Usage and health perception of cannabidiol-containing products among the population in Germany: a descriptive study conducted in 2020 and 2021

Khalsa J.H., Bunt G., Blum K., Maggirwar S.B., Galanter M., Potenza M.N.

There have been many debates, discussions, and published writings about the therapeutic value of cannabis plant and the hundreds of cannabinoids it contains. Many states and countries have attempted, are attempting, or have already passed bills to allow legal use of cannabinoids, especially cannabidiol (CBD), as medicines to treat a wide range of clinical conditions without having been approved by a regulatory body. Therefore, by using PubMed and Google Scholar databases, we have reviewed published papers during the past 30 years on cannabinoids as medicines and comment on whether there is sufficient clinical evidence from well-designed clinical studies and trials to support the use of CBD or any other cannabinoids as medicines. Current research shows that CBD and other cannabinoids currently are not ready for formal indications as medicines to treat a wide range of clinical conditions as promoted except for several exceptions including limited use of CBD for treating two rare forms of epilepsy in young children and CBD in combination with THC for treating multiple-sclerosis-associated spasticity. Research indicates that CBD and several other cannabinoids have potential to treat multiple clinical conditions, but more preclinical, and clinical studies and clinical trials, which follow regulatory guidelines, are needed to formally recommend CBD and other cannabinoids as medicines.

Casanova C., Ramier C., Fortin D., Carrieri P., Mancini J., Barré T.

Cannabidiol (CBD), a safe, non-intoxicating cannabis component, is growing in popularity in Europe and worldwide. However, CBD EU regulation is blurry, and consequent labelling and product quality issues may have implications for public health. There is therefore a need to assess the prevalence and perceived harmfulness of CBD use in EU countries, as well as to characterise CBD users. We aimed to do so in the French population. In December 2021, an online survey was conducted in a sample respecting the French adult population structure for key demographic variables. Sociodemographic, behavioural and CBD perception data were collected. Three separate regressions were performed to identify correlates of i) having heard of CBD, ii) using CBD, iii) perceived harmfulness of CBD. A hierarchical classification was also performed to identify profiles of CBD users. The study sample comprised 1969 adults, of whom 69.2% had heard of CBD and 10.1% used it. Less than half (46.8%) of the former considered it harmful. Having heard of CBD was associated with younger age, being born in France, tobacco use, and cannabis use. CBD use was associated with younger age, tobacco use, cannabis use, poor self-reported general health status, and positive perception of alternative medicines. Cluster analysis revealed four different CBD user profiles based on socio-demographics and behavioural characteristics. Ten percent of the adults in this French study used CBD, and several user profiles emerged. Our results indirectly advocate clearer European CBD regulations to ensure safe and high-quality products.

Alayli A.F., Kotz D., Kastaun S.

Turck D., Bohn T., Castenmiller J., De Henauw S., Hirsch‐Ernst K.I., Maciuk A., Mangelsdorf I., McArdle H.J., Naska A., Pelaez C., Pentieva K., Siani A., Thies F., Tsabouri S., Vinceti M., et. al.

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.

Peng J., Fan M., An C., Ni F., Huang W., Luo J.

Cannabidiol (CBD) is an abundant non-psychoactive phytocannabinoid in cannabis extracts which has high affinity on a series of receptors, including Type 1 cannabinoid receptor (CB1), Type 2 cannabinoid receptor (CB2), GPR55, transient receptor potential vanilloid (TRPV) and peroxisome proliferator-activated receptor gamma (PPARγ). By modulating the activities of these receptors, CBD exhibits multiple therapeutic effects, including neuroprotective, antiepileptic, anxiolytic, antipsychotic, anti-inflammatory, analgesic and anticancer properties. CBD could also be applied to treat or prevent COVID-19 and its complications. Here, we provide a narrative review of CBD's applications in human diseases: from mechanism of action to clinical trials.

Li J., Carvajal R., Bruner L., Kaminski N.E.

