Cannabis and Cannabinoid Research最新文献

Background: With more states legalizing recreational cannabis, examining cannabis retail and marketing is crucial, as it may influence consumers' perceptions and behaviors. Particularly understudied is online cannabis retail. Methods: In Spring 2022, coders collected and analyzed data regarding retailer characteristics, age verification, and marketing strategies (e.g., product availability, health-related content, promotions, website imagery) among 195 cannabis retail websites in five U.S. cities (Denver, Colorado; Seattle, Washington; Portland, Oregon; Las Vegas, Nevada; Los Angeles, California). Descriptive analyses characterized the websites overall and across cities. Results: Overall, 80.5% verified age for website entry, and 92.8% offered online purchases (92.3% of retailers in Seattle, where prohibited). Of these, 82.9% required age verification for purchases, and 30.9% offered delivery. Almost all (>92%) offered flower/bud, concentrates, edibles, vaping devices, topicals, and tinctures. Health warnings were displayed on 38.3% of websites. Although all five states required health warnings regarding use during pregnancy, only 10.3% had these warnings. In addition, 59.0% posted some unsubstantiated health claims, most often indicating physical and mental health benefits (44.6%). Although Colorado, Washington, and Oregon prohibit health claims, 51.2-53.8% of these retailers posted them. Discounts, samples, or promotions were present on 90.8% of websites; 63.6% had subscription/membership programs. Subpopulations represented in website content included the following: 27.2% teens/young adults, 26.2% veterans, 7.2% sexual/gender minorities, and 5.6% racial/ethnic minorities. Imagery also targeted young people (e.g., 29.7% party/cool/popularity, 18.5% celebrity/influencer endorsement). Conclusions: Regulatory efforts are needed to better monitor promotional strategies and regulatory compliance (e.g., health claims, youth-oriented content, underage access) among online cannabis retailers.

Introduction: Excessive alcohol consumption can result in alcoholic liver disease (ALD). There is no FDA-approved drug to specifically treat ALD and current management approaches have limited efficacy. Past studies indicate that monoacylglycerol lipase (MAGL) inhibition can have a positive impact on nonalcoholic fatty liver disease. However, the effect of MAGL inhibition in ALD has not been reported. Materials and Methods: We tested the highly selective and clinically evaluated MAGL inhibitor ABX-1431 in the Lieber-DeCarli liquid alcohol diet-induced model of ALD in C57BL/6 mice. Results: ABX-1431 failed to reduce ALD-associated steatosis and elevated levels of liver enzymes associated with hepatic injury. Furthermore, survival rate declined with increasing doses of ABX-1431 when compared with mice administered vehicle only. Conclusion: These data suggest that MAGL inhibition does not improve ALD and is unlikely to be a good strategy for this condition.

Background: In this review, we provide an updated assessment of available evidence on the pharmacokinetics (PK) of CBD and explore the impact of different factors on PK outcomes. Materials and Methods: This systematic review and meta-regression analysis was preregistered (PROSPERO: CRD42021269857). We systematically searched Medline, Embase, PsycInfo, and Web of Science Core Collection up to November 19, 2022. Trials of CBD in healthy adults were included if they reported at least one of the PK parameters of interest, including T_max, C_max, AUC_0-t, AUC_0-inf, and T_1/2, in serum or plasma. Studies of patient populations or CBD co-administration with other medications were excluded. The National Heart, Lung, and Blood Institute's Quality Assessment Tool for Before-After Studies with no Control Group was used. Random-effects multivariable meta-regression analysis was conducted. Results: A total of 112 trial arms from 39 studies were included; 26 trial arms had a "Good" quality, 70 "Fair," and 16 "Poor." Eight arms used inhalation CBD, 29 oromucosal, 73 oral, and 2 intravenous. CBD formulations could be categorized to nanotech (n=14), oil-based (n=21), alcohol-based (n=10), water-based (n=12), Sativex (n=17), and Epidiolex^® (n=22). For single-dose studies, CBD doses ranged between 2 and 100 mg in inhalation, 5-50 mg in oromucosal, and 0.42-6000 mg in oral administration. Sixty-six trial arms had only male participants or a higher number of male than female participants. The duration of the PK session was between 4 and 164 h. A higher CBD dose was associated with higher C_max, AUC_0-t, and AUC_0-inf. Compared with oral administration, oromucosal administration was associated with lower C_max, AUC_0-t, and AUC_0-inf. Fed status was associated with higher C_max and AUC_0-t when compared with the fasting status. A higher ratio of female participants was associated with lower T_max in oral administration and higher C_max. Conclusion: As expected, CBD dose, route of administration, and diet were major determinants of CBD PK with oral routes providing higher bioavailability and nanotechnology formulations a faster onset. Although CBD appeared to have a faster onset and longer duration in women, more studies are required to delineate the role of biological sex. Factors that influence CBD PK have implications for medication development and appropriate dosing in clinical practice.

