Evaluating possible 'next day' impairment in insomnia patients administered an oral medicinal cannabis product by night: a pilot randomized controlled trial.

Cannabis and its major constituents, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are being widely used to treat sleep disturbances. However, THC can cause acute cognitive and psychomotor impairment and there are concerns that driving and workplace safety might be compromised the day after evening use. Here, we examined possible 'next day' impairment following evening administration of a typical medicinal cannabis oil in adults with insomnia disorder, compared to matched placebo. This paper describes the secondary outcomes of a larger study investigating the effects of THC/CBD on insomnia disorder. Twenty adults [16 female; mean (SD) age, 46.1 (8.6) y] with physician-diagnosed insomnia who infrequently use cannabis completed two 24 h in-laboratory visits involving acute oral administration of combined 10 mg THC and 200 mg CBD ('THC/CBD') or placebo in a randomised, double-blind, crossover trial design. Outcome measures included 'next day' (≥9 h post-treatment) performance on cognitive and psychomotor function tasks, simulated driving performance, subjective drug effects, and mood. We found no differences in 'next day' performance on 27 out of 28 tests of cognitive and psychomotor function and simulated driving performance relative to placebo. THC/CBD produced a small decrease (-1.4%, p=.016, d=-0.6) in accuracy on the Stroop-Colour Task (easy/congruent) but not the Stroop-Word Task (hard/incongruent). THC/CBD also produced a small increase (+8.6, p=.042, d=0.3) in self-ratings of Sedated at 10 h post-treatment, but with no accompanying changes in subjective ratings of Alert or Sleepy (p's>0.05). In conclusion, we found a lack of notable 'next day' impairment to cognitive and psychomotor function and simulated driving performance following evening use of 10 mg oral THC, in combination with 200 mg CBD, in an insomnia population who infrequently use cannabis.

Product labeling accuracy and contamination analysis of commercially available cannabidiol product samples.

Background and objective: Commercially available cannabidiol (CBD) products are increasingly being used for medicinal purposes, including for the treatment of various neurological conditions, but there are growing concerns around adherence to quality control measures that protect consumers. This study was conducted to assess the purity and label accuracy of commercially available CBD products. Methods: Commercially available CBD products were chosen from the open stream of commerce in the United States based on formulations as a tincture, gummy, vape, or topical product. Cannabinoid concentrations were analyzed to verify label accuracy including "full spectrum," "broad spectrum," and "CBD isolate" claims on the product label. Analysis for the presence of contaminants included evaluation for heavy metals, pesticides, and residual solvents. Labeled and actual total amounts of CBD and levels of impurities such as heavy metals, residual solvents, and pesticides were measured. Results: A total of 202 CBD products (100 tinctures, 48 gummies, 34 vape products, and 20 topicals) were chosen to represent a broad sample in the United States. Of the products tested (full spectrum, n = 84; broad spectrum, n = 28; CBD isolate, n = 37), 26% did not meet the definition for product type claimed on the packaging. The majority of products (74%) deviated from their label claim of CBD potency by at least 10%. Heavy metals were detected 52 times across 44 of the 202 products tested, with lead being the most prevalent heavy metal. Residual solvents were detected 446 times across 181 of 202 products, with the highest concentrations reported for hexane, m/p-xylene, methanol, and o-xylene. Of 232 pesticides tested, 26 were found 55 times across 30 products. A total of 3% of heavy metals, 1% of residual solvents, and 1% of pesticides violated >1 regulatory threshold. Discussion: This study demonstrated that the majority of commercially available CBD products tested within the current study are inaccurately labeled. Heavy metals, residual solvents, and pesticides were found in several products, some of which violated regulatory thresholds. Thus, uniform compliance with CBD quality control measures is lacking and raises consumer protection concerns. Improved regulatory oversight of this industry is recommended.

Does acute cannabidiol (CBD) use impair performance? A meta-analysis and comparison with placebo and delta-9-tetrahydrocannabinol (THC).

Cannabidiol (CBD) is widely used and believed to be non-intoxicating, lacking acute performance effects (e.g., non-impairing). However, a synthesis of data has not evaluated this. This meta-analysis synthesized data from controlled human laboratory studies that evaluated if acute CBD use impairs performance. Performance on objective and subjective measures of cognitive and psychomotor function were used as markers for potential performance changes and impairment. Studies were identified through systematic database searches. Adult clinical trials measuring acute CBD effects (within 0-8 h of administration) were included. The primary outcome was the peak mean difference in performance measures between CBD and placebo. A secondary analysis utilizing delta-9-tetrahydrocannabinol (Δ9-THC) as a positive control for comparison to CBD was completed. Pooled Hedges' g estimates were calculated using robust variance estimation (RVE) meta-regression. The omnibus RVE meta-analysis indicated a statistically significant, but small effect size (Hedge's g < 0.2) for impaired performance following acute CBD consumption compared to placebo (N = 16 trials, Hedges' g = 0.122, 95% CI: 0.023-0.221, p = 0.019). Measure type was a significant moderator with larger mean differences between CBD and placebo when subjective measures, specifically self-reported sedation, were used versus objective performance tasks (Hedges' gSubjective = 0.288 versus Hedges' gObjective = 0.048). Δ9-THC had a significantly greater magnitude of impairment compared to CBD (N = 8, Hedges' g = 0.416, 95% CI: 0.017-0.816, p = 0.043). In summary, acute CBD consumption was associated with a small increase in subjective ratings of sedation, but no difference from placebo was observed across multiple domains of objectively assessed cognitive or psychomotor performance. These findings suggest that acute CBD alone is unlikely to significantly impair daily functioning or workplace performance.

Vaporized D-limonene selectively mitigates the acute anxiogenic effects of Δ9-tetrahydrocannabinol in healthy adults who intermittently use cannabis.

BACKGROUND: Cannabis contains hundreds of chemical constituents beyond delta-9-tetrahydrocannabinol (THC), which is believed to drive most of its acute pharmacodynamic effects. The entourage effect theory asserts that non-THC constituents can impact acute cannabis effects, but few empirical studies have systematically evaluated this theory in humans. This study assessed whether the cannabis terpenoid d-limonene mitigates the acute anxiogenic effects of THC. METHODS: Twenty healthy adults completed nine, double-blind outpatient sessions in which they inhaled vaporized THC alone (15mg or 30mg), d-limonene alone (1mg or 5mg), the same doses of THC and d-limonene together, or placebo; a subset of participants (n=12) completed a tenth session in which 30mg THC+15mg d-limonene was administered. Outcomes included subjective drug effects, cognitive/psychomotor performance, vital signs, and plasma THC and d-limonene concentrations. RESULTS: When d-limonene was administered alone, pharmacodynamic outcomes did not differ from placebo. Administration of 15mg and 30mg THC alone produced subjective, cognitive, and physiological effects typical of acute cannabis exposure. Ratings of anxiety-like subjective effects qualitatively decreased as d-limonene dose increased and concurrent administration of 30mg THC+15mg d-limonene significantly reduced ratings of "anxious/nervous" and "paranoid" compared with 30mg THC alone. Other pharmacodynamic effects were unchanged by d-limonene. D-limonene plasma concentrations were dose orderly, and concurrent administration of d-limonene did not alter THC pharmacokinetics. CONCLUSIONS: D-limonene selectively attenuated THC-induced anxiogenic effects, suggesting this terpenoid could increase the therapeutic index of THC. Future research should determine whether this effect extends to oral dose formulations and evaluate the interactions between other cannabis terpenoids or cannabinoids and THC.

Pharmacokinetics and pharmacodynamics of five distinct commercially available hemp-derived topical cannabidiol products.

Products containing cannabidiol (CBD) have proliferated after the 2018 Farm Bill legalized hemp (cannabis with ≤0.3% delta-9-tetrahydrocannabinol (Δ9-THC)). CBD-containing topical products have surged in popularity, but controlled clinical studies on them are limited. This study characterized the effects of five commercially available hemp-derived high CBD/low Δ9-THC topical products. Healthy adults (N = 46) received one of six study drugs: a CBD-containing cream (N = 8), lotion (N = 8), patch (N = 7), balm (N = 8), gel (N = 6) or placebo (N = 9; matched to an active formulation). The protocol included three phases conducted over 17 days: (i) an acute drug application laboratory session, (ii) a 9-day outpatient phase with twice daily product application (visits occurred on Days 2, 3, 7 and 10) (iii) a 1-week washout phase. In each phase, whole blood, oral fluid and urine specimens were collected and analyzed via liquid chromatography with tandem mass spectrometry (LC-MS-MS) for CBD, Δ9-THC and primary metabolites of each and pharmacodynamic outcomes (subjective, cognitive/psychomotor and physiological effects) were assessed. Transdermal absorption of CBD was observed for three active products. On average, CBD/metabolite concentrations peaked after 7-10 days of product use and were highest for the lotion, which contained the most CBD and a permeation enhancer (vitamin E). Δ9-THC/metabolites were below the limit of detection in blood for all products, and no urine samples tested "positive" for cannabis using current US federal workplace drug testing criteria (immunoassay cut-off of 50 ng/mL and confirmatory LC-MS-MS cut-off of 15 ng/mL). Unexpectedly, nine participants (seven lotions, one patch and one gel) exhibited Δ9-THC oral fluid concentrations ≥2 ng/mL (current US federal workplace threshold for a "positive" test). Products did not produce discernable pharmacodynamic effects and were well-tolerated. This study provides important initial data on the acute/chronic effects of hemp-derived topical CBD products, but more research is needed given the diversity of products in this market.

