Oxytocin, a Novel Treatment for Methamphetamine Use Disorder
, Elliot Thompson 1, Chandler E. Merriman 2, Mark R. Alvarez 2, E. Saunders Alpaugh 3, Elyse M. Cornett 4, Kevin S. Murnane 1,5,6, Rachel L. Kozinn 7, Mila Shah-Bruce 8, Adam M. Kaye 9 and Alan D. Kaye 4Round 1
Reviewer 1 Report
The manuscript by Edinoff and colleagues evaluates the potentiality of oxytocine to represent a novel efficacious molecule for the treatment of stimulant use disorders. The manuscript is well-written. In spite of it, some issues need a careful consideration.
Major comments
Paragraph 2.2.1. Please describe which are the limits of the currently used therapeutic approaches.
Paragraph 2.3. Clinical studies. I think that the title of the paragraph (clinical safety and efficacy) is not appropriate since 7 out of 8 studies commented are preclinical and just 1 is clinical. Title should be revised. The same is also valid for Table 1. In this table can be included only preclinical information and refer in the text the results of the single clinical trial. Alternatively, authors can appropriately revise the title of Table 1 and specify the type of each study conducted (preclinical or clinical).
Paragraph 2.4., 272-275. A comment on this discrepancy (ref. 50) is encouraged.
Minor comments
Conclusions, 437. Please include the reference of the relative study.
Author Response
Major comments
Paragraph 2.2.1. Please describe which are the limits of the currently used therapeutic approaches.
Answer: The main limitation is the lack of peer reviewed studies in the general population. A sentence has been added to reflect this. There are various sentences that highlight the limitations ot treatment in general in a few places in the section prior to the revision.
Paragraph 2.3. Clinical studies. I think that the title of the paragraph (clinical safety and efficacy) is not appropriate since 7 out of 8 studies commented are preclinical and just 1 is clinical. Title should be revised. The same is also valid for Table 1. In this table can be included only preclinical information and refer in the text the results of the single clinical trial. Alternatively, authors can appropriately revise the title of Table 1 and specify the type of each study conducted (preclinical or clinical).
Answer: This is a good point. We will change the title of it as there isn’t much evidence outside of the pre-clinical studies. We revised the table as well.
Paragraph 2.4., 272-275. A comment on this discrepancy (ref. 50) is encouraged.
Answer: A comment was added here on the discrepancy.
Reviewer 2 Report
This manuscript contains an interesting and timely topic, reviewing the literature regarding the role of endogenous oxytocin and the effect of exogenous oxytocin in methamphetamine-induced reward and reinforcement, and proposes oxytocin as a potential candidate for the treatment of methamphetamine addiction. Authors however have not considered the following issue:
Major:
While the content of the manuscript is of interest to the readers of the journal, the results of some of the studies do not support the hypothesis that oxytocin may be beneficial for the management of craving and relapse. For example, vasopressin blocked reinstatement of CPP but oxytocin did not (the authors state that it promoted reinstatement of methamphetamine-induced CPP). If a drug blocks extinction but not reinstatement, would that be clinically useful?
I am not sure if the section safety and efficacy has enough information to convince the readers about the safety and efficacy of oxytocin, as presented in this manuscript. Animals studies cannot dictate safety and efficacy in humans. Only one human study is listed in this section and that is irrelevant to safety and efficacy.
The other issue is the confusing description of some of the studies summarized at the end of the manuscript under safety and efficacy. The authors should use the information in the table since it is a better summary than the description given above the table for each study. Some of those are confusing to follow. Instead, the authors should summarize the content of their review article in a diagram.
The authors should also add some discussion regarding the possible application of oxytocin. For example, how one should administer oxytocin in humans? Would it be stable after systemic application? Oxytocin is effective via the intranasal route. Would this be an option to treat methamphetamine addiction? Any small molecule oxytocin receptor agonist is available for clinical use? If yes, these need to be discussed. If not, a statement should be included regarding developing small molecules to allow systemic administration and compliance.
Minor
The authors do not use the technical words used to describe the place conditioning paradigm. For example, the word place conditioning paradigm, chamber instead of room, expression vs. extinction, etc., need to be carefully described to remove confusion.
Please use oxytocin or its abbreviation (OT) throughout the manuscript. The authors go back and forth using both.
There are some typos and errors that need to be corrected. I have listed some of them below:
Introduction
Line 45-46, please use include and delete including.
Epidemiology
Line 94, please change 2 million to Two million since it is the start of the sentence.
Pathophysiology
Line 101, please also include the peripheral nervous system since those are the actions responsible for most of the cardiovascular damage.
