Keywords
Tetrahydrocannabinol, cannabidiol, Cannabis sativa, hemp, food supplements, risk assessment, drug effects
This article is included in the Agriculture, Food and Nutrition gateway.
Tetrahydrocannabinol, cannabidiol, Cannabis sativa, hemp, food supplements, risk assessment, drug effects
The text was clarified according to the comments of reviewer #3 regarding the specificity of our analysis for THC and the possible influence of interaction between THC and CBD for the risk assessment. Furthermore, the commentary in F1000Research 2020, 9:900 was considered during the revision.
See the authors' detailed response to the review by Linda A. Parker
See the authors' detailed response to the review by Volker Auwärter
See the authors' detailed response to the review by Arno Hazekamp
Since hemp has been re-approved for cultivation as an industrial crop in the form of low Δ9-tetrahydrocannabinol (∆9-THC) hemp varieties in the European Union, components of the hemp plant are increasingly used for the production of foods and other consumer products such as liquids for electronic cigarettes1.
From all hemp constituents, cannabidiol (CBD) is currently the compound with highest interest. In contrast to ∆9-THC, the major drug-constituent of hemp, CBD is a non-psychotropic cannabinoid. It is currently being tested for its possible antispasmodic, anti-inflammatory, anxiolytic and antiemetic effects as a drug, e.g. for the treatment of epilepsy2,3. However, CBD products of all kinds can now also be purchased in organic shops, drug stores, supermarkets and via the Internet, mostly by advertising dubious “cure-all” properties including anti-carcinogenic effects or various unspecific health advantages. The marketing of CBD products is based on the current “hype” around medicinal hemp products, whereby the CBD products are offered as a supposedly safe alternative, promised as being free of psychotropic components or their side-effects4. With the exception of the treatment of Dravet’s syndrome, there is little clinical data on the efficacy and safety of CBD, particularly in the treatment of cancer5,6. Cannabidiol is currently approved in the European Union (EU) in a single medicinal product, namely Epidiolex® for the treatment of seizures in patients with two rare, severe forms of childhood-onset epilepsy. Apart from that, extemporaneous preparations in pharmacies are legally available on prescription in Germany and some other countries. However, most of the CBD products worldwide are available as food supplements or additives in food.
Commercial CBD products are usually crude extracts from whole hemp plants (i.e., including flowers and stems). In other ways (e.g., in extracting the food-approved plant parts such as seeds), contents in the range of 1–10% CBD, which are typically advertised, cannot be achieved. Also, the limited available literature and manufacturer data confirm that CBD products are usually extracted by supercritical CO2 or with solvents such as ethanol or isopropanol from the entire hemp plant6,7. Probably due to cost reasons for some products, no further specific enrichment or purification of CBD is conducted, so that the commercial extracts are regularly a cannabinoid mixture rather than pure CBD. Otherwise, extracts may be cleaned with different processes such as winterization, or partial fractionation using supercritical CO2. These extracts, which are typically called “full spectrum extracts” in difference to chemically pure CBD, are then mixed into ordinary edible oils such as sunflower oil, olive oil or hemp seed oil to obtain the so-called CBD oil6.
The strategy to market CBD products as food supplements within the framework of food regulations seems to be the most common approach of CBD sellers. The most prevalent food supplement products are CBD oils in liquid form or CBD oil or hemp extract containing capsules. Some other products, derived from hemp extracts, are CBD chewing gum, and cannabis resin, wax or pollen products, while so-called “CBD flowers” are typically sold as plant material to prepare a tea-like infusion.
However, no significant food consumption of hemp extracts or hemp flowers containing CBD has been documented before 15 May 1997. These products are therefore classified as “novel” in the Novel Food catalogue of the European Commission under the entry “cannabinoids” and therefore require approval according to the Novel Food Regulation. Up to date (as of August 2020), no approved application is recorded. Basically, all available CBD products based on hemp extract marketed as food or food supplement within the EU are therefore illegally sold2. To circumvent the strict safety requirements for medicinal or food products, some CBD products may be sold as other product categories (e.g., cosmetics, veterinary supplements, waxes, air fresheners or room fragrances), but the off-label use, human consumption, is clearly intended.
Despite the enforcement efforts of the food and medicinal product control authorities (e.g. the EU’s rapid alert system for food and feed (RASFF) lists over 120 alerts for CBD since 2018), a multitude of CBD products is available over the internet and in some retail stores, so that CBD is currently easily available to consumers.
