Investigating the Relationship Between Cannabis Expectancies and Anxiety, Depression, and Pain Responses After Acute Flower and Edible Cannabis Use.

Objective: Cannabis has been touted for a host of pharmacological and therapeutic effects and users commonly report reduced symptoms of physical and mental health conditions, including anxiety, depression, and chronic pain. While there is existing empirical evidence supporting these effects of cannabis use, little is known about the extent to which these effects result from pharmacological versus expectancy factors. We evaluated the associations between participants' cannabis expectancies and their acute self-reported reactions after using legal market forms of cannabis with varying levels of cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) in three domains: anxiety, depression, and pain. Methods: Fifty-five flower and 101 edible cannabis users were randomly assigned and asked to purchase at a local dispensary one of three products containing varying levels of CBD and THC. Participants completed a baseline assessment where they reported expectancies about general health effects of cannabis use and an experimental mobile laboratory assessment where they administered their assigned products. Edible users also reported their domain-specific expectancies about cannabis use in improving anxiety, depression, and pain. Following administration, participants completed acute indicators of anxiety, depression, and pain operationalized through subjective acute tension, elation, and a single-item measure of pain. Results: Among flower users, more positive expectancies for cannabis to improve general health were correlated with greater reductions in tension at acute post-use. This finding was replicated among edible users. Unlike flower users, more positive expectancies for cannabis to improve general health were also correlated with greater increases in elation and greater reductions in pain among edible users. More positive expectancies for cannabis to improve depression and pain were also correlated with greater increases in elation and greater reductions in pain, respectively, among edible users. Conclusions: Cannabis users' expectancies significantly impacted some of the acute subjective effects of legal market cannabis products. Among both flower and edible users, consistent, significant expectancy effects were found. Results were consistent with prior findings and demonstrate the need to measure and control pre-existing expectancies in future research that involves cannabis administration. Clinical trial registration number: NCT03522103.

Acute and Extended Anxiolytic Effects of Cannabidiol in Cannabis Flower: A Quasi-Experimental ad libitum Use Study.

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.

Mindfulness mechanisms in alcohol use: Comparing top-down and bottom-up processes.

OBJECTIVE: This study compared two mechanisms by which mindfulness may reduce hazardous drinking: effortful control and craving, "top-down" and "bottom-up" processes, respectively. These relationships were compared in a secondary analysis of a randomized controlled trial of mindfulness-based relapse prevention (MBRP) versus relapse prevention (RP) treatments to explore if they differed based on more explicit versus subtle mindfulness training. METHOD: A total of 182 individuals (48.4% female; 21-60 years old) who reported drinking > 14/21 drinks/week (for females/males, respectively) in the past 3 months but who wished to quit/reduce their drinking were recruited from Denver and Boulder, CO, United States. Participants were randomly assigned to either 8 weeks of MBRP or RP treatment and completed assessments at baseline, halfway through treatment, and at the end of treatment. The Five-Factor Mindfulness Questionnaire-Short Form, Alcohol Urge Questionnaire, and Effortful Control Scale completed halfway through treatment assessed the predictor, dispositional mindfulness, and mediators, craving and effortful control, respectively. The Alcohol Use Disorder Identification Task was completed after treatment and measured hazardous drinking. Cross-group path analyses were conducted including both mediators/treatments in the same model. RESULTS: Comparing models with and without equality constraints across treatments, no paths significantly differed based on a chi-square test of difference, χ²(5) = 5.11, p = .40, and only the indirect effect of craving was significant (B = -1.01, p = .01). CONCLUSIONS: Findings suggest mindfulness may be associated with hazardous drinking reductions through craving but not effortful control and this indirect relationship works similarly across treatments engendering mindfulness explicitly and implicitly. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Acute Effects of Ad Libitum Use of Commercially Available Cannabis Products on the Subjective Experience of Aerobic Exercise: A Crossover Study.

