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Drug consumption estimates are traditionally based on surveys or information from police seizures. Alternatively, residues of illicit drugs in untreated wastewater (influent) can be used to calculate mass loads and subsequently estimate drug consumption in the community throughout the week. For this purpose, wastewater is commonly sampled for seven consecutive days within the Sewage analysis CORe group Europe (SCORE), while other sampling schemes may be implemented in long-term studies outside this consortium. The current study demonstrates how sampling frequency of illicit drug residues in the influent of wastewater treatment plants (WWTPs) affects the derived weekly average. Thirty WWTPs were sampled over the course of 12 years and influents were analyzed for five drugs (metabolites): 3,4-methylenedioxymethamphetamine (MDMA), methamphetamine, amphetamine, benzoylecgonine (a metabolite of cocaine), and 11-nor-9-Carboxy tetrahydrocannabinol (THC-COOH). Subsequently, small and large WWTPs were grouped with a threshold of 100,000 inhabitants. After data curation, standardized loads were calculated (mg/d per 1000 inhabitants). Weekly averages of loads of the drug residues were calculated based on six scenarios (sampling one to six weekdays) and compared to the weekly average in the control situation (sampling seven weekdays) in a Monte Carlo simulation. Results indicate that drug residues with more dynamic loads over a week require more frequent sampling. The analysis illustrates that a decreased sampling frequency (4 or 5 days per week) still leads to a representative weekly average for all drugs tested when a deviation up to a factor of 1.25 is deemed acceptable. However, knowledge on typical levels is necessary to define outliers. We therefore recommend to study dynamics in drug residue loads for WWTPs before reducing sampling frequency in long term monitoring programs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: There is growing recognition of the potential of cannabis to treat various medical conditions and symptoms, such as chronic pain, spasticity, and epilepsy. However, one of the biggest challenges is the assurance of a standardized cannabis product that contains a consistent amount of its main psychoactive substances delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), and which is compliant with predetermined specifications for these compounds. This is crucial not only to ensure consistent cannabis quality and dosage for patients but also to effectively translate research findings into clinical practice., Methods: This systematic literature review provides an overview of the effects of standardized cannabis products from Bedrocan, a leading Dutch producer of pharmaceutical-quality standardized medicinal cannabis., Results: Cannabis administration to healthy volunteers induces dose-dependent acute effects, such as rapidly rising THC and CBD blood concentrations, the subjective experience of high and anxiety, slower reaction time and impaired attention, learning and working memory. Patient studies suggest that treatment with medicinal cannabis reduces pain intensity across a broad range of chronic pain-related medical conditions. Medicinal cannabis showed a mild safety profile, with minor and transient side effects, such as feeling high, coughing and mental confusion. The strength of acute effects, the experience of side effects and the drop-out rate in patient studies may depend on cannabis dose, cannabis composition (CBD:THC ratio), and cannabis use history of participants., Conclusion: Safety and efficacy of standardized medicinal cannabis products should be further investigated in randomized clinical trials with sufficient sample size, with particular focus on cannabis dose and composition, age and differences between males and females., Competing Interests: Authors NL, MK, and MB were employed by Bedrocan International BV. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Leen, Kowal, Batalla and Bossong.)

Background: The survey of Copeia captured early 2022 patient-reported outcomes (PRO) in Germany under cannabis medicinal product (CAM) therapy, with particular attention to symptoms, symptom changes, indications, side effects, dosages, and cost bearers., Goal: This study investigated the question of whether associations emerge from the results that could play a role in the indication and treatment monitoring of CAM in chronically ill patients., Materials and Methods: A standardized questionnaire was administered online nationwide in dialogue form over a 15-week period to collect itemized symptoms and PRO. Recruitment was supported by pharmacies, prescribing physicians, and patient associations. Inclusion criteria included physician-prescribed CAM therapy., Results and Discussion: Of 1582 participants, 1030 data sets (65%) could be completely analyzed. There was a heterogeneous patient population, whose common feature was disease chronicity. The frequency distribution of symptoms showed a homogeneous pattern for the respective indications, in which the most frequent six (pain 71%, sleep disturbance 64%, stress/tension 52%, inner restlessness 52%, depressive mood 44% and muscle tension 43%) seem to have a special significance. According to subjective assessment, quality of life improved significantly in 84% of all participating patients., Conclusion: A symptom matrix (SMX) composed of different symptoms seems to play a special role in CAM therapy to improve the quality of life of chronically ill patients, regardless of the underlying disease. The SMX could contribute to the identification of an indication and to targeted treatment monitoring., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Chemotherapy-induced nausea and vomiting (CINV) is a debilitating side effect of cancer treatment, affecting many patients. Cannabinoid agonists, such as nabilone and Δ9-tetrahydrocannabinol (THC), the main psychoactive component of Cannabis sativa L., have shown efficacy as antiemetics. Here, we report the case of Michael Roberts (MR), who we believe is the first British patient reimbursed by the National Health Service (NHS) England for the cost of medicinal cannabis flowers to manage CINV. Medical data were obtained from NHS records and individual funding request (IFR) forms. Patient-reported outcome measures (PROMs) were collected using validated questionnaires as part of the standard of care at the specialized private clinics where the prescription of medicinal cannabis was initiated. The patient presented with rectosigmoid adenocarcinoma with lung metastases. He received FOLFIRI (folinic acid, fluorouracil, and irinotecan) chemotherapy and underwent an emergency Hartmann's procedure with subsequent second-line FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy and lung ablation. MR reported severe nausea and vomiting associated with the initial FOLFIRI treatment. Antiemetics metoclopramide and aprepitant demonstrated moderated efficacy. Antiemetics ondansetron, levomepromazine, and nabilone were associated with intolerable side effects. Inhalation of THC-predominant cannabis flowers in association with standard medication improved CINV, anxiety, sleep quality, appetite, overall mood, and quality of life. Our results add to the available evidence suggesting that medicinal cannabis flowers may offer valuable support in cancer palliative care integrated with standard-of-care oncology treatment. The successful individual funding request in this case demonstrates a pathway for other patients to gain access to these treatments, advocating for broader awareness and integration of cannabis-based medicinal products in national healthcare services., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: Guillermo Moreno-Sanz declare(s) employment from Khiron Europe. Khiron Europe is a drug manufacturer that commercializes unlicensed cannabis-based medicinal products in the UK. No other employee or executive of Khiron Europe was involved in the design of the work; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Other relationships: Michael Roberts is an author and the patient in this case report. The authors declare no other conflict of interest., (Copyright © 2024, Roberts et al.)

Hemp ( Cannabis sativa L.) is an important source of fibre and seed oil and protein. By-products of industrial hemp fibre production, like hemp seeds and cakes, can be used as feed for all animal species as fat and protein source and the whole hemp plant (including stalk and leaves) might be a suitable fibre source for ruminants. However, a previous feeding experiment with leaf-flower-seed hemp silage, made from an industrial hemp variety, demonstrated detrimental effects on cow health parameters and a significant transfer of several cannabinoids, including the psychoactive tetrahydrocannabinol (∆9-THC), into cow's milk, posing a potential risk to the safety of consumers. Based on those observations, the present study tested the hypothesis that anaerobic fermentation, as during ensiling, increases the content of ∆9-THC in hemp. Therefore, silages of whole plants from the industrial hemp Cannabis sativa L. var. Ivory were prepared in a multifactorial design, with the four treatments 1) untreated control (CON), 2) addition of 10 mL per kg fresh weight homofermentative lactobacilli at 10 5 cfu/mL (LBAC), 3) addition of 10 mL per kg fresh weight homofermentative lactobacilli at 10 5 cfu/mL plus 30 g molasses (LBACmol) and 4) addition of propionic acid (10 mL/kg fresh weight) (PRO). Ultra high performance liquid chromatography coupled with tandem mass spectrometry with electrospray ionisation (UHPLC-MS/MS) was performed for analysis of cannabinoids in fresh hemp material and after 10 and 90 days of ensiling. The study revealed that ensiling decreased all acid forms of analysed cannabinoids in hemp at about 40-65% of the initial values after 90 days of storage, with the exception of cannabinolic acid (CBNA), and CBGA, the acidic form of cannabigerol (CBG). This decrease in most acidic forms was accompanied by an increase of the corresponding non-acidic forms of all cannabinoids, including the psychoactive ∆9-THC. Thus, although ensiling decreases the total cannabinoid content, psychoactive compounds like ∆9-THC can increase, enhancing the risk for animal health and a transfer of these substances into animal derived products.