Anecdotal cases ranging from indisposition to ∆9-THC-like effects have been reported to our institute from food control authorities in the German Federal State of Baden-Württemberg in the context of consumer complaint cases regarding CBD products. Some case reports of side effects of CBD products were published8,9, and a survey of 135 CBD users in the USA detected a high prevalence of side effects (30% dry mouth, 22% feeling high, 20% change in appetite, 19% fatigue)10. Additionally, some pediatric studies in epilepsy patients with orally administered CBD also reported adverse effects such as drowsiness and fatigue that could be explained by pharmacological properties of ∆9-THC rather than of CBD11–13. Diarrhoea was an adverse outcome associated with CBD treatment in a meta-analysis of randomized clinical trials, after excluding studies of childhood epilepsy14. Post marketing safety surveillance of a full spectrum hemp extract reported gastrointestinal symptoms as most common adverse event, however, they were infrequent (0.03%)15.
Currently there are three hypotheses for the cause of the side effects: (i) a direct pharmacological effect of CBD, (ii) the degradation of CBD to ∆9-THC due to acidic hydrolysis in the stomach following oral consumption, and (iii) ∆9-THC directly contained in the products as by-product due to co-extraction and enrichment or contamination. In this article, the hypotheses are investigated including new evidence from original data.
To investigate CBD degradation into ∆9-THC under acidic conditions, differently concentrated CBD in methanolic solutions was used in a range corresponding to typical amounts consumed with supplements based on commercial CBD (Supelco Cerilliant, certified reference material, #C-045, 1.0 mg/mL in methanol) supplied by Merck (Darmstadt, Germany). These solutions were exposed to an artificial gastric juice as well as different incubation times and stress factors such as storage under light and heat (see Table 1 for full experimental design). The solutions were stored either in standard freezer (-18°C) or refrigerator (8°C) or at room temperature (20°C). Increased temperatures were achieved using a thermostatically controlled laboratory drying oven type “UT6120” (Heraeus, Langenselbold, Germany) set to either 37°C or 60°C. The daylight condition was achieved by storage at a window (south side). For ultraviolet light exposure, six 25 W ultraviolet (UV) fluorescent tubes type “excellent E” (99.1% UVA) built into a facial tanner type “NT 446 U” (Dr. Kern GmbH, Mademühlen, Germany) were placed 15 cm from the surface of the solutions (open sample vials). In deviation of an experimental protocol of Merrick et al.17, a gastric juice without addition of surfactants was used, which was strictly produced according to the European pharmacopoeia18 (0.020 g NaCl + 0.032 g pepsin + 0.8 mL HCl (1 mol/L), filled up to 10 mL with water). As pure CBD was available only in methanolic solution, the final experimental setups contained 0.08 mol/L HCl and 1% methanol due to dilution (methanol residues in this order of magnitude are not interfering with the analysis).
Experiment | Temperature (°C) | Light exposure | Storage time | Storage medium | CBD concentration in medium (μg/L) | Δ9-THC formation1 |
---|---|---|---|---|---|---|
Negative control | -18 | None | 14 days | Methanol | 1000 | 0% |
Light | 20 | None | 3 days | Methanol | 1000 | 0% |
20 | None | 14 days | Methanol | 1000 | 0% | |
20 | Daylight | 3 days | Methanol | 1000 | 0% | |
20 | Daylight | 14 days | Methanol | 1000 | 0% | |
20 | UVA | 1 h | Methanol | 1000 | 0% | |
20 | UVA | 3 h | Methanol | 1000 | 0% | |
Temperature | 20 | None | 5 days | Methanol | 1000 | 0% |
20 | None | 14 days | Methanol | 1000 | 0% | |
8 | None | 5 days | Methanol | 1000 | 0% | |
8 | None | 14 days | Methanol | 1000 | 0% | |
37 | None | 3 h | Methanol | 1000 | 0% | |
60 | None | 1 h | Methanol | 1000 | 0% | |
Simulated gastric juice | 37 | None | 1 h | Simulated gastric juice | 200 | 0% |
37 | None | 2 h | Simulated gastric juice | 200 | 0% | |
37 | None | 3 h | Simulated gastric juice | 200 | 0% | |
37 | None | 1 h | Simulated gastric juice | 400 | 0% | |
37 | None | 2 h | Simulated gastric juice | 400 | 0% | |
37 | None | 3 h | Simulated gastric juice | 400 | 0% | |
Positive control | 20 | None | 14 days | Methanol / 1 mol/L HCl (50:50) | 500 | 27% |
1 Average of LC-MS/MS and UPLC-QTOF measurements (n=2) (for raw results see dataset16, table sheet 1). Δ9-THC formation calculated as % in relation to original CBD content.
