Clinical and cognitive improvement following full-spectrum, high-cannabidiol treatment for anxiety: open-label data from a two-stage, phase 2 clinical trial.

BACKGROUND: Evidence suggests cannabidiol (CBD) has anxiolytic properties, indicating potential for novel treatment strategies. However, few clinical trials of CBD-based products have been conducted, and none thus far have examined the impact of these products on cognition. METHODS: For the open-label stage of clinical trial NCT02548559, autoregressive linear modeling assessed efficacy and tolerability of four-weeks of 1 mL t.i.d. treatment with a full-spectrum, high-CBD sublingual solution (9.97 mg/mL CBD, 0.23 mg/mL Δ-9-tetrahydrocannabinol) in 14 outpatients with moderate-to-severe anxiety, defined as ≥16 on the Beck Anxiety Inventory (BAI) or ≥11 on the Overall Anxiety Severity and Impairment Scale (OASIS). RESULTS: Findings suggest significant improvement on primary outcomes measuring anxiety and secondary outcomes assessing mood, sleep, quality of life, and cognition (specifically executive function) following treatment. Anxiety is significantly reduced at week 4 relative to baseline (BAI: 95% CI = [-21.03, -11.40], p < 0.001, OASIS: 95% CI = [-9.79, -6.07], p < 0.001). Clinically significant treatment response (≥15% symptom reduction) is achieved and maintained as early as week 1 in most patients (BAI = 78.6%, OASIS = 92.7%); cumulative frequency of treatment responders reached 100% by week 3. The study drug is well-tolerated, with high adherence/patient retention and no reported intoxication or serious adverse events. Minor side effects, including sleepiness/fatigue, increased energy, and dry mouth are infrequently endorsed. CONCLUSIONS: Results provide preliminary evidence supporting efficacy and tolerability of a full-spectrum, high-CBD product for anxiety. Patients quickly achieve and maintain symptom reduction with few side effects. A definitive assessment of the impact of this novel treatment on clinical symptoms and cognition will be ascertained in the ongoing double-blind, placebo-controlled stage.

Cannabidiol (CBD) is a compound found within the Cannabis sativa plant. Previous studies suggest CBD may reduce anxiety. In this clinical trial, 14 patients with anxiety were treated for four-weeks with a cannabis-derived study product with high levels of CBD, administered under their tongue 3 times each day. All patients knew that they were being given CBD. Following four weeks of treatment, patients reported reduced anxiety as well as improvements in mood, sleep, quality of life, and measures reflecting their self-control and ability to think flexibly. Patients did not experience any serious negative effects during the trial. The impact of this product is now being evaluated in more patients with anxiety.

Increased White Matter Coherence Following Three and Six Months of Medical Cannabis Treatment.

Background: Previous studies have demonstrated abnormal white matter (WM) microstructure in recreational cannabis consumers; however, the long-term impact of medical cannabis (MC) use on WM coherence is unknown. Accordingly, this study assessed the longitudinal impact of MC treatment on WM coherence. Given results from preclinical studies, we hypothesized that MC treatment would be associated with increased fractional anisotropy (FA) and reduced mean diffusivity (MD). Methods: As part of a larger, longitudinal investigation, patients interested in treating at least one medical condition with commercially available MC products of their choosing were assessed before initiating MC use (baseline n=37; female=25, male=12) and following three (n=31) and six (n=22) months of treatment. WM coherence was assessed via diffusion tensor imaging for bilateral regions of interest including the genu of the corpus callosum, anterior limb of the internal capsule, external capsule, and anterior corona radiata, as well as an occipital control region not expected to change over time. Results: In MC patients, FA values significantly increased bilaterally in several callosal regions relative to baseline following both 3 and 6 months of treatment; MD values significantly decreased in all callosal regions but only following 6 months of treatment. No significant changes in WM coherence were observed in the control region or in a pilot sample of treatment-as-usual patients (baseline n=14), suggesting that increased WM coherence observed in MC patients may be attributed to MC treatment as opposed to confounding factors. Interestingly, significant reductions in MD values correlated with higher cannabidiol (CBD) exposure but not Δ-9-tetrahydrocannabinol exposure. Conclusions: Overall, MC treatment was associated with increased WM coherence, which contrasts with prior research examining recreational cannabis consumers, likely related to inherent differences between recreational consumers and MC patients (e.g., product choice, age of onset). In addition, increased CBD exposure was associated with reduced MD following 6 months of treatment, extending evidence from preclinical research indicating that CBD may be neuroprotective against demyelination. However, additional research is needed to elucidate the clinical efficacy of MC treatment and the risks and benefits of long-term MC use.

An Observational, Longitudinal Study of Cognition in Medical Cannabis Patients over the Course of 12 Months of Treatment: Preliminary Results.

OBJECTIVE: Cannabis use has increased dramatically across the country; however, few studies have assessed the long-term impact of medical cannabis (MC) use on cognition. Studies examining recreational cannabis users generally report cognitive decrements, particularly in those with adolescent onset. As MC patients differ from recreational consumers in motives for use, product selection, and age of onset, we assessed cognitive and clinical measures in well-characterized MC patients over 1 year. Based on previous findings, we hypothesized MC patients would not show decrements and might instead demonstrate improvements in executive function over time. METHOD: As part of an ongoing study, MC patients completed a baseline visit prior to initiating MC and evaluations following 3, 6, and 12 months of treatment. At each visit, patients completed a neurocognitive battery assessing executive function, verbal learning/memory, and clinical scales assessing mood, anxiety, and sleep. Exposure to delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) was also quantified. RESULTS: Relative to baseline, MC patients demonstrated significant improvements on measures of executive function and clinical state over the course of 12 months; verbal learning/memory performance generally remained stable. Improved cognitive performance was not correlated with MC use; however, clinical improvement was associated with higher CBD use. Analyses suggest cognitive improvements were associated with clinical improvement. CONCLUSIONS: Study results extend previous pilot findings, indicating that MC patients may exhibit enhanced rather than impaired executive function over time. Future studies should examine distinctions between recreational and MC use to identify potential mechanisms related to cognitive changes and the role of clinical improvement.