Background: Although use of Cannabis sativa is not associated with serious adverse effects, recreational use of aminoalkylindole (AAI) cannabinoid receptor agonists found in K2/Spice herbal blends has been reported to cause adverse cardiovascular events, including angina, arrhythmia, changes in blood pressure, ischemic stroke, and myocardial infarction. Δ⁹-Tetrahydrocannabinol (Δ⁹-THC) is the primary CB₁ agonist found in cannabis and JWH-073 is one of the AAI CB₁ agonists found in K2/Spice brands sold to the public. Methods: This study used in vitro, in vivo, and ex vivo approaches to investigate potential differences on cardiac tissue and vascular effects betweenJWH-073 and Δ⁹-THC. Male C57BL/6 mice were treated with JWH-073 or Δ⁹-THC and cardiac injury was assessed by histology. Effects of JWH-073 and Δ⁹-THC on H9C2 cell viability and ex vivo mesenteric vascular reactivity were also determined. Results: JWH-073 or Δ⁹-THC induced typical cannabinoid effects of antinociception and hypothermia but did not promote death of cardiac myocytes. No differences in cell viability were observed in cultured H9C2 cardiac myocytes after 24 h of treatment. In isolated mesenteric arteries from drug-naive animals, JWH-073 produced significantly greater maximal relaxation (96%±2% vs. 73%±5%, p<0.05) and significantly greater inhibition of phenylephrine-mediated maximal contraction (Control 174%±11%K_MAX) compared with Δ⁹-THC (50%±17% vs. 119%±16%K_MAX, p<0.05). Discussion: These findings suggest that neither cannabinoid at the concentrations/dose studied caused cardiac cell death, but JWH-073 has the potential for greater vascular adverse events than Δ⁹-THC through an increased vasodilatory effect.

Objective: Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have varying pharmacological actions with differential effects on acute and extended affective states, incuding anxiety. We aimed to study these effects on anxiety in legal market forms of cannabis. Method: This study makes use of a nonequivalent control group quasiexperimental design. Forty-two participants with anxiety symptions who were not using cannabis were compared to 258 participants with anxiety symptoms who used cannabis flower (∼3-4 times per week). Participants who used cannabis were randomly assigned to one of three legal market cannabis conditions; THC-dominant (24% THC, <1% CBD), THC+CBD (12% THC, 12% CBD), or CBD-dominant (<1% THC, 24% CBD). Changes in anxiety symptoms over 4-weeks were measured by the Patient Global Impression of Change (PGIC) scale and the Depression, Anxiety, and Stress Scale (DASS). Acute changes in subjective mood immediately after cannabis use were measured by the Profile of Mood States (POMS) Elation, Tension, and Paranoia subscales and the Addiction Research Center Inventory intoxication scale. Results: While all participants reported anxiety reductions over the 4-week study on the PGIC (F=30.65, p<0.001) and DASS anxiety measures (F=115.88, p<0.001), ad libitum CBD-dominant cannabis use was associated with lower scores on the DASS anxiety subscale compared to THC-dominant use when accounting for frequency of use (difference=-1.03, SE=0.45, p=0.02). Similarly, acute CBD-dominant cannabis use was associated with lower scores on the POMS tension and paranoia subscales (POMS tension: CBD-dominant vs. THC-dominant: difference=-0.41 SE=0.1, p<0.001; CBD-dominant vs. THC+CBD: difference=-0.28, SE=0.07, p=0.04; POMS paranoia: CBD-dominant vs. THC-dominant: difference=-0.49, SE=0.1, p<0.001; CBD-dominant vs. THC+CBD: difference=-0.33, SE=0.09, p=0.01). Participants in all cannabis conditions experienced acute changes in positive mood and subjective drug effects. Conclusions: This study provides novel information on the impacts of legal market cannabis with varying ratios of THC to CBD in indviduals with anxiety symptoms. Findings suggest that THC did not increase anxiety and that CBD-dominant forms of cannabis were associated with acute tension reduction that may translate to longer-term reductions in anxiety symptoms. Clinical Trial Registration: NCT03491384.