To ensure the utmost analytical validity, all samples were independently measured on two different instruments, using a triple quadrupole mass spectrometer (TSQ Vantage, Thermo Fisher Scientific, San Jose, CA, USA) coupled with an LC system (1100 series, Agilent, Waldbronn, Germany) and also using a quadrupole time-of-flight (QTOF) mass spectrometer (X500, Sciex, Darmstadt, Germany) coupled with an UPLC system (1290 series, Agilent, Waldbronn, Germany). Both systems used the same type of separation column (Luna Omega Polar C18, 150 × 2.1 mm, 1.6 μm, 100 Å, Phenomenex, Aschaffenburg, Germany). The separation was isocratic with 25 % water (0.1 % formic acid) and 75 % acetonitrile (0.1 % formic acid) and a flow of 0.3 mL/min. In case of QTOF with 35 % water (0.1 % formic acid) and 65 % acetonitrile (0.1 % formic acid) and a flow of 0.45 mL/min. The evaluation took place after fragmentation of the mother ion into three mass traces for each compound. As quantifier for ∆9-THC and CBD, the mass transition m/z 315 to 193 was used. In case of QTOF, quantification was conducted over accurate mass and control of fragmentation pattern. CBD eluted as one of the first cannabinoids, a few minutes before ∆9-THC. As internal standards ∆9-THC-d3 (Supelco Cerilliant #T-011, 1.0 mg/mL in methanol) was used for the quantification of ∆9-THC (Supelco Cerilliant #T-005, 1.0 mg/mL in methanol), and cannabidiol-d3 (Supelco Cerilliant #C-084, 100 μg/mL in methanol) for quantification of CBD (Supelco Cerilliant #C-045, 1.0 mg/mL in methanol). The certified reference materials were obtained as solutions in ampoules of 1 mL, all supplied by Merck (Darmstadt, Germany). A limit of detection (LOD) of 5 ng/mL was determined. For both procedures, relative standard deviations better than 5% were achieved. Both methods are able to chromatographically separate ∆9-THC and CBD from their acids. Specificity was ensured using a certified reference material as a reference standard of THCA (Supelco Cerilliant #T-093, 1.0 mg/mL in acetonitrile). Baseline separation was achieved between ∆9-THC, ∆8-THC and THCA. Therefore, the reported values in this study are specific for ∆9-THC and CBD. In contrast to some previous studies based on gas chromatography, we do not report “total THC” or “total CBD”, which would be a sum of the free form and its acid.
To study the possible influence of natively contained ∆9-THC in hemp products as a cause for side effects, a sampling of all available CBD products registered as food supplement in the German State Baden-Württemberg, other available hemp extract products in retail, as well as all products available at the warehouse of a large internet retailer were sampled between December 2018 and December 2019. A total of 67 samples (see Table 2 for product designations) were analysed using the above described liquid chromatographic method with tandem mass spectrometry (LC-MS/MS) for ∆9-THC content. For toxicological evaluation of the results, the lowest observed adverse effect level (LOAEL) of 2.5 mg ∆9-THC per day published by the European food safety authority (EFSA) based on human data (central nervous system effects and pulse increase) was used20. Taking safety factors (factor 3 for extrapolation from LOAEL to no observed adverse effect level (NOAEL) and factor 10 for interindividual differences, total factor 30) into account, an acute reference dose (ARfD) of 1 μg ∆9-THC per kg body weight was derived20. In their assessment, the Panel on Contaminants in the Food Chain of EFSA also considered interaction between ∆9-THC and CBD, but found the information controversial and not consistently antagonistic20 . This is consistent with more recent research of Solowij et al.21 that the effects of ∆9-THC may even be enhanced by low-dose CBD (e.g., as found in food supplements) and may be particular prominent in infrequent cannabis users. However, the current scientific evidence does not allow for considering cumulative effects. The applicability of the acute reference dose (ARfD) of 1 μg ∆9-THC per kg body weight was re-confirmed by EFSA in 202022. For further details on interpretation of results and toxicity assessment, see Lachenmeier et al.2.