OBJECTIVE: The present study aimed to examine the acute effects of legal-market cannabis on regular cannabis users' subjective responses to exercise in a controlled laboratory environment. BACKGROUND: Given the stereotype that cannabis is associated with extreme sedentary behavior, there are concerns that cannabis legalization may exacerbate the US physical inactivity epidemic. However, despite these concerns, recent years have seen considerable public interest in the use of cannabis concurrently with exercise (e.g., running). METHODS: The present study compared participants' experiences of exercise without cannabis to their experiences of exercise after acute ad libitum use of one of two commercially available cannabis flower products: a Δ9-tetrahydrocannabinol-dominant or a cannabidiol-dominant product. Participants (N = 42) were regular cannabis users between the ages of 21 and 39 years (mean = 30.81 years, standard deviation = 4.72 years). RESULTS: Although participants reported a more positive affect (p < 0.001), enjoyment (p < 0.001), and runner's high symptoms (p < 0.001) during their cannabis (vs non-cannabis) exercise appointment, they also reported more exertion (p = 0.04). Pain levels were very low and did not differ between appointments (p = 0.45). Effects appeared to depend, in part, on cannabinoid content; there was a larger difference in enjoyment (p = 0.02), and a smaller difference in exertion (p = 0.02), between the cannabis and non-cannabis exercise appointments among participants in the cannabidiol (vs Δ9-tetrahydrocannabinol) condition. CONCLUSIONS: To our knowledge, this is the first study to investigate the acute effects of commercially available cannabis on subjective responses to exercise in a laboratory environment. Our findings suggest that, among regular cannabis users who use cannabis in combination with exercise, cannabis use prior to exercise may lead to increases in both positive and negative aspects of the subjective exercise experience. Research using diverse samples, exercise modalities, and methodologies (e.g., placebo-controlled trials) is needed to establish the generalizability of these findings.

Maternal Childhood Maltreatment, Internal Working Models, and Perinatal Substance Use: Is There a Role for Hyperkatifeia? A Systematic Review.

The parent-infant relationship is critical for socioemotional development and is adversely impacted by perinatal substance use. This systematic review posits that the mechanisms underlying these risks to mother-infant relationships center on 3 primary processes: (1) mothers' childhood maltreatment experiences; (2) attachment styles and consequent internal working models of interpersonal relationships; and (3) perinatal substance use. Further, the review considers the role of hyperkatifeia, or hypersensitivity to negative affect which occurs when people with substance use disorders are not using substances, and which drives the negative reinforcement in addiction. The authors performed a systematic review of articles (published 2000-2022) related to these constructs and their impact on mother-infant relationships and offspring outcomes, including original clinical research articles addressing relationships between these constructs, and excluding case studies, reviews, non-human animal studies, intervention studies, studies with fewer than 30% female-sex participants, clinical guidelines, studies limited to obstetric outcomes, mechanistic/biological studies, and studies with methodological issues precluding interpretation. Overall 1844 articles were screened, 377 were selected for full text review, and data were extracted from 157 articles. Results revealed strong relationships between mothers' childhood maltreatment experiences, less optimal internal working models, and increased risk for perinatal substance use, and importantly, all of these predictors interacted with hyperkatifeia and exerted a marked impact on mother-infant relationships with less data available on offspring outcomes. These data strongly support the need for future studies addressing the additive impact of maternal childhood maltreatment experiences, suboptimal internal working models, and perinatal substance use, with hyperkatifeia as a potential moderator, and their interacting effects on mother-infant socioemotional outcomes.

Brain volumes in alcohol use disorder: Do females and males differ? A whole-brain magnetic resonance imaging mega-analysis.

