Does Cannabidiol (CBD) in Food Supplements Pose a Serious Health Risk? Consequences of the EFSA Clock Stop Regarding Novel Food Authorisation

Abstract

In the European Union (EU), cannabidiol products require pre-marketing authorisation under the novel food regulation. Currently, 19 CBD applications are under assessment at the European Food Safety Authority (EFSA). During the initial assessment of the application files, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) located several knowledge gaps in their 07 June 2022 statement on safety of cannabidiol as a novel food that need to be addressed before the evaluation of CBD can be concluded. Namely, the effect of CBD on the liver, gastrointestinal tract, endocrine system, nervous system, psychological function, and reproductive system needs to be clarified. Nevertheless, the available literature allows a benchmark dose (BMD)-response modelling of several bioassays, resulting in a BMD lower confidence limit (BMDL) of 20 mg/kg bw/day for liver toxicity in rats. Human data in healthy volunteers found increases in the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in a study at 4.3 mg/kg bw/day, which was defined by EFSA NDA panel as a lowest observed adverse effect level (LOAEL). The EFSA NDA panel currently concluded that the safety of CBD as a novel food cannot be evaluated, leading to a so-called clock stop of the applications until the applicants provide the required data. Meanwhile, the authors suggest that CBD products still available as food supplements on the EU market despite the lack of authorisation must be considered as “unsafe”. Products exceeding a health-based guidance value of 10 mg/day must be considered as being “unfit for consumption” (Article 14(1) and (2) (b) of Regulation No 178/2002), while the ones in exceedance of the human LOAEL must be considered “injurious to health” (Article 14(1) and (2) (a) of Regulation No 178/2002).

Full text

Article
Does Cannabidiol (CBD) in Food Supplements Pose a
Serious Health Risk? Consequences of the European Food
Safety Authority (EFSA) Clock Stop Regarding Novel Food
Authorisation
Dirk W. Lachenmeier*, Constanze Sproll, Patricia Golombek and Stephan G. Walch
Chemisches und Veterinäruntersuchungsamt (CVUA) Karlsruhe, Weissenburger Strasse 3,
76187 Karlsruhe, Germany; constanze.sproll@cvuaka.bwl.de (C.S.); patricia.golombek@cvuaka.bwl.de (P.G.);
stephan.walch@cvuaka.bwl.de (S.G.W.)
* Correspondence: lachenmeier@web.de; Tel.: +49-721-926-5434
Abstract: In the European Union (EU), cannabidiol products require pre-marketing authorisation
under the novel food regulation. Currently, 19 CBD applications are under assessment at the Euro-
pean Food Safety Authority (EFSA). During the initial assessment of the application files, the EFSA
Panel on Nutrition, Novel Foods and Food Allergens (NDA) located several knowledge gaps in
their 07 June 2022 statement on safety of cannabidiol as a novel food that need to be addressed
before the evaluation of CBD can be concluded. Namely, the effect of CBD on the liver, gastrointes-
tinal tract, endocrine system, nervous system, psychological function, and reproductive system
needs to be clarified. Nevertheless, the available literature allows a benchmark dose (BMD)-re-
sponse modelling of several bioassays, resulting in a BMD lower confidence limit (BMDL) of 20
mg/kg bw/day for liver toxicity in rats. Human data in healthy volunteers found increases in the
liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in a study at
4.3 mg/kg bw/day, which was defined by EFSA NDA panel as a lowest observed adverse effect level
(LOAEL). The EFSA NDA panel currently concluded that the safety of CBD as a novel food cannot
be evaluated, leading to a so-called clock stop of the applications until the applicants provide the
required data. Meanwhile, the authors suggest that CBD products still available as food supple-
ments on the EU market despite the lack of authorisation must be considered as “unsafe”. Products
exceeding a health-based guidance value of 10 mg/day must be considered as being “unfit for con-
sumption” (Article 14(1) and (2) (b) of Regulation No 178/2002), while the ones in exceedance of the
human LOAEL must be considered “injurious to health” (Article 14(1) and (2) (a) of Regulation No
178/2002).