The popularity of cannabidiol (CBD) in consumer products is soaring as consumers are using CBD for general health and well-being as well as to seek relief from ailments especially pain, inflammation, anxiety, depression, and sleep disorders. However, there are limited data currently in the public domain that provide support for these benefits. By contrast, a significant amount of safety evaluation data for CBD have been obtained recently from pre-clinical and clinical studies of the CBD therapeutic Epidiolex®. Yet some key data gaps concerning the safe use of CBD still remain. Furthermore, current regulations on CBD use in consumer products remain uncertain and often conflict between the state and federal level. In light of the rapidly expanding popularity of CBD-related products in the marketplace, here we review the current understanding of the benefits, safety, and regulations surrounding CBD in consumer products. This review does not advocate for or against the use of CBD in consumer products. Rather this review seeks to assess the state-of-the-science on the health effects and safety of CBD, to identify critical knowledge gaps for future studies, and to raise the awareness of the current regulations that govern CBD use in consumer products. • A review of the health effects of CBD in consumer products. • Assess the state-of-the-science on the safety of CBD and identify critical knowledge gaps for future studies. • Summarize the current regulations that govern CBD use in consumer products.

Lange B.M., Zager J.J.

Following decades of tight restrictions, recent legislative adjustments have decriminalized the use of products derived from cannabis (Cannabis sativa L.) in many countries and jurisdictions. This has led to a renewed interest in better understanding the chemical basis of physiological effects attributed to cannabis use. The present review article summarizes our current knowledge regarding the 130 structures of cannabinoids that have been characterized from cannabis extracts to date. We are also providing information on the methods employed for structure determination to help the reader assess the quality of the original structural assignments. Cannabinoid chemical diversity is discussed in the context of current knowledge regarding the enzymes involved in cannabinoid biosynthesis. We briefly assess to what extent cannabinoid levels are determined by the genotype of a given chemovar and discuss the limits of enzymatic control over the cannabinoid profile.

Bhamra S.K., Desai A., Imani‐Berendjestanki P., Horgan M.

The market value of cannabidiol (CBD) is growing as people seek holistic ways of managing their health. The aim of this study was to explore the public's perceptions and use of CBD products, including where products were sourced, knowledge transfer and opinions on quality, safety and efficacy of CBD products. An online questionnaire was distributed via social and professional networks, in addition to face-to-face data collection days, which employed convenience and snowball sampling methods. A total of 597 participant responses were analysed, of which 10.9% (n = 65) claimed to use CBD products for a range of ailments, including anxiety and pain. CBD products were bought from healthcare stores, vape stores, pharmacies and online. Of those who did not personally use CBD (n = 532), 35% claimed they would like to try it. A positive attitude towards the safety and efficacy of CBD was attributed to CBD being a natural product. The study highlighted that the public continue to seek natural alternatives to supplement and maintain their health; hence, the popularity of CBD continues to rise. The lack of clinical evidence and regulation of CBD needs to be addressed to facilitate safe and effective use of CBD.

Goodman S., Wadsworth E., Schauer G., Hammond D.

Objectives: This study aimed to characterize use and perceptions of cannabidiol (CBD) products. Materials and Methods: Participants aged 16-65 years in Canada (n=15,042) and the United States (n=30,288) completed measures on prevalence and patterns of CBD product use and perceptions of CBD oil as part of the 2019 International Cannabis Policy Study online survey. Results: Past 12-month CBD product use was significantly more prevalent among respondents in the United States (26.1%) than in Canada (16.2%). Consumers in the United States and Canada reported using a range of CBD products, including drops (46.3% vs. 47.3%, respectively), topicals (26.0% vs. 16.7%), edibles/foods (23.8% vs. 17.6%), vape oils (18.9% vs. 13.3%), capsules (13.3% vs. 16.7%), and dried flower (10.1% vs. 16.1%). CBD was most commonly reported for management of pain, anxiety, and depression. Over half of CBD consumers in both countries reported that CBD oil was beneficial for health. Conclusions: Use of CBD products is common in both the United States and Canada, primarily to manage self-reported health conditions for which there is little or no evidence of efficacy. Clearer public health messaging regarding the therapeutic effects of CBD is warranted.

