The Challenge of Risk Assessment of Tetrahydrocannabinol (THC) in Cannabidiol (CBD) Oils and Food Supplements: An Approach for Deriving Maximum Limits
and Dirk W. Lachenmeier *
Round 1
Reviewer 1 Report
L16 - "Notable" is the term used for classification or author used to express, if the latter one, I recommend rewriting this sentence.
L18 - provide the list of important adverse effects in a bracket.
L21 - report what is the higher concentration that is not safe.
L35-39 - Should be split into two-sentence, and provide different references for those sentences.
L39-42 - It is confusing, the author did not describe the novel status of CBD products, and just by saying court law and these products become infringement, is not convincing the reader, until unless provide the clear fact with evidence of what are those court statement is.
L54 - is the level 2.5 acceptable level as it does not produce any narcotic effect? If I understand clearly, the author's point of view on adverse effects is just the narcotic effect? if so why not use directly 'narcotic effect' instead of other terms?
-Why are so many small paragraphs in the introduction? I recommend the authors combine into 3 main paragraphs.
-As mentioned in L42 - if the products are infringement according to food law, then what is the allowed dose of CBD? and in L61 mentioned there will be a revision in the dose from 2.5 to 3.0, will those products still be in infringement?
-I recommend authors to keep information that is straight to the hypothesis as the author proposed in the introduction part, instead of providing so many details, which are difficult to connect and conclude.
-Please check L96 - is really the materials and method section needed for the viewpoint articles?
-In data findings, the author used the age factor also? as CBD is not for everyone's age group right?
-No statistical analysis, how author process the obtained data from the system for fluctuations, or expecting trends?
-is CBD in the list of GRAS?
-L140-147 - as the authors mentioned allowed intake of THC in the form of CBD is 12mg/d, but table 1 is too high than the report, no country in the EU regulates this ? or author mention it correctly? please check!!
-Product group "Food Supplements" - but the author should provide the list of food supplements they include for this study, general term can't provide a clear view, as not every food supplement is intended to add CBD.
Author Response
L16 - "Notable" is the term used for classification or author used to express, if the latter one, I recommend rewriting this sentence.
RESPONSE: We have rephrased the sentence.
L18 - provide the list of important adverse effects in a bracket.
RESPONSE: The important adverse effects were added.
L21 - report what is the higher concentration that is not safe.
RESPONSE: The concentration was added as requested.
L35-39 - Should be split into two-sentence, and provide different references for those sentences.
RESPONSE: The sentence was split but the reference for both claims is the same.
L39-42 - It is confusing, the author did not describe the novel status of CBD products, and just by saying court law and these products become infringement, is not convincing the reader, until unless provide the clear fact with evidence of what are those court statement is.
RESPONSE: There is so much literature about novel food status that we do not want to go into further detail here. Novel food status is basically a politically based decision depending if the food was on the market before 1997 and has nothing to do with composition of the food or risk of THC or CBD. Therefore, in this paper we want to focus on the risk assessment.
L54 - is the level 2.5 acceptable level as it does not produce any narcotic effect? If I understand clearly, the author's point of view on adverse effects is just the narcotic effect? if so why not use directly 'narcotic effect' instead of other terms?
RESPONSE: Yes, levels below 2.5 mg/day would not have a risk of narcotic effects, or any other effects. The endpoints that EFSA has assessed in their risk assessment are now mentioned in the text (line 54).
-Why are so many small paragraphs in the introduction? I recommend the authors combine into 3 main paragraphs.
RESPONSE: We have sorted the introduction into 3 main sections.
-As mentioned in L42 - if the products are infringement according to food law, then what is the allowed dose of CBD? and in L61 mentioned there will be a revision in the dose from 2.5 to 3.0, will those products still be in infringement?
RESPONSE: Yes, as mentioned above. Infringement of novel food law has nothing to do with composition, i.e. it is independent of the levels of THC or CBD. At the end of the discussion, we have considerably expanded this point mentioning a new EFSA opinion regarding this question. The EFSA has currently made a so-called clock stop to all novel food applications because lack of necessary data provided by the applicants. Therefore, our argument is still standing that currently not one CBD food has been approved on the EU market and all foods you are currently still finding are marketed with infringement of the EU food law. Obviously, there appears to be a lack of effective enforcement of this law.
