of the treatment strategy, it seemed paramount to discuss (…)’ – not making sense. Why is the relevance notorious?

l.130, 141… - grammar (consistency of tense)

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report

Contextualization

·      Table 1. why is the risk of addiction relevant here?

·      The typical and atypical categories of psychedelics: I can’t find a justification in the reference (Yaden et al.), and the distinction is not made clear. Can you add reference form research/literature to support this? If the distinction is between the ways each substances affects brain neurochemistry and perception, then this should be stated.

·      Line numbers start randomly after a few pages

·      L. 5-6: Is the theme that they are endangered? What is the ethical theme to be addressed here?

·      L. 8-9: legal challenges aren’t identical to ethical ones. Please add a sentence here to link to the ethical issues you intend to discuss.

·      L. 4-18: This paragraph is confusing. There seems to be two separate descriptions of how you will proceed. If the second part is about the themes based on your review, please clarify this.

Results

·      This section shouldn’t be results, it should be methods.

 

Inclusion and exclusion criteria (L. 432 onwards)

·      There is no rationale. Why have you chosen those criteria?

·      It’s not clear whether you’re including only studies, or also opinion pieces – and how you can then think about design (opinion pieces, for instance, where would they fall?).

·      I would suggest you use a framework to formulate eligibility criteria (PICOS, SPIDER etc) to address this issue.

 

Data extraction, analysis

·      Thematic analysis: Themes should be organised as overarching, sub-themes etc. A list of themes in each article isn’t enough (please make these changes to the table in the appendix too)

 

It seems to me that the whole document needs to be restructured, different parts appear to be in the wrong order (Materials and methods are after the discussion, for example)

 

 

 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 3

Reviewer 3 Report

Please can you make sure to be specific and refer. For example, line 250 - "While Indigenous people constitute a significant percentage of the population, they make up only a small proportion (4,6%) of research participants" - Where is this the case? Please add references. Another example lines 204-205. Please be mindful of making claims without references.

Line 156-165: It's not clear what the 'take home message' of this paragraph is.

The examples of Maria Sabina and Timothy Leary are treated rather superficially and selectively to illustrate the authors' points. But social relatie and events were much more complex around both and they should be considered in your analysis. 

Media influence paragraph in analysis: Please add/elaborate what your point is about the media beyond stating that the media influences opinions and beliefs.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf