Ryan Vandrey

Purpose Hope has been identified as a beneficial factor for enhancing quality of life (QoL), particularly for individuals with chronic disease, including chronic pain. However, significant gaps remain in understanding how hope and QoL intersect and relate to one another. The current study investigated whether daily hope frequency, defined as how often participants felt hopeful each day, can predict next-day QoL among individuals with chronic pain who are using cannabis and opioids to manage pain. Methods This was an observational study, approved by the Institutional Review Board of the Johns Hopkins Bloomberg School of Public Health (Protocol: IRB00009327). Participants (N = 132) using opioids and cannabis for chronic pain completed a baseline survey and 30-day daily diaries assessing hope frequency, QoL, and sleep satisfaction. Participants (mean age = 42.7, SD = 13.9) were predominantly male (58.3%) and Non-Hispanic White (63.6%). Linear mixed-effects models were used to test the lagged effects of daily hope frequency, decomposed into between- and within-person components, on next-day QoL, controlling for baseline variables, daily sleep satisfaction, and previous-day QoL. Intraindividual variabilities were also examined. Results Higher hope frequency was significantly associated with greater next-day QoL both between participants (i.e., participants with higher average hope reported higher QoL) and within participants (i.e., on days when hope was higher than a participant’s own average), even after controlling for previous-day QoL and sleep satisfaction. While higher baseline hope and QoL scores were associated with higher average QoL over the 30-day period, intraindividual variability in hope was not significantly associated with QoL. Conclusions Our daily diary study found that previous-day hope frequency — both stable individual differences and day-to-day fluctuations — was associated with next-day QoL in individuals with chronic pain who were co-using cannabis and opioids.

Introduction: This narrative review systematically examines the available empirical evidence for interactions between delta-9-tetrahydrocannabinol (Δ9-THC or THC) and C. sativa’s other phytochemical constituents hypothesized to underpin the popular yet controversial notion of ‘entourage effects’ experienced with botanical cannabis. Many relevant preclinical and clinical studies have been conducted in the last decade to elucidate the individual contributions of various phytocannabinoids and bioactive terpenes to the pharmacodynamic effects of C. sativa. However, their varied methods and results complicate their interpretation. Here, a particular emphasis is placed on synthesizing data from clinical studies of THC’s modulation by Cannabis sativa’s other phytochemical constituents. Methods: A systematic search of the scientific literature indexed in PubMed was conducted to identify controlled clinical and preclinical studies evaluating the modulation of THC’s effects by individual phytochemicals. Studies that evaluated the phytocannabinoids cannabidiol (CBD), cannabinol (CBN), tetrahydrocannabivarin (THCV), cannabigerol (CBG), cannabichromene (CBC), and cannabis terpenes α-pinene, d-limonene, β-myrcene, linalool, α-humulene, β-caryophyllene, bisabolol, terpinene, and terpineol were included in the literature search for discussion. Results: Cannabidiol and THC interactions have been extensively studied, with recent findings showing significant exacerbation of THC effects when orally coadministered, but not when inhaled. Clinical studies examining THC interactions with constituents beyond CBD remain comparatively limited. Recent clinical evidence suggests that THCV may reduce certain subjective and cognitive effects of THC. At the same time, some terpenes, such as limonene, can selectively modulate adverse effects associated with high THC doses in humans. Clinical studies have often failed to translate the interactive effects between THC and minor phytocannabinoids/terpenes observed in animal models. Discussion: Although interest in the clinical pharmacology of minor cannabinoids and terpenes has grown in recent years, the evidence supporting meaningful modulation of THC’s effects in humans remains exceptionally limited. The mixed results from preliminary studies underscore the complexity of phytochemical interactions and the inherent challenges of translating preclinical findings into measurable clinical outcomes. Conclusion: Well-designed, controlled clinical studies of individual phytochemical interactions on subjective, therapeutic, and adverse effects are still required to support entourage effects in humans. In particular, the effects of many bioactive terpenes and trace cannabinoids have not yet begun to be evaluated in humans, either as individual phytochemicals or when combined with THC.