The psychedelic effects of cannabis: A review of the literature.

Cannabis and classic psychedelics are controlled substances with emerging evidence of efficacy in the treatment of a variety of psychiatric illnesses. Cannabis has largely not been regarded as having psychedelic effects in contemporary literature, despite many examples of historical use along with classic psychedelics to attain altered states of consciousness. Research into the "psychedelic" effects of cannabis, and delta-9-tetrahydrocannabinol (THC) in particular, could prove helpful for assessing potential therapeutic indications and elucidating the mechanism of action of both cannabis and classic psychedelics. This review aggregates and evaluates the literature assessing the capacity of cannabis to yield the perceptual changes, aversiveness, and mystical experiences more typically associated with classic psychedelics such as psilocybin. This review also provides a brief contrast of neuroimaging findings associated with the acute effects of cannabis and psychedelics. The available evidence suggests that high-THC cannabis may be able to elicit psychedelic effects, but that these effects may not have been observed in recent controlled research studies due to the doses, set, and settings commonly used. Research is needed to investigate the effects of high doses of THC in the context utilized in therapeutic studies of psychedelics aimed to occasion psychedelic and/or therapeutic experiences. If cannabis can reliably generate psychedelic experiences under these conditions, high-THC dose cannabis treatments should be explored as potential adjunctive treatments for psychiatric disorders and be considered as an active comparator in clinical trials involving traditional psychedelic medications.

Randomized controlled trial of zolpidem as a pharmacotherapy for cannabis use disorder.

BACKGROUND: Sleep disturbance is commonly reported among individuals meeting criteria for cannabis use disorder (CUD), and people who use cannabis frequently report sleep disturbance as a contributor to failed quit attempts. The purpose of this study was to measure sleep in individuals enrolled in treatment for CUD, and to determine whether use of hypnotic medication during treatment increased abstinence rates. METHOD: The study enrolled 127 adults seeking treatment for CUD in a 12-week clinical trial and randomized to receive extended-release zolpidem (zolpidem-XR) or placebo. All participants received computerized behavioral therapy and abstinence-based contingency management. The study conducted in-home ambulatory polysomnography (PSG) assessments at baseline and during treatment to objectively measure sleep. Self-report measures of recent sleep, Insomnia Severity Index (ISI), and drug use (Timeline Follow-Back) were collected at each study visit, and the study confirmed self-reported abstinence via quantitative urine drug testing. RESULT: Participants randomized to placebo, but not zolpidem-XR exhibited significant sleep disturbance during week 1 of treatment. Sleep disturbance emerged in the zolpidem-XR group after study medication was stopped at the end of treatment. Though participants assigned to the zolpidem-XR condition had qualitatively greater rates of abstinence compared with placebo (27 % versus 15 % negative at end of treatment), the difference was not statistically significant. Treatment retention was poor (about 50 % drop out in both groups) and medication adherence was a challenge without the use of contingent incentives. CONCLUSION: Results from this randomized controlled trial suggest that zolpidem-XR can attenuate abstinence-induced sleep disturbance early in treatment for CUD, but that sleep problems are likely to emerge after the medication is stopped. Further research should identify alternative pharmacotherapies and behavioral treatments for CUD and elucidate the role of sleep disturbance in the development and maintenance of CUD.

Parameters of EMA Compliance and Self-Reported Reactivity in a Longitudinal Study of Young Adult Cannabis and Tobacco Co-Users.