Adolescents commonly co-abuse many drugs including anabolic androgenic steroids either they are athletes or non-athletes. Stanozolol is the major anabolic used in recent years and was reported grouped with cannabis. The current study aimed at evaluating the biochemical and histopathological changes related to the hypertrophic effects of stanozolol and/or cannabis whether in condition of exercise practice or sedentary conditions. Adult male Wistar albino rats received either stanozolol (5 mg/kg, s.c), cannabis (10 mg/kg, i.p.), and a combination of both once daily for two months. Swimming exercise protocol was applied as a training model. Relative heart weight, oxidative stress biomarkers, cardiac tissue fibrotic markers were evaluated. Left ventricular morphometric analysis and collagen quantification was done. The combined treatment exhibited serious detrimental effects on the heart tissues. It increased heart tissue fibrotic markers (Masson's trichrome stain (p < 0.001), cardiac COL3 (p < 0.0001), and VEGF-A (p < 0.05)), lowered heart glutathione levels (p < 0.05) and dramatically elevated oxidative stress (increased malondialdehyde (p < 0.0001) and 8-OHDG (p < 0.0001)). Training was not ameliorating for the observed effects. Misuse of cannabis and stanozolol resulted in more hypertrophic consequences of the heart than either drug alone, which were at least largely assigned to oxidative stress, heart tissue fibrotic indicators, histological alterations, and morphometric changes., (© 2024. The Author(s).)

Introduction: ∆-8 tetrahydrocannabinol (THC) is a psychoactive cannabinoid and structural isomer of ∆-9 THC that is technically legal under United States Federal law. Commercial ∆-8-THC products being sold are currently unregulated. This study aims to (1) describe the advertising and labeling of Δ-8 THC retail products; (2) compare the advertised amount of Δ-8 THC for each product to that found during independent laboratory analysis; and (3) evaluate the presence and amount of other cannabinoids in those products., Methods: Twenty ∆-8 THC products were purchased from retail stores in Pittsburgh, PA, USA. Samples were analyzed to determine cannabinoid content using a validated UPLC-MS/MS method. Descriptive statistics were calculated for all variables. Spearman's rank order correlation was calculated for the labeled ∆-8 THC content compared to ∆-8 THC content found on our analysis. Differences in continuous variables were compared using ANOVA, Wilcoxon Rank Sum, or Kruskal-Wallis tests., Results: ∆-8 THC was detected in 95% (N=19) of the sample products. A weakly positive correlation (Spearman's rho =0.40) was found between the advertised ∆-8 THC content and our analysis results. Factors associated with decreased difference in these variables included (1) solid matrix (chocolate, gummies) and (2) absence of a "lab-tested" label. Δ-9 THC was found in 35% (N=7) of the products, and CBD was found in one., Conclusion: A majority of the products analyzed contained ∆-8 THC in amounts that could cause intoxication. The range of ∆-8 THC content on independent analysis was wide and weakly correlated to the advertised content. ∆-8 THC, ∆-9 THC, and CBD were the only cannabinoids detected., (© 2023. American College of Medical Toxicology.)

Neuropathic pain (NP) is often treated with opioids, the prolonged use of which causes tolerance to their analgesic effect and can potentially cause death by overdose. The phytocannabinoid delta-9-tetrahydrocannabinol (THC) may be an effective alternative analgesic to treat NP in morphine-tolerant subjects. Male Wistar rats developed NP after spared nerve injury, and were then treated with increasing doses of THC (1, 1.5, 2, 2.5, and 5 mg/kg, intraperitoneally), which reduced mechanical allodynia at the dose of 2.5 and 5 mg/kg. Another group of NP rats were treated with morphine (5 mg/kg, twice daily for 7 days, subcutaneously), until tolerance developed, and on day 8 received a single dose of THC (2.5 mg/kg), which significantly reduced mechanical allodynia. To evaluate the modulation of THC in the descending pain pathway, in vivo electrophysiological recordings of pronociceptive ON cells and antinociceptive OFF cells in the rostroventral medulla (RVM) were recorded after intra-PAG microinjection of THC (10 μg/μl). NP rats with morphine tolerance, compared to the control one, showed a tonic reduction of the spontaneous firing rate of ON cells by 44%, but the THC was able to further decrease it (a hallmark of many analgesic drugs acting at supraspinal level). On the other hand, the firing rate, of the antinociceptive OFF cells was increased after morphine tolerance by 133%, but the THC failed to further activate it. Altogether, these findings indicate that a single dose of THC produces antiallodynic effect in individuals with NP who are tolerant to morphine, acting mostly on the ON cells of the descending pain pathways, but not on OFF cells., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The assessment of human postmortem concentrations of Δ 9 -THC (THC) and its metabolites, 11-nor-9-carboxy-THC (THCCOOH) and 11-hydroxy-THC (11-OH-THC), is routinely performed in forensic toxicology laboratories. However, the literature on cannabinoids postmortem redistribution (PMR) is scarce and highlights their complex postmortem changes. This study aims to investigate the postmortem behavior of THC and its metabolites in order to provide practitioners with potential indicators of PMR. To do so, antemortem and postmortem cases positive for cannabinoids were compiled in a database. Its analysis shows significantly higher THC concentrations in postmortem blood than in antemortem blood. Antemortem and postmortem blood also present significantly different profiles for their THC to THCCOOH ratios. Whereas antemortem blood generally shows THCCOOH concentrations higher or equal to THC, several postmortem cases show the opposite, with THC concentrations higher than THCCOOH. While occurrence of postmortem redistribution (PMR) is difficult to measure directly, an evaluation was performed using the central to peripheral (C/P) blood concentrations ratio as a proxy. With a C/P significantly lower than 1.0 for THC and significantly higher than 1.0 for THCCOOH, the PMR hypothesis is supported for both compounds, with redistribution towards peripheral blood for THC and towards central blood for THCCOOH. On the other hand, 11-OH-THC does not show a C/P significantly different than 1.0, suggesting the absence of PMR. Influence of body mass index, conservation state and postmortem interval on C/P was statistically analyzed and no significant impact was observed. To compare and contrast C/P observed in the database with those published in the literature, a meta-analysis was performed using a median of median (MM) model. THC PMR towards peripheral blood is supported by a global estimate of 0.81 (CI 95% : 0.51 to 1.2). Redistribution towards femoral blood appears to be stronger than towards iliac blood; indeed, the median estimate of C/P decreases to 0.64 (CI 95% : 0.40 to 1.1) when studies with iliac blood were removed from the meta-analysis. THCCOOH PMR towards central blood is supported by a C/P median estimate of 1.3 (CI 95% : 0.97 to 1.6). THC PMR can be suspected when these indicators are observed (i) high THC blood concentration (>50 ng/mL), (ii) THC C/P lower than 1.0 (iii) blood THC/THCCOOH concentration ratios greater than 1.0 and (iv) non-detectability of THCCOOH in urine. In postmortem samples, many factors may contribute to the overestimation of THC concentration, therefore a careful interpretation is required, relying on both central and peripheral blood samples., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Hyperhidrosis can significantly curtail patient quality of life, from debilitating physical symptoms to social stigmatization and reduced life opportunities. Current treatments often prove unsatisfactory, especially in sufferers of generalized hyperhidrosis. In this open trial, we present the case of a refractory generalized hyperhidrosis treated with cannabinoids. We found a remarkable reduction in the volume of sweat and an improvement to the patient's quality of life using this novel low-cost and low-impact approach.

Purpose Marijuana use has been increasing in the adolescent population. Our objective was to examine the prevalence of marijuana use among a sample of adolescents and young adults, determine an association with risk-taking behaviors, identify reported medical symptoms, and delineate common beliefs about marijuana use. Methods A questionnaire was administered to a sample of patients aged between 12 and 23 years old presenting to the emergency department of Penn State Hershey Medical Center, Hershey, Pennsylvania. Data were stratified by marijuana users and non-users, and further stratified by traditional (vape, pipe, edibles) and non-traditional (oils/concentrates, topical creams) use. Results The analysis was based on 200 questionnaires. Thirty-nine percent (n=78) reported marijuana use. Marijuana users were more likely to report previous sexual intercourse (79.5% vs. 32.8%; p=<0.0001), as well as the use of alcohol (50.0% vs. 10.7%; p=<0.0001), cigarettes (41% vs. 8.2%; p=<0.0001), prescription pain medications (20.5% vs. 4.1%; p=0.002), and cocaine (14.1% vs. 0.8%; p=0.0017). Users more likely reported texting while driving (41.0% vs. 13.1%; p=0.005) and experienced physical or electronic victimization due to bullying (43.6% vs. 19.7%; p=0.002). Users were more likely to report gastroesophageal reflux disease (GERD), attention deficit disorder (ADD), anxiety, and depression. The most common symptoms associated with marijuana use were anxiety (65.4%), headache (61.6%), nausea/vomiting (53.8%), cough (51.3%), and abdominal pain (47.4%). Sixty-nine percent of respondents believed marijuana was "safer than other drugs". Conclusion Based on our sample, we identified risk-taking behaviors, medical symptoms, and beliefs associated with marijuana use. Healthcare professionals may use these data to provide screening and anticipatory guidance to adolescents who use marijuana and consider marijuana use in their differential diagnosis., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Cumbo et al.)

A highly selective microfluidic integrated metal oxide gas sensor for THC detection is reported based on MIP nanoparticles (MIP NPs). We synthesized MIP NPs with THC recognition sites and coated them on a 3D-printed microfluidic channel surface. The sensitivity and selectivity of coated microfluidic integrated gas sensors were evaluated by exposure to THC, cannabidiol (CBD), methanol, and ethanol analytes in 300-700 ppm at 300 °C. For comparison, reference signals were obtained from a microfluidic channel coated with nonimprinted polymers (NIP NPs). The MIP and NIP NPs were characterized using scanning electron microscopy (SEM) and Raman spectroscopy. MIP and NIP NPs channels response data were combined and classified with 96.3% accuracy using the Fine KNN classification model in MATLAB R2021b Classification Learner App. Compared to the MIP NPs coated channel, the NIP NPs channel had poor selectivity towards THC, demonstrating that the THC recognition sites in the MIP structure enabled selective detection of THC. The findings demonstrated that the recognition sites of MIP NPs properly captured THC molecules, enabling the selective detection of THC compared to CBD, methanol, and ethanol., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)

Background: Marijuana is legal in many Western countries and Thailand. In Taiwan, Marijuana remains a category-2 narcotic; however, some legislative candidates recently advocated legalization of medical marijuana. This study surveyed a large sample of Taiwanese to gain a better understanding of the public's knowledge and attitudes towards legalizing marijuana., Methods: This cross-sectional mixed-methods study included demographic data and responses to a survey questionnaire, "Knowledge and Attitudes of Legalizing Marijuana" (KALM). The survey included 15 statements about four categories: public health, social impact, medical applications of THC (Δ 9 -tetrahydrocannabinol), and legal and tax consequences; and two yes/no questions about medical use and legalization of marijuana. Knowledge was scored as disagree = 0, no knowledge = 2, or agree = 4; attitude was scored from 0 = very unimportant to 4 = very important. Responses to an open-ended question asking for additional comments/concerns were analysed with content analysis. The survey was conducted from February 15 to March 1, 2023., Results: Data were analysed from 38,502 respondents, aged 15 to > 56 years. Most were female (67.1%) and parents (76.4%). Scores were higher for respondents who were parents, religious, ≥ 36 years of age, had a high-income status, no history of substance abuse, knowledge of medical marijuana, and did not support legalization of marijuana. Medical personnel had greater knowledge of marijuana, but their attitude indicated they viewed legalization as less important. In the open-ended question, many respondents requested more information about marijuana be provided to the public before considering legalization., Conclusions: Taiwanese respondents considered legalization of marijuana a significant concern, especially as it relates to impacts on public health., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Increasing popularity and known shortfalls in the regulation of electronic cigarettes (ECs) emphasises the urgent need for closer content monitoring and for comprehensible information on their possible health effects. This study investigated components of EC liquids in samples submitted from 2014 to 2021 and discussed the trends driven by legislation changes. Samples originating from prisoners, teenagers and 'test purchases' of commercially available ECs were analysed by gas chromatography-mass spectrometry (GC-MS). For those containing delta-9-tetrahydrocannabinol (THC) and/or cannabidiol (CBD), the content of these components was quantified by liquid chromatography with quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) to show variation of these compounds in EC liquids; 112 EC liquids were included in this study. Nicotine was detected in 87 (78%) of the EC liquids analysed. Twenty-two, including samples from before and after introduction of the UK Psychoactive Substances Act (2016), contained one or more synthetic cannabinoid receptor agonist (SCRA). THC was detected in only 11 samples, whereas a single sample was found to contain CBD only. Six samples contained a mixture of THC and CBD. In all cases where information was available, the THC/CBD content was less than that stated on the product label. The data collected showed great variation in EC liquid content. Therefore, it is important that users are educated regarding risks associated with EC use. Additionally, substances now controlled under both the UK Misuse of Drugs Act and Psychoactive Substances Act were present. These substances each carry a potential risk to health, which is possibly exacerbated if multiple compounds are inhaled concomitantly., (© 2022 John Wiley & Sons Ltd.)

Background: This paper examines the factors that led to the collapse of hemp grown for cannabidiol (CBD) in Arizona, the United States of America (USA), and particularly in Yuma County, which is a well-established agricultural area in the state., Methods: This research uses a combination of mapping analysis along with a survey of hemp farmers to assess the reasons why the hemp industry collapsed as well as to foster solutions to these problems., Results: In 2019, 5430 acres were sown with hemp seed in Arizona with 3890 acres inspected by the state to determine if they could be harvested. By 2021, there were only 156 acres planted, and only 128 of those acres were inspected by the state for compliance. (Crop mortality accounts for the difference between acres sown and acres inspected.) CONCLUSIONS: A lack of knowledge about the hemp life cycle greatly contributed to the failure of high CBD hemp crops in Arizona. Other problems included noncompliance with tetrahydrocannabinol limits, poor sources for seeds and inconsistent genetics of the hemp varieties sold to farmers, and diseases that hemp plants were susceptible to such as Pythium crown and root rot and beet curly top virus. Addressing these factors will go far in making hemp a profitable and widespread crop in Arizona. Additionally, hemp grown for other traditional uses (e.g., fiber or seed oil) as well as new applications (e.g., microgreens, hempcrete, and phytoremediation) offers other pathways for successful hemp agriculture in this state., (© 2023. The Author(s).)

The bioavailability levels of cannabidiol (CBD) and tetrahydrocannabinol (THC) determine their pharmacological effects. Therefore, for medical purposes, it is essential to obtain extracts containing the lowest possible content of the psychogenic component THC. In our extract, the CBD/THC ratio was 16:1, which is a high level compared to available medical preparations, where it is, on average, 1:1. This study assessed the bioavailability and stability of CBD and THC derived from Cannabis sativa L. with reduced THC content. The extract was orally administered (30 mg/kg) in two solvents, Rapae oleum and Cremophor, to forty-eight Wistar rats. The whole-blood and brain concentrations of CBD and THC were measured using liquid chromatography coupled with mass spectrometry detection. Much higher concentrations of CBD than THC were observed for both solvents in the whole-blood and brain after oral administration of the Cannabis sativa extract with a decreased THC content. The total bioavailability of both CBD and THC was higher for Rapae oleum compared to Cremophor. Some of the CBD was converted into THC in the body, which should be considered when using Cannabis sativa for medical purposes. The THC-reduced hemp extract in this study is a promising candidate for medical applications., Competing Interests: The authors declare no conflict of interest.