Aims: The United States Drug Enforcement Administration's (DEA) proposed rescheduling of cannabis from Schedule I to Schedule III under the Controlled Substances Act marks a significant shift in federal policy. Understanding public sentiment toward this policy is critical for guiding the current cannabis rescheduling effort as well as future reforms. The objective of this study is to characterize public comments submitted to Regulations.gov regarding the DEA's cannabis rescheduling proposal and identify underlying justifications for support or opposition. Design: A mixed‐methods analysis was conducted. Setting: Online public comments submitted to Regulations.gov regarding the DEA's cannabis rescheduling proposal. Participants: 42 913 public comments submitted between 21 May and 22 July 2024. Measurements: Comments were analyzed for sentiment towards the proposed rescheduling (support, oppose or insufficient rescheduling) and thematic justifications using manual and automated natural language processing techniques. A two‐stage annotation approach was employed: manual coding of 200 randomly sampled comments by multiple independent evaluators, followed by automated classification of all 42 913 comments using open source Large Language Model (LLM) validated against the manual annotations. Findings: Using LLM‐based classification validated against human annotations [88% agreement, F1 (harmonic mean of precision and recall) = 0.86], we found that among 42 913 comments, 28.85% [95% confidence interval (CI) = 28.44%–29.24%] supported rescheduling, 6.74% (95% CI = 6.50%–6.99%) opposed and 63.50% (95% CI = 63.06%–63.99%) deemed the proposal insufficient, favoring further rescheduling or complete de‐scheduling of cannabis. Among the 200 manually annotated comments, therapeutic benefits (56.7%, 95% CI = 46.7%–66.7%) and economic impacts (27.8%, 95% CI = 18.9%–37.8%) were the most common justifications among supporters. Public health risks (100.0%, 95% CI = 100.0%–100.0%), addictiveness concerns (71.4%, 95% CI = 42.9%–100.0%) and concerns about underage use (57.1%, 95% CI = 14.3%–85.7%) were predominant in opposing comments. Insufficient rescheduling comments cited therapeutic benefits (37.8%, 95% CI = 28.5%–48.0%), economic impacts (28.6%, 95% CI = 19.4%–37.8%) and criminal justice reform (26.5%, 95% CI = 18.4%–35.7%) as primary justifications. Conclusions: Public sentiment on Regulations.gov supports the United States Drug Enforcement Administration's proposal for cannabis rescheduling, though the majority views the proposed Schedule III classification as inadequate and supports further rescheduling or complete de‐scheduling of cannabis.

Purpose of Review In the U.S., cannabis products containing at least 0.3% tetrahydrocannabinol (THC), are legal for adult use in 22 states (including the District of Columbia) and in 16 additional states for medicinal use. There is a growing body of literature to understand how these products are marketed. The objective of this narrative review is to summarize recent research examining cannabis advertising. We characterized the research reviewed across three primary domains: (1) content of cannabis advertising; (2) prevalence of cannabis advertising exposure; and (3) effects of cannabis advertising on user perceptions. Recent Findings Research indicates that cannabis is marketed in a variety of ways, including via tactics (e.g., price promotions) found to be effective in increasing use of other commercial products (e.g., tobacco). Moreover, cannabis marketing tactics may be appealing to youth or mislead consumers via unsubstantiated health claims. Exposure to cannabis advertising is common among both youth and adults, occurring through a variety of pathways including storefront signage, social media and billboards. Finally, several studies have found associations between exposure to cannabis marketing and cannabis use; however, studies designed to estimate causal effects of exposure were limited, warranting additional research in this area. Summary Understanding the prevalence and effects of exposure to cannabis advertising, along with the content of this advertising, can inform the operationalization and implementation of regulations and interventions designed to mitigate harms associated with advertising exposure.