Emerging evidence suggests distinct neurobiological correlates of alcohol use disorder (AUD) between sexes, which however remain largely unexplored. This work from ENIGMA Addiction Working Group aimed to characterize the sex differences in gray matter (GM) and white matter (WM) correlates of AUD using a whole-brain, voxel-based, multi-tissue mega-analytic approach, thereby extending our recent surface-based region of interest findings on a nearly matching sample using a complementary methodological approach. T1-weighted magnetic resonance imaging (MRI) data from 653 people with AUD and 326 controls was analyzed using voxel-based morphometry. The effects of group, sex, group-by-sex, and substance use severity in AUD on brain volumes were assessed using General Linear Models. Individuals with AUD relative to controls had lower GM volume in striatal, thalamic, cerebellar, and widespread cortical clusters. Group-by-sex effects were found in cerebellar GM and WM volumes, which were more affected by AUD in females than males. Smaller group-by-sex effects were also found in frontotemporal WM tracts, which were more affected in AUD females, and in temporo-occipital and midcingulate GM volumes, which were more affected in AUD males. AUD females but not males showed a negative association between monthly drinks and precentral GM volume. Our results suggest that AUD is associated with both shared and distinct widespread effects on GM and WM volumes in females and males. This evidence advances our previous region of interest knowledge, supporting the usefulness of adopting an exploratory perspective and the need to include sex as a relevant moderator variable in AUD.

Comparing the Efficacy of Mindfulness-Based Relapse Prevention Versus Relapse Prevention for Alcohol Use Disorder: A Randomized Control Trial.

OBJECTIVE: This study compared the efficacy of mindfulness-based relapse prevention (MBRP) with relapse prevention (RP) on reducing alcohol consumption. Secondary, exploratory aims assessed moderation of treatment effects by sex and cannabis use. METHOD: A total of 182 individuals (48.4% female; 21-60 years old) who reported drinking more than 14/21 drinks/week (for women and men, respectively) in the past 3 months but who wished to quit/reduce their drinking were recruited from Denver and Boulder, Colorado. Individuals were randomly assigned to 8 weeks of individual-based MBRP or RP treatment. Participants completed substance use assessments at baseline, halfway through and at the end of treatment, and 20 and 32 weeks after treatment. Primary outcomes were Alcohol Use Disorders Identification Test-consumption questions (AUDIT-C) scores, heavy drinking days (HDD), and drinks per drinking day (DDD). RESULTS: Across treatments, drinking decreased over time (ps < .001), with a significant time-by-treatment interaction found for HDD (F = 3.50, p < .01). HDD initially decreased in both treatments but remained stable or increased after treatment for MBRP and RP participants, respectively. At follow-up, MBRP participants had significantly less HDD than RP participants. Sex did not moderate treatment effects (ps > .17), whereas cannabis use moderated treatment effects on DDD and HDD (F = 4.89, p < .001, and F = 4.30, p < .005, respectively). High cannabis use frequency was associated with continued posttreatment decreases in HDD/DDD for MBRP participants but increased HDD for RP participants. At low cannabis use frequency levels, HDD/DDD remained stable after treatment across groups. CONCLUSIONS: Drinking decreases were comparable across treatments, but HDD improvements diminished for RP participants after treatment. In addition, cannabis use moderated treatment efficacy for HDD/DDD.

An Interpretable and Predictive Connectivity-Based Neural Signature for Chronic Cannabis Use.

BACKGROUND: Cannabis is one of the most widely used substances in the world, with usage trending upward in recent years. However, although the psychiatric burden associated with maladaptive cannabis use has been well established, reliable and interpretable biomarkers associated with chronic use remain elusive. In this study, we combine large-scale functional magnetic resonance imaging with machine learning and network analysis and develop an interpretable decoding model that offers both accurate prediction and novel insights into chronic cannabis use. METHODS: Chronic cannabis users (n = 166) and nonusing healthy control subjects (n = 124) completed a cue-elicited craving task during functional magnetic resonance imaging. Linear machine learning methods were used to classify individuals into chronic users and nonusers based on whole-brain functional connectivity. Network analysis was used to identify the most predictive regions and communities. RESULTS: We obtained high (∼80% out-of-sample) accuracy across 4 different classification models, demonstrating that task-evoked connectivity can successfully differentiate chronic cannabis users from nonusers. We also identified key predictive regions implicating motor, sensory, attention, and craving-related areas, as well as a core set of brain networks that contributed to successful classification. The most predictive networks also strongly correlated with cannabis craving within the chronic user group. CONCLUSIONS: This novel approach produced a neural signature of chronic cannabis use that is both accurate in terms of out-of-sample prediction and interpretable in terms of predictive networks and their relation to cannabis craving.

