Are adverse effects of cannabidiol (CBD) products caused by tetrahydrocannabinol (THC) contamination?
Abstract
Cannabidiol (CBD)-containing products are widely marketed as over the counter products, mostly as food supplements. Adverse effects reported in anecdotal consumer reports or during clinical studies were first assumed to be due to hydrolytic conversion of CBD to psychotropic Δ ⁹ -tetrahydrocannabinol (Δ ⁹ -THC) in the stomach after oral consumption. However, research of pure CBD solutions stored in simulated gastric juice or subjected to various storage conditions such as heat and light with specific liquid chromatographic/tandem mass spectrometric (LC/MS/MS) and ultra-high pressure liquid chromatographic/quadrupole time-of-flight mass spectrometric (UPLC-QTOF) analyses was unable to confirm THC formation. Another hypothesis for the adverse effects of CBD products may be residual Δ ⁹ -THC concentrations in the products as contamination, because most of them are based on hemp extracts containing the full spectrum of cannabinoids besides CBD. Analyses of 293 food products of the German market (mostly CBD oils) confirmed this hypothesis: 28 products (10%) contained Δ ⁹ -THC above the lowest observed adverse effect level (2.5 mg/day). Hence, it may be assumed that the adverse effects of some commercial CBD products are based on a low-dose effect of Δ ⁹ -THC, with the safety of CBD itself currently being unclear with significant uncertainties regarding possible liver and reproductive toxicity. The safety, efficacy and purity of commercial CBD products is highly questionable, and all of the products in our sample collection showed various non-conformities to European food law such as unsafe Δ ⁹ -THC levels, hemp extracts or CBD isolates as non-approved novel food ingredients, non-approved health claims, and deficits in mandatory food labelling requirements. In view of the growing market for such lifestyle products, the effectiveness of the instrument of food business operators' own responsibility for product safety and regulatory compliance must obviously be challenged, and a strong regulatory framework for hemp products needs to be devised.
... Typically, THC isomers, HHC derivatives, and CBN are classified as Schedule 1 according to the Controlled Substance Act [7]. It has been reported that transformed products formed during the processing, degradation, and storage of CBD-based products may have psychotropic effects [8,9]. Therefore, it is necessary to elucidate the transformed products and investigate their formation pathways during chemical reactions pertinent to CBD. ...
... In addition, a study analysing 84 CBD products sold online found that 42% of the products contained more CBD than stated on the label, 26% were under-dosed, while only 31% contained the stated amount, showing concerning variations in dosage [74]. Lastly, Lachenmeier et al. (2019) showed through the analysis of 293 food products from the German market (mainly CBD oils) that 28 products (10%) contained 9-THC above the lowest observed adverse effect level (2.5 mg/day) suggesting that the adverse effects of some commercial CBD products might be based on a low-dose effect of 9-THC [75]. ...
Objectives:
To date, very few cannabis-based specialities are authorised on the French market despite a growing demand from patients and health professionals. The objective of this study is to review the tolerance profile and the French legislative status of the two main cannabinoids used for therapeutic purposes: tetrahydrocannabiol (THC) associated with psychoactive effects and non-psychoactive cannabidiol (CBD).
Methods:
This review is based on relevant articles retrieved by a search in Google Scholar and PubMed databases and on an assessment of the legal texts and summaries of product characteristics available in France.
Results:
Evidence for the tolerability of CBD during chronic use is reassuring, but a significant risk of drug interactions exists. THC use appears to be associated with a higher proportion of serious adverse effects, including neuropsychological and cardiovascular effects. Inhaled cannabis appears to be associated with greater toxicity than the oral route. These data are presented together with the pharmacokinetic and pharmacodynamic data of THC and CBD.
Conclusion:
The literature reports several frequent but rarely serious adverse effects of CBD during chronic use as well as a significant risk of drug interactions. THC use seems to be associated with a higher proportion of serious adverse effects compared to CBD, particularly at the neuropsychological and cardiovascular levels. Health professionals should be up to date on the particularities of therapeutic cannabis in terms of efficacy, safety and drug interactions.