-I recommend authors to keep information that is straight to the hypothesis as the author proposed in the introduction part, instead of providing so many details, which are difficult to connect and conclude.
RESPONSE: We have carefully revised the text and made many deletions and rearrangements to improve the “red thread”.
-Please check L96 - is really the materials and method section needed for the viewpoint articles?
RESPONSE: The article type was changed to standard article on the editor’s request, so this now would be mandatory.
-In data findings, the author used the age factor also? as CBD is not for everyone's age group right?
RESPONSE: The food products on the market refer to the general population. Only some products exclude children use, e.g. some of the CBD oils marketed as food supplements. The public RASFF system does not provide labelling information, however. Therefore, we do not want to go deeper into this discussion. Obviously for children, the threshold doses would be lower because of lower bodyweight. This can be assessed in the individual expert opinion of the products on a case-by-case basis.
-No statistical analysis, how author process the obtained data from the system for fluctuations, or expecting trends?
RESPONSE: The normal probability distribution in Figure 1 is a statistical analysis, as are the descriptive statistics in Table 1. We have also added results from ANOVA analysis showing significant differences in the collectives.
-is CBD in the list of GRAS?
RESPONSE: No, the FDA is indicating that it cannot conclude that CBD is generally recognized as safe (GRAS).
https://www.fda.gov/news-events/press-announcements/fda-warns-15-companies-illegally-selling-various-products-containing-cannabidiol-agency-details
-L140-147 - as the authors mentioned allowed intake of THC in the form of CBD is 12mg/d, but table 1 is too high than the report, no country in the EU regulates this ? or author mention it correctly? please check!!
RESPONSE: No, this is not an allowed intake, but the maximum possible intake from the product with the highest content (worst case). As we have indicated there is currently no specific legislation regarding THC in supplements in the EU, apart from the general food safety demands in the basic regulation.
-Product group "Food Supplements" - but the author should provide the list of food supplements they include for this study, general term can't provide a clear view, as not every food supplement is intended to add CBD.
RESPONSE: We have only assessed CBD food supplements, not any other food supplements without CBD. The materials section was clarified.
Reviewer 2 Report
The manuscript challenges-1778979 presents a very sound and pertinent viewpoint that could influence the policymakers (EU and overall international safety regulations) with respect to the Δ9-tetrahydrocannabinol (Δ9-THC) content in cannabidiol (CBD) oils and food supplements.
The manuscript is very clearly presented.
The references and data are pertinent.
The conclusion explicitly points out the need for systematic data about the risk assessment of Δ9-THC in food, and about fixing well-justified limits, within the context of the novel food approval procedure that is currently ongoing for the various CBD products.
I fully recommend this manuscript for publication in Challenges, without any change.
Author Response
The manuscript challenges-1778979 presents a very sound and pertinent viewpoint that could influence the policymakers (EU and overall international safety regulations) with respect to the Δ9-tetrahydrocannabinol (Δ9-THC) content in cannabidiol (CBD) oils and food supplements.
The manuscript is very clearly presented.
The references and data are pertinent.
The conclusion explicitly points out the need for systematic data about the risk assessment of Δ9-THC in food, and about fixing well-justified limits, within the context of the novel food approval procedure that is currently ongoing for the various CBD products.
I fully recommend this manuscript for publication in Challenges, without any change.
RESPONSE: Thank you for the assessment of our paper!
Reviewer 3 Report
I understand that a number of CBD products have been scanned for the amounts of THC present. Based on these studies it is concluded that a maximum level of THC in CBD products should be introduced. I must admit that I do not understand tables 1 and 2 unless the above statement is correct. However, this conclusion is also made in ref. 2. Thus, I am not convinced about what new this manuscript reports.
A precursor for THC and CBD is THC-carboxylic acid and CBD-carboxylic acid . These will decarboxylate during smoking, but I do not know if they will be decarboxylated in the gastrointestinal system. That could mean that the amounts of THC measured do not correspond to the dose obtained 1oral intake of the cannabis oil. The amount might be bigger because of THC formed by decarboxylation. It might be wise to investigate this problem.