Background: Co-use of cannabis and tobacco has become increasingly popular among young adults. Interactive voice response (IVR) based ecological momentary assessment (EMA) allows for measurement of behavior in or near real-time, but has limitations including non-compliance, missing data, and potential for reactivity (e.g., behavior change) from frequent assessments. Methods: This study examined tobacco and cannabis use characteristics and factors associated with IVR compliance and self-reported reactivity in 97 young adults who reported cannabis and tobacco co-use at baseline and completed daily IVR surveys of co-use behavior at three random times per day for 28 days. Results: Overall IVR compliance was 55%, with a modal compliance of 60%. Compliance rates did not differ across morning, midday, and evening surveys, but significantly declined over time. The sample was divided into high frequency responders (>70% calls completed, n=35) and low frequency responders (<70%, calls completed n=62). There were no differences between high and low frequency responders on any baseline demographic, tobacco use (nicotine dependence severity), alcohol, or cannabis use characteristics (past 30-day frequency of use). Participants were receptive to IVR-based EMA monitoring and, 16.5% reported purposely decreasing nicotine/tobacco use due to monitoring, while 19.6% reported purposely decreasing cannabis use, which predicted lower cannabis use post-EMA monitoring. Conclusions: Real-time assessment of co-use behavior among young adults does not appear to be impacted by specific demographics or substance use severity (nicotine dependence, heavy drinking). Data suggest some predictive utility of IVR-based EMA monitoring on short-term behavior change. More intensive approaches are needed to improve compliance among young adult cannabis and tobacco co-users.

Evaluation of Cytochrome P450-Mediated Cannabinoid-Drug Interactions in Healthy Adult Participants.

Understanding cannabis-drug interactions is critical given regulatory changes that have increased access to and use of cannabis. Cannabidiol (CBD) and Δ-9-tetrahydrocannabinol (Δ9-THC), the most abundant phytocannabinoids, are in vitro reversible and time-dependent (CBD only) inhibitors of several cytochrome P450 (CYP) enzymes. Cannabis extracts were used to evaluate quantitatively potential pharmacokinetic cannabinoid-drug interactions in 18 healthy adults. Participant received, in a randomized cross-over manner (separated by ≥ 1 week), a brownie containing (i) no cannabis extract (ethanol/placebo), (ii) CBD-dominant cannabis extract (640 mg CBD + 20 mg Δ9-THC), or (iii) Δ9-THC-dominant cannabis extract (20 mg Δ9-THC and no CBD). After 30 minutes, participants consumed a cytochrome P450 (CYP) drug cocktail consisting of caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A). Plasma and urine samples were collected (0-24 hours). The CBD + Δ9-THC brownie inhibited CYP2C19 > CYP2C9 > CYP3A > CYP1A2 (but not CYP2D6) activity, as evidenced by an increase in the geometric mean ratio of probe drug area under the plasma concentration-time curve (AUC) relative to placebo (AUCGMR ) of omeprazole, losartan, midazolam, and caffeine by 207%, 77%, 56%, and 39%, respectively. In contrast, the Δ9-THC brownie did not inhibit any of the CYPs. The CBD + Δ9-THC brownie increased Δ9-THC AUCGMR by 161%, consistent with CBD inhibiting CYP2C9-mediated oral Δ9-THC clearance. Except for caffeine, these interactions were well-predicted by our physiologically-based pharmacokinetic model (within 26% of observed interactions). Results can be used to help guide dose adjustment of drugs co-consumed with cannabis products and the dose of CBD in cannabis products to reduce interaction risk with Δ9-THC.

Within-subject, double-blind, randomized, placebo-controlled evaluation of combining the cannabinoid dronabinol and the opioid hydromorphone in adults with chronic pain.

The potential synergistic effects of combining cannabinoids and opioids for analgesia has received considerable attention. No studies to date have evaluated this combination in patients with chronic pain. The present study aimed to evaluate the combined analgesic and drug effects of oral opioid (hydromorphone) and delta-9-tetrahydrocannabinol (dronabinol), as well as their effects on physical and cognitive functioning, and human abuse potential (HAP) outcomes among individuals with knee osteoarthritis (KOA). This was a within-subject, double-blind, randomized, placebo-controlled study. Participants (N = 37; 65% women; mean age = 62) diagnosed with knee osteoarthritis of ≥3/10 average pain intensity were included. Participants received (1) placebo-placebo, (2) hydromorphone (4 mg)-placebo; (3) dronabinol (10 mg)-placebo, and (4) hydromorphone (4 mg)-dronabinol (10 mg). Clinical and experimentally-induced pain, physical and cognitive function, subjective drug effects, HAP, adverse events, and pharmacokinetics were evaluated. No significant analgesic effects were observed for clinical pain severity or physical functioning across all drug conditions. Little enhancement of hydromorphone analgesia by dronabinol was observed on evoked pain indices. While subjective drug effects and some HAP ratings were increased in the combined drug condition, these were not significantly increased over the dronabinol alone condition. No serious adverse events were reported; hydromorphone produced more mild adverse events than placebo, but hydromorphone + dronabinol produced more moderate adverse events than both placebo and hydromorphone alone. Only hydromorphone impaired cognitive performance. Consistent with laboratory studies on healthy adults, the present study shows minimal benefit of combining dronabinol (10 mg) and hydromorphone (4 mg) for analgesia and improving physical functioning in adults with KOA.