Line 131, please delete "effects" at the end of this sentence.
Section 2.2.1.
Line 148, please delete "active neurons" at the end of this sentence.
Section 2.2.2.
Line 188, a comma is missing between antinociception and autonomic regulation.
Section 2.3.
Line 188, a comma is missing between ventral pallidum and globus pallidus.
Lines 219-220, The statement below needs to be revised:
"One understood mechanism of oxytocin neuromodulation in substance abuse is through glutamate receptors actions,"
Line 225, Please change "reduce mesocorticolimbic glutamate and dopamine", to "mesocorticolimbic dopaminergic and corticolimbic glutamatergic pathways" because there is no mesocorticolimbic glutamatergic pathway or neuron.
Line 232, please change "return" to "reversal".
Section 2.3. is repeated twice. I think it would be ideal to remove the Safety and efficacy subheading as this section is not pertinent to that.
Clinical Saftety and Efficacy
Line 238, please change the methamphetamine reward system to methamphetamine reward.
There are many typos in the studies summarized. There is also repetition of the same information in this section, and it is better to remove them and instead use the table, as I requested above. Also, the table contains more studies that are not summarized in the earlier section.
The table caption should be a better description of the table. For example, the authors can include a statement like"Summary of studies showing a modulatory role of oxytocin on methamphetamine reward and reinforcement" or something along this line.
In the study by Subiah et al. in the table, the authors state more potential for relapse. Doesn't this represent an opposite view to that the authors propose in this review?
Everette, Baracz et al., please change the methamphetamine reward system to methamphetamine reward.
Stauffer et al., under the finding, please change "lee" to "led".
The study found better attendance. I am not sure if this will lead to compliance. Also, if oxytocin did not reduce methamphetamine use during those sessions, the next statement is not relevant.
For the table, please use left-justified so there is no overlap of the content of one column with the other.
Author Response
Major:
While the content of the manuscript is of interest to the readers of the journal, the results of some of the studies do not support the hypothesis that oxytocin may be beneficial for the management of craving and relapse. For example, vasopressin blocked reinstatement of CPP but oxytocin did not (the authors state that it promoted reinstatement of methamphetamine-induced CPP). If a drug blocks extinction but not reinstatement, would that be clinically useful?
Answer: It can be clinically useful if abstinence is used. It seems from the study that it is when methamphetamine is reinstated into the body then the behaviors come back. A statement with that relative study was added in this revision.
I am not sure if the section safety and efficacy has enough information to convince the readers about the safety and efficacy of oxytocin, as presented in this manuscript. Animals studies cannot dictate safety and efficacy in humans. Only one human study is listed in this section and that is irrelevant to safety and efficacy.
Answer: This section has been renamed as many of the studies are just preclinical in nature. It’s been renamed “preclinical” and the only available human study was placed in his own section.
The other issue is the confusing description of some of the studies summarized at the end of the manuscript under safety and efficacy. The authors should use the information in the table since it is a better summary than the description given above the table for each study. Some of those are confusing to follow. Instead, the authors should summarize the content of their review article in a diagram.
Answer: We feel that a table would be better to summarize the articles as a diagram may be more confusing for the reader to follow since there are some contradictory results.
The authors should also add some discussion regarding the possible application of oxytocin. For example, how one should administer oxytocin in humans? Would it be stable after systemic application? Oxytocin is effective via the intranasal route. Would this be an option to treat methamphetamine addiction? Any small molecule oxytocin receptor agonist is available for clinical use? If yes, these need to be discussed. If not, a statement should be included regarding developing small molecules to allow systemic administration and compliance.
Answer: The only inference that can be made regarding administration would be from a single human study. The participants in this study received it intranasally. This fact was placed in the manuscript in this study. To answer about stability or other agonists more studies would have to be performed on human subjects. That is simply not known at this time so it cannot be included in this manuscript.
Minor
The authors do not use the technical words used to describe the place conditioning paradigm. For example, the word place conditioning paradigm, chamber instead of room, expression vs. extinction, etc., need to be carefully described to remove confusion.
Answer: We have tried to revise this in this revision. The term extinction was defined in the text in this revision as we felt that it was still necessary to use but hope that the definition helps clear up the confusion by the potential readers.
Please use oxytocin or its abbreviation (OT) throughout the manuscript. The authors go back and forth using both.
Answer: OT actually stands for oxytocin therapy so when oxytocin is used it I just spelled out.
There are some typos and errors that need to be corrected. I have listed some of them below:
Introduction
Line 45-46, please use include and delete including.