Sample ID | Product | CBD [mg/day] (recommended daily dose according to labelling) | CBD [mg/day] (analysis)1 | Δ9-THC [mg/day] (analysis)1 | Toxicity assessment according to Ref. 2 |
---|---|---|---|---|---|
190267605 | CBD oil | 20002 | 3140 | 30 | THC > LOAEL |
180630663 | CBD oil supplement | 200 | -3 | 9 | THC > LOAEL |
190595270 | Hemp tea with flowers | -4 | -3 | 5 | THC > LOAEL |
180776480 | CBD oil supplement | 74 | 51 | 4 | THC > LOAEL |
190490183 | Hemp tea with flowers | -4 | 19 | 4 | THC > LOAEL |
190595273 | Hemp tea with flowers | -4 | -3 | 3.6 | THC > LOAEL |
190595267 | Hemp tea with flowers | -4 | 16 | 3.3 | THC > LOAEL |
190203194 | CBD pollen | -4 | -3 | 2.6 | THC > LOAEL |
180598182 | CBD hemp flower supplement | 500 | -3 | (2.3)5 | THC > LOAEL |
190495001 | Hemp tea with flowers | (3.8 % CBD/ package) | -3 | (2.3)5 | THC > LOAEL |
190203193 | CBD wax | 660 | 860 | (1.7)5 | THC > LOAEL |
180781746 | CBD chewing gum | 15 | 30 | (1.5)5 | THC > LOAEL |
190400870 | Hemp tea with flowers | "high CBD content" | 16 | (1.4)5 | THC > LOAEL |
180198245 | CBD buds (hemp flowers & leaves) | -4 | -3 | (1.3)5 | THC > LOAEL |
180198246 | CBD buds (hemp flowers & leaves) | -4 | -3 | (1.3)5 | THC > LOAEL |
180598187 | CBD hemp flower supplement | 250 | -3 | (1.3)5 | THC > LOAEL |
190176314 | Hemp tea with leaves and flowers | 50 | 9 | (0.5)5 | THC > LOAEL |
190141197 | CBD oil supplement | 22.32 | -3 | 1.6 | ARfD < THC < LOAEL |
190203191 | Supplement with hemp extract | -4 | -3 | 0.7 | ARfD < THC < LOAEL |
190698985 | CBD oil supplement | 40 | -3 | 0.6 | ARfD < THC < LOAEL |
190400871 | Hemp tea with flowers | -4 | 8 | 0.6 | ARfD < THC < LOAEL |
190199739 | Supplement with hemp extract | -4 | 34 | 0.5 | ARfD < THC < LOAEL |
190660814 | CBD oil supplement | 30 | -3 | 0.5 | ARfD < THC < LOAEL |
190207787 | CBD oil supplement | 67.5 | 95 | 0.4 | ARfD < THC < LOAEL |
190332551 | CBD oil supplement | 42 | -3 | 0.3 | ARfD < THC < LOAEL |
190332552 | CBD oil supplement | 84 | -3 | 0.3 | ARfD < THC < LOAEL |
190332553 | CBD oil supplement | 166 | -3 | 0.3 | ARfD < THC < LOAEL |
190540832 | Supplement with hemp extract | -4 | -3 | 0.3 | ARfD < THC < LOAEL |
180565755 | CBD oil supplement | 24 | 18 | 0.2 | ARfD < THC < LOAEL |
180565756 | CBD oil supplement | 12 | 9 | 0.2 | ARfD < THC < LOAEL |
190203189 | Supplement with hemp extract | -4 | -3 | 0.2 | ARfD < THC < LOAEL |
190480260 | Supplement with hemp juice powder | -4 | -3 | 0.2 | ARfD < THC < LOAEL |
190180559 | CBD wax | 700 | -3 | 0.2 | ARfD < THC < LOAEL |
190480266 | Hemp tea with leaves | -4 | -3 | 0.2 | ARfD < THC < LOAEL |
190394018 | CBD oil supplement | 2000 | -3 | 0.2 | ARfD < THC < LOAEL |
190351382 | CBD oil supplement | 24 | -3 | 0.2 | ARfD < THC < LOAEL |
190480263 | Supplement with hemp extract | -4 | -3 | 0.2 | ARfD < THC < LOAEL |
190595265 | Syrup with hemp flower extract | -4 | -3 | 0.2 | ARfD < THC < LOAEL |
190080916 | Supplement with hemp extract | -4 | -3 | 0.1 | ARfD < THC < LOAEL |
190080917 | Supplement with hemp extract | -4 | 4 | 0.1 | ARfD < THC < LOAEL |