Background: Sex differences in the response to the anxiety-related effects of cannabinoid drugs have been reported, with females being more sensitive than males. Evidence suggests that, according to sex and estrous cycle phase (ECP), the content of the endocannabinoids (eCBs) N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) varies in brain areas involved in the anxiety-like behavior. Methods: Considering the lack of studies evaluating sex and ECP differences in the eCB system in anxiety, using URB597, a fatty acid amide hydrolase inhibitor, or MJN110, a monoacylglycerol lipase inhibitor, we explored the effects of increasing AEA or 2-AG levels, respectively, in cycling and ovariectomized (OVX) female adult Wistar rats, as well as males, subjected to the elevated plus maze. Results: The administration of URB597 (0.1 or 0.3mg/kg; intraperitoneally) either increased or reduced the percentage of open arms time (%OAT) and open arms entries (%OAE), being anxiolytic in diestrus and anxiogenic in estrus. No effects were observed in proestrus or when all ECPs were analyzed together. Both doses produced anxiolytic-like effects in males. In OVX females, the anxiolytic-like effect of URB597 0.1 was associated with low levels of estradiol, whereas the anxiogenic-like effect of URB597 0.3 was spared by estradiol pretreatment. The systemic administration of MJN110 3.0 mg/kg reduced the risk assessment behavior (RAB), suggesting an anxiolytic-like effect independent of the ECP. When considering the ECP, MJN110 3.0 increased the %OAT and reduced the RAB, being anxiolytic in estrus and diestrus. No effects were observed in proestrus. Both doses of MJN110 were anxiogenic in males. In OVX females, the anxiolytic-like effect of MJN110 was dependent on low estradiol levels. Conclusion: Together, our findings support the evidence that females react differently to the effects of cannabinoids in the anxiety-like behavior; in addition, AEA and 2-AG modulation elicits anxiety-like responses that are closely influenced by hormone levels, mainly estradiol.

Introduction: A growing number of females report consuming cannabis products. There is a paucity of data on sex differences in safety and subjective effects after repeated use of varying oral doses of Δ9-tetrahydrocannabinol (THC; the primary psychoactive constituent of cannabis). Materials and Methods: Data were from two randomized, double-blind, placebo-controlled, multiple-dose, between-subject trials of two THC-containing oral cannabis products. Healthy adults received placebo, low-dose THC (∼2.5 or ∼5 mg per dose), or high-dose THC (∼7.5 or ∼10 mg per dose) twice daily for 7 days. There were 38 males (8 placebo, 17 low-dose THC, 13 high-dose THC) and 46 females (8 placebo, 17 low-dose THC, 21 high-dose THC). Analyses compared adverse events (AEs) and subjective effects between males and females, by THC dose. Results: In the placebo and low-dose THC groups, there were no sex differences in the relative rate of AEs. In the high-dose THC group, females versus males reported 3.08 (95% confidence interval [CI]=1.31-8.33) times as many AEs. There were no significant interactions of sex×low-dose THC group for any subjective effect. In the high-dose THC group, females versus males reported greater "relaxed" ratings (b=15.14, 95% CI=1.44-28.84, p=0.027), whereas in the placebo group, males versus females reported greater ratings of "liking the effect" (b=-30.01, 95% CI=2.77-57.26, p=0.028). Although analyses were underpowered to assess the sex×THC dose×day interaction, the initial sex disparity in AEs and some subjective effects in the high-dose THC group appeared to shrink after the first day. Conclusions: In this exploratory analysis, sex differences in some responses to oral THC were nuanced. Females appeared more sensitive than males to AEs and some subjective effects at higher but not lower doses. Males reported higher ratings than females on some subjective effects in response to placebo. Initial sex differences in response to higher doses of oral THC tended to diminish over 7 days of dosing. If replicated, findings could help inform sex-specific dosing strategies of medical cannabis products and could help educate medical cannabis patients on any temporality of effects.