Keywords: food safety; risk assessment; Cannabis sativa; tetrahydrocannabinol; food supplements;
cannabidiol; benchmark dose; health-based guidance value (HBGV); liver toxicity
1. Introduction
In the European Union (EU), foods and food ingredients evaluated as novel need a
pre-marketing approval in the form of an implementing regulation issued by the Euro-
pean Commission (EC) [1]. Before that, the European Food Safety Authority (EFSA) is
asked to provide a risk assessment for the novel food, on which the EC decision is based.
The novelty of a food is determined by a lack of significant history of consumption prior
to 15 May 1997 [2]. Regarding the hemp plant Cannabis sativa L., only the seeds and seed-
derived products have a history of consumption and are treated as “not novel”. In con-
trast, extracts and derived products containing cannabinoids, such as cannabidiol (CBD),
but also synthetic cannabinoids are considered novel foods [3]. Hence, CBD products,
which are intended to be marketed as foods or food supplements in the EU, need prior
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authorisation. Despite being widely advertised and sold in increasing quantities, all avail-
able CBD oils and CBD-containing food supplements in the EU are, therefore, currently
placed on the market with an infringement of the food laws [4]. This is not a niche any-
more as the total EU CBD market was valued at EUR 1.6 billion in 2020 [5]. Apparently, it
is a worldwide phenomenon that illegality is not a deterrent for producers, as CBD food
products may be readily available in jurisdictions where they are illegal because jurisdic-
tional enforcement is lenient [6].
As of mid-March 2022, the industry has so far provided more than 150 novel food
applications for CBD products and 19 are currently under assessment by the EFSA Panel
on Nutrition, Novel Foods and Food Allergens (NDA). Most of the applications are for
CBD extracted from hemp plants, but there are also several applications with chemically
synthesised CBD [7].
During the initial assessment of the application files, the EFSA NDA panel located
several knowledge gaps that need to be addressed before the safety evaluation of CBD
can be concluded. Namely, the effect of CBD on the liver, gastrointestinal tract, endocrine
system, nervous system, psychological function, and reproductive system needs to be
clarified [7]. One of the major adverse effects of CBD at therapeutic dosages appears to be
liver injury, which may lead to symptoms of hepatitis even in healthy adults [8]. Literature
was searched and reviewed by the EFSA NDA panel, but no observed adverse effect level
(NOAEL) could not be identified in both animal and human studies [7]. The EFSA NDA
panel currently concluded that the safety of CBD as a novel food cannot be evaluated,
leading to a so-called clock stop of the applications until the applicants provide the re-
quired data [7].
This article aims to provide an in-depth look into the available data about CBD and
provide an interim judgement about the risk of products currently on the market. As NO-
AEL were not available or uninformative, benchmark dose-response modelling of the data
highlighted by EFSA NDA panel was conducted to provide an alternative point of depar-
ture (POD) for toxicological risk assessment.
2. Materials and Methods
The data analysed in this study were obtained from the statement of the EFSA NDA
panel [7]. No additional searches for data were conducted, apart from inclusion of another
informative study of Dziwenka et al. [9] not included in the EFSA statement [7].
The data were checked for the suitability of benchmark dose-response modelling ac-
cording to the criteria of Hindelang et al. [10]: (i) a study considered for inclusion in this
research had to have administered at least 3 different doses and a control group receiving
vehicle, while dose spacing was not considered relevant, (ii) applied doses had to be ad-
ministered in mg/kg of body weight, (iii) the number of animals per dose group had to be
declared, and (iv) studies reporting concomitant treatment with other medications were
not included.
The eligible studies were then assessed using the benchmark dose (BMD) approach
according to the guidelines of the United States (US) Environmental Protection Agency
(EPA) [11]. The BMD and its respective lower confidence interval, the BMDL, were calcu-
lated by fitting multiple statistical models using the US EPA benchmark dose v. 3.2.0.1
(rel. 2022-03-15) software (BMDS) [12], which performs automated fitting of selected mod-
els to dose-response data retrieved from toxicological studies. The most suitable model
was determined based on the Akaike information criteria generated in the output. All set-
tings of BMDS were at default.