Cannabis products are widely used for medical and non-medical reasons worldwide and vary in content of cannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Resting state functional connectivity offers a powerful tool to investigate the effects of cannabinoids on the human brain. We systematically reviewed functional neuroimaging evidence of connectivity during acute cannabinoid administration. A pre-registered (PROSPERO ID: CRD42020184264) systematic review of 13 studies comprising 318 participants (mean age of 25 years) was conducted and reported using the PRISMA checklist. During THC and THCv exposure vs placebo reduced connectivity with the NAcc was widely reported. Limited evidence shows that such effects are offset by co-administration of CBD. NAcc-frontal region connectivity was associated with intoxication levels. Cannabis intoxication vs placebo was associated with lower striatal-ACC connectivity. CBD and CBDv vs placebo were associated with both higher and lower connectivity between striatal-prefrontal/other regions. Overall, cannabis and cannabinoids change functional connectivity in the human brain during resting state as a function of the type of cannabinoid examined., Competing Interests: Conflicts of interest The authors declare no conflict of interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

As marijuana use during adolescence has been increasing, the need to understand the effects of its long-term use becomes crucial. Previous research suggested that marijuana consumption during adolescence increases the risk of developing mental illnesses, such as schizophrenia, depression, and anxiety. Ghrelin is a peptide produced primarily in the gut and is important for feeding behavior. Recent studies have shown that ghrelin and its receptor, the growth hormone secretagogue receptor (GHSR), play important roles in mediating stress, as well as anxiety and depression-like behaviors in animal models. Here, we investigated the effects of chronic tetrahydrocannabinol (THC) administration during late adolescence (P42-55) in GHSR (GHSR -/- ) knockout mice and their wild-type littermates in relation to anxiety-like behaviors. We determined that continuous THC exposure during late adolescence did not lead to any significant alterations in the anxiety-like behaviors of adult mice, regardless of genotype, following a prolonged period of no exposure (1 month). These data indicate that in the presence of intact or impaired ghrelin/GHSR signaling, THC exposure during late adolescence has limited if any long-term impact on anxiety-like behaviors in mice.

Cannabidiol (CBD) products have ascribed an uprising trend for their health-promoting effects worldwide. In contrast to Δ 9 -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-Δ 9 -THC (THC-OH), 11-nor-9-carboxy-Δ 9 -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., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: With anti-inflammatory properties, cannabinoids may be a potential strategy to reduce immune activation in people living with HIV (PLWH) but more information on their safety and tolerability is needed., Methods: We conducted an open-label interventional pilot study at the McGill University Health Centre in Montreal, Canada. PLWH were randomized to oral Δ9-tetrahydrocannabinol (THC): cannabidiol (CBD) combination (THC 2.5 mg/CBD 2.5 mg) or CBD-only capsules (CBD 200 mg). Individuals titrated doses as tolerated to a maximum daily dose THC 15 mg/CBD 15 mg or 800 mg CBD, respectively, for 12 weeks. The primary outcome was the percentage of participants without any significant toxicity based on the WHO toxicity scale (Grades 0-2 scores)., Results: Out of ten individuals, eight completed the study. Two from the CBD-only arm were withdrawn for safety concerns: phlebotomy aggravating pre-existing anemia and severe hepatitis on 800 mg CBD with newly discovered pancreatic adenocarcinoma, respectively. Seven did not have any significant toxicity. Cannabinoids did not alter hematology/biochemistry profiles. CD4 count, CD4/CD8 ratio, and HIV suppression remained stable. Most adverse effects were mild-moderate., Conclusions: In PLWH, cannabinoids seem generally safe and well-tolerated, though larger studies are needed. Screening for occult liver pathology should be performed and hepatic enzymes monitored, especially with high CBD doses.

Background: The prevalence of opioid use disorder has increased across the United States, but the rural population of Appalachia has been disproportionately impacted. Concurrently, the slow, but steady progress in the legalization of marijuana may be affecting perception of marijuana use in pregnancy. However, marijuana use in pregnancy has been associated with adverse perinatal outcomes. Concomitant use of opioids and marijuana in pregnancy has not been evaluated., Objective: The primary aim of the study was to evaluate the association between confirmed marijuana use in late pregnancy and preterm birth in opioid-exposed pregnancies., Methodology: A retrospective chart review was conducted that included all births from July 2011 to June 2016 from 6 delivery hospitals in South-Central Appalachia. Out of 18,732 births, 2368 singleton pregnancies indicated opioid use and met remaining inclusion criteria, with 108 of these mothers testing positive for marijuana at delivery. Independent sample t -test and Chi-Square analyses compared marijuana and non-marijuana exposed groups on maternal and neonatal outcomes. Regression analyses controlled for confounding variables in predicting neonatal abstinence syndrome (NAS), NICU admission, preterm birth, small for gestational age, and low birth weight outcomes as shown in Table 1., Results: Neonates born to marijuana-positive women in opioid-exposed pregnancy were more likely to be born preterm, small for gestational age, have low birth weight, and be admitted to NICU. After statistically controlling for parity, marital status, tobacco and benzodiazepine use, preterm birth and low birth weight remained statistically significant with aOR of 2.35 (1.30-4.24) and 2.01 (1.18-3.44), respectively., Conclusions: Maternal use of marijuana in any opioid-exposed pregnancy may increase risk of preterm birth and low-birth weight infants. Prospective studies need to examine the dose and timing of marijuana and opioid use in pregnancy to better delineate perinatal effects. Nonetheless, pregnant women using opioids, including recommended medication assisted treatment for opioid use disorder, should be educated about the risks of concurrent marijuana use during pregnancy and may need to be counseled to abstain from marijuana use during pregnancy for an optimal outcome.

Recent studies highlight the therapeutic virtues of cannabidiol (CBD). Furthermore, due to their molecular enriched profiles, cannabis inflorescences are biologically superior to a single cannabinoid for the treatment of various health conditions. Thus, there is flourishing demand for Cannabis sativa varieties containing high levels of CBD. Additionally, legal regulations around the world restrict the cultivation and consumption of tetrahydrocannabinol (THC)-rich cannabis plants for their psychotropic effects. Therefore, the use of cannabis varieties that are high in CBD is permitted as long as their THC content does not exceed a low threshold of 0.3%-0.5%, depending on the jurisdiction. These chemovars are legally termed 'hemp'. This controlled cannabinoid requirement highlights the need to detect low levels of THC, already in the field. In this review, cannabis profiling and the existing methods used for the detection of cannabinoids are firstly evaluated. Then, selected valuable biosensor technologies are discussed, which suggest portable, rapid, sensitive, reproducible, and reliable methods for on-site identification of cannabinoids levels, mainly THC. Recent cutting-edge techniques of promising potential usage for both cannabis and hemp analysis are identified, as part of the future cultivation and agricultural improvement of this crop., Competing Interests: Declaration of Competing Interest The authors declared no potential conflicts of interest concerning the research, authorship, and/or publication of this article., (Copyright © 2022 Elsevier Inc. All rights reserved.)

With the recent legalization of marijuana in several countries for recreational use, a controversial belief is spreading about it being "safe". In this systematic review, we decided to investigate this belief and present the adverse effects of marijuana and tobacco smoking on the cardiovascular system. We carried out an electronic search on databases including PubMed, PubMed Central, and Medline. Medical Subject Headings (MeSH) terms and different keywords were used for data collection. We included studies published in the last 10 years that were in English. All types of study subjects were accepted. Grey literature, books, case reports and case series, overlapping and duplicate studies, and studies older than 10 years were excluded. In this review, we included 18 studies, which we then separated into the "tobacco and cardiovascular disease" arm and the "cannabinoids and cardiovascular disease" arm. We had 11 and seven studies for each of the arms, respectively. The types of articles included in this review were traditional and systematic reviews and meta-analyses. After reviewing all the data included in this article, we found out that cannabinoid consumption has a more devastating effect on the cardiovascular system when compared to tobacco. The shocking fact was that in several cases, deadly adverse effects were observed in patients within a few hours after consumption or even during their first time using cannabinoids., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Abu Jad et al.)