Almeida D.L., Devi L.A.

Cannabidiol (CBD) is the second most abundant component of the Cannabis plant and is known to have effects distinct from Δ9 -tetrahydrocannabinol (THC). Many studies that examined the behavioral effects of CBD concluded that it lacks the psychotomimetic effects attributed to THC. However, CBD was shown to have a broad spectrum of effects on several conditions such as anxiety, inflammation, neuropathic pain, and epilepsy. It is currently thought that CBD engages different targets and hence CBD's effects are thought to be due to multiple molecular mechanisms of action. A well-accepted set of targets include GPCRs and ion channels, with the serotonin 5-HT1A receptor and the transient receptor potential cation channel TRPV1 channel being the two main targets. CBD has also been thought to target G protein-coupled receptors (GPCRs) such as cannabinoid and opioid receptors. Other studies have suggested a role for additional GPCRs and ion channels as targets of CBD. Currently, the clinical efficacy of CBD is not completely understood. Evidence derived from randomized clinical trials, in vitro and in vivo models and real-world observations support the use of CBD as a drug treatment option for anxiety, neuropathy, and many other conditions. Hence an understanding of the current status of the field as it relates to the targets for CBD is of great interest so, in this review, we include findings from recent studies that highlight these main targets.

Zheljazkov V.D., Sikora V., Dincheva I., Kačániová M., Astatkie T., Semerdjieva I.B., Latkovic D.

Hemp (Cannabis sativa L.) is currently one of the most controversial and promising crops. This study compared nine wild hemp (C. sativa spp. spontanea V.) accessions with 13 registered cultivars, eight breeding lines, and one cannabidiol (CBD) hemp strain belonging to C. sativa L. The first three groups had similar main essential oil (EO) constituents, but in different concentrations; the CBD hemp had a different EO profile. The concentration of the four major constituents in the industrial hemp lines and wild hemp accessions varied as follows: β-caryophyllene 11–22% and 15.4–29.6%; α-humulene 4.4–7.6% and 5.3–11.9%; caryophyllene oxide 8.6–13.7% and 0.2–31.2%; and humulene epoxide 2, 2.3–5.6% and 1.2–9.5%, respectively. The concentration of CBD in the EO of wild hemp varied from 6.9 to 52.4% of the total oil while CBD in the EO of the registered cultivars varied from 7.1 to 25%; CBD in the EO of the breeding lines and in the CBD strain varied from 6.4 to 25% and 7.4 to 8.8%, respectively. The concentrations of δ9-tetrahydrocannabinol (THC) in the EO of the three groups of hemp were significantly different, with the highest concentration being 3.5%. The EO of wild hemp had greater antimicrobial activity compared with the EO of registered cultivars. This is the first report to show that significant amounts of CBD could be accumulated in the EO of wild and registered cultivars of hemp following hydro-distillation. The amount of CBD in the EO can be greater than that in the EO of the USA strain used for commercial production of CBD. Furthermore, this is among the first reports that show greater antimicrobial activity of the EO of wild hemp vs. the EO of registered cultivars. The results suggest that wild hemp may offer an excellent opportunity for future breeding and the selection of cultivars with a desirable composition of the EO and possibly CBD-rich EO production.

Wheeler M., Merten J.W., Gordon B.T., Hamadi H.

Huestis M.A., Solimini R., Pichini S., Pacifici R., Carlier J., Busardò F.P.

