Are adverse effects of cannabidiol (CBD) products caused by tetrahydrocannabinol (THC) contamination?
Abstract and Figures
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 181 food products of the German market (mostly CBD oils) confirmed this hypothesis: 21 products (12%) contained Δ ⁹ -THC above the lowest observed adverse effect level (2.5 mg/day). Inversely, CBD was present in the products below the no observed adverse effect level. 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 and not due to effects of CBD itself. 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.
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... These products are not as strictly monitored as medicinal products resulting in impurities and residual concentrations of THC [8,9]. According to the German Narcotic Drugs Act, CBD products containing 0.2% or more THC are considered illegal [10]. ...
... Besides CBD products containing THC, spontaneous conversion of CBD to THC in an acidic environment like simulated gastric fluid has been reported in the literature [11][12][13]. However, results of in vitro experiments have not been consistent in this regard [8]. In vivo conversion of CBD to THC has only been reported in rats [14], whereas it has not been observed in other in vivo studies in animals and humans [15][16][17][18][19][20]. ...
... The predominantly negative results of in vivo experiments can be attributed to the limited solubility of CBD in a hydrophilic environment, i.e., gastric fluid. This hypothesis is supported by the investigation of Lachenmeier et al. [8] who has replicated the experiment of Merrick et al. without using a surfactant which gave a negative result for THC. According to the study of Merrick et al. [13], a surfactant such as sodium dodecyl sulfate (SDS) can increase the aqueous solubility of CBD. ...
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.
... The authors also believe that the principle of precautionary public health protection demands the use of those data. In a previous article, the authors commented on the THC contamination of CBD products, stating that it is a "scandal" because unapproved and potentially unsafe products are being placed on the food market within the EU [20]. Other authors have similarly characterised the CBD market as containing "black sheep" who disregard regulations and try to make quick money with the hype surrounding cannabis legalisation [21]. ...
In the European Union (EU), cannabidiol (CBD) products extracted from Cannabis sativa L. require pre-marketing authorisation under the novel food regulation. Currently, 19 CBD applications are being assessed by the European Food Safety Authority (EFSA). During the initial assessment of the dossiers, the EFSA Panel on Nutrition, Novel Foods, and Food Allergens (NDA) identified several knowledge gaps that need to be addressed before the evaluation of CBD can be finalised. The effects of CBD on the liver, gastrointestinal tract, endocrine system, nervous system, psychological function, and reproductive system need to be clarified. The contribution of this research is to provide an evidence-based assessment of the potential risks associated with CBD products, and to provide recommendations for risk management in the European Union while awaiting the finalisation of novel food applications. The available literature allows for 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 showed increases in the liver enzymes alanine aminotransferase and aspartate aminotransferase in one study at 4.3 mg/kg bw/day, which was defined by the EFSA NDA panel as the lowest observed adverse effect level (LOAEL). The EFSA NDA panel recently concluded that the safety of CBD as a novel food cannot be assessed, resulting in a so-called clock stop for the applications until the applicants provide the required data. The authors suggest that certain CBD products still available on the EU market as food supplements despite the lack of authorisation should be considered "unsafe". Products exceeding a health-based guidance value (HBGV) of 10 mg/day should be considered "unfit for consumption" (Article 14(1) and (2)(b) of Regulation No. 178/2002), while those exceeding the human LOAEL should be considered "injurious to health" (Article 14(1) and (2)(a) of Regulation No 178/2002).
... It is worth noting that CBD, unlike other cannabinoids, shows no signals of drug abuse liability [7,8] and no significant side-effects at therapeutic doses [9]. ...
Cannabidiol (CBD) is the main non-psychotropic cannabinoid derived from cannabis (Cannabis sativa L., fam. Cannabaceae). CBD has received approval by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of seizures associated with Lennox–Gastaut syndrome or Dravet syndrome. However, CBD also has prominent anti-inflammatory and immunomodulatory effects; evidence exists that it could be beneficial in chronic inflammation, and even in acute inflammatory conditions, such as those due to SARS-CoV-2 infection. In this work, we review available evidence concerning CBD’s effects on the modulation of innate immunity. Despite the lack so far of clinical studies, extensive preclinical evidence in different models, including mice, rats, guinea pigs, and even ex vivo experiments on cells from human healthy subjects, shows that CBD exerts a wide range of inhibitory effects by decreasing cytokine production and tissue infiltration, and acting on a variety of other inflammation-related functions in several innate immune cells. Clinical studies are now warranted to establish the therapeutic role of CBD in diseases with a strong inflammatory component, such as multiple sclerosis and other autoimmune diseases, cancer, asthma, and cardiovascular diseases.