Nonalcoholic fatty liver disease (NAFLD), alcohol-induced liver disease (ALD), and viral hepatitis are the main causes of morbidity and mortality related to chronic liver diseases (CLDs) worldwide. New therapeutic approaches to prevent or reverse these liver disorders are thus emerging. Although their etiologies differ, these CLDs all have in common a significant dysregulation of liver metabolism that is closely linked to the perturbation of the hepatic endocannabinoid system (eCBS) and inflammatory pathways. Therefore, targeting the hepatic eCBS might have promising therapeutic potential to overcome CLDs. Experimental models of CLDs and observational studies in humans suggest that cannabis and its derivatives may exert hepatoprotective effects against CLDs through diverse pathways. However, these promising therapeutic benefits are not yet fully validated, as the few completed clinical trials on phytocannabinoids, which are thought to hold the most promising therapeutic potential (cannabidiol or tetrahydrocannabivarin), remained inconclusive. Therefore, expanding research on less studied phytocannabinoids and their derivatives, with a focus on their mode of action on liver metabolism, might provide promising advances in the development of new and original therapeutics for the management of CLDs, such as NAFLD, ALD, or even hepatitis C-induced liver disorders.

Cannabis use and depression management have been studied, with a preponderance of exacerbating effects, but there are few studies on postpartum depression (PPD). Depression affects a significant number of women, with a portion of it manifesting as PPD in childbearing women in the United States each year. The pharmacologic management approaches have disadvantages such as side effects, cost-benefit ratio, contraindications, use reluctance, medication adherence, and stigmatization in patients. Anecdotal claims of medical cannabis' therapeutic benefits have led to widespread legalization in several regions, making cannabis and its extracts a possible alternative. Cannabis is widely used during pregnancy and in general. Even though substance use disorders exacerbating depression symptoms have been reported, there are increasing reports and evidence about the therapeutic benefit of dose-dependent cannabis or its extracts in some depression symptoms, such as acute psychosocial stress relief, its purported anxiolytic effect, appetite, and sleep quality, thus stimulating more interest that may be inferred to depression. PPD marijuana use is unclear. This paper reviewed works of literature that claimed cannabis' therapeutic benefit in treating depression and, by extension, PPD. Our findings show the link between cannabis and PPD has not been fully explored. Self-reported studies link marijuana uses to positive mood, anxiety relief, sleep regulation, nausea and vomiting reduction, and appetite stimulation-all PPD symptoms. Others opposed postpartum marijuana use., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Ayisire et al.)

The widespread use of phytocannabinoids or cannabis extracts as ingredients in numerous types of products, in combination with the legal restrictions on THC content, has created a need for the development of new, rapid, and universal analytical methods for their quantitation that ideally could be applied without separation and standards. Based on previously described qNMR studies, we developed an expanded 1 H qNMR method and a novel 2D-COSY qNMR method for the rapid quantitation of ten major phytocannabinoids in cannabis plant extracts and cannabis-based products. The 1 H qNMR method was successfully developed for the quantitation of cannabidiol (CBD), cannabidiolic acid (CBDA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), cannabigerol (CBG), cannabigerolic acid (CBGA), Δ9-tetrahydrocannabinol (Δ9-THC), Δ9-tetrahydrocannabinolic acid (Δ9-THCA), Δ8-tetrahydrocannabinol (Δ8-THC), cannabielsoin (CBE), and cannabidivarin (CBDV). Moreover, cannabidivarinic acid (CBDVA) and Δ9-tetrahydrocannabivarinic acid (Δ9-THCVA) can be distinguished from CBDA and Δ9-THCA respectively, while cannabigerovarin (CBGV) and Δ8-tetrahydrocannabivarin (Δ8-THCV) present the same 1 H-spectra as CBG and Δ8-THC, respectively. The COSY qNMR method was applied for the quantitation of CBD, CBDA, CBN, CBG/CBGA, and THC/THCA. The two methods were applied for the analysis of hemp plants; cannabis extracts; edible cannabis medium-chain triglycerides (MCT); and hemp seed oils and cosmetic products with cannabinoids. The 1 H-NMR method does not require the use of reference compounds, and it requires only a short time for analysis. However, complex extracts in 1 H-NMR may have a lot of signals, and quantitation with this method is often hampered by peak overlap, with 2D NMR providing a solution to this obstacle. The most important advantage of the COSY NMR quantitation method was the determination of the legality of cannabis plants, extracts, and edible oils based on their THC/THCA content, particularly in the cases of some samples for which the determination of THC/THCA content by 1 H qNMR was not feasible.

E-cigarette, or vaping, product use-associated lung injury (EVALI) outbreak was linked to vitamin E acetate (VEA) used as a solvent for tetrahydrocannabinol (THC). Several studies were conducted to assess the products of VEA (and THC/VEA mixtures) thermal degradation as a result of vaporizing/aerosolizing from a traditional type (coil-cotton wick) and ceramic type coil vape pens. The particle size distribution (PSD) of VEA aerosol and the temperature VEA and THC/VEA mixtures are heated to were also measured for a few types of traditional and ceramic vape pens. The current study assessed the PSD of the aerosol generated from THC, VEA, and a number of THC/VEA mixtures using a dab-type vape pen under two different temperature settings and two puffing flow rates. Thermal degradation of THC, VEA, and THC/VEA mixtures were also assessed, and coil temperature was measured. Results showed the dependence of the PSD upon the chemical content of the aerosolized mixture as well as upon the puffing flow rate. Minimal thermal degradation was observed. Flaws in the vape pen's design, which most likely affected results, were detected. The suitability of VEA, THC, and THC/VEA mixtures with certain types of vape pens was discussed.

Background: Despite the absence of rigorous prospective studies, there has been an increase in the use of cannabis-based medicinal products. During the study period, the use of medical cannabis in Israel was tightly regulated by national policy. Through a prospective study of approximately 10,000 patients, we aimed to characterize the medical cannabis patient population as well as to identify treatment adherence, safety, and effectiveness., Methods and Findings: In this study of prescribed medical cannabis patients, adherence, safety, and effectiveness were assessed at 6 months. Treatment adherence was assessed by the proportion of patients purchasing the medication out of the total number of patients (excluding deceased cases and patients transferred to another cannabis clinic). Safety was assessed by the frequency of the side-effects, while effectiveness was defined as at least moderate improvement in the patient condition without treatment cessation or serious side-effects. The most frequent primary indications requiring therapy were cancer (49.1%), followed by non-specific pain (29.3%). The average age was 54.6 ± 20.9 years, 51.1% males; 30.2% of the patients reported prior experience with cannabis. During the study follow-up, 1,938 patients died (19.4%) and 1,735 stopped treatment (17.3%). Common side-effects, reported by 1,675 patients (34.2%), were: dizziness (8.2%), dry mouth (6.7%), increased appetite (4.7%), sleepiness (4.4%), and psychoactive effect (4.3%). Overall, 70.6% patients had treatment success at 6 months. Multivariable logistic regression analysis revealed that the following factors were associated with treatment success: cigarette smoking, prior experience with cannabis, active driving, working, and a young age. The main limitation of this study was the lack of data on safety and effectiveness of the treatment for patients who refused to undergo medical assessment even at baseline or died within the first 6 months., Conclusions: We observed that supervised medical-cannabis treatment is associated with high adherence, improvement in quality of life, and a decrease in pain level with a low incidence of serious adverse events., Competing Interests: This study was supported by the funding from Tikun Olam - Cannbit Pharmaceuticals. The funder had the following involvement with the study: data collection. Lihi Bar-Lev Schleider is an employee of Tikun-Olam Cannbit Pharmaceuticals Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bar-Lev Schleider, Mechoulam, Sikorin, Naftali and Novack.)