190303096 | CBD chewing gum | 5 | -3 | 0.1 | ARfD < THC < LOAEL |
190304229 | CBD chewing gum | 5 | -3 | 0.1 | ARfD < THC < LOAEL |
190696141 | CBD oil supplement | 7 | -3 | 0.1 | ARfD < THC < LOAEL |
190689579 | CBD oil supplement | 24 | -3 | 0.1 | ARfD < THC < LOAEL |
190480151 | Supplement with hemp juice powder | -4 | -3 | 0.1 | ARfD < THC < LOAEL |
190578889 | Hemp seed with leaves (tea) | -4 | -3 | 0.1 | ARfD < THC < LOAEL |
190203192 | Supplement with hemp extract | -4 | -3 | 0.07 | THC > German guideline6 THC < ARfD |
190639434 | CBD oil supplement | 50 | -3 | 0.07 | THC > German guideline6 THC < ARfD |
190639431 | CBD oil supplement | 38 | -3 | 0.07 | THC > German guideline6 THC < ARfD |
190304228 | CBD supplement | 20 | -3 | 0.05 | THC > German guideline6 THC < ARfD |
190468594 | CBD oil supplement | 4 | -3 | 0.05 | THC > German guideline6 THC < ARfD |
190626611 | Supplement with hemp juice powder | -4 | -3 | 0.05 | THC > German guideline6 THC < ARfD |
190626620 | Supplement with hemp juice powder | -4 | -3 | 0.04 | THC > German guideline6 THC < ARfD |
190629508 | CBD oil supplement | 18 | -3 | 0.03 | THC > German guideline6 THC < ARfD |
190629507 | Supplement with hemp extract | 12 | -3 | 0.02 | THC > German guideline6 THC < ARfD |
190348163 | Supplement with hemp extract | 2 | -3 | 0.02 | THC > German guideline6 THC < ARfD |
190272024 | CBD oil | 27 | 38 | 0.01 | THC > German guideline6 THC < ARfD |
190601859 | Supplement with hemp extract | 100 | -3 | 0.01 | THC > German guideline6 THC < ARfD |
190387558 | CBD supplement | 10 | -3 | 0.01 | THC > German guideline6 THC < ARfD |
190664273 | Cannabis shot (one portion) | -4 | -3 | 0.008 | THC > German guideline6 THC < ARfD |
190387560 | CBD supplement | 5 | -3 | 0.006 | THC > German guideline6 THC < ARfD |
190378411 | CBD Hemp Bears | 20 | -3 | 0.004 | THC > German guideline6 THC < ARfD |
190672010 | CBD oil supplement | 14 | -3 | 0.002 | THC > German guideline6 THC < ARfD |
190387553 | CBD supplement | 5 | -3 | 0.002 | THC > German guideline6 THC < ARfD |
190203186 | Supplement with hemp extract | -4 | -3 | Not detectable | - |
190387556 | CBD supplement | 4 | -3 | Not detectable | - |
190539777 | CBD Lollipop | -4 | -3 | Not detectable | - |
1 Average of 1–8 replicates measured with LC-MS/MS reported (for raw results see dataset16, table sheet 2). Data reported for chromatographically separated CBD and Δ9-THC, not including their acids.
2 No labelling about dosage provided on the label. For this reason, the consumption of the whole bottle at once was assumed as worst-case exposure scenario. Because the product was only labelled as “oil” and not as “food supplement”, this scenario is not deemed unrealistic, specifically since CBD is a novelty on the market and the product may be mistaken for a conventional edible oil.
3 Not analysed or outside calibration (most sample dilutions made for Δ9-THC analysis by far exceed the linear range for CBD, so that a separate dilution would have to be made to obtain a valid result, which was not possible in the context of the current study).
