Cannabis and Cannabinoid Research最新文献

Background: Cannabis sativa is a psychoactive plant indigenous to Central and South Asia, traditionally used both for recreational and religious purposes, in addition to folk medicine. Cannabis is a rich source of natural compounds, the most important of which are commonly known as cannabinoids that cause a variety of effects through interaction with the endocannabinoid system. Materials and Methods: In this study, a high-performance liquid chromatography-ultraviolet/photodiode array (PDA) method was developed and validated for the analysis of 15 cannabinoids in cannabis plant materials and cannabis-based marketed products. These cannabinoids are cannabidivarinic acid, cannabidivarin, cannabidiolic acid, cannabigerolic acid, cannabigerol, cannabidiol, delta-9-tetrahydrocannabivarin, delta-9-tetrahydrocannabivarinic acid, cannabinol, delta-9-tetrahyrocannabinol, delta-8-tetrahyrocannabinol, cannabicyclol, cannabichromene, delta-9-tetrahyrocannabinolic acid A, and cannabichromenic acid. The separation was carried out using a reversed-phase Luna^® C18(2) column and a mobile phase consisting of 75% acetonitrile and 0.1% formic acid in water. A PDA detector was used, and data were extracted at λ=220 nm. Principal component analysis of cannabis four varieties was performed. Results: The method was linear over the calibration range of 5-75 μg/mL with R²>0.999 for all cannabinoids. This method was sensitive and gave good baseline separation of all examined cannabinoids with limits of detection ranging between 0.2 and 1.6 μg/mL and limits of quantification ranging between 0.6 and 4.8 μg/mL. The average recoveries for all cannabinoids were between 81% and 104%. The measured repeatability and intermediate precisions (% relative standard deviation) in all varieties ranged from 0.35% to 9.84% and 1.11% to 5.26%, respectively. Conclusions: The proposed method is sensitive, selective, reproducible, and accurate. It can be applied for the simultaneous determination of these cannabinoids in the C. sativa biomass and cannabis-derived marketed products.

Introduction: Oral cannabidiol (CBD) product use is increasingly growing among women; however, there is a lack of data on sex differences in the pharmacokinetics (PKs) of CBD and its primary metabolites, 7-hydroxy-CBD (7-OH-CBD) and 7-carboxy-CBD (7-COOH-CBD), after repeated doses. Materials and Methods: The present study is a secondary analysis of data from a randomized, double-blind, placebo-controlled multiple-dose trial of a commercially available, CBD-dominant oral cannabis product. Healthy participants (n=17 males and 15 females) were randomized to receive 120 to 480 mg of CBD daily for 7 days. Dosing groups were pooled for all analyses due to sample size limitations. Analyses compared plasma PK parameters by sex, day, and sex×day. Results: For raw PK parameters for CBD and metabolites, there were no statistically significant effects of sex×day or sex (all p-values >0.05). For metabolite-to-parent ratios (MPRs) of AUC_0-t, there were significant effects of the sex×day interactions for 7-OH-CBD (F=6.89, p=0.016) and 7-COOH-CBD (F=5.96, p=0.021). For 7-OH-CBD, follow-up analyses showed significant simple effects of day within females (t=4.13, p<0.001), but not within males (t=0.34, p=0.73), such that 7-OH-CBD MPRs increased significantly from day 1 to 7 for females, but not for males. For 7-COOH-CBD, follow-up analyses revealed significant simple effects of day within females (t=8.24, p<0.001) and males (t=5.20, p<0.001), therefore 7-COOH-CBD MPRs increased significantly from day 1 to 7 in both sexes, but the increase was significantly greater among females than among males. Within dosing days, there were no statistically significant simple effects of sex on MPRs of 7-OH-CBD or 7-COOH-CBD. Conclusions: Females exhibited greater relative exposure to CBD metabolites in plasma over time, which may reflect sex differences in CBD metabolism or elimination. Further research assessing the safety implications of higher relative exposure to CBD metabolites over longer periods of time is warranted to mirror typical consumer use patterns.