Background: Currently, there is a great interest in the potential medical use of cannabidiol (CBD), a non-intoxicating cannabinoid. Productive pharmacological research on CBD occurred in the 1970s and intensified recently with many discoveries about the endocannabinoid system. Multiple preclinical and clinical studies led to FDA-approval of Epidiolex®, a purified CBD medicine formulated for oral administration for the treatment of infantile refractory epileptic syndromes, by the US Food and Drug Administration in 2018. The World Health Organization considers rescheduling cannabis and cannabinoids. CBD use around the world is expanding for diseases that lack scientific evidence of the drug’s efficacy. Preclinical and clinical studies also report adverse effects (AEs) and toxicity following CBD intake. Methods: Relevant studies reporting CBD’s AEs or toxicity were identified from PubMed, Cochrane Central, and EMBASE through January 2019. Studies defining CBD’s beneficial effects were included to provide balance in estimating risk/benefit. Results: CBD is not risk-free. In animals, CBD AEs included developmental toxicity, embryo-fetal mortality, central nervous system inhibition and neurotoxicity, hepatocellular injuries, spermatogenesis reduction, organ weight alterations, male reproductive system alterations, and hypotension, although at doses higher than recommended for human pharmacotherapies. Human CBD studies for epilepsy and psychiatric disorders reported CBD-induced drug-drug interactions, hepatic abnormalities, diarrhea, fatigue, vomiting, and somnolence. Conclusion: CBD has proven therapeutic efficacy for serious conditions such as Dravet and Lennox-Gastaut syndromes and is likely to be recommended off label by physicians for other conditions. However, AEs and potential drug-drug interactions must be taken into consideration by clinicians prior to recommending off-label CBD.

Manthey J.

In this contribution, I summarize recent trends of cannabis use in Europe and their public health implications. The first trend refers to an increase of treatment demand for cannabis problems by 76% while prevalence of cannabis use remained largely stable in the same period, based on available data. There are good reasons to assume that this trend reflects increases in the prevalence of cannabis use disorders, however, data to support this claim are not available. Potential drivers for a rising prevalence of cannabis use disorders comprise changes in consumption patterns and increasing levels of THC in available cannabis products. While an increasing prevalence of cannabis use disorders seem likely, the estimates of the Global Burden of Disease studies suggest the opposite. The second trend refers to an emerging market for cannabidiol (CBD) products in European countries, where regulations on CBD are lacking. Given the lack of data on users of CBD products, it can hardly be assessed if current abstainers will initiate using other cannabis products after trying CBD products for medicinal or recreational purposes. However, regulations should be implemented and enforced in order to make CBD products safer for consumers, for instance by ensuring reliable potency levels and by reducing the presence of toxic substances through quality control measures. In summary, a substantial transition of the epidemiology of cannabis use is under way, accompanied by changes in potency, treatment demand and new products. In order to assess the public health implications of this transition, data on population exposure of specific cannabinoids are required.

Rao J.N., Scott A.J.

The impact of survey design on standard multinomial-based methods for a multiway contingency table is studied, under nested loglinear models. The asymptotic null distribution of the Pearson chi-squared test statistic, $X^2$ (or the likelihood ratio test statistic, $G^2$) is obtained as a weighted sum of independent $\chi^2_1$ random variables, and the weights are then related to the familiar design effects (deffs) used by survey samplers. A simple correction to $X^2$ (or $G^2$) is also obtained which requires the knowledge of only the cell deffs and the deffs for collapsed tables (marginals), whenever the model admits a direct solution of likelihood equations under multinomial sampling. Finally, an example on the relative performance of $X^2$ and some corrected $X^2$ statistics in a three-way table is given, using some data from the Canada Health Survey, 1978-1979.

Engeli B.E., Lachenmeier D.W., Diel P., Guth S., Villar Fernandez M.A., Roth A., Lampen A., Cartus A.T., Wätjen W., Hengstler J.G., Mally A.