3. Results
From the studies assessed by the EFSA NDA panel [7], only 3 animal studies were
identified with suitable dose-response data for benchmark dose modelling, and addition-
ally a study of Dziwenka et al. [9] was included. Two of the studies (GWTX1412 and
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GWTX1413) were published in the context of the approval process of the CBD medicinal
product Epidiolex as part of the application review files on the US Food and Drug Ad-
ministration (FDA) website [13]. Another study, by Marx et al. [14], was published in the
peer-reviewed literature, but the test object was a hemp extract and not isolated CBD. As
the extract was of a comparably high purity of CBD, the authors decided to still include
the study for comparative reasons. Similarly, Dziwenka et al. [9,15] recently provided 2
studies of hemp extracts; while the 2020 study [15] did not provide raw data necessary for
BMD modelling, the 2021 study [9] was included for comparative reasons as well.
The results of the dose-response modelling are presented in Table 1. An example for
the BMD modelling of the GWTX1412 study, which was judged as being the most in-
formative, is shown in Figure 1. The full BMD modelling reports of all studies included in
Table 1 are provided as supplementary materials (documents S1-S5).
Table 1. Dose-response modelling results for cannabidiol (CBD) in different animal experiments.
Study, ani-
mal model
Study design,
CBD doses Endpoint Sex
Model a p-value b
BMD c
(mg/kg
bw/day)
BMDL d
(mg/kg
bw/day)
GWTX1412
[13], rats
26-week oral at
doses of 0, 15, 50,
and 150 mg/kg
bw/day
(n=15/sex/group)
Liver, centrilobu-
lar hypertrophy e
Males + fe-
males com-
bined f
Dichoto-
mous Hill 0.9989 41 20
GWTX1413
[13], dogs
39-week oral at
doses of 0, 10, 50,
and 100 mg/kg
bw/day
(n=4/sex/group)
Liver, hepatocyte
hypertrophy e
Males + fe-
males com-
bined f
Log-Probit
0.5771 (3) g (2) g
Marx et al.
[14], rats
90-day oral at
doses of 0, 25, 90,
and 180 mg/kg
bw/day
(n=10/sex/group)
h
Liver weight
Males i
Exponential
2 0.5235 (52) j (43) j
Females i
Polynomial
3 0.9771 (52) j (34) j
Dziwenka et
al. [9], rats
90-day oral at
doses of 0, 6.3,
22.7 and 81.6
mg/kg bw/day
(n=10/sex/group)
k
Relative liver
weight Females
Exponential
2 0.1941 (39) j (26) j
a Data of the viable recommended model selected with BMDS 3.2.0.1 (rel. 2022-03-15) software are
presented. b A p-value greater than 0.1 indicated that the model fits the data (p-value 1.0 = perfect
fit). c BMD: benchmark dose for a benchmark response of 1 standard deviation (continuous mod-
els) or 10% extra risk (dichotomous data). d BMDL: 95% lower one-sided confidence limit of the
BMD. e The sum of incidences for all grades of liver effects was evaluated. f A single curve is fitted
to both sexes as the analysis revealed no significant differences in dose-response between the
sexes. g BMD and BMDL are both 3x lower than the lowest non-zero dose and the model must be
cautiously interpreted. h The study of Marx et al. [14] was conducted with a hemp extract contain-
ing 26% of cannabinoids of which 96% is CBD. The dose levels were adjusted to reflect pure CBD. i
Due to lack of raw data, the sexes could not be combined in this case, despite no obvious differ-
ences between the sexes in this study as well. j Data shown for comparative reasons only because
CBD was applied in the form of a hemp mixture with other phytochemicals. k The study of Dzi-
wenka et al. [9] was conducted with a hemp oil extract containing 28.14% cannabinoids and 25.2%
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CBD. The levels were adjusted to reflect pure CBD. The dose-response models for males were
questionable (data not shown).
Figure 1. Benchmark dose (BMD) modelling of cannabidiol (CBD) for centrilobular hypertrophy of
the liver in a 26-week oral study in rats (GWTX1412, see Table 1): frequentist dichotomous Hill
model with benchmark response (BMR) of 10% extra risk for the BMD and 95% lower confidence
limit (BMDL).
From the animal study modelling results, the authors suggest to use the BMDL of 20
mg/kg bw/day from the GWTX1412 study in rats as POD, as this is the lowest, i.e., most
conservative, value from the informative studies. The authors do not believe that the
BMDL of the GWTX1413 study is meaningful because the dose-response model led to
considerable extrapolation beyond the lowest non-zero dose. The other studies in hemp
extracts confirm the correctness of the order of magnitude of the GWTX1412 data because
the BMDL values were quite similar considering the uncertainties of BMD modelling ef-
forts.