Cortical profiles of numerous psychiatric disorders and normal development share a common pattern.

The neurobiological bases of the association between development and psychopathology remain poorly understood. Here, we identify a shared spatial pattern of cortical thickness (CT) in normative development and several psychiatric and neurological disorders. Principal component analysis (PCA) was applied to CT of 68 regions in the Desikan-Killiany atlas derived from three large-scale datasets comprising a total of 41,075 neurotypical participants. PCA produced a spatially broad first principal component (PC1) that was reproducible across datasets. Then PC1 derived from healthy adult participants was compared to the pattern of CT differences associated with psychiatric and neurological disorders comprising a total of 14,886 cases and 20,962 controls from seven ENIGMA disease-related working groups, normative maturation and aging comprising a total of 17,697 scans from the ABCD Study® and the IMAGEN developmental study, and 17,075 participants from the ENIGMA Lifespan working group, as well as gene expression maps from the Allen Human Brain Atlas. Results revealed substantial spatial correspondences between PC1 and widespread lower CT observed in numerous psychiatric disorders. Moreover, the PC1 pattern was also correlated with the spatial pattern of normative maturation and aging. The transcriptional analysis identified a set of genes including KCNA2, KCNS1 and KCNS2 with expression patterns closely related to the spatial pattern of PC1. The gene category enrichment analysis indicated that the transcriptional correlations of PC1 were enriched to multiple gene ontology categories and were specifically over-represented starting at late childhood, coinciding with the onset of significant cortical maturation and emergence of psychopathology during the prepubertal-to-pubertal transition. Collectively, the present study reports a reproducible latent pattern of CT that captures interregional profiles of cortical changes in both normative brain maturation and a spectrum of psychiatric disorders. The pubertal timing of the expression of PC1-related genes implicates disrupted neurodevelopment in the pathogenesis of the spectrum of psychiatric diseases emerging during adolescence.

Association between the oral microbiome and brain resting state connectivity in schizophrenia.

Recent microbiome-brain axis findings have shown evidence of the modulation of microbiome community as an environmental mediator in brain function and psychiatric illness. This work is focused on the role of the microbiome in understanding a rarely investigated environmental involvement in schizophrenia (SZ), especially in relation to brain circuit dysfunction. We leveraged high throughput microbial 16s rRNA sequencing and functional neuroimaging techniques to enable the delineation of microbiome-brain network links in SZ. N=213 SZ and healthy control (HC) subjects were assessed for the oral microbiome. Among them, 139 subjects were scanned by resting-state functional magnetic resonance imaging (rsfMRI) to derive brain functional connectivity. We found a significant microbiome compositional shift in SZ beta diversity (weighted UniFrac distance, p= 6×10 -3 ; Bray-Curtis distance p = 0.021). Fourteen microbial species involving pro-inflammatory and neurotransmitter signaling and H 2 S production, showed significant abundance alterations in SZ. Multivariate analysis revealed one pair of microbial and functional connectivity components showing a significant correlation of 0.46. Thirty five percent of microbial species and 87.8% of brain functional network connectivity from each component also showed significant differences between SZ and HC with strong performance in classifying SZ from HC, with an area under curve (AUC) = 0.84 and 0.87, respectively. The results suggest a potential link between oral microbiome dysbiosis and brain functional connectivity alteration in relation to SZ, possibly through immunological and neurotransmitter signaling pathways and the hypothalamic-pituitary-adrenal axis, supporting for future work in characterizing the role of oral microbiome in mediating effects on SZ brain functional activity.

Recalibrating single-study effect sizes using hierarchical Bayesian models.