A cross-sectional survey on cannabis: Characterizing motives, opinions, and subjective experiences associated with the use of various oral cannabis products.

BACKGROUND: Cannabis-infused products available for oral consumption include food and drink items (i.e., edibles) (e.g., baked goods, gummy-, chocolate-, and hard-candies, beverages/drinks) as well as non-food formulations (e.g., oils/tinctures, pills/capsules). This study characterized the motives, opinions, and subjective experiences associated with the use of these seven subtypes of oral cannabis products. METHODS: This web-based survey collected cross-sectional, self-report data from a convenience sample of 370 adults regarding various use-motives, self-reported cannabinoid content, subjective experiences, and opinions related to ingesting oral cannabis products with alcohol and/or food. Advice participants had received about modifying oral cannabis product effects, in general, was also collected. RESULTS: Participants reported consuming cannabis baked goods and gummy candies most frequently over the past year (68% and 63%, respectively). Participants were less likely to use oils/tinctures for enjoyment/desire relative to other product types and more likely to use oils/tinctures for therapeutic purposes (e.g., medication-replacement). Self-reported cannabinoid content was highly variable across participants and within product subtype. Participants reported feeling stronger and longer-lasting effects when consuming oral cannabis products on an empty stomach and 43% received advice to "eat a snack or meal" to mitigate effects that are too strong, which contrasts with controlled studies. Finally, 43% of participants reported modifying their experiences with alcohol at least some of time. CONCLUSIONS: These findings underscore the need to further evaluate use-motives as well as the interaction between dietary factors, cannabinoid pharmacokinetics, and subjective drug effects and the interactive effects of oral cannabis products and alcohol in a controlled laboratory setting.

Assessment of Orally Administered Δ9-Tetrahydrocannabinol When Coadministered With Cannabidiol on Δ9-Tetrahydrocannabinol Pharmacokinetics and Pharmacodynamics in Healthy Adults: A Randomized Clinical Trial.

Importance: Controlled clinical laboratory studies have shown that cannabidiol (CBD) can sometimes attenuate or exacerbate the effects of Δ9-tetrahydrocannabinol (Δ9-THC). No studies have evaluated differences in pharmacokinetics (PK) of Δ9-THC and pharmacodynamics (PD) between orally administered cannabis extracts that vary with respect to Δ9-THC and CBD concentrations. Objective: To compare the PK and PD of orally administered Δ9-THC-dominant and CBD-dominant cannabis extracts that contained the same Δ9-THC dose (20 mg). Design, Setting, and Participants: This randomized clinical trial was a within-participant, double-blind, crossover study conducted from January 2021 to March 2022 at the Johns Hopkins University Behavioral Pharmacology Research Unit, Baltimore, MD. Eighteen healthy adults completed 3 randomized outpatient experimental test sessions that were each separated by at least 1 week. Interventions: Brownies containing (1) no cannabis extract (ie, placebo); (2) Δ9-THC-dominant extract (20 mg Δ9-THC with no CBD); and (3) CBD-dominant extract (20 mg Δ9-THC + 640 mg CBD) were administered to participants 30 minutes prior to administering a cytochrome P450 (CYP) probe drug cocktail, which consisted of 100 mg caffeine, 20 mg omeprazole, 25 mg losartan, 30 mg dextromethorphan, and 2 mg midazolam. Main Outcomes and Measures: Change-from-baseline plasma concentrations for Δ9-THC or Δ9-THC metabolites and scores for subjective drug effects, cognitive and psychomotor performance, and vital signs. The area under the plasma vs concentration vs time curve (AUC) and maximum plasma concentration (Cmax) were determined. Results: The participant cohort of 18 adults included 11 males (61.1%) and 7 females (38.9%) with a mean (SD) age of 30 (7) years who had not used cannabis for at least 30 days prior to initiation of the study (mean [SD] day since last cannabis use, 86 [66] days). The CYP cocktail + placebo brownie and the CYP cocktail did not affect any PD assessments. Relative to CYP cocktail + Δ9-THC, CYP cocktail + Δ9-THC + CBD produced a higher Cmax and area under the plasma concentration vs time curve for Δ9-THC, 11-OH-Δ9-THC, and Δ9-THC-COOH. The CYP cocktail + Δ9-THC + CBD increased self-reported anxiety, sedation, and memory difficulty, increased heart rate, and produced a more pronounced impairment of cognitive and psychomotor performance compared with both CYP cocktail + Δ9-THC and CYP cocktail + placebo. Conclusions and Relevance: In this randomized clinical trial of oral Δ9-THC and CBD, stronger adverse effects were elicited from a CBD-dominant cannabis extract compared with a Δ9-THC-dominant cannabis extract at the same Δ9-THC dose, which contradicts common claims that CBD attenuates the adverse effects of Δ9-THC. CBD inhibition of Δ9-THC and 11-OH-Δ9-THC metabolism is the likely mechanism for the differences observed. An improved understanding of cannabinoid-cannabinoid and cannabinoid-drug interactions are needed to inform clinical and regulatory decision-making regarding the therapeutic and nontherapeutic use of cannabis products. Trial Registration: clinicaltrials.gov Identifier: NCT04201197.