None of the human studies reported by the EFSA NDA panel [7] was sufficient for
dose-response modelling. Therefore, the lowest LOAEL of 4.3 mg/kg bw/day, specifically
highlighted by the EFSA panel in their presentation [16], was used as POD. The original
study from which the EFSA NDA panel derived this LOAEL was a randomized clinical
trial in 120 healthy male and female healthcare professionals receiving 300 mg of CBD for
28 days. Four participants (6.8%) had elevated levels of the liver enzymes alanine ami-
notransferase (ALT) and aspartate aminotransferase (AST) (1 critical and 3 mild) [17].
The PODs from animal and human data were then used to estimate health-based
guidance values (HBGV) using suitable uncertainty factors (Table 2). Overall, the authors
suggest to use the human HBGV of 0.14 mg/kg bw/day for preliminary risk assessment,
as it is more conservative than the animal HBGV and human data should be preferred in
any case. Nevertheless, as both animal and human HBGV are in excellent agreement, the
animal data provide independent validation of the correct magnitude of the human
HBGV.
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 20 40 60 80 100 120 140
Response
Dose
Estimated Probability
Response at BMD
Data
BMD
BMDL
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Table 2. Calculation of reference doses (RfD) for cannabidiol (CBD) based on animal and human
data.
CBD Animal data Human data
Type of point of departure
(POD) BMDL, see Table 1 LOAEL [7,17]
Value of point of departure
(POD)
20 mg/kg bw/day
(1,400 mg/day a)
4.3 mg/kg bw/day
(300 mg/day a)
Uncertainty factor (UF) 100 b 30 c
Reference dose (RfD) 0.20 mg/kg bw/day
(14 mg/day a)
0.14 mg/kg bw/day
(10 mg/day a)
a Calculation for a 70-kg human standard weight [18]. b Default UF of 100 (10 for inter-species vari-
ability x 10 for intra-human variability [18]). c Overall UF of 30 (3 for extrapolation from the
LOAEL to a NOAEL x 10 for intra-human variability, as previously suggested by EFSA for tetra-
hydrocannabinol (THC) [19].
4. Discussion
Despite the lack of data on CBD safety, correctly specified by the EFSA NDA panel
[7] and also in a recent review by Nyland and Moyer [6], the authors believe that the avail-
able data allow to make at least a preliminary risk assessment if the dose-response infor-
mation contained in the available data is appropriately considered. The authors also be-
lieve that the principle of precautionary public health protection demands the use of that
data. The authors have previously commented regarding THC contamination of CBD
products that it is short of a “scandal” because unapproved and potentially unsafe prod-
ucts are placed on the food market within the EU [20]. Other authors similarly character-
ised the CBD market as containing “black sheep” disregarding regulations trying to make
a quick profit with the hype surrounding cannabis legalisation [21].
This preliminary risk assessment of available bioassays and human data on CBD tox-
icity strengthens this assessment, as many products on the market would be exceeding
the estimated HBGV of 10 mg/day. For example, there are several CBD oil products on
the market containing 10% of CBD, which means that the HBGV would be contained in
an amount of 0.1 g, which is typically contained in only 3–4 drops of the product. The
usually recommended dosage of several drops per day may, therefore, exceed the HBGV.
For some products, which may contain even higher concentrations of CBD, the possible
intake can even exceed the LOAEL of about 300 mg/day.
The HBGV of 10 mg/day proposed in this article is very similar to another approach
for risk assessment by the Swiss Federal Food Safety and Veterinary Office (FSVO) deter-
mining an oral daily dose of 12 mg CBD/adult, which should not be exceeded [22]. The
FSVO based its recommendation on a healthy volunteer phase I study, in which 5 out of
12 healthy subjects developed ALT elevations above the normal range at 5 mg/kg/day
during the three-week treatment period [23]. The FSVO has used an uncertainty factor of
30, similar to the proposal in this study (Table 2), to calculate the guidance value.
The liver effects that are consistently observed in all tested species, including hu-
mans, are clearly a major cause for concern. It must be considered that this risk assessment
concerns foods, for which safety must be generally guaranteed, unlike medicinal products
for which risk-benefit considerations must be included. For CBD-containing foods, it must
also be considered that they may be consumed daily a life-long without medical supervi-
sion or any form of nutrivigilance, which is not mandatory in the EU.