Introduction: There are growing concerns about commonly inflated effect sizes in small neuroimaging studies, yet no study has addressed recalibrating effect size estimates for small samples. To tackle this issue, we propose a hierarchical Bayesian model to adjust the magnitude of single-study effect sizes while incorporating a tailored estimation of sampling variance. Methods: We estimated the effect sizes of case-control differences on brain structural features between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis and non-dependent participants for 21 individual studies (Total cases: 903; Total controls: 996). Then, the study-specific effect sizes were modeled using a hierarchical Bayesian approach in which the parameters of the study-specific effect size distributions were sampled from a higher-order overarching distribution. The posterior distribution of the overarching and study-specific parameters was approximated using the Gibbs sampling method. Results: The results showed shrinkage of the posterior distribution of the study-specific estimates toward the overarching estimates given the original effect sizes observed in individual studies. Differences between the original effect sizes (i.e., Cohen's d) and the point estimate of the posterior distribution ranged from 0 to 0.97. The magnitude of adjustment was negatively correlated with the sample size (r = -0.27, p < 0.001) and positively correlated with empirically estimated sampling variance (r = 0.40, p < 0.001), suggesting studies with smaller samples and larger sampling variance tended to have greater adjustments. Discussion: Our findings demonstrate the utility of the hierarchical Bayesian model in recalibrating single-study effect sizes using information from similar studies. This suggests that Bayesian utilization of existing knowledge can be an effective alternative approach to improve the effect size estimation in individual studies, particularly for those with smaller samples.

Cannabinoid Exposure and Subjective Effects of THC and CBD in Edible Cannabis Products.

Background: The popularity of edible cannabis products continues to grow in states with legal cannabis access, but few studies have investigated the acute effects of these commercially available products. The present study sought to explore the effects of three commercially available edible products with different levels of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Methods: A sample of regular cannabis users (N=99) were evaluated. Fifty participants completed the study procedures in-person, whereas 49 participants completed the study procedures remotely via Zoom. Subjective effects and plasma cannabinoid levels (in-person participants only) were assessed before and 2 h after participants self-administered one of three products ad libitum: a THC-dominant edible product, a CBD-dominant edible product, or a THC+CBD edible product. Results: At the 2-h post-use assessment, among in-person participants, plasma THC and CBD levels were robustly correlated with self-reported milligrams of THC and CBD consumed, respectively. Across all three conditions, in-person and remote participants experienced (1) an increase in subjective intoxication and elation, (2) a decrease in tension, and (3) no change in paranoia from pre-use to post-use. At post-use, participants who used a CBD product reported less intoxication relative to participants who used a THC+CBD or THC-only product. Participants who used a THC+CBD product reported consuming less THC-and displayed lower plasma THC levels (in-person participants)-relative to participants who used a THC-only product, despite reporting similar levels of positive (intoxication, elation, liking) and psychotomimetic (paranoia, tension) effects. Psychotomimetic effects were very low among both in-person and remote participants across all three conditions, and there were no post-use differences across conditions. Conclusions: Findings suggest that experienced users who consumed a THC+CBD product reported similar levels of positive and psychotomimetic effects relative to those who consumed a THC-only product, despite consuming less THC and displaying lower plasma THC concentrations. Given the potential harms associated with acute cannabis reward and long-term THC exposure, further research is needed to establish whether edible cannabis products with CBD pose less risk to users. Future studies should examine whether these effects generalize to samples of infrequent users, who may have less experience with edible cannabis use. ClinicalTrials.gov ID: NCT03522103.

Associations Between Age and Resting State Connectivity Are Partially Dependent Upon Cardiovascular Fitness.