5 Values in brackets mean that the LOAEL is not directly exceeded based on the recommended daily dose according to labelling, but may be exceeded in realistic exposure scenarios. For example, Δ9-THC (mg/day) is calculated for food supplements on the basis of the recommended daily maximum dose or for 1 portion (if labelling of maximum recommended daily dose is missing). The LOAEL for these products may be exceeded with a probable intake of 2 portions/day. For tea products, a daily consumption of 8 g has been assumed if no other labelling was provided. However, much higher tea consumption is possible, so that a worst-case scenario has to be considered. For example, the very small portion size of 2.5 g labelled on the product with sample ID 190176314, would lead to a Δ9-THC intake of 0.5 mg per day. However, if only 5 times this amount is consumed, which is neither unexpected nor impossible considering typically herbal tea consumption, the LOAEL may be exceeded. For all products, a case-by-case judgement was conducted, also considering manufacturers’ warning labels drawing attention to not exceeding the recommended daily intake.
6 The German guideline value for total THC (i.e. the sum of Δ9-THC and Δ9-tetrahydrocannabinolic acid (THCA)) content is 5 μg/kg in beverages, 5000 μg/kg in edible oils and 150 μg/kg in other food products (including food supplements)19. Exceedance of the guideline value reported for Δ9-THC alone without consideration of THCA.
There is not much evidence to assume that chemically pure CBD may exhibit ∆9-THC-like side-effects. The World Health Organization (WHO) judged the compound as being well tolerated with a good safety profile3. CBD doses in the food supplements on the market are typically much lower than the ones tested in clinical studies. Additionally, there is a 90-day experiment in rats with a hemp extract (consisting of 26% cannabinoids, out of which 96% were CBD and less than 1% ∆9-THC) from which a NOAEL of 100 mg/kg bw/day could be derived23. Based on 100 mg/kg bw/day × 26% × 96%, this would be about 25 mg/kg bw/day for CBD (or 1750 mg/day for a person with a body weight of 70 kg). This NOAEL would not typically be reached by the CBD dosages in food supplements.
Some, partly older, in vitro studies put up hypotheses about the conversion of CBD to ∆9-THC under acidic conditions such as in artificial gastric juice17,24–26. If these proposals could be confirmed with in vivo data, consumers taking CBD orally could be exposed to such high ∆9-THC levels that the threshold for pharmacological action could be exceeded27. However, taking a closer look at these in vitro studies raises some doubts. If CBD was to be converted to ∆9-THC in the stomach, typical ∆9-THC metabolites should be detectable in blood and urine, but this has not been observed in oral CBD studies28,29. Due to the contradicting results, a replication of the in vitro study of Merrick et al.17 was conducted using an extended experimental design. A more selective LC-MS/MS method and also an ultra-high pressure liquid chromatographic method with quadrupole time-of-flight mass spectrometry (UPLC-QTOF) were used to investigate the CBD degradation.
Under these conditions in contrast to Merrick et al.17, no conversion of CBD to ∆9-THC was observed in any of the samples. Only in case of the positive control (2 week storage in 0.5 mol/L HCl and 50% methanol), a complete degradation of CBD into 27% ∆9-THC and other not identified products (with fragments similar to the ones found in cannabinol and ∆9-THC fragmentations but with other retention times) was observed (Table 1, underlying data16). From an analytical viewpoint, the use of less selective and specific analytical methods, especially from the point of chromatographic separation, could result in a situation in which certain CBD degradation products might easily be confused with ∆9-THC due to structural similarities. Thus, similar fragmentation patterns and potentially overlapping peaks under certain chromatographic conditions might have led to false positive results in the previous studies. In conclusion of our degradation experiments, we agree with more recent literature30,31 that CBD would not likely react to ∆9-THC under in vivo conditions. The only detectable influence leading to degradation is strong acidity, which should be avoided in CBD formulations to ensure stability of products32.
Out of 67 samples, 17 samples (25% of the collective) have the potential to exceed the ∆9-THC LOAEL and were assessed as harmful to health. 29 samples (43% of the collective) were classified as unsuitable for human consumption due to exceeding the ARfD (see Table 2, underlying data16). Furthermore, all samples (100%) have been classified as non-compliant to Regulation (EU) 2015/2283 of the European Parliament and of the Council of 25 November 2015 on novel foods33 and therefore being unauthorized novel foods34. The labelling of all samples (100%) was also non-compliant to Regulation (EU) No 1169/2011 of the European Parliament and of the Council of 25 October 2011 on the provision of food information to consumers35, e.g. due to lack of mandatory food information such as ingredients list or use of unapproved health claims in accordance to Regulation (EC) No 1924/2006 of the European Parliament and of the Council of 20 December 2006 on nutrition and health claims made on foods36. In summary, none of the products in our survey was found as being fully compliant with European food regulations.