Introduction: The debate over the legal status of many cannabis- and hemp-derived products, including delta-8 tetrahydrocannabinol (THC), is in question. Although low concentrations of delta-8 THC are legal at the Federal level, many states have implemented their own regulations to both allow and restrict its use and sale. Of concern, sellers with unknown legal credentials have appeared online and are actively selling this product. Materials and Methods: We characterized the marketing, sale, and compliance of online delta-8 THC sellers using (1) data collected from the Twitter Application Programming Interface with delta-8 THC-related keywords; (2) unsupervised topic modeling using the Biterm Topic Model to identify clusters of tweets involved in marketing and selling; (3) inductive coding to identify marketing and selling characteristics; and (4) web forensics and simulated shopping to determine compliance with state restrictions for delta-8 THC sales. Results: In total, 110 unique hyperlinks associated with 7085 tweets that included marketing and selling activity for delta-8 THC were collected. From these links, we conducted simulated purchasing in January 2021 to identify compliant and noncompliant websites. Among the vendors, age verification was not found in over half of websites (59, 53.63%); 60 (54.55%) did not report a physical address; and 74 (65.45%) sold delta-8 products direct-to-consumer. Sixty-seven (90.54%) of detected vendors shipped delta-8 products to addresses in states that prohibit sales. Forty-three (64.18%) of Internet Protocol addresses were located within the United States; all others were international. Conclusion: Our analysis suggests that online storefronts are illegally selling and shipping cannabinoid derivatives to U.S. consumers. Further research is needed to understand downstream health and regulatory impacts from this unregulated access.

Background: Cannabis use may impair cognitive function (CF) differently in men and women, due to sex-specific differences in neurobiological mechanisms and environmental risk factors. Objective: Assess sex differences in the association between cumulative exposure to cannabis and cognitive performance in middle age. Methods: We studied participants from the Coronary Artery Risk Development in Young Adults (CARDIA) Study, including Black and White men and women 18-30 years old at baseline followed over 30 years. Our cross-sectional analysis of CF scores at year 30 was stratified by sex. We computed categories of cumulative exposure in "cannabis-years" (1 cannabis-year=365 days of use) from self-reported use every 2 to 5 years over 30 years. At years 25 and 30, we assessed CF with the Rey Auditory Verbal Learning Test (verbal memory), the Digit Symbol Substitution Test (processing speed), and the Stroop Interference Test (executive function). At year 30, additional measures included Category and Letter Fluency Test (verbal ability) and the Montreal Cognitive Assessment (global cognition). We computed standardized scores for each cognitive test and applied multivariable adjusted linear regression models for self-reported cumulative cannabis use, excluding participants who used cannabis within 24 h. In a secondary analysis, we examined the association between changes in current cannabis use and changes in CF between years 25 and 30. Results: By year 30, 1,352 men and 1,793 women had measures of CF; 87% (N=1,171) men and 84% (N=1,502) women reported ever cannabis use. Men had a mean cumulative use of 2.57 cannabis-years and women 1.29 cannabis-years. Self-reported cumulative cannabis use was associated with worse verbal memory in men (e.g., -0.49 standardized units [SU] for ≥5 cannabis-years of exposure; 95% CI=-0.76 to -0.23), but not in women (SU=0.02; 95% CI=-0.26 to 0.29). Other measures of CF were not associated with cannabis. Changes in current cannabis use between years 25 and 30 were not associated with CF in men or women. Conclusions: Self-reported cumulative cannabis exposure was associated with worse verbal memory in men but not in women. Researchers should consider stratified analyses by sex when testing the association between cannabis and cognition.

