A Randomized Placebo-Controlled Trial of \u3cem\u3eN\u3c/em\u3e-Acetylcysteine for Cannabis Use Disorder in Adults

Background—Cannabis use disorder (CUD) is a prevalent and impairing condition, and established psychosocial treatments convey limited efficacy. In light of recent findings supporting the efficacy of N-acetylcysteine (NAC) for CUD in adolescents, the objective of this trial was to evaluate its efficacy in adults. Methods—In a 12-week double-blind randomized placebo-controlled trial, treatment-seeking adults ages 18–50 with CUD (N=302), enrolled across six National Drug Abuse Treatment Clinical Trials Network-affiliated clinical sites, were randomized in a 1:1 ratio to a 12-week course of NAC 1200 mg (n=153) or placebo (n=149) twice daily. All participants received contingency management (CM) and medical management. The primary efficacy measure was the odds of negative urine cannabinoid tests during treatment, compared between NAC and placebo participants. Results—There was not statistically significant evidence that the NAC and placebo groups differed in cannabis abstinence (odds ratio = 1.00, 95% confidence interval 0.63 – 1.59; p=0.984). Overall, 22.3% of urine cannabinoid tests in the NAC group were negative, compared with 22.4% in the placebo group. Many participants were medication non-adherent; exploratory analysis within medication-adherent subgroups revealed no significant differential abstinence outcomes by treatment group. Conclusions—In contrast with prior findings in adolescents, there is no evidence that NAC 1200 mg twice daily plus CM is differentially efficacious for CUD in adults when compared to placebo plus CM. This discrepant finding between adolescents and adults with CUD may have been influenced by differences in development, cannabis use profiles, responses to embedded behavioral treatment, medication adherence, and other factors

Cannabidiol (CBD) content in vaporized cannabis does not prevent tetrahydrocannabinol (THC)-induced impairment of driving and cognition

BACKGROUND: The main psychoactive component of cannabis, delta-9-tetrahydrocannabinol (THC), can impair driving performance. Cannabidiol (CBD), a non-intoxicating cannabis component, is thought to mitigate certain adverse effects of THC. It is possible then that cannabis containing equivalent CBD and THC will differentially affect driving and cognition relative to THC-dominant cannabis. AIMS: The present study investigated and compared the effects of THC-dominant and THC/CBD equivalent cannabis on simulated driving and cognitive performance. METHODS: In a randomized, double-blind, within-subjects crossover design, healthy volunteers (n = 14) with a history of light cannabis use attended three outpatient experimental test sessions in which simulated driving and cognitive performance were assessed at two timepoints (20-60 min and 200-240 min) following vaporization of 125 mg THC-dominant (11% THC; < 1% CBD), THC/CBD equivalent (11% THC, 11% CBD), or placebo (< 1% THC/CBD) cannabis. RESULTS/OUTCOMES: Both active cannabis types increased lane weaving during a car-following task but had little effect on other driving performance measures. Active cannabis types impaired performance on the Digit Symbol Substitution Task (DSST), Divided Attention Task (DAT) and Paced Auditory Serial Addition Task (PASAT) with impairment on the latter two tasks worse with THC/CBD equivalent cannabis. Subjective drug effects (e.g., "stoned") and confidence in driving ability did not vary with CBD content. Peak plasma THC concentrations were higher following THC/CBD equivalent cannabis relative to THC-dominant cannabis, suggesting a possible pharmacokinetic interaction. CONCLUSIONS/INTERPRETATION: Cannabis containing equivalent concentrations of CBD and THC appears no less impairing than THC-dominant cannabis, and in some circumstances, CBD may actually exacerbate THC-induced impairment

Relationships between the Nicotine Metabolite Ratio and a Panel of Exposure and Effect Biomarkers: Findings from Two Studies of U.S. Commercial Cigarette Smokers.

BackgroundWe examined the nicotine metabolite ratio's (NMR) relationship with smoking intensity, nicotine dependence, and a broad array of biomarkers of exposure and biological effect in commercial cigarette smokers.MethodsSecondary analysis was conducted on two cross-sectional samples of adult, daily smokers from Wave 1 (2013-2014) of the Population Assessment of Tobacco Use and Health (PATH) Study and baseline data from a 2014-2017 randomized clinical trial. Data were restricted to participants of non-Hispanic, white race. The lowest quartile of NMR (&lt;0.26) in the nationally representative PATH Study was used to distinguish slow from normal/fast nicotine metabolizers. NMR was modeled continuously in secondary analysis.ResultsCompared with slow metabolizers, normal/fast metabolizers had greater cigarettes per day and higher levels of total nicotine equivalents, tobacco-specific nitrosamines, volatile organic componds, and polycyclic aromatic hydrocarbons. A novel finding was higher levels of inflammatory biomarkers among normal/fast metabolizers versus slow metabolizers. With NMR modeled as a continuous measure, the associations between NMR and biomarkers of inflammation were not significant.ConclusionsThe results are suggestive that normal/fast nicotine metabolizers may be at increased risk for tobacco-related disease due to being heavier smokers, having higher exposure to numerous toxicants and carcinogens, and having higher levels of inflammation when compared with slow metabolizers.ImpactThis is the first documentation that NMR is not only associated with smoking exposure but also biomarkers of biological effects that are integral in the development of tobacco-related disease. Results provide support for NMR as a biomarker for understanding a smoker's exposure and potential risk for tobacco-related disease

Effects of immediate versus gradual nicotine reduction in cigarettes on biomarkers of biological effects.