Persistent reservoirs and chronic immune activation are hallmarks of HIV, despite the effectiveness of antiretroviral therapy (ART) in suppressing viral replication. Here, we use rhesus macaques and primary and induced pluripotent stem cell (iPSC)-derived human immune cells to evaluate the virologic and immunologic consequences of cannabidiol (CBD) exposure during HIV/SIV infection. We show that CBD, in the absence of ART, suppresses viral replication and establishment of the viral reservoir to levels comparable with first-line therapies during acute SIV infection of rhesus macaques. This antiviral effect of CBD extended to in vitro HIV infection of human macrophages, T cells, and microglia. Immunologically, we observe CBD slowed CD4+ T cell decline and polarization, decreased CD14+CD16+ monocyte expansion, and reduced interferon-inducible cytokine release in rhesus macaques. We identify comparable effects on cytokine production with in vitro CBD treatment of human macrophages, T cells, and microglia. Importantly, we find CBD inhibits cytokines only when an immune response is elicited by HIV, suggesting it is not broadly immunosuppressive. Finally, we determine CBD regulates endocannabinoid receptors, modulators, and transporters and inhibits NF-κb and STAT1 activation when mediating its antiviral and anti-inflammatory effects. These findings show beneficial effects of CBD in laboratory models of untreated HIV, thus placebo-controlled clinical trials to evaluate the safety and effectiveness of adjunctive CBD use with ART is warranted.

Introduction. Cannabis contains hundreds of chemical constituents beyond delta-9-tetrahydrocannabinol (Δ9-THC), which is thought to be the primary driver of most of its acute pharmacodynamic effects. The entourage effect theory asserts that the pharmacological and therapeutic effects of cannabis are not solely attributable to Δ9-THC, but are influenced by other constituents, such as minor cannabinoids and terpenes, through distinct pharmacological action. However, empirical studies that have systematically evaluated this theory in humans remain limited. This study tested the hypothesis that the terpene α-pinene can attenuate the acute memory-impairing effects of inhaled Δ9-THC in humans. Methods. Participants (N = 19; last cannabis use 39 days, on average, prior to first test session [SD = 84; range = 2–365]) completed six double-blind outpatient drug administration sessions during which they inhaled, using a Mighty Medic hand-held vaporizer, α-pinene alone (15 mg), Δ9-THC alone (30 mg), Δ9-THC and α-pinene together (30 mg Δ9-THC + 0.5 mg α-pinene; 30 mg Δ9-THC + 5 mg α-pinene; 30 mg Δ9-THC + 15 mg α-pinene), or placebo (ambient air) in a randomized order. Outcomes, which were collected up to 6 hours post drug exposure, included subjective drug effects, cognitive/psychomotor performance, and vital signs. Results. Administration of 15 mg α-pinene alone produced no significant pharmacodynamic effects compared to placebo. Administration of 30 mg Δ9-THC alone elicited subjective, cognitive, and physiological effects consistent with acute Δ9-THC-dominant cannabis exposure, including impairment of cognitive performance and working memory ability compared to placebo. The co-administration of α-pinene with Δ9-THC did not mitigate Δ9-THC-induced memory impairment or significantly alter other acute subjective, cognitive, or physiological effects. Conclusions. Inhaled α-pinene, at doses at and above those naturally found in cannabis flowers, did not mitigate Δ9-THC-induced cognitive impairments as hypothesized or influence other common acute effects of Δ9-THC in this sample of healthy adults. This result is inconsistent with some cannabis industry claims and speculation by some cannabis researchers. By systematically varying both Δ9-THC and terpene exposure and assessing their interaction across multiple pharmacodynamic domains, this work provides a model for future investigations into Δ9-THC-terpene interactions. As cannabis use continues to expand for both medicinal and non-medicinal purposes, more research is needed to better understand the acute effects of lesser studied chemical constituents of the plant and how they interact with predominant phytocannabinoids like Δ9-THC. This can inform cannabinoid drug development and product policy considerations.