The ∆9-THC dose leading to intoxication is considered to be in the range of 10 to 20 mg (very high dose in heavy episodic cannabis users up to 60 mg) for cannabis smoking37. The resorption of orally ingested ∆9-THC varies greatly inter-individually with respect to both total amount and resorption rate38. This might be one of the reasons for the individually very different psychotropic effects. A single oral dose of 20 mg THC resulted in symptoms such as tachycardia, conjunctival irritation, “high sensation” or dysphoria in adults within one to four hours. In one in five adults, a single dose of 5 mg already showed corresponding symptoms39.
Some of the CBD oil supplements contained ∆9-THC in doses up to 30 mg (in this case in the whole bottle of 10 ml), which can easily explain the adverse effects observed by some consumers. Most of the CBD oils with dosage of around 1 mg ∆9-THC per serving offer the possibility to achieve intoxicating and psychotropic effects due to this compound if the products are used off-label (i.e. increase of the labelled maximum recommended daily dose by factors of 3–5, which is probably not an unlikely scenario. Some manufacturers even suggest an increase of daily dosage over time). Generally, these products pose a risk to human health, especially in light of the German guideline value for total THC in these kind of products19,40. The German guideline value of 150 μg total THC/kg for foods in general including food supplements is several orders of magnitude below the actual contents of ∆9-THC in the CBD products, even without consideration of THCA.
Hence our results provide compelling evidence that THC natively contained in CBD products by contamination may be a direct cause for side effects of these products. Obviously, there is an involuntary or deliberate lack of quality control of CBD products. Claims of “THC-free”, used by most manufacturers, even of the highly contaminated products – sometimes based on unsuitable analytical methodologies with limits of detection in the percentage range –, have to be treated as fraudulent or deceptive food information.
In light of the discussion about the three potential causative factors for side effects of CBD products, the described effects can be explained most probably by the presence of native THC as contaminant in the products rather than by direct action of CBD or its chemical transformation. The conclusions and findings of this study are further supported by the findings of Hazekamp6 reporting data from the Netherlands on cannabis oils according to which the labelling information for CBD and ∆9-THC was often different from the actual contents. In 26 out of 46 products the ∆9-THC content was >1 g/100 mL. Further corresponding results were reported in a study from the USA, in which the CBD content was correctly declared for only 26 of 84 CBD products and 18 of the products had ∆9-THC contents >0.317 g/100 g41.
CBD degradation products are currently unknown and need to be characterized and toxicologically assessed, e.g. within the context of the novel food registration process. Until then, the safety of the products remains questionable. Furthermore, standardization and purification of the extracts need to be improved and stability of commercial products during shelf life should be checked (e.g. to prevent CBD degradation by avoiding acidity in ingredients etc.).
In our opinion the systematically high ∆9-THC content of CBD products is clearly a “scandal” on the food market. Obviously, the manufacturers have – deliberately or in complete ignorance of the legal situation – placed unsafe and unapproved products on the market and thus exposed the consumer to an actually avoidable risk. In view of the growing market for such lifestyle food supplements, the effectiveness of the instrument of food business operators’ own responsibility for food safety must obviously be challenged.
It has been claimed by C. Hillard that “many CBD products would be delivering enough THC along with it to provide a bit of a high and that’s more likely where the relief is coming from”42 and our results have partially corroborated this opinion for a substantial number of products on the German market. Similarly, a recent survey reported that 22% out of 135 users of CBD products reported “feeling high” as common side effect10.
According to P. Pacher considering the situation in the USA, CBD users must be aware that they may be “participating in one of the largest uncontrolled clinical trials in history”42. Currently we have no evidence that this claim is not also valid for the CBD market in the European Union, where obviously considerable numbers of unsafe and misleadingly labelled products are available. Due to consistent deficits in mandatory labelling including a lack of maximum recommended daily dose, dosages up to psychotropic levels (for THC) or pharmacological levels (for CBD) cannot be excluded with certainty. The risk also includes positive cannabis urine tests for several days, which may be expected from daily oral doses of more than 1 mg ∆9-THC1,2,43. Therefore, more than 1/4 of products in our study would probably lead to false-positive urine tests, which could have grave consequences for persons occupationally or otherwise required to prove absence of drug use or of doping in professional sports44,45.