AimA previous study showed significantly greater reductions in number of cigarettes smoked and biomarkers of toxicant and carcinogen exposure in smokers assigned to immediate reduction of nicotine in cigarettes to very low levels versus gradually over time or continued smoking of normal nicotine content cigarettes. This study examines the effects of these approaches on selected biomarkers associated with harmful biological effects.DesignThree-arm, randomized controlled trial.SettingTen United States academic institutional sites.ParticipantsDaily smokers uninterested in quitting smoking with a mean age of 45.1 [standard deviation (SD)&nbsp;=&nbsp;13.4)] years and smoking 17.1 (SD&nbsp;=&nbsp;8.5) cigarettes/day; 43.9% (549 of 1250) female; 60.6% (758 of 1250) white ethnicity.Interventions(1) Smoking cigarettes where nicotine content was immediately reduced to very low levels (n&nbsp;=&nbsp;503); (2) smoking cigarettes where nicotine content was gradually reduced, with dose changes occurring monthly (n&nbsp;=&nbsp;498); and (3) continued smoking with normal nicotine content cigarettes (n&nbsp;=&nbsp;249).MeasurementsSmokers were assessed at baseline while smoking their usual brand cigarettes, and again at 4, 8, 12, 16 and 20&nbsp;weeks. Outcomes were areas under the concentration time curve (AUC) for the period of study of biomarkers of inflammation, oxidative stress and hematological parameters.FindingsNo consistent significant differences were observed across groups (Bayes factors showing data to be insensitive), with the only exception being red blood cell size variability, which was observed to be lower in the immediate versus gradual nicotine reduction [mean difference&nbsp;=&nbsp;&nbsp;-0.11; 95% confidence interval (CI)&nbsp;=&nbsp;-0.18, -0.04, P&nbsp;=&nbsp;0.004] and normal nicotine control groups (mean difference&nbsp;=&nbsp;-&nbsp;0.15, 95% CI&nbsp;=&nbsp;-0.23, -0.06, P&nbsp;=&nbsp;0.001).ConclusionIt remains unclear whether switching to very low nicotine cigarettes leads to a short-term reduction in biomarkers of tobacco-related harm

Effects of immediate versus gradual nicotine reduction in cigarettes on biomarkers of biological effects.

AimA previous study showed significantly greater reductions in number of cigarettes smoked and biomarkers of toxicant and carcinogen exposure in smokers assigned to immediate reduction of nicotine in cigarettes to very low levels versus gradually over time or continued smoking of normal nicotine content cigarettes. This study examines the effects of these approaches on selected biomarkers associated with harmful biological effects.DesignThree-arm, randomized controlled trial.SettingTen United States academic institutional sites.ParticipantsDaily smokers uninterested in quitting smoking with a mean age of 45.1 [standard deviation (SD)&nbsp;=&nbsp;13.4)] years and smoking 17.1 (SD&nbsp;=&nbsp;8.5) cigarettes/day; 43.9% (549 of 1250) female; 60.6% (758 of 1250) white ethnicity.Interventions(1) Smoking cigarettes where nicotine content was immediately reduced to very low levels (n&nbsp;=&nbsp;503); (2) smoking cigarettes where nicotine content was gradually reduced, with dose changes occurring monthly (n&nbsp;=&nbsp;498); and (3) continued smoking with normal nicotine content cigarettes (n&nbsp;=&nbsp;249).MeasurementsSmokers were assessed at baseline while smoking their usual brand cigarettes, and again at 4, 8, 12, 16 and 20&nbsp;weeks. Outcomes were areas under the concentration time curve (AUC) for the period of study of biomarkers of inflammation, oxidative stress and hematological parameters.FindingsNo consistent significant differences were observed across groups (Bayes factors showing data to be insensitive), with the only exception being red blood cell size variability, which was observed to be lower in the immediate versus gradual nicotine reduction [mean difference&nbsp;=&nbsp;&nbsp;-0.11; 95% confidence interval (CI)&nbsp;=&nbsp;-0.18, -0.04, P&nbsp;=&nbsp;0.004] and normal nicotine control groups (mean difference&nbsp;=&nbsp;-&nbsp;0.15, 95% CI&nbsp;=&nbsp;-0.23, -0.06, P&nbsp;=&nbsp;0.001).ConclusionIt remains unclear whether switching to very low nicotine cigarettes leads to a short-term reduction in biomarkers of tobacco-related harm

Longitudinal stability in cigarette smokers of urinary biomarkers of exposure to the toxicants acrylonitrile and acrolein.

The urinary metabolites cyanoethyl mercapturic acid (CEMA) and 3-hydroxypropyl mercapturic acid (3-HPMA) have been widely used as biomarkers of exposure to acrylonitrile and acrolein, respectively, but there are no published data on their consistency over time in the urine of cigarette smokers. We provided, free of charge over a 20 week period, Spectrum NRC600/601 research cigarettes to cigarette smokers in the control arm of a randomized clinical trial of the reduced nicotine cigarette. Urine samples were collected at weeks 4, 8, 12, 16, and 20 and analyzed for CEMA and 3-HPMA, and total nicotine equivalents (TNE) using validated methods. Creatinine-corrected intra-class correlation coefficients for CEMA, 3-HPMA, and TNE were 0.67, 0.46, and 0.68, respectively, indicating good longitudinal consistency for CEMA, while that of 3-HPMA was fair. A strong correlation between CEMA and TNE values was observed. These data support the use of CEMA as a reliable biomarker of tobacco smoke exposure. This is the first report of the longitudinal stability of the biomarkers of acrylonitrile and acrolein exposure in smokers. The data indicate that CEMA, the biomarker of acrylonitrile exposure, is consistent over time in cigarette smokers, supporting its use. While 3-HPMA levels were less stable over time, this biomarker is nevertheless a useful monitor of human acrolein exposure because of its specificity to this toxicant