... The authors also believe 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 products are placed on the food market within the EU [20]. Other authors similarly characterised the CBD market as containing "black sheep" disregarding regulations trying to make a quick profit with the hype surrounding cannabis legalisation [21]. ...
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).
... The filter paper was then extracted with methanol and the extract was analyzed using LC-MS/MS. 9 Institutional review board approval was not required because this study was purely experimental and did not involve any human participants. Table 1 presents the recovery of D 9 -THC in the condensates of vaporized liquids compared with the D 9 -THC concentrations measured in pure CBD liquids. ...
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.
... The authors also believe 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 products are placed on the food market within the EU [20]. Other authors similarly characterised the CBD market as containing "black sheep" disregarding regulations trying to make a quick profit with the hype surrounding cannabis legalisation [21]. ...
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).
Cannabidiol (CBD) is the primary active pharmacologic component in Cannabis sativa l., which is non‐psychoactive. CBD shows anti‐tumor, anti‐inflammatory, sedative and many other activities, thus demonstrating potential therapeutic utilities in neurodegenerative diseases, epilepsy, cancer and other diseases. There have been numerous pharmacokinetic studies of CBD, which indicate the main metabolic sites are 6‐ and 7‐position of monoterpene and alkyl chain of the olivetol. While only few studies are available for the metabolic sites of the benzene ring. In this paper, the aromatic hydrogen on the benzene ring was deuterated, and the antitumor activity, hERG potassium channel activity and liver microsome stability of 3′,5′‐d2‐cannabidiol (D2CBD) and CBD were compared. The results show that the antitumor activity and hERG potassium channel activity are slightly improved, whereas liver microsomes stability of D2CBD is not significantly improved. The aromatic hydrogen on the benzene ring of cannabidiol (CBD) was deuterated, and the antitumor activity, hERG potassium channel activity and liver microsome stability of 3′,5′‐d2‐cannabidiol (D2CBD) and CBD were compared. The results show that the antitumor activity and hERG potassium channel activity are slightly improved, whereas liver microsomes stability of the former is not significantly improved.
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.
Die EFSA hat aktuell die Bewertung sämtlicher Novel-Food-Anträge zu CBD ausgesetzt (sog. Clock-Stop), da der Behörde keine ausreichenden Daten über die Sicherheit von CBD in Bezug auf zahlreiche Organsysteme des Menschen vorgelegt wurden, die im Tierversuch festgestellte Gefahren gesundheitsschädlicher Wirkungen widerlegen würden. Dieser Beitrag schlägt toxikologische Schwellenwerte vor, bei deren Überschreitung CBD-Produkte bereits zu diesem Zeitpunkt als nicht sichere Lebensmittel beurteilt werden können.
Background: The endocannabinoid (eCB) system plays an important role in homeostatic regulation of anxiety and stress responses; however, the eCB system can be disrupted following traumatic stressors. Additionally, traumatic or chronic stressors that occur during adulthood or early life can cause long-lasting disturbances in the eCB system. These alterations interfere with hypothalamic-pituitary-adrenal axis function and may be involved in lifelong increased fear and anxiety behaviors as well as increased risk for development of post-traumatic stress disorder (PTSD). Methods: This review focuses on the implications of trauma and significant stressors on eCB functionality and neural pathways, both in adolescence and into adulthood, as well as the current state of testing for CBD efficacy in treating pediatric and adult patients suffering from stress-induced eCB dysregulation. Articles were searched via Pubmed and included studies examining eCB modulation of stress-related disorders in both clinical settings and preclinical models. Conclusion: Given the potential for lifelong alterations in eCB signaling that can mediate stress responsiveness, consideration of pharmaceutical or nutraceutical agents that impact eCB targets may improve clinical outcomes in stress-related disorders. However, caution may be warranted in utilization of medicinal cannabinoid products that contain delta-9-tetrahydrocannabinol due to pronounced euphorigenic effects and potential to exacerbate stress-related behaviors. Other cannabinoid products, such as cannabidiol (CBD), have shown promise in reducing stress-related behaviors in pre-clinical models. Overall, pre-clinical evidence supports CBD as a potential treatment for stress or anxiety disorders resulting from previously stressful events, particularly by reducing fearful behavior and promoting extinction of contextual fear memories, which are hallmarks of PTSD. However, very limited clinical research has been conducted examining the potential effectiveness of CBD in this regard and should be examined further.