Introduction: Dramatic shifts in marijuana laws, along with federal deregulation of hemp with the 2018 Farm Bill, have resulted in increased availability and use of cannabidiol (CBD) supplements throughout the United States (US). Given the rapid increase in CBD use in the U.S. general population, in this study, we aim to characterize primary care physician (PCP) attitudes and practice behaviors and to assess whether differences in provider attitudes and behaviors vary as a function of marijuana legalization (ML) status in the state of practice. Materials and Methods: Data are from an online provider survey on CBD supplement-related attitudes, beliefs, and behaviors administered to 508 PCPs as part of a larger mixed methods study. Participating PCPs were recruited from the Mayo Clinic Healthcare Network and provided medical care in primary care settings across four U.S. states (Minnesota, Wisconsin, Florida, and Arizona). Results: The survey response rate was 45.4% (n=236/508). According to providers, CBD was frequently brought up in PCP settings, typically by patients. PCPs were generally hesitant to screen for or discuss CBD with their patients and identified multiple barriers to open patient-provider dialogue about CBD. PCPs practicing in states that had passed ML were more receptive to patients using CBD supplements, whereas PCPs practicing in states that had not passed ML were more concerned about CBD-related side effects. Regardless of state ML status, most PCPs did not feel that they should be recommending CBD supplements to their patients. Most PCPs reported believing that CBD was unhelpful for most conditions for which it is marketed, with chronic non-cancer pain and anxiety/stress being exceptions. PCP respondents generally felt that they had insufficient knowledge/training around CBD. Conclusions: Results from this mixed methods study show that PCPs practicing in the U.S. rarely screen for or discuss CBD use with their patients and report several barriers to engage in proactive CBD-focused practice behaviors. Furthermore, survey results show that some PCP attitudes, practice behaviors, and barriers vary as a function of state ML status. These findings may guide medical education efforts and inform primary care practice modifications aimed at enhancing screening and monitoring of patient CBD use by PCPs.

Background: Studies have reported that cannabinoids, in particular Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and cannabidiol (CBD), significantly reduce cancer cell viability in vitro. Unfortunately, treatment conditions vary significantly across reports. In particular, a majority of reports utilize conditions with reduced serum concentrations (0-3%) that may compromise the growth of the cells themselves, as well as the observed results. Objectives: This study was designed to test the hypothesis that, based on their known protein binding characteristics, cannabinoids would be less effective in the presence of fetal bovine serum (FBS). Moreover, we wished to determine if the treatments served to be cytotoxic or cytostatic under these conditions. Methods: Six cancer cell lines, representing two independent lines of three different types of cancer (glioblastoma, melanoma, and colorectal cancer [CRC]), were treated with 10 μM pure Δ⁹-THC, CBD, KM-233, and HU-331 for 48 h (in the presence or absence of FBS). Cell viability was measured with the MTT assay. Dose-response curves were then generated comparing the potencies of the four cannabinoids under the same conditions. Results: We found that serum-free medium alone produces cell cycle arrest for CRC cells and slows cell growth for the other cancer types. The antineoplastic effects of three of the four cannabinoids (Δ⁹-THC, CBD, and KM-233) increase when serum is omitted from the media. In addition, dose-response curves for these drugs demonstrated lower IC₅₀ values for serum-free media compared with the media with 10% serum in all cell lines. The fourth compound, HU-331, was equally effective under both conditions. A further confound we observed is that omission of serum produces dramatic binding of Δ⁹-THC and CBD to plastic. Conclusions: Treatment of cancer cells in the absence of FBS appears to enhance the potency of cannabinoids. However, omission of FBS itself compromises cell growth and represents a less physiological condition. Given the knowledge that cannabinoids are 90-95% protein bound and have well-known affinities for plastic, it may be ill-advised to treat cells under conditions where the cells are not growing optimally and where known concentrations cannot be assumed (i.e., FBS-free conditions).

Introduction: Medical cannabis users tend not to trust or rely on health care providers regarding cannabis advice. Previous surveys of physicians have focused on favorability toward medical cannabis. The current study assesses how physicians interact with patients regarding cannabis in their day-to-day practice, and whether and how they address important topics such as use patterns and substituting cannabis for medications. We predicted that physicians would generally perceive cannabis dispensary staff and caretakers as not competent in addressing patient health needs and would not be likely to use their recommendations. Methods: Physicians in a university-affiliated health system completed an anonymous online survey. The survey assessed physicians' cannabis related education experiences, perceptions of their knowledge of and competence regarding medical cannabis, and the content of cannabis related discussions with patients. We also examined perceptions of the sources of influence on patients regarding cannabis and physicians' attitudes toward medical cannabis dispensary staff and medical cannabis caregivers (MCCs). Results: A few physicians (10%) had ever signed a medical cannabis authorization form for their patients, consistent with their perceptions of low knowledge and competence in this area. Discussions on cannabis primarily focus on risks (63%) rather than dosage (6%) and harm reduction (25%). Physicians see their influence on patients as weak compared with other information sources and have generally unfavorable attitudes toward medical cannabis dispensary staff and MCCs. Conclusion: Greater integration of medical cannabis knowledge is needed at all levels of medical and clinical education to address the potential harm to patients if they receive no guidance. Continued research is needed to provide a strong scientific basis for developing treatment guidelines and standardized medical education for medical cannabis use.