Answer: We’re not understanding what needed to be included in this revision note. We did notice that the term stimulant abuse was used so we changed this to be more patient-centered in terms of the language used.
Epidemiology
Line 94, please change 2 million to Two million since it is the start of the sentence.
Answer: This has been revised.
Pathophysiology
Line 101, please also include the peripheral nervous system since those are the actions responsible for most of the cardiovascular damage.
Answer: This was included in this revision, however, the details of it were left out as we were focused on the effects it has on the brain.
Line 131, please delete "effects" at the end of this sentence.
Answer: This has been deleted.
Section 2.2.1.
Line 148, please delete "active neurons" at the end of this sentence.
Answer: this has been deleted
Section 2.2.2.
Line 188, a comma is missing between antinociception and autonomic regulation.
Answer: The comma was added.
Section 2.3.
Line 188, a comma is missing between ventral pallidum and globus pallidus.
Answer: This comma has been added.
Lines 219-220, The statement below needs to be revised:
"One understood mechanism of oxytocin neuromodulation in substance abuse is through glutamate receptors actions,"
Answer: This has been revised.
Line 225, Please change "reduce mesocorticolimbic glutamate and dopamine", to "mesocorticolimbic dopaminergic and corticolimbic glutamatergic pathways" because there is no mesocorticolimbic glutamatergic pathway or neuron.
Answer: This has been changed
Line 232, please change "return" to "reversal".
Answer: This has been changed
Section 2.3. is repeated twice. I think it would be ideal to remove the Safety and efficacy subheading as this section is not pertinent to that.
Answer: This subheading has been changed with this revision. The section numbers have been revised
Clinical Saftety and Efficacy
Line 238, please change the methamphetamine reward system to methamphetamine reward.
Answer: This has been changed
There are many typos in the studies summarized. There is also repetition of the same information in this section, and it is better to remove them and instead use the table, as I requested above. Also, the table contains more studies that are not summarized in the earlier section.
Answer: This point was addressed in an earlier comment. The table is to serve as a reference for what is in the manuscript. That is why there is repetition. If we removed the text, this section would be just a table and a lot of the details would be lost.
The table caption should be a better description of the table. For example, the authors can include a statement like"Summary of studies showing a modulatory role of oxytocin on methamphetamine reward and reinforcement" or something along this line.
Answer: This has been changed.
In the study by Subiah et al. in the table, the authors state more potential for relapse. Doesn't this represent an opposite view to that the authors propose in this review?
Answer: This is possible but that is a possibility in all treatments for any kind of substance use disorder. It seems that the relapse happened once the drug was reintroduced. This means that once the drug is back in the system then it seems to reinstate its previous effects. It doesn’t mean that it’s not effective but that abstinence may be a key in its success. This is pointed out in the revision in an additional sentence.
Everette, Baracz et al., please change the methamphetamine reward system to methamphetamine reward.
Answer: This has been changed
Stauffer et al., under the finding, please change "lee" to "led".
Answer: This is not found in the text but may have already been changed in the revisions with the other reviewer.
The study found better attendance. I am not sure if this will lead to compliance. Also, if oxytocin did not reduce methamphetamine use during those sessions, the next statement is not relevant.
Answer: the conclusion was made by the authors of this study since they had negative drug tests. This statement was found to be relevant because of this data point.
For the table, please use left-justified so there is no overlap of the content of one column with the other.
Answer: This has been changed
Round 2
Reviewer 2 Report
The authors addressed some of the comments/concerns of the previous version. However, the manuscript still contains unnecessary statements and duplication of the same materials. Proper terminology should be used when preclinical studies are described, e.g., room vs. chamber; room preference vs. place preference. Also, I suggested replacing the table or the summary of the studies with a diagram but that was not done. Now the summaries are better described although still need some minor changes. Although I think this manuscript contains useful information, the authors should try to capture both sides of the coin. If oxytocin is facilitating the extinction of CPP but not affecting its reinstatement, would oxytocin be useful for the treatment of addiction? If it affects self-administration but reduces locomotor activity, how one can differentiate between whether animals are unable to self-administer due to the sedative effect of oxytocin versus inhibition of self-administration processes? They state that majority of the studies suggest that oxytocin may be useful for methamphetamine addiction but this may not be true if one analyzes each study separately and only a few studies are discussed in this manuscript and there is no clinical data regarding oxytocin and methamphetamine abuse or addiction. I also asked a series of questions about how this would be applicable to humans, but the authors did not address those. Those should be included in the Discussion section. The authors can find my comments in the attached PDF.