Meanwhile, the authors suggest that CBD products still available on the EU food
market despite the lack of authorisation must be assessed if they might be “unsafe” in the
sense of Article 14 (1) of the Basic Food Regulation No 178/2002 [24]. If they exceed the
HBGV, they would be “unfit for consumption” (Article 14(1) and 14 (2) (b) of the Basic
Regulation [24] or corresponding national regulations such as §12 of the German food and
feed law). Products in exceedance of the human LOAEL of 4.3 mg/kg bw/day should be
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considered as being “injurious to health” (Article 14(1) and (2) (a) of the Basic Regulation
[24]) and they should also be considered as being a serious risk to health in the sense of
the criteria for the EU Rapid Alert System for Food and Feed (RASFF), similar to the prac-
tice for THC risk assessment [25].
5. Conclusions
There is clearly a growing consumer demand for CBD and other cannabinoid prod-
ucts, which has not been adequately followed up by policy leading to a huge market of
unregulated CBD food supplement products, which are also marketed in the supposed
legal loopholes as cosmetic mouth sprays, non-food flavours or even phantasy products
for mythical animals [26]. This situation is completely unsatisfactory for consumers, in-
dustry and control authorities alike. The unregulated market also leads to safety problems
beyond cannabinoids, e.g., contamination with pesticides, heavy metals, or microbiologi-
cal risks, or even the addition of synthetic cannabinoids [6]. Apart from that, quality con-
trol is lacking leading to inconsistent labelling making dosing unpredictable [27].
As the EFSA NDA panel has convincingly highlighted the lack of data necessary for
final risk assessment, novel food approval could still take years, including the time re-
quired to conduct the chronic toxicity studies for the missing endpoints in the low-dose
range expected in foods. The authors would now expect a response by the risk manage-
ment of the European Commission and national authorities, how to go forward during
the years until the completion of the novel food applications. Continuation of the complete
prohibition of CBD food supplements is obviously not a considerate policy, as this has not
worked in the past 5 years and consumers are still ingesting CBD in considerable amounts.
The authors currently can envision at least 3 pathways to proceed: (i) low-dose CBD food
supplements (up to 10 mg/day and less than 300 mg/package) could be approved in an
intermediary basis including warning labels about the potential toxic effects (see the post-
brexit UK approach), (ii) regulation of low-dose CBD products as over-the-counter me-
dicinal products only available in pharmacies, as an additional category to the already
available prescription-based high-dose CBD medicinal products (see suggestion by
Health Canada [28]), or (iii) regulation of CBD products outside the scope of foods or
medicines inside a separate framework, e.g., within the currently planned controlled dis-
tribution of cannabis to adults for recreational use in licensed stores in Germany. This is
now a political decision to be made and the authors hope that the legislator does not again
turn a blind eye to the problem as in the past.
Supplementary Materials: BMDS 3.0 analysis reports S1: GWTX1412; S2: GWTX1413; S3: Marx et
al. 2018 (males); S4: Marx et al. 2018 (females); S5: Dziwenka et al. 2021.
Author Contributions: Conceptualization, D.W.L. and C.S.; methodology, D.W.L.; software,
D.W.L.; validation, D.W.L.; formal analysis, D.W.L.; investigation, D.W.L.; resources, S.G.W.; data
curation, D.W.L.; writing—original draft preparation, D.W.L.; writing—review and editing, C.S.,
P.G. and S.G.W.; visualization, D.W.L.; supervision, D.W.L.; project administration, D.W.L.; fund-
ing acquisition, S.G.W. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Publicly available datasets were analysed in this study. This data can
be found here: https://www.accessdata.fda.gov/drugsat-
fda_docs/nda/2018/210365Orig1s000PharmR.pdf (accessed 29 July 2022).
Acknowledgments: Janin Gerstenlauer and Tabea Dietz are thanked for help in the retrieval of FDA
data on cannabidiol. The graphical abstract was AI-generated using the phrase “a bottle of canna-
bidiol oil and a hemp leaf in front of a stop sign” using DALL-E 2 on OpenAI.com.
Conflicts of Interest: The authors declare no conflict of interest.
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