In this study, an automated online micro-solid-phase extraction (μSPE)-liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the detection of metabolites of cannabidiol (CBD), Δ8-tetrahydrocannabinol (Δ8-THC), and Δ9-tetrahydrocannabinol (Δ9-THC), particularly 7-carboxy- cannabidiol (7-COOH-CBD), 11-nor-9-carboxy-Δ8-tetrahydrocannabinol (Δ8-THCCOOH), 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (Δ9-THCCOOH), and 11-nor-9-carboxy-Δ9- tetrahydrocannabinol-glucuronide (Δ9-THCCOOH-glu) in urine. An instrument top sample preparation (ITSP) cartridge was introduced to increase the sensitivity toward analytes and decrease the matrix effect of the urine. LC-MS/MS analysis was performed in the multiple-reaction monitoring mode, and the analytes were separated using an Acquity UPLC HSS T3 (2.1 × 100 mm, 1.8 µm) column and gradient elution with water containing 0.05 % acetic acid and methanol as the mobile phase. The calibration range was 0.5-200 ng/mL for all the analytes, with a correlation coefficient (r) of ≥0.996 and a weighting factor of 1/x2. The limits of detection for 7-COOH-CBD, Δ8-THCCOOH, Δ9-THCCOOH, and Δ9-THCCOOH-glu were 0.06, 0.02, 0.03, and 0.1 ng/mL, respectively. The intra- and inter-day accuracy ranged from -8.0 to 6.2 % and -7.3 to 7.8 % with a precision of ≤7.2 % and ≤6.2 %, respectively. The method was also validated for selectivity, recovery, matrix effect, stability, and dilution integrity. The developed method was successfully applied to the analysis of 78 urine samples, and 7-COOH-CBD, Δ8-THCCOOH, Δ9-THCCOOH, and Δ9-THCCOOH-glu were detected in 54 urine samples at normalized concentrations of 1.1, 0.6-939.1, 0.9-2595.0, and 1.3-527.6 ng/mg creatinine, respectively.
Cannabidiol (CBD) products have ascribed an uprising trend for their health-promoting effects worldwide. In contrast to Δ⁹-tetrahydrocannabinol (THC), CBD exhibits no state of euphoria. Since conversion of CBD into THC in an acidic environment has been reported, it has not been proved whether this degradation will also occur in human gastric fluid. A total of 9 subjects ingested 400 mg CBD as a water-soluble liquid together with lecithin as an emulsifier and ethanol as a solubilizer. Blood samples were taken up to 4 h, and urine samples were submitted up to 48 h. THC, 11-hydroxy-Δ⁹-THC (THC-OH), 11-nor-9-carboxy-Δ⁹-THC (THC-COOH), CBD, 7-hydroxy cannabidiol (7-OH-CBD), and 7-carboxy cannabidiol (7-CBD-COOH) were determined in blood and THC-COOH and 7-CBD-COOH in urine by LC–MS/MS. Neither THC, THC-OH, nor THC-COOH were detectable in any serum specimen. Only two urine samples revealed THC-COOH values slightly above the threshold of 10 ng/ml, which could also be caused by trace amounts of THC being present in the CBD liquid. It can be concluded that negative consequences for participants of a drug testing program due to a conversion of CBD into THC in human gastric fluid appear unlikely, especially considering a single intake of dosages of less than 400 mg. Nevertheless, there is a reasonable risk for consumers of CBD products being tested positive for THC or THC metabolites. However, this is probably not caused by CBD cyclization into THC in human gastric fluid but is most likely due to THC being present as an impurity of CBD products.
Introduction: Recent research claimed that CBD in commercial electronic cigarette (e-cigarette) liquids can be converted into psychotropic amounts of Δ9-THC. This study aims to validate this claim using a realistic e-cigarette setup. In addition, this study also investigates if such a conversion may occur during smoking of CBD-rich cannabis joints. Materials and Methods: Two different CBD liquids were vaporized using two different e-cigarette models, one of which was operated at extreme energy settings (0.2 Ω and 200 W). The smoke of six CBD joints was collected using a rotary smoking machine according to ISO 4387:2019. Analyses were conducted using nuclear magnetic resonance spectrometry as well as liquid chromatography tandem mass spectrometry. Results: For the condensed e-cigarette liquids, no increase in THC concentration could be observed. For the CBD joints, no THC formation was provable. The recovered THC concentrations were ranging between 1% and 48% (0.034 and 0.73 mg) of the THC amount initially contained in the joints before smoking. Conclusions: Using realistic conditions of consumer exposure, relevant conversion of CBD to THC appears to not be occurring. The health risk of CBD liquids for e-cigarettes, as well as low-THC cannabis intended for smoking, can be assessed by concentrations in the source material without the need to consider significant changes in psychotropic compounds during use by consumers.