Background: Cannabidiol (CBD) is a cannabinoid present in the hemp plant (Cannabis sativa L.). Non-medicinal CBD oils with typically 5–40% CBD are advertised for various alleged positive health effects. While such foodstuffs containing cannabinoids are covered by the Novel Food Regulation in the European Union (EU), none of these products have yet been authorized. Nevertheless, they continue to be available on the European market. Methods: The Permanent Senate Commission on Food Safety (SKLM) of the German Research Foundation (DFG) reviewed the currently available data on adverse and potential beneficial effects of CBD in the dose range relevant for foods. Results: Increased liver enzyme activities were observed in healthy volunteers following administration of 4.3 mg CBD/kg bw/day and higher for 3–4 weeks. As lower doses were not tested, a no observed adverse effect level (NOAEL) could not be derived, and the dose of 4.3 mg/kg bw/day was identified as the lowest observed adverse effect level (LOAEL). Based on the CBD content and dose recommendations of CBD products on the market, the SKLM considered several exposure scenarios and concluded that the LOAEL for liver toxicity may be easily reached, e.g., via consumption of 30 drops of an oil containing 20% CBD, or even exceeded. A critical evaluation of the available data on potential beneficial health effects of CBD in the dose range at or below the LOAEL of 4.3 mg/kg bw/day revealed no scientific evidence that would substantiate health claims, e.g., in relation to physical performance, the cardiovascular, immune, and nervous system, anxiety, relaxation, stress, sleep, pain, or menstrual health. Conclusions: The SKLM concluded that consumption of CBD-containing foods/food supplements may not provide substantiated health benefits and may even pose a health risk to consumers.

Choi N.G., Marti C.N., Choi B.Y.

Choi N.G., Marti C.N., Choi B.Y.

Barré T., Cazorla G., Beo V.D., Lopez F., Radoszycki L., Maradan G., Baunez C., Carrieri P.

Perry R.N., Ethier-Gagnon M.A., Helmick C., Spinella T.C., Tibbo P.G., Stewart S.H., Barrett S.P.

Background: Cannabidiol (CBD) impacts brain regions implicated in anxiety reactivity and stress reactivity (e.g., amygdala, anterior cingulate cortex (ACC), anterior insula (AI)); however, placebo-controlled studies are mixed regarding CBD’s anxiolytic effects. We previously reported that CBD expectancy alone can alter subjective, physiological, and endocrine markers of stress/anxiety; however, it is unclear whether these findings reflect altered brain reactivity. This study evaluated whether CBD expectancy independently alters amygdala resting-state functional connectivity (rsFC) with the ACC and AI following acute stress. Method: Thirty-eight (20 females) healthy adults were randomly assigned to receive accurate or inaccurate information regarding the CBD content of a CBD-free oil administered during a single experimental session. Following a baseline resting state MRI scan, participants administered their assigned oil sublingually, engaged in a stress task (serial subtraction with negative feedback) inside the scanner, and underwent another resting state MRI scan. Amygdala rsFC with the ACC and AI was measured during each scan, and the subjective state was assessed at six time points. Outcomes were analyzed using ANCOVA. Results: CBD expectancy (vs CBD-free expectancy) was associated with significantly weaker rsFC between the left amygdala and right ACC ( p = 0.042), but did not systematically alter amygdala-AI rsFC ( p-values > 0.05). We also replicated our previously reported CBD expectancy effects on subjective stress/anxiety in the scanner context. Conclusion: CBD placebo effects may be sufficient to alter neural responses relevant to its purported anxiolytic and stress-relieving properties. Future work is needed to replicate these results and determine whether CBD expectancy and pharmacology interact to alter neural anxiety reactivity and stress reactivity.

Wisotzki E., Franke H., Sproll C., Walch S.G., Lachenmeier D.W.

Cannabidiol (CBD), a non-psychotropic main component of the Cannabis plant, has been approved as a drug in the European Union (EU) under the name “Epidyolex”. However, its approval process as a food ingredient under the Novel Food Regulation was paused by the European Food Safety Authority (EFSA) due to a lack of safety data. Nevertheless, there is a growing, unregulated market in which CBD is advertised with various health claims and dosage instructions. Of particular concern is its toxic effect on the liver and possible reproductive toxicity in humans. Studies suitable for calculating the benchmark dose were identified from the available data. Animal studies yielded a benchmark dose lower confidence limit (BMDL) of 43 mg/kg bw/day, which translates into a safe human dose of approximately 15 mg/day. Only the Lowest-Observed-Adverse-Effect Level (LOAEL) of 4.3 mg/kg bw/day could be identified from the human data. This updated risk assessment confirmed a health-based guidance value (HBGV) of 10 mg/day based on human LOAEL. Despite the existing data gaps, preliminary regulation appears advisable because the current form of the gray CBD market is unacceptable from the standpoint of consumer safety and protection.