Obviously, the current regulatory framework is insufficient to adequately regulate products in the grey area between medicines and food supplements. For cannabis-derived products, such as CBD, the problem is aggravated by conflicting regulations in the narcotic, medicinal, and food law areas. For example, hemp extract-based products of similar composition could be treated as illegal narcotics, prescription-based medicinal products, or novel foods. According to press information, the EU commission is currently considering classifying cannabidiol products as narcotics, and hence as non-food products46. Clearly for CBD products alongside other medicinal cannabis products, a regulated legalization (see e.g. Anderson et al.47) would be preferable, introducing stricter regulations, such as mandatory labelling requirements, safety assessment, testing and pre-marketing approval (also see 29,48).
Open Science Framework: Dataset for “Are side effects of cannabidiol (CBD) products caused by delta9-tetrahydrocannabinol (THC) contamination?” (Version 2) https://doi.org/10.17605/OSF.IO/F7ZXY16
This project contains the following underlying data:
Dataset for 'Are side effects of cannabidiol (CBD) products caused by delta9-tetrahydrocannabinol (THC) contamination' F1000 Research.xlsx (Version 2) (Excel spreadsheet with data underlying Table 1 and Table 2, missing data/empty cells correspond to values outside calibration (CBD) or not measured)
Data are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).
The authors would like to thank Sylvia Ullrich, Jutta Neumeister and Ingrid Kübel for their excellent technical support, sample preparation and measurements using LC-MS.
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Competing Interests: No competing interests were disclosed.
Reviewer Expertise: medicinal cannabis cultivation, quality control, development of administration forms, clinical trials, patient surveys.
Is the work clearly and accurately presented and does it cite the current literature?
Partly
Is the study design appropriate and is the work technically sound?
Partly
Are sufficient details of methods and analysis provided to allow replication by others?
Partly
If applicable, is the statistical analysis and its interpretation appropriate?
Not applicable
Are all the source data underlying the results available to ensure full reproducibility?
Partly
Are the conclusions drawn adequately supported by the results?
Partly
References
1. McPartland JM, Duncan M, Di Marzo V, Pertwee RG: Are cannabidiol and Δ(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review.Br J Pharmacol. 2015; 172 (3): 737-53 PubMed Abstract | Publisher Full TextCompeting Interests: No competing interests were disclosed.
Reviewer Expertise: Forensic Toxicology, Metabolism, NPS, Cannabinoids
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: medicinal cannabis cultivation, quality control, development of administration forms, clinical trials, patient surveys.
Is the work clearly and accurately presented and does it cite the current literature?
Yes
Is the study design appropriate and is the work technically sound?
Yes
Are sufficient details of methods and analysis provided to allow replication by others?
Yes
If applicable, is the statistical analysis and its interpretation appropriate?
Yes
Are all the source data underlying the results available to ensure full reproducibility?
Yes
Are the conclusions drawn adequately supported by the results?
Yes
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Cannabinoids, nausea, CBD, rat models, addiction, learning
Is the work clearly and accurately presented and does it cite the current literature?
Yes
Is the study design appropriate and is the work technically sound?
Partly
Are sufficient details of methods and analysis provided to allow replication by others?
Partly
If applicable, is the statistical analysis and its interpretation appropriate?
Partly
Are all the source data underlying the results available to ensure full reproducibility?
Partly
Are the conclusions drawn adequately supported by the results?
Partly
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: medicinal cannabis cultivation, quality control, development of administration forms, clinical trials, patient surveys.
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References
1. Golombek P, Müller M, Barthlott I, Sproll C, Lachenmeier DW. Conversion of Cannabidiol (CBD) into Psychotropic Cannabinoids Including Tetrahydrocannabinol (THC): A Controversy in the Scientific Literature. Toxics. 2020; 8(2):41. https://doi.org/10.3390/toxics8020041
References
1. Golombek P, Müller M, Barthlott I, Sproll C, Lachenmeier DW. Conversion of Cannabidiol (CBD) into Psychotropic Cannabinoids Including Tetrahydrocannabinol (THC): A Controversy in the Scientific Literature. Toxics. 2020; 8(2):41. https://doi.org/10.3390/toxics8020041