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.
The use of cannabidiol (CBD) in electronic cigarettes is widespread. Previously, it was reported that CBD is partly transformed to THC in case smoking as a cigarette, however, the pyrolysis of this compound has not been assessed extensively. The aim of our study was to investigate the effect of temperature on the composition of pyrolysis products of CBD. The experiments were performed in the typical operating temperature range of e-cigarettes (250–400 °C) and at 500 °C under both inert and oxidative conditions, and the pyrolysis products were identified and quantified by GC–MS. Depending on the temperature and atmosphere, 25–52% of CBD was transformed into other chemical substances: Δ⁹-THC, Δ⁸-THC, cannabinol and cannabichromene were the predominant pyrolysates in both conditions, all formed by cyclization reaction. THC was the main pyrolysis product at all temperatures under both oxidative and inert conditions. Our results point out that CBD in e-cigarettes can be considered as a precursor of THC, thus it bears all the dangers related to this psychoactive compound. Our findings are fundamental contributions to the safety profile of CBD-based e-cigarettes.
According to the World Anti‐Doping Agency (WADA) regulations, cannabinoids use is prohibited in competition except for cannabidiol (CBD) use. For an adverse analytical finding (AAF) in doping control, cannabinoid misuse is based on identification of the pharmacologically inactive metabolite 11‐nor‐delta‐9‐carboxy‐tetrahydrocannabinol‐9‐carboxylic acid (carboxy‐THC) in urine at a concentration greater than 180 ng/mL. All other (minor) cannabinoids are reported as AAF when identified, except for CBD that has been explicitly excluded from the class of cannabinoids on WADA's Prohibited List since 2018. However, due to the fact that CBD isolated from cannabis plants may contain additional minor cannabinoids, the permissible use of CBD can lead to unintentional violations of anti‐doping regulations.
An assay for the detection of 16 cannabinoids in human urine was established. The sample preparation consisted of enzymatic hydrolysis of glucuronide conjugates, liquid‐liquid extraction, trimethylsilylation, and analysis by gas chromatography/tandem mass spectro‐metry (GC‐MS/MS). Spot urine samples from CBD users, as well as specimens obtained from CBD administration studies conducted with 15 commercially available CBD products were analyzed, and assay characteristics such as selectivity, reproducibility of detection at the Minimum Required Performance Level, limit of detection, and limit of identification were determined.
An ethical committee approved controlled single dose commercially‐available CBD products administration study was conducted to identify 16 cannabinoids in urine samples collected after ingestion or application of the CBD products as well as their presence in spot urine samples of habitual CBD users. Variable patterns of cannabinoids or their metabolites were observed in the urine samples, especially when full spectrum CBD products were consumed. The presence of minor cannabinoids or their metabolites in an athlete´s in‐competition urine sample represents a substantial risk of an anti‐doping rule violation.
Cannabidiol (CBD) is a naturally occurring, non-psychotropic cannabinoid of the hemp plant Cannabis sativa L. and has been known to induce several physiological and pharmacological effects. While CBD is approved as a medicinal product subject to prescription, it is also widely sold over the counter (OTC) in the form of food supplements, cosmetics and electronic cigarette liquids. However, regulatory difficulties arise from its origin being a narcotic plant or its status as an unapproved novel food ingredient. Regarding the consumer safety of these OTC products, the question whether or not CBD might be degraded into psychotropic cannabinoids, most prominently tetrahydrocannabinol (THC), under in vivo conditions initiated an ongoing scientific debate. This feature review aims to summarize the current knowledge of CBD degradation processes, specifically the results of in vitro and in vivo studies. Additionally, the literature on psychotropic effects of cannabinoids was carefully studied with a focus on the degradants and metabolites of CBD, but data were found to be sparse. While the literature is contradictory, most studies suggest that CBD is not converted to psychotropic THC under in vivo conditions. Nevertheless, it is certain that CBD degrades to psychotropic products in acidic environments. Hence, the storage stability of commercial formulations requires more attention in the future.
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.
Introduction
Cannabidiol (CBD) has become a popular supplement in consumer products in recent years, resulting in part from normalization of the cultivation of low THC cannabis in 2018. However, the actual content of CBD-labeled products is frequently uncertain, as oversight of such products is minimal. To date, there is little pragmatic knowledge regarding exposures to products labeled as containing CBD.
Methods
Cases reported to Poison Control Centers from April 1, 2019 and March 31, 2020, the first year in which CBD was identified uniquely as a substance in the National Poison Data System, were analyzed for demographic, temporal, and clinical trends.