At present, foods containing cannabidiol (CBD) and other cannabinoids are internationally being widely advertised and sold in increasing quantities. In the European Union (EU), these products require pre-marketing authorisation under the novel food regulation, so that all available CBD oils and CBD-containing food supplements in the EU are currently placed on the market with an infringement of the food laws. Currently, 19 CBD applications are under assessment at the European Food Safety Authority (EFSA). During the initial assessment of the application files, EFSA 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. 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 as a lowest observed adverse effect level (LOAEL). The EFSA 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 on the EU market despite the lack of authorisation must be considered as “unsafe”. Products exceeding a reference dose 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).
The European Commission has determined that cannabidiol (CBD) can be considered as a novel food (NF), and currently, 19 applications are under assessment at EFSA. While assessing these, it has become clear that there are knowledge gaps that need to be addressed before a conclusion on the safety of CBD can be reached. Consequently, EFSA has issued this statement, summarising the state of knowledge on the safety of CBD consumption and highlighting areas where more data are needed. Literature searches for both animal and human studies have been conducted to identify safety concerns. Many human studies have been carried out with Epidyolex®, a CBD drug authorised to treat refractory epilepsies. In the context of medical conditions, adverse effects are tolerated if the benefit outweighs the adverse effect. This is, however, not acceptable when considering CBD as a NF. Furthermore, most of the human data referred to in the CBD applications investigated the efficacy of Epidyolex (or CBD) at therapeutic doses. No NOAEL could be identified from these studies. Given the complexity and importance of CBD receptors and pathways, interactions need to be taken into account when considering CBD as a NF. The effects on drug metabolism need to be clarified. Toxicokinetics in different matrices, the half-life and accumulation need to be examined. The effect of CBD on liver, gastrointestinal tract, endocrine system, nervous system and on psychological function needs to be clarified. Studies in animals show significant reproductive toxicity, and the extent to which this occurs in humans generally and in women of child-bearing age specifically needs to be assessed. Considering the significant uncertainties and data gaps, the Panel concludes that the safety of CBD as a NF cannot currently be established.
Importance
Frontline health care professionals who work with patients with COVID-19 have an increased incidence of burnout symptoms. Cannabidiol (CBD) has anxiolytic and antidepressant properties and may be capable of reducing emotional exhaustion and burnout symptoms.
Objective
To investigate the safety and efficacy of CBD therapy for the reduction of emotional exhaustion and burnout symptoms among frontline health care professionals working with patients with COVID-19.
Design, Setting, and Participants
This prospective open-label single-site randomized clinical trial used a 1:1 block randomization design to examine emotional exhaustion and burnout symptoms among frontline health care professionals (physicians, nurses, and physical therapists) working with patients with COVID-19 at the Ribeirão Preto Medical School University Hospital in São Paulo, Brazil. Participants were enrolled between June 12 and November 12, 2020. A total of 214 health care professionals were recruited and assessed for eligibility, and 120 participants were randomized in a 1:1 ratio by a researcher who was not directly involved with data collection.
Interventions
Cannabidiol, 300 mg (150 mg twice per day), plus standard care or standard care alone for 28 days.
Main Outcomes and Measures
The primary outcome was emotional exhaustion and burnout symptoms, which were assessed for 28 days using the emotional exhaustion subscale of the Brazilian version of the Maslach Burnout Inventory–Human Services Survey for Medical Personnel.
Results
A total of 120 participants were randomized to receive either CBD, 300 mg, plus standard care (treatment arm; n = 61) or standard care alone (control arm; n = 59) for 28 days. Of those, 118 participants (59 participants in each arm; 79 women [66.9%]; mean age, 33.6 years [95% CI, 32.3-34.9 years]) received the intervention and were included in the efficacy analysis. In the treatment arm, scores on the emotional exhaustion subscale of the Maslach Burnout Inventory significantly decreased at day 14 (mean difference, 4.14 points; 95% CI, 1.47-6.80 points; partial eta squared [ηp²] = 0.08), day 21 (mean difference, 4.34 points; 95% CI, 0.94-7.73 points; ηp² = 0.05), and day 28 (mean difference, 4.01 points; 95% CI, 0.43-7.59 points; ηp² = 0.04). However, 5 participants, all of whom were in the treatment group, experienced serious adverse events: 4 cases of elevated liver enzymes (1 critical and 3 mild, with the mild elevations reported at the final 28-day assessment) and 1 case of severe pharmacodermia. In 2 of those cases (1 with critical elevation of liver enzymes and 1 with severe pharmacodermia), CBD therapy was discontinued, and the participants had a full recovery.
Conclusions and Relevance
In this study, CBD therapy reduced symptoms of burnout and emotional exhaustion among health care professionals working with patients during the COVID-19 pandemic. However, it is necessary to balance the benefits of CBD therapy with potential undesired or adverse effects. Future double-blind placebo-controlled clinical trials are needed to confirm the present findings.