Background: Δ9-tetrahydrocannabinol (THC) has been shown to decreased intraocular pressure (IOP). This project aims to define the relationship between plasma THC levels and IOP in healthy adult subjects., Methods: Eleven healthy subjects received a single dose of inhaled cannabis that was self-administered in negative pressure rooms. Measurements of IOP and plasma THC levels were taken at baseline and every 30 min for 1 h and afterwards every hour for 4 h. IOP reduction and percent change in IOP over time were calculated. Linear regression models were used to measure the relationship between IOP and plasma THC levels. Two line linear regression models with F-tests were used to detect change points in the regression. Then, Pearson correlations were computed based on the change point., Results: Twenty-two eyes met inclusion criteria. The average peak percentage decrease in IOP was 16% at 60 min. Percent IOP reduction as well as total IOP reduction demonstrated a negative correlation with THC plasma levels showing r-values of -0.81 and -0.70, respectively. F -tests revealed a change point in the regression for plasma levels >20 ng/ml. For levels >20 ng/ml, the correlation coefficients changed significantly with r -values of 0.21 and 0.29 ( p < 0.01)., Conclusion: Plasma THC levels are significantly correlated with IOP reduction up to plasma levels of 20 ng/ml. Plasma levels >20 ng/ml were not correlated with further decrease in IOP. More research is needed to determine the efficacy of THC in reducing IOP for eyes with ocular hypertension and glaucoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mosaed, Smith, Liu, Minckler, Fitzgerald, Grelotti, Sones, Weinreb and Marcotte.)

Depression and anxiety disorders are two of the most common and growing mental health concerns in adolescents. Consequently, antidepressant medication (AD) use has increased widely during the last decades. Several classes of antidepressants are used mainly to treat depression, anxiety, and obsessive-compulsive disorders by targeting relevant brain neurochemical pathways. Almost all randomized clinical trials of antidepressants examined patients with no concomitant medications or drugs. This does not address the expected course of therapy and outcome in cannabis users. Cannabis is the most commonly used illicit substance globally. Substantial changes in its regulation are recently taking place. Many countries and US states are becoming more permissive towards its medical and recreational use. The psychological and physiological effects of cannabis (mainly of its major components, tetrahydrocannabinol (THC) and cannabidiol (CBD)) have been extensively characterized. Cannabis use can be a risk factor for depressive and anxiety symptoms, but some constituents or mixtures may have antidepressant and/or anxiolytic potential. The aim of this literature review is to explore whether simultaneous use of AD and cannabis in adolescence can affect AD treatment outcomes. Based on the current literature, it is reasonable to assume that antidepressants are less effective for adolescents with depression/anxiety who frequently use cannabis. The mechanisms of action of antidepressants and cannabis point to several similarities and conjunctions that merit future investigation regarding the potential effectiveness of antidepressants among adolescents who consume cannabis regularly.

The use of natural products has been increasing at a rapid pace, worldwide, with the aim to maintain a healthy lifestyle and to modify one's dietary habits. Ayurveda is a domain that has numerous wealth of information concerning medicinal plants and its part in controlling numerous ailments, such as neoplastic, cardiovascular, neurological plus immunological ailments. The use of such medicinal plants is important for preventing such diseases, especially "cancer" which is the succeeding foremost cause of mortality collectively. Even though abundant developments have been made in the management and control of cancer progression, substantial deficits and scope for advancement still continue to be unchanged. Several lethal adjacent consequences occur throughout the course of chemotherapy. Natural treatments, such as the use of plant-derived products in the treatment of cancer, might reduce the hostile side effects. Presently, a few plant-based products and its phytoconstituents are being utilized for the management of cancer. Here we have focused on numerous plant-derived phytochemicals and promising compounds from these plants to act as anticancer agents, along with their mechanisms of action., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Multiple sclerosis (MS) treatment has radically improved over the last years; however, MS symptom management is still challenging. The novel Spasticity-Plus syndrome was conceptualized to frame several spasticity-related symptoms that can be addressed together with broad-spectrum medication, such as certain cannabinoid-based drugs. The aim of this project was to gain insight into Spanish neurologists' clinical experience on MS spasticity and associated symptoms, and to assess the acknowledgment and applicability of the Spasticity-Plus syndrome concept in patients with MS. Methods: Ten online meetings were conducted using the Workmat ® methodology to allow structured discussions. Fifty-five Spanish neurologists, experts in MS management, completed and discussed a set of predefined exercises comprising MS symptom assessment and its management in clinical practice, MS symptoms clustering in clinical practice, and their perception of the Spasticity-Plus syndrome concept. This document presents the quantitative and qualitative results of these discussions. Results: The specialists considered that polytherapy is a common concern in MS and that simplifying the management of MS spasticity and associated manifestations could be useful. They generally agreed that MS spasticity should be diagnosed before moderate or severe forms appear. According to the neurologists' clinical experience, symptoms commonly associated with MS spasticity included spasms/cramps (100% of the specialists), pain (85%), bladder dysfunction (62%), bowel dysfunction (42%), sleep disorders (42%), and sexual dysfunction (40%). The multiple correspondence analysis revealed two main symptom clusters: spasticity-spasms/cramps-pain, and ataxia-instability-vertigo. Twelve out of 16 symptoms (75%) were scored >7 in a 0-10 QoL impact scale by the specialists, representing a moderate-high impact. The MS specialists considered that pain, spasticity, spasms/cramps, bladder dysfunction, and depression should be a treatment priority given their frequency and chance of therapeutic success. The neurologists agreed on the usefulness of the new Spasticity-Plus syndrome concept to manage spasticity and associated symptoms together, and their experience with treatments targeting the cannabinoid system was satisfactory. Conclusions: The applicability of the new concept of Spasticity-Plus in MS clinical practice seems possible and may lead to an integrated management of several MS symptoms, thus reducing the treatment burden of disease symptoms., Competing Interests: The study was funded by an investigational grant from Almirall SA. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Authors' views and opinions are not necessarily aligned with those of Almirall SA. OF has received honoraria as consultant in advisory boards, as chair/lecturer in meetings, and from participation in clinical trials and other research projects promoted by Actelion, Allergan, Almirall, Bayer-Schering, Biogen-Idec, Genzyme, Merck-Serono, Novartis, Orizon, Roche, and Teva. LC-F has received honoraria as consultant in advisory boards, travel support, and speaker fees and from participation in clinical trials and other research projects promoted by Almirall, Bayer, Biogen-Idec, Biopas, Bristol Myers Squibb, Merck-Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. MM-G has received compensation for consulting services and speaking fees and from participation in clinical trials from Almirall, Bayer-Schering, Biogen-Idec, Bristol Myers Squibb, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. PM has received honoraria as consultant in advisory boards, travel support, and speaker fees and from participation in clinical trials and other research projects promoted by Allergan, Almirall, Biogen-Idec, Merck-Serono, Merz, Sanofi-Genzyme and, Teva. JP-G has received honoraria as consultant for Bayer Pharmaceuticals, Biogen Spain S.L., Genzyme Corporation, Merck Serono, Novartis Pharmaceuticals Corporation, Sanofi, Teva Pharmaceutical Industries, Roche Pharma, Almirall Prodesfarma S.A., and Celgene España S.L. JP-G has participated as lecturer/moderator at meetings and/or symposia organized by Almirall Prodesfarma S.A., Bayer Pharmaceuticals, Biogen Spain S.L., Genzyme Corporation, Merck Serono, Novartis Pharmaceuticals Corporation, Sanofi, Teva Pharmaceutical Industries, and Roche Pharma. JP-G has received funding for research projects from Almirall Prodesfarma S.A., Biogen Spain S.L., Novartis Pharmaceutical Corporation, Teva Pharmaceutical Industries, and Sanofi. LR-T has received honoraria as consultant in advisory boards, as chair/lecturer in meetings, and from participation in clinical trials and other research projects promoted by Almirall, Bayer, Biogen-Idec, Sanofi, Genzyme, Merck, Novartis, Roche, Bristol-Myers, and Teva., (Copyright © 2021 Fernandez, Costa-Frossard, Martínez-Ginés, Montero, Prieto-González and Ramió-Torrentà.)