Results
Poison Control Centers handled 1581 cases exposures to CBD-containing products between April 1, 2019 and March 31, 2020. There was a significant trend of over 5 additional cases related to this substance per month (linear regression coefficient = 5.2, 95% CI: 1.52–8.98). Patients under age 13 years made up 44.0% of reported exposures. Mild CNS depression (10.3%), tachycardia (5.7%), dizziness/vertigo (5.3%), vomiting (4.9%), nausea (4.5%), and agitation (4.4%) were the most frequently reported symptoms. 13% of cases were coded as having “moderate” or “severe” medical outcomes. There were no fatalities.
Conclusions
Cases reported to Poison Control Centers regarding exposures to CBD-labeled products have been increasing, representing an emerging trend of interest to Poison Control Center professionals, clinicians, and public health officials. Further monitoring of this trend is recommended.
Objectives
Older (aged 50+) cannabis users are growing in numbers, but research on poison control center (PCC) cases has not focused on them. In this study, we examined: (1) changing trends in cannabis forms reported in PCC cases; (2) demographic and clinical factors associated with different cannabis forms; and (3) associations between cannabis forms and medical outcomes.
Methods
We used the American Association of Poison Control Centers’ National Poison Data System (NPDS), January 1, 2009–December 31, 2019, to examine the 5201 cases aged 50+ in which cannabis was the only or primary substance. Following descriptive analyses, multinomial logistic regression was fit to examine associations of three cannabis forms (dried/undried plant, other preparations, and synthetic cannabinoids/e-cigarettes for cannabis delivery) with cases’ demographic and clinical characteristics, and binary logistic regression was fit to examine associations of medical outcomes (major/potentially major vs. nonmajor) with cannabis forms.
Results
Cannabis-related cases involving older adults increased 18-fold (from 61 to 1074) between 2009 and 2019. Compared to plant forms, other preparations had 51.24 times greater odds of appearing in 2018–2019 than in 2009–2011 (95% CI = 27.74–94.67), and synthetic cannabinoids/e-cigarettes had 2.19 times greater odds of appearing in 2014–2015 (95% CI = 1.64–2.93) but lower odds of appearing in 2016–2017 (RRR = 0.67, 95% CI = 0.50–0.89). Other preparations were positively associated with older age, adverse reactions, and suicide attempts but negatively associated with medical cannabis legal states. Synthetic cannabinoids/e-cigarettes were positively associated with being male, intentional misuse/abuse, and chronic use. Compared to plant forms, major medical outcomes/death were less likely among those who used other preparations (OR = 0.75, 95% CI = 0.56–0.99) but more likely among those who used synthetic cannabinoids/e-cigarettes (OR = 2.07, 95% CI = 1.60–2.66).
Conclusions
Although PCC cannabis cases involving older adults are relatively few, cases of other cannabis preparations than plant forms increased rapidly in recent years while cases of synthetic cannabinoids decreased. The rate of major medical outcomes also appears to be high.
The growing popularity of supplements containing cannabidiol (CBD), mainly CBD oils, in self-medication of humans and the increased interest in this compound in different preclinical and clinical trials stimulates the development of procedures of CBD analysis in plasma for the study of CBD pharmacology in people and animals or in establishing dose–therapeutic effect relationships of this compound. Preliminary removal of protein by its precipitation from plasma is still one of the willingly applied plasma sample preparation methods in many analytical procedures estimating plasma drug concentration, including CBD. The present paper shows that a significant amount of CBD transforms to Δ9-tetrahydrocannabinol (Δ9-THC) in a hot GC injection system when acidic precipitation agents, such as TFA, TCA, HClO4, H2SO4, ZnSO4 or CHCl3, are used for plasma protein precipitation. The transformation degree depends on the temperature of the GC injector, the concentration of the precipitation agent and the incubation time of plasma with the precipitating agent. At the CBD plasma concentration equal to 50 ng/ml, which is approximately the mean level for patients treated for epileptic syndromes, the CBD transformation degree can exceed 20 %. For a reliable estimate of CBD in blood plasma, neutral precipitation agents (e.g. ACN, MeOH, acetone) should be used when plasma deproteinization precedes GC analysis.The presented results are important not only for analysts cooperating with pharmacologists and for medicine doctors examining the activity of CBD-containing drugs in the therapeutic process, but also for forensic scientists who may erroneously find innocent people guilty of using marijuana or its preparations.