Previous research suggests a marked impact of aging on structural and functional connectivity within the frontoparietal control network (FPCN) and default mode network (DMN). As aging is also associated with reductions in cardiovascular fitness, age-related network connectivity differences reported by past studies could be partially due to age-related declines in fitness. Here, we use data collected as part of a 16-week exercise intervention to explore relationships between fitness and functional connectivity. Young and older adults completed baseline assessments including cardiovascular fitness, health and functioning measures, and an fMRI session. Scan data were acquired on a Siemens 3T MRI scanner with a 32-channel head coil. Results from regression analyses indicated that average connectivity did not differ between young and older adults. However, individual ROI-to-ROI connectivity analyses indicated weaker functional correlations for older adults between specific regions in the FPCN and DMN and, critically, many of these differences were attenuated when fitness was accounted for. Taken together, findings suggest that fitness exerts regional rather than global effects on network connectivity.

Cannabis Use and Resting State Functional Connectivity in the Aging Brain.

Several lines of evidence suggest that older adults (aged 65+) sharply increased their cannabis use over the last decade, highlighting a need to understand the effects of cannabis in this age group. Pre-clinical models suggest that cannabinoids affect the brain and cognition in an age-dependent fashion, having generally beneficial effects on older animals and deleterious effects on younger ones. However, there is little research on how cannabis affects the brains of older adults or how older adults differ from younger adults who use cannabis. Resting state functional connectivity (rsFC) measures provide sensitive metrics of age-related cognitive decline. Here we compared rsFC in older adults who are either regular users of cannabis or non-users. We found stronger connectivity between sources in the hippocampus and parahippocampal cortex, and targets in the anterior lobes of the cerebellum in older adult cannabis users relative to non-users. A similar pattern of strengthened connectivity between hippocampal and cerebellar structures was also present in 25-35 year old non-users in comparison to 60-88 year old non-users. These findings suggest that future studies should examine both the potential risks of cannabinoids, as well as a potential benefits, on cognition and brain health for older adults.

Effects of cannabidiol in cannabis flower: Implications for harm reduction.

Using a federally compatible, naturalistic at-home administration procedure, the present study examined the acute effects of three cannabis flower chemovars with different tetrahydrocannabinol (THC) to cannabidiol (CBD) ratios, in order to test whether chemovars with a higher CBD content produce different effects. Participants were randomly assigned to ad libitum administration of one of three chemovars (THC-dominant: 24% THC, 1% CBD; THC+CBD: 9% THC, 10% CBD; CBD-dominant: 1% THC, 23% CBD); 159 regular cannabis users (male = 94, female = 65) were assessed in a mobile pharmacology lab before, immediately after, and 1 h after ad libitum administration of their assigned chemovar. Plasma cannabinoids as well as positive (e.g., high, elation) and negative (e.g., paranoia and anxiety) subjective effects were assessed at each time points. Participants who used the CBD-dominant and THC + CBD chemovars had significantly less THC and more CBD in plasma samples compared to participants who used the THC-dominant chemovar. Further, the THC + CBD chemovar was associated with similar levels of positive subjective effects, but significantly less paranoia and anxiety, as compared to the THC-dominant chemovar. This is one of the first studies to examine the differential effects of various THC to CBD ratios using chemovars that are widely available in state-regulated markets. Individuals using a THC + CBD chemovar had significantly lower plasma THC concentrations and reported less paranoia and anxiety while also reporting similar positive mood effects as compared to individuals using THC only, which is intriguing from a harm reduction perspective. Further research is needed to clarify the harm reduction potential of CBD in cannabis products.

A naturalistic study of orally administered vs. inhaled legal market cannabis: cannabinoids exposure, intoxication, and impairment.