Clinical Trial Design Challenges and Opportunities for Emerging Treatments for Opioid Use Disorder: A Review.

Importance: Novel treatments for opioid use disorder (OUD) are needed to address both the ongoing opioid epidemic and long-standing barriers to existing OUD treatments that target the endogenous µ-opioid receptor (MOR) system. The goal of this review is to highlight unique clinical trial design considerations for the study of emerging treatments for OUD that address targets beyond the MOR system. In November 2019, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration sponsored a meeting to discuss the current evidence regarding potential treatments for OUD, including cannabinoids, psychedelics, sedative-hypnotics, and immunotherapeutics, such as vaccines. Observations: Consensus recommendations are presented regarding the most critical elements of trial design for the evaluation of novel OUD treatments, such as: (1) stage of treatment that will be targeted (eg, seeking treatment, early abstinence/detoxification, long-term recovery); (2) role of treatment (adjunctive with or independent of existing OUD treatments); (3) primary outcomes informed by patient preferences that assess opioid use (including changes in patterns of use), treatment retention, and/or global functioning and quality of life; and (4) adverse events, including the potential for opioid-related relapse or overdose, especially if the patient is not simultaneously taking maintenance MOR agonist or antagonist medications. Conclusions and Relevance: Applying the recommendations provided here as well as considering input from people with lived experience in the design phase will accelerate the development, translation, and uptake of effective and safe therapeutics for individuals struggling with OUD.

A crowdsourcing survey study on the subjective effects of delta-8-tetrahydrocannabinol relative to delta-9-tetrahydrocannabinol and cannabidiol.

Delta-8-tetrahydrocannabinol (Δ8-THC) has emerged as a new retail cannabinoid product in the U.S. This study queried Δ8-THC users about product use characteristics and self-reported drug effects. Participants were recruited via a large online crowdsourcing platform (Amazon Mechanical Turk). Adults (N = 252) with past year Δ8-THC use (35% with at least weekly use) completed surveys and open-ended questions related to their reasons for using and past experiences with Δ8-THC-containing retail products. Participants with past year use of Δ9-tetrahydrocannabinol (Δ9-THC) and/or cannabidiol (CBD; 81% and 63%) compared the effects of Δ8-THC to those of Δ9-THC and/or CBD by rating drug effects on a visual analog scale from -50 to + 50 where negative scores indicated Δ8-THC effects are weaker, positive scores indicated Δ8-THC effects are stronger, and a score of 0 indicated equal effects to Δ9-THC or CBD. Compared to Δ9-THC, self-reported ratings for "Drug effect," "Bad effect," "Sick," "Anxiety," "Paranoia," "Irritability," "Restlessness," "Memory Problems," and "Trouble Performing Routine Tasks" were lower for Δ8-THC (d = -0.21 to -0.44). Compared to CBD, ratings for Δ8-THC effects were higher for "Drug effect," "Good effect," "High," "Relaxed," "Sleepy," "Hunger/Have the Munchies," "Memory Problems," "Trouble Performing Routine Tasks," and "Paranoia" (d = 0.27-1.02). Qualitative responses indicated that participants used Δ8-THC because it is perceived as (a) legal, (b) a substitute or similar to Δ9-THC, and/or (c) less intense than Δ9-THC. Δ8-THC is an understudied psychoactive component of cannabis that shares more characteristics with Δ9-THC than CBD and should be characterized further with human laboratory studies. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Immediate Switching to Reduced Nicotine Cigarettes in a U.S.-Based Sample: The Impact on Cannabis Use and Related Variables at 20 Weeks.