Background: Patients with cancer have played a key role in advocating for legal access to cannabis, but little is known about links between cancer and cannabis use or cannabis-related beliefs. The authors used data from a national survey to study these relationships., Methods: Nationally representative data collected by the National Survey on Drug Use and Health from 2015 to 2019 were acquired. Patterns of cannabis use and cancer history were examined and tested within age group subpopulations via domain analysis using survey weights., Results: Data for 214,505 adults, including 4741 individuals (3.8%) with past (>1 year ago) cancer diagnosis and 1518 individuals (1.2%) with recent (≤1 year ago) cancer diagnosis, were examined. Cannabis use was less common in those with past (8.9%; 95% CI, 8.0%-9.8%) or recent (9.9%; 95% CI, 6.9%-11.1%) cancer diagnosis than in those without a history of cancer (15.9%; 95% CI, 15.7%-16.1%). However, when analyses were stratified by age group, those 18 to 34 years of age were more likely to report past cannabis use, and those 35 to 49 years of age were more likely to report past or recent cannabis use if they had a history of cancer. Younger patients felt that cannabis was more accessible and less risky if they had a history of cancer., Conclusions: Patients with cancer were less likely to report cannabis use, but there were different cannabis perceptions and use patterns by age. Age should be considered in studies of cannabis and cancer, and policy initiatives may be needed to aid provision of quality information on cannabis risk to those with cancer., Lay Summary: Cannabis (marijuana) use is increasing in the United States, but we do not have much information on the relationship between cannabis use and cancer. We studied information from a representative group of people and found that younger patients generally reported more past and/or recent cannabis use if they had been diagnosed with cancer whereas older individuals did not. Beliefs about cannabis risk and accessibility differed by age. Clinical trials to study cannabis should account for patient age, and accurate information about cannabis should be provided to help patients with cancer make decisions about cannabis use., (© 2021 American Cancer Society.)

High consumer demand for cannabidiol (CBD) has made high-CBD hemp ( Cannabis sativa ) an extremely high-value crop. However, high demand has resulted in the industry developing faster than the research, resulting in the sale of many hemp accessions with inconsistent performance and chemical profiles. These inconsistencies cause significant economic and legal problems for growers interested in producing high-CBD hemp. To determine the genetic and phenotypic consistency in available high-CBD hemp varieties, we obtained seed or clones from 22 different named accessions meant for commercial production. Genotypes (∼48,000 SNPs) and chemical profiles (% CBD and THC by dry weight) were determined for up to 8 plants per accession. Many accessions-including several with the same name-showed little consistency either genetically or chemically. Most seed-grown accessions also deviated significantly from their purported levels of CBD and THC based on the supplied certificates of analysis. Several also showed evidence of an active tetrahydrocannabinolic acid (THCa) synthase gene, leading to unacceptably high levels of THC in female flowers. We conclude that the current market for high-CBD hemp varieties is highly unreliable, making many purchases risky for growers. We suggest options for addressing these issues, such using unique names and developing seed and plant certification programs to ensure the availability of high-quality, verified planting materials., Competing Interests: MJ and JW were involved in the development of new hemp varieties (licensed through the University of Georgia) and received research funds to this end from GaXtracts, where MJ was subsequently employed., (Copyright © 2021 Johnson and Wallace.)

Background: Cannabis growing practices and particularly indoor cultivation conditions have a great influence on the production of cannabinoids. Plant-associated microbes may affect nutrient acquisition by the plant. However, beneficial microbes influencing cannabinoid biosynthesis remain largely unexplored and unexploited in cannabis production., Objective: To summarize study outcomes on bacterial and fungal communities associated with cannabis using high-throughput sequencing technologies and to uncover microbial interactions, species diversity, and microbial network connections that potentially influence secondary metabolite production in cannabis., Materials and Method: A mini review was conducted including recent publications on cannabis and their associated microbiota and secondary metabolite production., Results: In this review, we provide an overview of the potential role of the soil microbiome in production of cannabinoids, and discussed that manipulation of cannabis-associated microbiome obtained through soil amendment interventions of diversified microbial communities sourced from natural forest soil could potentially help producers of cannabis to improve yields of cannabinoids and enhance the balance of cannabidiol (CBD) and tetrahydrocannabinol (THC) proportions., Conclusion: Cannabis is one of the oldest cultivated crops in history, grown for food, fiber, and drugs for thousands of years. Extension of genetic variation in cannabis has developed into wide-ranging varieties with various complementary phenotypes and secondary metabolites. For medical or pharmaceutical purposes, the ratio of CBD to THC is key. Therefore, studying soil microbiota associated with cannabis and its potential impact on secondary metabolites production could be useful when selecting microorganisms as bioinoculant agents for enhanced organic cannabinoid production.

Although still not approved at the federal level for medical or adult recreational use, cannabis has been approved in the United States (USA) by individual states for both of these purposes. A total of 15 states now regulate cannabis for adult use and 36 states for medical use. In more recent years, cannabis has gained popularity for the treatment of chronic conditions, inflammatory bowel disease (IBD) being one of them. However, the exact role of cannabis in the treatment of IBD remains uncertain. While cannabis may help in some instances with symptom management, it has not been proven to help with inflammation or to fundamentally correct underlying disease processes. Additionally, along with the perceived symptom benefits of cannabis come concerning issues like dosing inconsistencies, dependence, and cannabinoid hyperemesis syndrome. In this review article, we explore the nuanced relationship between cannabis and the treatment of IBD by summarizing the current research. We also use clinical vignettes to discuss the more practical considerations surrounding its use., (© 2021. The Author(s).)

Demand for cannabidiol (CBD), the predominant cannabinoid in hemp (Cannabis sativa), has favored cultivars producing unprecedented quantities of CBD. We investigated the ancestry of a new cultivar and cannabinoid synthase genes in relation to cannabinoid inheritance. A nanopore-based assembly anchored to a high-resolution linkage map provided a chromosome-resolved genome for CBDRx, a potent CBD-type cultivar. We measured cannabinoid synthase expression by cDNA sequencing and conducted a population genetic analysis of diverse Cannabis accessions. Quantitative trait locus mapping of cannabinoids in a hemp × marijuana segregating population was also performed. Cannabinoid synthase paralogs are arranged in tandem arrays embedded in long terminal repeat retrotransposons on chromosome 7. Although CBDRx is predominantly of marijuana ancestry, the genome has cannabidiolic acid synthase (CBDAS) introgressed from hemp and lacks a complete sequence for tetrahydrocannabinolic acid synthase (THCAS). Three additional genomes, including one with complete THCAS, confirmed this genomic structure. Only cannabidiolic acid synthase (CBDAS) was expressed in CBD-type Cannabis, while both CBDAS and THCAS were expressed in a cultivar with an intermediate tetrahydrocannabinol (THC) : CBD ratio. Although variation among cannabinoid synthase loci might affect the THC : CBD ratio, variability among cultivars in overall cannabinoid content (potency) was also associated with other chromosomes., (© 2021 The Authors New Phytologist © 2021 New Phytologist Foundation.)

Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most notable Cannabis components with pharmacological activity and their content in the plant flowers and extracts are considered as critical quality parameters. The new Medical Cannabis industry needs to adopt the quality standards of the pharmaceutical industry, however, the variability of phytocannabinoids content in the plant material often exerts an issue in the inconsistency of the finished product quality parameters. Sampling problems and sample representativeness is a major limitation in the end-point testing, particularly when the expected variation of the product quality parameters is high. Therefore, there is an obvious need for the introduction of Process Analytical Technology (PAT) for continuous monitoring of the critical quality parameters throughout the production processes. Infrared spectroscopy is a promising analytical technique that is consistent with the PAT requirements and its implementation depends on the advances in instrumentation and chemometrics that will facilitate the qualitative and quantitative aspects of the technique. Our present work aims in highlighting the potential of mid-infrared (MIR) spectroscopy as PAT in the quantification of the main phytocannabinoids (THC and CBD), considered as critical quality/material parameters in the production of Cannabis plant and extract. A detailed assignment of the bands related to the molecules of interest (THC, CBD) was performed, the spectral features of the decarboxylation of native flowers were identified, and the specified bands for the acid forms (THCA, CBDA) were assigned and thoroughly explained. Further, multivariate models were constructed for the prediction of both THC and CBD content in extract and flower samples from various origins, and their prediction ability was tested on a separate sample set. Savitskzy-Golay smoothing and the second derivative of the native MIR spectra (1800-400 cm -1 region) resulted in best-fit parameters. The PLS models presented satisfactory R2Y and RMSEP of 0.95 and 3.79% for THC, 0.99 and 1.44% for CBD in the Cannabis extract samples, respectively. Similar statistical indicators were noted for the Partial least-squares (PLS) models for THC and CBD prediction of decarboxylated Cannabis flowers (R2Y and RMSEP were 0.99 and 2.32% for THC, 0.99 and 1.33% for CBD respectively). The VIP plots of all models demonstrated that the THC and CBD distinctive band regions bared the highest importance for predicting the content of the molecules of interest in the respected PLS models. The complexity of the sample (plant tissue or plant extract), the variability of the samples regarding their origin and horticultural maturity, as well as the non-uniformity of the plant material and the flower-ATR crystal contact (in the case of Cannabis flowers) were governing the accuracy descriptors. Taking into account the presented results, ATR-MIR should be considered as a promising PAT tool for THC and CBD content estimation, in terms of critical material and quality parameters for Cannabis flowers and extracts., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Cannabis/cannabinoids are widely used for recreational and therapy purposes, but their risks are largely disregarded. However, cannabinoid-associated use disorders and dependence are alarmingly increasing and an effective treatment is lacking. Recently, the growth hormone secretagogue receptor (GHSR1A) antagonism was proposed as a promising mechanism for drug addiction therapy. However, the role of GHS-R1A and its endogenous ligand ghrelin in cannabinoid abuse remains unclear. Therefore, the aim of our study was to investigate whether the GHS-R1A antagonist JMV2959 could reduce the tetrahydrocannabinol (THC)-induced conditioned place preference (CPP) and behavioral stimulation, the WIN55,212-2 intravenous self-administration (IVSA), and the tendency to relapse. Following an ongoing WIN55,212-2 self-administration, JMV2959 3 mg/kg was administered intraperitoneally 20 min before three consequent daily 120-min IVSA sessions under a fixed ratio FR1, which significantly reduced the number of the active lever-pressing, the number of infusions, and the cannabinoid intake. Pretreatment with JMV2959 suggested reduction of the WIN55,212-2-seeking/relapse-like behavior tested in rats on the twelfth day of the forced abstinence period. On the contrary, pretreatment with ghrelin significantly increased the cannabinoid IVSA as well as enhanced the relapse-like behavior. Co-administration of ghrelin with JMV2959 abolished/reduced the significant efficacy of the GHS-R1A antagonist in the cannabinoid IVSA. Pretreatment with JMV2959 significantly and dose-dependently reduced the manifestation of THC-induced CPP. The THC-CPP development was reduced after the simultaneous administration of JMV2959 with THC during conditioning. JMV2959 also significantly reduced the THC-induced behavioral stimulation in the LABORAS cage. Our findings suggest that GHS-R1A importantly participates in the rewarding/reinforcing effects of cannabinoids., Competing Interests: We declare no conflicts of interests.

Cannabis sativa ( Cannabis ) is one of the world's most well-known, yet maligned plant species. However, significant recent research is starting to unveil the potential of Cannabis to produce secondary compounds that may offer a suite of medical benefits, elevating this unique plant species from its illicit narcotic status into a genuine biopharmaceutical. This review summarises the lengthy history of Cannabis and details the molecular pathways that underpin the production of key secondary metabolites that may confer medical efficacy. We also provide an up-to-date summary of the molecular targets and potential of the relatively unknown minor compounds offered by the Cannabis plant. Furthermore, we detail the recent advances in plant science, as well as synthetic biology, and the pharmacology surrounding Cannabis. Given the relative infancy of Cannabis research, we go on to highlight the parallels to previous research conducted in another medically relevant and versatile plant, Papaver somniferum (opium poppy), as an indicator of the possible future direction of Cannabis plant biology. Overall, this review highlights the future directions of cannabis research outside of the medical biology aspects of its well-characterised constituents and explores additional avenues for the potential improvement of the medical potential of the Cannabis plant.

Objective: To evaluate the use of a Cannabis sativa oil in the management of patients diagnosed with primary burning mouth syndrome (BMS)., Design: Prospective, open-label, single-arm pilot study., Setting: University hospital., Subjects: Seventeen patients with diagnosed BMS were included., Methods: Subjects were treated for 4 weeks with a full cannabis plant extract, which was prepared from standardized plant material (cannabis flos) in specialized pharmacies by means of Romano-Hazekamp extraction and was diluted in oil (1 g of cannabis in 10 g of olive oil). The primary outcome was the change in pain intensity (assessed by the visual analog scale, Present Pain Intensity scale, McGill Pain Questionnaire, and Oral Health Impact Profiles) at the end of the protocol and during the succeeding 24 weeks; the neuropathic pain was also investigated with a specific interview questionnaire (DN4-interview [Douleur Neuropathique en 4 Questions]). Levels of anxiety and depression were considered as secondary outcomes, together with reported adverse events due to the specified treatment., Results: Subjects showed a statistically significant improvement over time in terms of a clinical remission of the oral symptoms. Levels of anxiety and depression also changed statistically, displaying a favorable improvement. No serious reactions were detailed. None of the patients had to stop the treatment due to adverse events., Conclusions: In this pilot evaluation, the C. sativa oil provided was effective and well tolerated in patients with primary BMS. Further bigger and properly defined randomized controlled trials, with different therapeutic approaches or placebo control, are needed, however., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cannabis is commonly used among people who drink alcohol, but findings are mixed regarding the direction of this relationship. The type of cannabis used [high-cannabidiol (CBD) vs. high-delta-9tetrahydrocannabinol (THC)] and motives for use (i.e., whether cannabis is used to treat a medical condition) may influence the relationship between cannabis and drinking. Specifically, CBD has shown preclinical promise in reducing alcohol consumption, and medical cannabis users report using cannabis to reduce drinking. This study leverages survey data from cannabis users who drink alcohol ( N = 533). Respondents were categorized as using cannabis to treat (CTT) a medical condition or as individuals whose cannabis use is not intended to treat (NCTT) a medical condition and grouped based on the THC/CBD ratio of the flower or edible cannabis they typically use (e.g., "High-THC/CBD," "Medium-THC/CBD" and "Low-THC/CBD"). The CTT group ( n = 412) reported drinking significantly less frequently than the NCTT group ( n = 121). Cannabinoid content of flower cannabis was associated with alcohol consumed on cannabis-use days, such that individuals in the High-THC/CBD group drink more on cannabis-use days compared to the Medium-THC/CBD group. Cannabinoid content of edible cannabis was associated with drinks per drinking occasion, such that the High-THC/CBD group consumed the most drinks and the Low-THC/CBD group consumed the fewest. For both edible and flower groupings, higher-THC/CBD cannabis was associated with more frequent co-use than lower-THC/CBD cannabis. Results suggest that whether someone uses cannabis to treat a medical condition may impact their drinking frequency, and the cannabinoid content in flower and edible cannabis impacts alcohol consumption., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Karoly, Mueller, Andrade and Hutchison.)