The authors should carefully read the highlighted sections and make the proper adjustment. Please click on each highlighted section, you will see my comments and respond accordingly.
Comments for author File: 
Comments.pdf
Author Response
We thank you for your help to improve this manuscript. We have attached the answers to your points in the PDF of this manuscript.
Author Response File: Author Response.pdf
Round 3
Reviewer 2 Report
Thanks to the authors for making some corrections to the text. However, although they state that "we revised", "we added to" the text but I still see the same issues in many places in this further revised version. The authors need to prepare a graphical presentation of the theme of this review. This is useful for readers to easily understand the current manuscript.
The authors should go over each change and compare it to the final version to ensure that change is incorporated. If the authors want to reject them, it is perfectly fine but provide a point-by-point rationale for why those changes are not incorporated.
The review is better now but still needs additional work.
Author Response
Thanks to the authors for making some corrections to the text. However, although they state that "we revised", "we added to" the text but I still see the same issues in many places in this further revised version. The authors need to prepare a graphical presentation of the theme of this review. This is useful for readers to easily understand the current manuscript.
Answer: Each and every point was addressed in the PDF that you were kind enough to include with some sections completely reworked so it may have been hard to find the revisions that were requested. We have attached a comment by comment mostly with the lines where you can find the revisions or answers to your questions. Although we prefer the table for a summary, we have replaced it with a graphic.
The authors should go over each change and compare it to the final version to ensure that change is incorporated. If the authors want to reject them, it is perfectly fine but provide a point-by-point rationale for why those changes are not incorporated.
Answer: Again, please find attached the point by point answers to the queries as they have been addressed in the PDF but maybe lost in the revision with the reworks.
The review is better now but still needs additional work.
Author Response File: Author Response.pdf
Round 4
Reviewer 2 Report
The authors did a better job this round in addressing the comments of the reviewers. I still observe a few minor issues that need to be addressed.
- Line 296, please remove the word between and instead please state which group had lower dopamine compared to the other group.
- Line 306, please change "OT" to oxytocin.
- Lines 341-342, please change this sentence to "Glutamate was increased in the mPFC of mice that received oxytocin."
- Line 351, please change "intraperitoneal" to "intraperitoneally".
- Lines 461-462, please ensure that this clause is correct "to evaluate the effects of oxytocin enhanced motivational group therapy on......". It seem something is missing between oxytocin and enhanced.
- Figure 1, please change "OT" to "oxytocin". Also, please change the description under methamphetamine to "Increases the availability of catecholamine neurotransmitters, primarily known for its effects on dopamine and norepinephrine, in nerve terminals in the central nervous system. For Oxytocin, please change to "Primarily known for its role in parturition, lactation and in interpersonal attachment in the central nervous system.
- Figure 1, what is 183? Is that a reference? Also, please leave a space between comma and the subsequent word.
Author Response
We would like to say prior to addressing the comments that when the paper was redownloaded the lines were shifted and misnumbered. We will try to point out where they are in this manuscript with their new lines.
- Line 296, please remove the word between and instead please state which group had lower dopamine compared to the other group.
- We're not sure if this is what you are referring to but around lines 308 it states "Notably, there were significantly lower striatal dopamine levels between the oxytocin group and the methamphetamine-oxytocin group." This sentence highlights that that there were lower levels in the oxytocin group (who received no meth) and the meth group that also received oxytocin. This was not revised as it was already clearly stated in the manuscript.
- Line 306, please change "OT" to oxytocin.
- This has been changed but it was further down at line 314
- Lines 341-342, please change this sentence to "Glutamate was increased in the mPFC of mice that received oxytocin."
- This was changed and was found around line 420-421
- Line 351, please change "intraperitoneal" to "intraperitoneally".
- This was changed. It was in line 431.
- Lines 461-462, please ensure that this clause is correct "to evaluate the effects of oxytocin enhanced motivational group therapy on......". It seem something is missing between oxytocin and enhanced.
- It was. "used with" was added to the sentence. This was in line 567.
- Figure 1, please change "OT" to "oxytocin". Also, please change the description under methamphetamine to "Increases the availability of catecholamine neurotransmitters, primarily known for its effects on dopamine and norepinephrine, in nerve terminals in the central nervous system. For Oxytocin, please change to "Primarily known for its role in parturition, lactation and in interpersonal attachment in the central nervous system.
- This has been changed in the figure
- Figure 1, what is 183? Is that a reference? Also, please leave a space between comma and the subsequent word.
- This has been removed from the figure. The 183 and the space.