Introduction: Cannabis use is associated with brain functional changes in regions implicated in prominent neuroscientific theories of addiction. Emerging evidence suggests that cannabidiol (CBD) is neuroprotective and may reverse structural brain changes associated with prolonged heavy cannabis use. In this study, we examine how an ∼10-week exposure of CBD in cannabis users affected resting-state functional connectivity in brain regions functionally altered by cannabis use. Materials and Methods: Eighteen people who use cannabis took part in a ∼10 weeks open-label pragmatic trial of self-administered daily 200 mg CBD in capsules. They were not required to change their cannabis exposure patterns. Participants were assessed at baseline and post-CBD exposure with structural magnetic resonance imaging (MRI) and a functional MRI resting-state task (eyes closed). Seed-based connectivity analyses were run to examine changes in the functional connectivity of a priori regions-the hippocampus and the amygdala. We explored if connectivity changes were associated with cannabinoid exposure (i.e., cumulative cannabis dosage over trial, and plasma CBD concentrations and Δ⁹-tetrahydrocannabinol (THC) plasma metabolites postexposure), and mental health (i.e., severity of anxiety, depression, and positive psychotic symptom scores), accounting for cigarette exposure in the past month, alcohol standard drinks in the past month and cumulative CBD dose during the trial. Results: Functional connectivity significantly decreased pre-to-post the CBD trial between the anterior hippocampus and precentral gyrus, with a strong effect size (d=1.73). Functional connectivity increased between the amygdala and the lingual gyrus pre-to-post the CBD trial, with a strong effect size (d=1.19). There were no correlations with cannabinoids or mental health symptom scores. Discussion: Prolonged CBD exposure may restore/reduce functional connectivity differences reported in cannabis users. These new findings warrant replication in a larger sample, using robust methodologies-double-blind and placebo-controlled-and in the most vulnerable people who use cannabis, including those with more severe forms of Cannabis Use Disorder and experiencing worse mental health outcomes (e.g., psychosis, depression).

Background: The use of cannabis with various forms of exercise (e.g., running) has received increased media attention in recent years, contradicting the popular stereotype that cannabis is associated with sedentary behavior. Although cross-sectional evidence suggests a positive association between cannabis use and exercise engagement, to date, the acute effects of cannabis on exercise remain unclear. Methods: The present within-subjects crossover study compared participants' experiences of running after ad libitum use of legal market cannabis (cannabis run) to running without cannabis (non-cannabis run) in a real-world setting. Participants (n=49) were cannabis users between the ages of 21 and 49 years (mean=30.82, standard deviation [SD]=6.21). The majority of participants were male (61.5%) and non-Hispanic White (81.6%). Results: Participants (n=49) ran an average of 3.88 miles (SD=2.28) during their cannabis and non-cannabis runs. Although participants ran an average of 31 seconds/mile slower during their cannabis run, this difference was not statistically significant (p=0.12). Participants reported experiencing (1) less negative affect (p=0.03), (2) greater feelings of positive affect (p<0.001), tranquility (p=0.004), enjoyment (p=0.004), and dissociation (p=0.001), and (3) more runner's high symptoms (p<0.001) during their cannabis (vs. non-cannabis) runs. Participants also reported lower pain levels after their cannabis (vs. non-cannabis) run (p=0.03). Perceived exertion did not differ between runs (p=0.33). Cannabis form, cannabinoid content, and feelings of "high" were largely unrelated to participants' experience of exercise while under the influence of cannabis. Conclusions: Results suggest that acute cannabis use may be associated with a more positive exercise experience among regular cannabis users. Research using varied methodologies, a range of exercise modalities, and diverse populations is needed to establish the long-term harms and benefits associated with this behavior, as well as the generalizability of these findings to other populations and settings.