The numbering of the carbon skeleton should be shown in the structure.
Notice that two numbering systems are used for THC meaning that 1delta-THC might be the same compound as 9deltaTHC.
Author Response
I understand that a number of CBD products have been scanned for the amounts of THC present. Based on these studies it is concluded that a maximum level of THC in CBD products should be introduced. I must admit that I do not understand tables 1 and 2 unless the above statement is correct. However, this conclusion is also made in ref. 2. Thus, I am not convinced about what new this manuscript reports.
A precursor for THC and CBD is THC-carboxylic acid and CBD-carboxylic acid . These will decarboxylate during smoking, but I do not know if they will be decarboxylated in the gastrointestinal system. That could mean that the amounts of THC measured do not correspond to the dose obtained 1oral intake of the cannabis oil. The amount might be bigger because of THC formed by decarboxylation. It might be wise to investigate this problem.
RESPONSE: The toxicological assessment by EFSA is for oral delta-9-THC. All food supplement product are consumed as such without heating or smoking. Therefore, we have not to consider decarboxylation effects. Herbal smoking products (i.e. CBD joints) are currently not contained within the framework of RASFF, which we have evaluated. Please note that the risk assessment of smoked products is a completely different topic, which we have considered in a separate paper:
Hindelang, P., Scharinger, A., Golombek, P., Laible, M., Tamosaite, S., Walch, S. G., & Lachenmeier, D. W. (2022). Absence of Relevant Thermal Conversion of Cannabidiol (CBD) to Tetrahydrocannabinol (THC) in E-Cigarette Vapor and Low-THC Cannabis Smoke. ChemRxiv. https://doi.org/10.26434/chemrxiv-2022-spw0d-v3
The numbering of the carbon skeleton should be shown in the structure.
RESPONSE: The numbering of the carbon skeleton was added.
Notice that two numbering systems are used for THC meaning that 1delta-THC might be the same compound as 9deltaTHC.
RESPONSE: Thank you. The numbering system is now shown.
Round 2
Reviewer 1 Report
The paper is revised well, and it can be accepted for publication.
Author Response
Thank you for all the help in improving our paper!
Reviewer 3 Report
I fear that the authors have not understood my query concerning THC-carboxylic acid. They state that this manuscript does not concern smoking. My question was will THC-carboxylic aid present in the product decarboxylate in the gastrointestinal system? The authors answer That this manuscript does not concern smoking. However, what evidence exists for the absence of metabolic decarboxylation of THC-carboxylic acid in the gastrointestinal system or elsewhere in the body?
Author Response
RESPONSE: Thank you for the clarification of your question. We have really misunderstood during the previous revision, as we in fact never did hear about the possibility of non-thermic decarboxylation, e.g. in vivo in the gastrointestinal system. An excellent review about this topic is available from Moreno-Sanz [1], which concluded: “THCA-A does not seem to convert to THC in vivo”. The German Federal Institute for Risk Assessment (BfR) remarked in its opinion on assessing hemp-containing foodstuff that in cases when a particular product will not undergo further thermal treatment, the measured Delta-9-THC content should be used for comparison with the acute reference dose (and not the sum of THC and THCA, as in cases of possible thermal treatment). The BfR also remarked that cases where no thermal treatment is to be expected are dietary supplements. For these reasons, we believe that there is currently no evidence available that the risk assessment of dietary supplements or other products, which do not undergo thermal treatment, should be based on total-THC. Hence, we believe that our assessment, which does not include the non-psychotropic THCA-A, is accurate. We have included a short summary of the remarks on THCA-A into the material and methods section of the paper.
[1] Guillermo Moreno-Sanz. Can You Pass the Acid Test? Critical Review and Novel Therapeutic Perspectives of Δ9-Tetrahydrocannabinolic Acid A. Cannabis and Cannabinoid Research. Dec 2016. 124-130. http://doi.org/10.1089/can.2016.0008
[2] BfR Opinion No 006/2021 issued 17 February 2021. The BfR recommends acute reference dose as basis for assessing hemp-containing foodstuff. DOI 10.17590/20210226-114214
Note: We have additionally conducted a careful English language revision focused on the changed sections of both review rounds due to the major changes.