Introduction: Despite efforts to curb nicotine use, 8.1 million adults in the United States use e-cigarettes. Notably, the majority of nicotine-containing e-cigarette users report wanting to quit in the near future, yet there is a dearth of research surrounding intervention efforts. Cannabidiol (CBD) has potential to facilitate e-cigarette quit attempts by decreasing withdrawal symptom intensity and anxiety during nicotine e-cigarette abstinence. Methods: This study employed an open-label, crossover design (n=20) to test the hypothesis that among daily nicotine-containing e-cigarette users, oral administration of 320 mg CBD would reduce self-reported nicotine withdrawal severity and state anxiety following a 4-h e-cigarette abstinence period compared to withdrawal and anxiety reported after abstinence in the absence of CBD. Results: After controlling for participants' positive CBD expectancies, results were consistent with hypotheses, suggesting CBD reduced both nicotine withdrawal symptom severity and state anxiety during e-cigarette abstinence. Conclusion: These preliminary findings suggest testing the impact of CBD on e-cigarette cessation attempts is warranted.

Background: Cannabidiol (CBD), a nonpsychoactive cannabinoid found in the cannabis plant, has gained interest for its purported stress- and anxiety-reducing effects. However, the mechanisms underlying these effects remain unclear. Our group previously found that CBD expectancy alone resulted in lower state anxiety (vs. CBD-free expectancy) among those who strongly believed it was helpful for such purposes, in addition to influencing physiological measures (i.e., heart rate variability). Aims: Using data collected as part of this previously published larger study, we aimed to explore the extent to which CBD expectancy alone impacts cortisol in the context of a laboratory stressor. Methods: A sample of 43 healthy adults (23 female) participated in one orientation and two experimental laboratory sessions. They received the same oil (CBD-free) during both experimental sessions but were told they received CBD oil in counterbalanced order in one of their sessions. Participants then engaged in a laboratory stressor (the Maastricht Acute Stress Test; MAST) and salivary cortisol samples were collected throughout [T1: baseline; T2: 90-min postabsorption (PA); T3: poststress (0-PS); T4: 10-min poststress (10-PS); T5: 30-min poststress (30-PS)]. Linear marginal models were used for analyses. Results: Findings indicated that a physiological stress response was elicited in the context of the MAST, which is consistent with what has been reported previously. Interestingly, while cortisol levels were significantly lower in the CBD expectancy condition (vs. CBD-free) immediately following the MAST (0-PS) and 10-min later (10-PS), this effect seems to be largely driven by males, evidenced by a three-way interaction. Cortisol levels did not reliably vary across expectancy conditions at any other time point. Conclusion: Overall, these results suggest that CBD expectancy appears to blunt cortisol in anticipation of a stressor, particularly in males. Findings suggest that it is important to consider the impact of drug-related expectations when assessing CBD-related effects on stress-related processes.

Introduction: Cannabis is the most used illicit drug in the United States. With many states passing legislation to permit its recreational use, there is concern that cannabis use among adolescents could increase dramatically in the coming years. Historically, it has been difficult to model real-world cannabis use to investigate the causal relationship between cannabis use in adolescence and behavioral and neurobiological effects in adulthood. Materials and Methods: We used a response-contingent vapor administration model to investigate long-term effects of cannabis use during adolescence on the medial prefrontal cortex (mPFC) and mPFC-dependent behaviors in male and female rats. Results: Adolescent (35- to 55-day-old) female rats had significantly higher rates of responding for vaporized Δ⁹-tetrahydrocannabinol (THC)-dominant cannabis extract (CAN_THC) compared with adolescent males. In adulthood (70-110 days old), female, but not male, CAN_THC rats also took more trials to reach criterion and made more regressive errors in an automated attentional set-shifting task compared with vehicle rats, thereby indicating sex differences in behavioral flexibility impairments. Notably, sex-treatment interactions were not observed when rats of each sex were exposed to a noncontingent CAN_THC vapor dosing regimen that approximated CAN_THC vapor deliveries earned by females. No differences were observed in effort-based decision making in either sex. In the mPFC, female (but not male) CAN_THC rats displayed more reactive microglia with no changes in myelin basic protein expression or dendritic spine density. Conclusion: Altogether, these data reveal important sex differences in rates of responding for CAN_THC vapor in adolescence that may confer enduring alterations to mPFC structure and function and suggest that there may be subtle differences in the effects of response-contingent versus noncontingent cannabis exposure that should be systematically examined in future studies.