INTRODUCTION: The FDA proposed rule-making to reduce nicotine in cigarettes to minimally addictive levels. Research suggests decreasing nicotine levels (i.e. very low nicotine content cigarettes [VLNCs]) produced greater quit attempts, reduced smoking, and reduced exposure to harmful constituents among smokers. The impact of long-term VLNC use among people who co-use cigarettes and cannabis on non-tobacco-specific toxicant and carcinogen exposure has not been investigated. AIMS AND METHODS: This study presents secondary analyses of a controlled clinical trial examining switching to VLNC (versus a normal nicotine cigarettes control group [NNCs]) between people who co-use cigarettes and cannabis (n = 174) versus smoked cigarettes (n = 555). Linear mixed-effects models compared changes in smoking behavior, and tobacco-specific (i.e. total nicotine equivalents [TNE], 4-[methylnitrosamino]-1-[3-pyridyl]-1-butanone [NNK; total NNAL]) and non-tobacco-specific (i.e. carbon monoxide (CO), 2-cyanoethylmercapturic acid [CEMA], phenanthrene tetraol [PheT]) toxicant and carcinogen exposure at week 20 (with random intercept for participants). Cannabis use was measured among co-use groups. RESULTS: CO was significantly lower only among the cigarette-only group assigned VLNCs (interaction: p = .015). Although both VLNC groups demonstrated decreased CEMA, greater decreases emerged among the cigarette-only group (interaction: p = .016). No significant interactions emerged for TNE, cigarettes per day (CPD), NNAL, and PheT (ps > .05); both VLNC groups decreased in TNE, CPD, and NNAL. Only the cigarette-only group assigned VLNCs demonstrated decreased PheT (p < .001). The VLNC co-use group showed increased cannabis use over time (p = .012; 0.5 more days per week by week 20). CONCLUSIONS: Those who co-use cannabis and cigarettes may still be at risk for greater exposure to non-tobacco-specific toxicants and carcinogens compared to those who only smoke cigarettes. IMPLICATIONS: The present study is the longest longitudinal, prospective comparison study of smoking behavior and exposure to harmful constituents among those who co-use cigarettes and cannabis versus cigarette-only after immediately switching to very low nicotine content cigarettes (VLNC). Those who co-use experienced similar reductions in CPD and tobacco-specific exposure, compared to those who only use cigarettes. However, co-use groups experienced smaller reductions in non-tobacco-specific toxicants and carcinogens compared to the cigarette-only group, potentially because of combustible cannabis use. Additionally, those who co-use and switched to VLNC may be susceptible to slight increases in cannabis use (approximately two more days per year).

Online survey of medicinal cannabis users: Qualitative analysis of patient-level data.

Aim: To characterize perceived benefits and challenges experienced by medicinal cannabis users. Methods: An anonymous online survey collected demographics, health information, and open-ended responses from medicinal cannabis users regarding perceptions, motivations, and experience of treatment. Qualitative open-ended responses were thematically analyzed. Results: Respondents (N = 808) were predominantly White (79%), female (63%), with a mean (SD) age of 38 (20). Two hundred eighty-four (35%) respondents provided data on a dependent family member (e.g., child; 22% of total sample). Most used cannabidiol (CBD)-dominant products (58%), primarily for neurological disorders (38%) or pain (25%). Primary motivations for medicinal cannabis use were based on beliefs that traditional treatments were ineffective and/or had intolerable side effects (51%), positive scientific or media portrayals of the safety/efficacy of cannabis as a therapeutic (29%), or preference for "natural" treatments over pharmaceuticals (21%). A majority of respondents (77%) attributed positive effects to the medicinal use of cannabis/cannabinoids. These included physical symptom improvements such as reduced pain (28%), improved sleep (18%), and seizure reduction (18%), and mental health improvements including reduced anxiety (22%) and improved mood (11%). Additionally, respondents reported reduced use of other medications (e.g., opioids) (12%), and improved quality of life (14%). Problems associated with use were cited by 41% of respondents, and included unwanted side effects (16%), lack of information or medical support (16%), prohibitive costs (12%), and legal concerns (10%). Conclusion: Most participants reported benefits from cannabis use for a variety of conditions where traditional treatments were ineffective or unacceptable. Concerns regarding cannabis side effects, legality, lack of information, and cost were raised. Data indicate greater research and education on the safety and efficacy of medicinal cannabis/cannabinoid use is warranted.