Lindekamp N., Weigel S., Sachse B., Schäfer B., Rohn S., Triesch N.

AbstractNineteen cannabinoids, including Δ9-THC (tetrahydrocannabinol) and CBD (cannabidiol), were quantified in 22 CBD oils, 2 CBG (cannabigerol) oils, and 2 CBN (cannabinol) oils, marketed as food supplements, aroma oils, or cosmetic preparations. Analyses were conducted using high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS). The declared concentrations of CBD (or CBG, CBN) in the oils ranged from 2.5 to 20%. Actual concentrations compared to declared concentrations ranged from 81 to 226%. CBD concentrations of up to 9 mg per drop were found. Δ9-THC was detected in 20 of 26 samples, with concentrations ranging from 5 to 1576 mg/kg (mean = 536 mg/kg). Considering the highest daily intake suggested by one manufacturer (20 drops) and a body weight of 70 kg, the measured Δ9-THC concentration in 50% (n = 13) of the products would exceed the acute reference dose (ARfD) of 1 µg/kg body weight (bw) derived for Δ9-THC by the European Food Safety Authority (EFSA). For 7 samples, only 2 drops of oil would be sufficient to exceed the ARfD of Δ9-THC.

Manthey J.

AbstractCannabis use and treatment demand has risen in the past decade. Previous analyses of treatment demand are limited by methodological constraints or are outdated. Cross-country differences and trends in cannabis treatment demand are described using data from the European Monitoring Centre for Drugs and Drug Addiction. Two novel indicators are employed: firstly, the cannabis-attributable treatment fraction (CATF) is obtained by dividing the number of treatment entrants for cannabis use problems by the number of treatment entrants for any substance use problem, accounting for possible changes in the reporting system. Secondly, comparing the number of treatment entrants for cannabis use problems to the number of people who use cannabis (near) daily yields the treated-user-ratio (TUR), which considers a proxy for treatment need (frequent use). Across 30 countries with available data, the importance of cannabis in European treatment facilities varies greatly (CATF: min = 3%; max = 65%), with lower estimates in Eastern European countries. Across 20 countries with complete data, the CATF has risen from 29.4% in 2013 to 37.1% in 2020. The TUR calculated on 26 countries suggests that about 3 in 100 frequent users have sought treatment for their cannabis use problems. Over time, treatment demand has increased at a slower pace than treatment need in most countries. One in three treatment entrants for substance use problems in Europe are due to cannabis, with large variations between countries. There are indications for a widening treatment gap for cannabis use problems. In countries liberalising cannabis laws, monitoring changes in treatment access and demand is warranted.

Barré T., Lahaie E., Di Beo V., Carrieri P., Andler R., Nguyen‐Thanh V., Beck F.

AbstractIntroductionCannabidiol (CBD) is a non‐intoxicating cannabis compound found in diverse commercial products worldwide. However, its use may not be fully harmless. Accordingly, it is important to document the prevalence of CBD use and user characteristics in the general population.MethodsWe conducted a nationwide survey from a random sample of adults living in France using computer‐assisted telephone interviews between 2 March and 9 July 2022. We estimated the prevalence of CBD awareness and CBD use, and explored the different routes of administration. We also performed logistic regression models to identify factors associated with past‐year CBD use.ResultsBased on data from 3229 participants, we estimated that 71.0% (95% confidence interval) (69.0–73.0) of the French adult population had heard of CBD, and 10.1% (8.7–11.4) had used it in the previous year. Past‐year CBD use was associated with younger age, a higher educational level, not living in a middle‐sized urban unit, tobacco consumption and e‐cigarette use. The most common route of administration was smoking (56.1%).Discussion and ConclusionPast‐year CBD use prevalence in France appeared to be as high as that for cannabis. Proper prevention, regulation and control of CBD products is necessary to ensure that people have access to safe and high‐quality products. Reliable information on CBD should be sought and disseminated, especially regarding the harms associated with smoking the compound.