RATIONALE: Published studies examining the effects of cannabis have largely utilized forms of cannabis that are not representative of the legal market products currently available. OBJECTIVES: The present study aimed to characterize naturalistic use of legal market flower and edible products by examining associations among blood cannabinoids and amount of THC consumed as well as physiological, cognitive, and subjective effects in users of edible and flower forms. METHOD: Eighty-four participants who used cannabis at least 1 × /week (55 flower cannabis using participants; 29 edible cannabis using participants mean age = 31.95 years, 44% female) participated. At the experimental appointment in our mobile laboratory, participants completed a blood draw to assess plasma cannabinoids, measures of heart rate, subjective drug effects, and cognition both before and after ad libitum use of legal market flower or edible cannabis. RESULTS: Average self-reported THC consumed was 15.97 mg (SD = 22.40) in edible users and 51.25 mg (SD = 45.23) in flower users. In the edible group, but not the flower group, strong correlations emerged between self-reported ad libitum THC consumed and plasma THC. Plasma THC was significantly higher after use of inhaled cannabis, but similar levels of plasma THC metabolites and similar levels of subjective intoxication and verbal memory impairment were observed in both flower and edible users. CONCLUSIONS: Findings support strong correlations among ad libitum THC consumed and THC plasma levels after edible cannabis use and suggest few differences in intoxication and impairment between edible and flower cannabis users after ad libitum use. This novel study provides important preliminary data on the pharmacology and effects of legal market edible cannabis.

Investigating Associations Between Inflammatory Biomarkers, Gray Matter, Neurofilament Light and Cognitive Performance in Healthy Older Adults.

Background: Exploring biological variables that may serve as indicators of the development and progression of cognitive decline is currently a high-priority research area. Recent studies have demonstrated that during normal aging, individuals experience increased inflammation throughout the brain and body, which may be linked to cognitive impairment and reduced gray matter volume in the brain. Neurofilament light polypeptide (NfL), which is released into the circulation following neuronal damage, has been proposed as a biomarker for neurodegenerative diseases, and may also have utility in the context of normal aging. The present study tested associations between age, peripheral levels of the pro-inflammatory cytokine IL-6, peripheral NfL, brain volume, and cognitive performance in a sample of healthy adults over 60 years old. Methods: Of the 273 individuals who participated in this study, 173 had useable neuroimaging data, a subset of whom had useable blood data (used for quantifying IL-6 and NfL) and completed a cognitive task. Gray matter (GM) thickness values were extracted from brain areas of interest using Freesurfer. Regression models were used to test relationships between IL-6, NfL, GM, and cognitive performance. To test putative functional relationships between these variables, exploratory path analytic models were estimated, in which the relationship between age, IL-6, and working memory performance were linked via four different operationalizations of brain health: (1) a latent GM variable composed of several regions linked to cognitive impairment, (2) NfL alone, (3) NfL combined with the GM latent variable, and (4) the hippocampus alone. Results: Regression models showed that IL-6 and NfL were significantly negatively associated with GM volume and that GM was positively associated with cognitive performance. The path analytic models indicated that age and cognitive performance are linked by GM in the hippocampus as well as several other regions previously associated with cognitive impairment, but not by NfL alone. Peripheral IL-6 was not associated with age in any of the path models. Conclusions: Results suggest that among healthy older adults, there are several GM regions that link age and cognitive performance. Notably, NfL alone is not a sufficient marker of brain changes associated with aging, inflammation, and cognitive performance.

Exploring relationships between alcohol consumption, inflammation, and brain structure in a heavy drinking sample.

BACKGROUND: Chronic alcohol consumption is associated with structural brain changes and increased inflammatory signaling throughout the brain and body. Increased inflammation in the brain has been associated with structural damage. Recent studies have also shown that neurofilament light polypeptide (NfL) is released into the systemic circulation following neuronal damage. Although NfL has thus been proposed as a biomarker for neurodegenerative diseases, its connection to alcohol use disorder has not been explored. For this secondary data analysis, we proposed a conceptual model linking alcohol consumption, the pro-inflammatory cytokine IL-6, brain structure, and NfL in heavy drinking participants. METHODS: Of the 182 individuals enrolled in this study, 81 participants had usable data on gray matter (GM) thickness and 80 had usable data on white matter (WM) diffusivity. A subset of participants had NfL (n = 78) and IL-6 (n = 117) data. An estimate of GM thickness was extracted from middle frontal brain regions using FreeSurfer. Estimated mean WM diffusivity values were extracted from Tract Based Spatial Statistics. NfL and IL-6 were measured in blood. Regression models were used to test individual linkages in the conceptual model. Based on significant regression results, we created a simplified conceptual model, which we tested using path analysis. RESULTS: In regressions, negative relationships emerged between GM and both drinks per drinking day (DPDD) (p = 0.018) and NfL (p = 0.004). A positive relationship emerged between WM diffusivity and DPDD (p = 0.033). IL-6 was not significantly associated with alcohol use, GM or WM. The final path model demonstrated adequate fit to the data and showed significant, negative associations between DPDD and middle frontal gyrus (MFG) thickness, and between MFG thickness and NfL, but the association between DPDD and NfL was not significant. CONCLUSIONS: This is the first study to show that heavy drinking is associated with lower GM thickness and higher WM diffusivity and that lower GM thickness is associated with higher circulating NfL. The analyses also show that the effects of drinking do not involve the pro-inflammatory cytokine IL-6.