The effects of oral and vaporized cannabis alone, and in combination with alcohol, on driving performance using the STISIM driving simulator: A two-part, double-blind, double-dummy, placebo-controlled, randomized crossover clinical laboratory protocol.

The legalization of cannabis for medicinal and non-medicinal purposes, and the corresponding increase in diversity of cannabis products, has resulted an urgent need for cannabis regulatory science. Among the most pressing needs is research related to impairment due to cannabis exposure, especially on driving performance. The present project was designed to evaluate the impact of oral and vaporized cannabis, when administered alone or in combination with alcohol, on simulated driving performance (STISIM driving simulator), cognitive/psychomotor ability, and field sobriety performance. Healthy adults will complete two, double-blind, double-dummy, placebo-controlled, randomized crossover clinical laboratory studies, one with oral cannabis (16 men/16 women) and the second with vaporized cannabis (16 men/16 women). In each study, participants will complete seven experimental sessions during which acute doses of placebo or high Δ9-THC cannabis containing 0, 10, or 25 mg Δ9-THC will be administered both alone and in combination with placebo or alcohol-containing beverages (target breath alcohol concentrations, BAC, of 0.0% or 0.05%). A positive control session (i.e., alcohol at target BAC of 0.08% with placebo cannabis) will also be completed. Simulated driving performance tests (available for download; see Methods), field sobriety assessments, subjective drug effect questionnaires, a mobile device impairment test (DRUID app), and collection of whole blood specimens will be completed repeatedly during each session. Linear mixed models will be used to test for differences across experimental conditions and a priori planned comparisons will be used to determine differences between conditions of interest (e.g., cannabis alone vs cannabis with alcohol). This research is designed to extend prior studies of cannabis and alcohol on driving performance by using oral and vaporized routes of cannabis administration. By increasing understanding of impairment associated with co-use of alcohol and these novel forms of cannabis, this research could inform impairment detection standards for cannabis and alcohol and have important implications for law enforcement, public policy decisions regarding accessibility of these substances, and education of the general population who may use cannabis and/or alcohol. Lastly, this manuscript provides interested researchers with access to the simulated driving scenarios and data extraction tools developed for this study as a means of facilitating future cross-study comparisons, which is important given the heterogeneity in methods used across laboratories in prior research.

Real-Time Monitoring of Cannabis and Prescription Opioid Co-Use Patterns, Analgesic Effectiveness, and the Opioid-Sparing Effect of Cannabis in Individuals With Chronic Pain.

Despite a rapid expansion of cannabis use for pain management, how cannabis and prescription opioids are co-used and whether co-use improves analgesia and promotes reduction of opioid use in the daily lives of individuals with chronic pain is poorly understood. Based upon ecological momentary assessment (EMA), the present study examined 1) how pain and use of opioids and/or cannabis in the previous moment is associated with individuals' choice of opioids and/or cannabis in the next moment, 2) the effects of co-use on pain severity and pain relief, and 3) whether daily total opioid consumption differs on days when people only used opioids versus co-used. Adults with chronic pain (N = 46) using both opioids and cannabis who were recruited online completed a 30-day EMA. Elevated pain did not increase the likelihood of co-use in subsequent momentary assessments. Switching from sole use of either opioids and cannabis to co-use was common. Neither co-use nor sole use of either cannabis or opioids were associated with reductions in pain in the next moment. However, participants reported the highest daily perceived pain relief from co-use compared to cannabis and opioid use only. Post hoc analysis suggested recall bias as a potential source of this discrepant findings between momentary versus retrospective assessment. Lastly, there was no evidence of an opioid-sparing effect of cannabis in this sample. The present study shows preliminary evidence on cannabis and opioid co-use patterns, as well as the effects of co-use on pain and opoid dose in the real-world setting. PERSPECTIVE: This article presents the overall patterns and effects of co-using cannabis and prescription opioids among individuals with chronic pain employing ecological momentary assessment. There were conflicting findings on the association between co-use and analgesia. Co-use was not associated with a reduction in daily opioid consumption in this sample.