Trial Registration
ClinicalTrials.gov Identifier: NCT04504877
Objective
Cannabidiol (CBD) has been reported to have anti-diabetic effects in pre-clinical and clinical studies but its inhibitory effects on α -glucosidase, a carbohydrate hydrolyzing enzyme, remain unknown. Herein, we evaluated CBD’s inhibitory effects on α -glucosidase using in vitro assays and computational studies.
Methods
CBD’s inhibitory effect on α -glucosidase activity was evaluated in a yeast enzymatic assay and by molecular docking. The stability of CBD in simulated gastric and intestinal fluids was evaluated by high-performance liquid chromatography analyses.
Results
CBD, at 10, 19, 38, 76, 152, 304, 608, and 1216 μM, inhibited α -glucosidase activity with inhibition of 17.1, 20.4, 48.1, 56.6, 59.1, 63.7, 74.1, and 95.4%, respectively. Acarbose, the positive control, showed a comparable inhibitory activity (with 85.1% inhibition at 608 μM). CBD’s inhibitory effect on α -glucosidase was supported by molecular docking showing binding energy (-6.39 kcal/mol) and interactions between CBD and the α -glucosidase protein. CBD was stable in simulated gastric and intestinal fluids for two hours (maintained ≥ 90.0%).
Conclusions
CBD showed moderate inhibitory effect against yeast α -glucosidase activity and was stable in gastric and intestinal fluids. However, further studies on CBD’s anti- α -glucosidase effects using cellular and in vivo models are warranted to support its potential application for the management of type II diabetes mellitus.
Background:
Recreational cannabidiol (CBD) is frequently promoted as a medicinal or therapeutic cannabis product worldwide. Nationwide population-based data on awareness and use of recreational CBD are currently lacking.
Objective:
This study estimates the prevalence of recreational CBD awareness and use among the population in Germany. It also explores potential associations with socio-demographic characteristics, tobacco smoking, and e-cigarette use.
Methods:
We used data from a cross-sectional household survey (German Study on Tobacco Use, DEBRA) fielded across two waves in October-November 2020 and February-March 2021. Data were collected using computer-assisted face-to-face interviews among participants aged ≥14 years (n = 4026). Outcome variables were CBD awareness (yes/no) and CBD ever use (yes/no). The sample was weighted to ensure representativeness of the prevalence estimates. Associations with socio-demographic variables, tobacco smoking, and e-cigarette use were assessed using multivariable logistic regression.
Results:
Approximately half of the population in Germany (48.3%, 95% CI: 46.8-49.9) was aware of recreational CBD products, and 4.3% (95% CI: 3.7-5.0) had ever used them (including 1.1% current users). Awareness was associated with younger age, higher education levels, female sex, living in urban regions, no migration background, tobacco smoking, and e-cigarette use. Ever use was associated with higher education levels, living in urban regions, tobacco smoking, and e-cigarette use.
Conclusions:
Awareness of recreational CBD products is high but ever use is currently low in Germany. Given the uncertain legal framework regarding the marketing of recreational CBD products, the changing retail landscape, and potential harms of CBD use, structured monitoring is warranted for public health purposes.
Background
Regulation has not kept pace with the growth of the hemp-derived CBD market. We have evaluated the risk of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) contamination in 80 unregulated products with comparison to a regulated control, Epidiolex®.
Methods
Local and national brands of hemp-derived oil products were purchased online and from local retailers in central Kentucky (which carry both national and local brands). These were extracted by solvent extraction and quantified by liquid-chromatography tandem mass-spectrometry (LC-MS/MS) using a validated method.
Results
Of the 80 unregulated products and Epidiolex®, Δ⁹-THC was detected above the limit of quantification (LOQ = 0.005 mg/mL) of the assay in 52 samples, ranging from 0.008 mg/mL to 2.071 mg/mL. Twenty-one of the products tested were labelled as “THC-Free”, and 5 of these products contained detectable levels of Δ⁹-THC ranging from 0.015 mg/mL to 0.656 mg/mL.
Conclusions
Consumers are taking hemp-derived CBD products without understanding the risks of unintentional consumption of Δ⁹-THC. This accidental use of Δ⁹-THC could have adverse effects on health and safety as well as potential legal consequences (e.g., child custody, impaired driving), as Δ⁹-THC drug test findings could impact employment, military, and sport eligibility status.
Purpose
Cannabidiol products remains largely unregulated in the US. Unlike the Rx formulation of CBD [EpidiolexR], little information is available regarding labeling accuracy (does the product contain what the label says it does), lot to lot variability, nor long-term product stability.