The Effects of Exercise Duration and Intensity on Breast Cancer-Related DNA Methylation: A Randomized Controlled Trial.

Emerging research suggests that one mechanism through which physical activity may decrease cancer risk is through its influence on the methylation of genes associated with cancer. The purpose of the current study was to prospectively test, using a rigorous experimental design, whether aerobic exercise affects DNA methylation in genes associated with breast cancer, as well as whether quantity of exercise completed affects change in DNA methylation in a dose-response manner. 276 women (M age = 37.25, SD = 4.64) were recruited from the Denver metro area for a randomized controlled trial in which participants were assigned to a supervised aerobic exercise program varying in a fully crossed design by intensity (55-65% versus 75-85% of VO2max) and duration (40 versus 20 min per session). DNA methylation was assessed via blood samples provided at baseline, after completing a 16-week supervised exercise intervention, and six months after the intervention. 137 participants completed the intervention, and 81 had viable pre-post methylation data. Contrary to our hypotheses, total exercise volume completed in kcal/kg/week was not associated with methylation from baseline to post-intervention for any of the genes of interest. An increase in VO2max over the course of the intervention, however, was associated with decreased post-intervention methylation of BRCA1, p = 0.01. Higher levels of self-reported exercise during the follow-up period were associated with lower levels of GALNT9 methylation at the six-month follow-up. This study provides hypothesis-generating evidence that increased exercise behavior and or increased fitness might affect methylation of some genes associated with breast cancer to reduce risk.

Associations between self-reported cannabis use frequency, potency, and cannabis/health metrics.

BACKGROUND: Research shows that cannabis use frequency is associated with cannabis dependence and health metrics. However, much less is known about how self-reported cannabis potency (THC and CBD) may be associated with the same metrics, and whether any associations exist after accounting for frequency of cannabis use. Moreover, even less is known about how these relations may differ across cannabis product forms. This exploratory study examined 1) associations between cannabis frequency, potency, and cannabis/health metrics, and 2) whether associations between potency and cannabis/health metrics remained after controlling for frequency of use. METHODS: Using a sample of adult recreational cannabis users in Colorado (N = 300), we tested the relationship between self-reported cannabis use metrics of frequency and potency of flower, edible, and concentrate products with separate measures of problematic cannabis use (i.e., dependence, withdrawal, craving), depression, anxiety, and general perceived health. RESULTS: Greater frequency of flower and concentrate (but not edible) use were associated with greater problematic cannabis use, and greater concentrate use frequency was also associated with more mental health problems. Partial correlations controlling for average frequency of use across all product forms and CBD potency per product showed that one significant association between THC potency and cannabis/health metrics remained (i.e., higher THC concentrate potency with better health), and one emerged (i.e., higher THC concentrate potency with lower cannabis withdrawal). CONCLUSIONS: Frequency of use is reliably associated with problematic cannabis use for flower and concentrates, but it did not account for all observed associations in this study. Differences in patterns of associations between frequency and potency and cannabis/health metrics across cannabis forms suggest a need for better understanding user reports of THC and CBD potency, individual differences among users, and improved measurement.