There is limited data on the comparative pharmacokinetics of cannabidiol (CBD) across oral and vaporized formulations. This within-subject, double-blind, double-dummy, placebo-controlled laboratory study analyzed the pharmacokinetic profile of CBD, ∆⁹-tetrahydrocannabinol (∆⁹-THC) and related metabolites in blood and oral fluid (OF) after participants (n = 18) administered 100 mg of CBD in each of the following formulations: (1) oral CBD, (2) vaporized CBD and (3) vaporized CBD-dominant cannabis containing 10.5% CBD and 0.39% ∆⁹-THC (3.7 mg); all participants also completed a placebo condition. Oral CBD was administered in three formulations: (1) encapsulated CBD, (2) CBD suspended in pharmacy-grade syrup and (3) Epidiolex, allowing for pharmacokinetic comparisons across oral formulations (n = 6 per condition). An optional fifth experimental condition was completed for six participants in which they fasted from all food for 12 h prior to oral ingestion of 100 mg of CBD. Blood and OF samples were collected immediately before and for 57–58 h after each drug administration. Immunoassay screening and LC–MS-MS confirmatory tests were performed, the limit of quantitation was 0.5 ng/mL for ∆⁹-THC and 1 ng/mL for CBD. The mean C_max and range of CBD blood concentrations for each product were as follows: vaporized CBD-dominant cannabis, 171.1 ng/mL, 40.0–665.0 ng/mL, vaporized CBD 104.6 ng/mL, 19.0–312.0 ng/mL and oral CBD, 13.7 ng/mL, 0.0–50.0 ng/mL. Of the three oral formulations, Epidiolex produced the greatest peak concentration of CBD (20.5 ng/mL, 8.0–37.0 ng/mL) relative to the capsule (17.8 ng/mL, 2.0–50.0 ng/mL) and syrup (2.8 ng/mL, 0–7.0 ng/mL). ∆⁹-THC was detected in the blood of 12/18 participants after vaporized CBD-dominant cannabis use, but neither ∆⁹-THC nor its metabolite THC-COOH were detected in the blood of any participants after vaporized or oral CBD-only administration. These data demonstrate that different oral and vaporized formulations produce substantial variability in the pharmacokinetics of CBD and that CBD alone is unlikely to convert to ∆⁹-THC or produce positive drug tests for ∆⁹-THC or its metabolite.

Introduction: Despite widespread legalization, the impact of medicinal cannabis use on patient-level health and quality of life (QOL) has not been carefully evaluated. The objective of this study was to characterize self-reported demographics, health characteristics, QOL, and health care utilization of Cannabis Users compared with Controls. Methods: A longitudinal, cross-sectional web-based survey study was completed between April 2016 and February 2018. Study participants ( n =1276) were a convenience sample of either patients with a diagnosed health condition or caregivers of a patient with a diagnosed health condition registered with the Realm of Caring Foundation (a nonprofit organization dedicated to therapeutic cannabis research and education). Participants were invited through e-mail to complete follow-up assessments every 3 months with 33% of participants completing one or more prospective follow-ups. Assessments included self-reported demographics, health care utilization, medication use, pain, anxiety, depression, sleep, and QOL. Cannabis Users ( n =808) were compared with Controls ( n =468) using negative binomial regression and linear mixed effects models testing the effect of initiation, cessation, and maintenance of medicinal cannabis use. Results: Cannabis Users self-reported significantly better QOL [ t (1054)=−4.19, p t (1045)=−4.14, p t (224)=2.90, p t (758)=3.03, p t (1150)=2.34, p t (1151)=4.38, p t (1210)=5.77, p <0.001] compared with Controls. Cannabis Users reported using fewer prescription medications (rate ratio [RR]=0.86; 95% confidence interval [CI]: 0.77–0.96) and were less likely to have a past-month emergency department visit (RR=0.61; 95% CI: 0.44–0.84) or hospital admission (RR=0.54; 95% CI: 0.34–0.87). Controls who initiated cannabis use after baseline showed significant health improvements at follow-up, and the magnitude of improvement mirrored the between-group differences observed at baseline. Conclusions: Cannabis use was associated with improved health and QOL. Longitudinal testing suggests that group differences may be due to the medicinal use of cannabis. Although bias related to preexisting beliefs regarding the health benefits of cannabis in this sample should be considered, these findings indicate that clinical trials evaluating the efficacy of defined cannabinoid products for specific health conditions are warranted.

Background: The lack of an agreed international minimum approach to measuring cannabis use hinders the integration of multidisciplinary evidence on the psychosocial, neurocognitive, clinical and public health consequences of cannabis use.Methods: A group of 25 international expert cannabis researchers convened to discuss a multidisciplinary framework for minimum standards to measure cannabis use globally in diverse settings.Results: The expert‐based consensus agreed upon a three‐layered hierarchical framework. Each layer—universal measures, detailed self‐report and biological measures—reflected different research priorities and minimum standards, costs and ease of implementation. Additional work is needed to develop valid and precise assessments.Conclusions: Consistent use of the proposed framework across research, public health, clinical practice and medical settings would facilitate harmonisation of international evidence on cannabis consumption, related harms and approaches to their mitigation.