Understanding these properties are fundamental if these products are to be used in patients with epilepsy, where product variability of traditional AEDs has been suspected to result in inadequate seizure control.
Therefore, we analyzed commercial CBD products, including oils, aqueous products (i.e., beverages), and various Other products for cannabinoid content vs label claims and stability under United States Pharmacopeia (USP) standards.
Method
Samples were diluted and analyzed by HPLC for CBD, THC, and CBN concentrations in order to assess product label accuracy. Products with <90% of label claim CBD were denoted over-labeled, products with >110% of label claim CBD were denoted under-labeled, and products between 90% and 110% of label claim CBD were denoted appropriately labeled, per USP standards.
Results
Among commercial CBD Oils (n = 11), mean CBD concentration vs label claim was 91.56% [95% CI, 66.02–117.10%], although 18.18% of oils (n = 2) made nonspecific label claims of “hemp extract” in lieu of CBD. Among all oils, 36.36% (n = 4) were appropriately labeled, another 36.4% (n = 4) of all oils were under-labeled, maximum 128.3% label claim, and finally, 9.09% (n = 1) of oils were over-labeled. The remaining 18.18% (n = 2) of oils lacked specific CBD label claims, minimum of 0.3 mg CBD per 1-ml “dose”. THC was detected in 54.55% (n = 6) of oils with a maximum concentration of 0.2% w/v and a minimum concentration of 0.036% w/v. Cannabinol was detectable in only 9.1% (n = 1) of products at a concentration of 0.00465% w/v.
Among aqueous products (n = 21) tested, only 66.67% (n = 14) gave specific CBD label claims, with mean CBD concentration vs label claim of 59.93% [95% CI, 38.24–81.63%]. Only 7.14% (n = 1) of aqueous products with a label claim were appropriately labeled, 14.29% (n = 2) were found to be under-labeled, and 78.57% (n = 11) over-labeled. THC was detected in 23.81% (n = 5) of aqueous products tested with a maximum THC concentration of 0.0005% w/v, and a minimum concentration of 0.0002% w/v. Cannabinol was detected in 9.52% (n = 2) of aqueous products, both at a concentration of 0.0015% w/v.
“Other” products (n = 7) tested ranged from chocolate bars to transdermal patches. Some 42.86% (n = 3) gave specific CBD label claims, with mean CBD concentration vs label claim of 67.01% [95% CI, 0.87–133.14%]. Among these three “Other” products with specific label claims, 33% (n = 1) was appropriately labeled, and 66.67% (n = 2) were over-labeled, with CBD concentrations vs label claim ranging from a minimum of 39.30% to a maximum of 101.99%.
The remaining 57.14% (n = 5) of “Other” products tested made nonspecific CBD label claims, denoting CBD content in terms of “full spectrum hemp extract” or “activated cannabinoids”. One such product was labeled with a “40–50-mg CBD” range instead of a single, specific value. Tetrahydrocannabinol was detected in 71.43% (n = 5) of Other products tested with a maximum concentration of 0.0046% w/w, and a minimum concentration of 0.0008% w/w. Cannabinol was detected in 14.3% (n = 1) of Other products at a concentration of 0.0001% w/w.
Conclusion
We demonstrate that commercial CBD products, especially aqueous beverages, can show inconsistent labeling, vary largely from their label claims should they make them, and show lot-to-lot variability making dosing unpredictable.
The aim of this work was to validate a high-performance liquid chromatography (HPLC) method for determination of the stability of cannabidiol, ∆9-tetrahydrocannabinol, and cannabinol. Furthermore, degradation kinetics were also investigated. Five stress conditions—acid degradation, alkaline degradation, oxidation, thermal degradation, and photodegradation—were evaluated. The results showed that the HPLC method had a linear response (R2 ≥ 0.9999) in the test range of 1–200 μg/mL. The method was specific, precise, and accurate. The limits of both detection and quantitation are also reported. According to the stress test, the three cannabinoids (cannabidiol, ∆9-tetrahydrocannabinol, cannabinol) were stable during exposure to a range of thermal conditions for 24 h. They were unstable when being subjected to acid conditions; cannabidiol under alkaline conditions was extremely unstable. Degradation kinetic analysis demonstrated that the compounds remained at a level of approximately 8% after 5 h, and approached a first-order reaction (R2 = 0.9930) with a rate constant of − 0.5057 h− 1. In summary, the obtained data can be used as a guide for the formulation development of cannabis products in order to maintain their active compounds as well as their activities.