No pain, all gain? Interim analyses from a longitudinal, observational study examining the impact of medical cannabis treatment on chronic pain and related symptoms.

Previous studies have demonstrated improvements in pain following short-term medical cannabis (MC) use, suggesting long-term MC treatment may alleviate symptoms associated with chronic pain. The goal of this observational and longitudinal study was to examine patients using MC to treat chronic pain pre versus post MC treatment. These interim analyses included 37 patients with chronic pain evaluated prior to initiation of MC treatment and following 3 and 6 months of MC use; pain, clinical state, sleep, quality of life, and conventional medication use were assessed. Correlation analyses examined the relationship between changes in pain and other clinical measures, assessed the impact of cannabinoid exposure on pain and clinical ratings, and assessed whether baseline cannabis expectancies influenced outcome variables. Additionally, a pilot group of treatment-as-usual patients (n = 9) who did not use MC were examined at baseline and 3 months later. Relative to baseline, following 3 and 6 months of treatment, MC patients exhibited improvements in pain which were accompanied by improved sleep, mood, anxiety, and quality of life, and stable conventional medication use. Reduced pain was associated with improvements in aspects of mood and anxiety. The results generally suggest increased THC exposure was related to pain-related improvement, while increased CBD exposure was related to improved mood. Cannabis expectancies were not related to observed improvements. Pilot analyses revealed that treatment-as-usual patients do not demonstrate the same pattern of improvement. Findings highlight the potential efficacy of MC treatment for pain and underscore the unique impact of individual cannabinoids on specific aspects of pain and comorbid symptoms. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The Impact of Micronutrient Fortified Foods on Cognitive Functioning among Low-Income Children: A Pilot and Feasibility Study.

Brain development continues throughout childhood and requires micronutrients for optimal maturation, but studies have typically examined only a limited number of micronutrients and there has been inconsistent use of validated cognitive measures. This study evaluated the impact of providing low-income children with a daily fortified meal (570 kcal) in the form of a bar and shake containing >75% of the FDA Daily Values for all essential vitamins and minerals, as well as macronutrients (e.g., omega-3 and omega-6 fatty acids and protein), in an afterschool care setting (instead of the usual meal provided) on cognitive functioning. Students aged 8-12 were randomly assigned to intervention (n = 19) or control (n = 16) meals. Students completed the Stroop Color Word Task, Trail Making Test, and Conner's Continuous Performance Task (CPT) at baseline and 3 months post-intervention. Differences in cognitive scores were examined using 2 × 2 mixed model ANOVAs (Stroop and CPT) and ANCOVAs (Trail Making Test). Significant main effects of time indicated improvements in both intervention and control groups, but there were no significant main effects of group or group*time interactions. When the amount of meal consumed was examined, most results became non-significant, suggesting that overall meal consumption significantly impacted the observed results. Overall, this pilot study suggests that there may be limited additional benefits to short-term consumption of micronutrient fortified meals among low-income children in an afterschool care setting, and potential benefits observed may be directly related to the amount of food consumed.

Smaller Hippocampal Volume in Posttraumatic Stress Disorder: A Multisite ENIGMA-PGC Study: Subcortical Volumetry Results From Posttraumatic Stress Disorder Consortia.

BACKGROUND: Many studies report smaller hippocampal and amygdala volumes in posttraumatic stress disorder (PTSD), but findings have not always been consistent. Here, we present the results of a large-scale neuroimaging consortium study on PTSD conducted by the Psychiatric Genomics Consortium (PGC)-Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) PTSD Working Group. METHODS: We analyzed neuroimaging and clinical data from 1868 subjects (794 PTSD patients) contributed by 16 cohorts, representing the largest neuroimaging study of PTSD to date. We assessed the volumes of eight subcortical structures (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, and lateral ventricle). We used a standardized image-analysis and quality-control pipeline established by the ENIGMA consortium. RESULTS: In a meta-analysis of all samples, we found significantly smaller hippocampi in subjects with current PTSD compared with trauma-exposed control subjects (Cohen's d = -0.17, p = .00054), and smaller amygdalae (d = -0.11, p = .025), although the amygdala finding did not survive a significance level that was Bonferroni corrected for multiple subcortical region comparisons (p < .0063). CONCLUSIONS: Our study is not subject to the biases of meta-analyses of published data, and it represents an important milestone in an ongoing collaborative effort to examine the neurobiological underpinnings of PTSD and the brain's response to trauma.

The Grass Might Be Greener: Medical Marijuana Patients Exhibit Altered Brain Activity and Improved Executive Function after 3 Months of Treatment.

The vast majority of states have enacted full or partial medical marijuana (MMJ) programs, causing the number of patients seeking certification for MMJ use to increase dramatically in recent years. Despite increased use of MMJ across the nation, no studies thus far have examined the specific impact of MMJ on cognitive function and related brain activation. In the present study, MMJ patients seeking treatment for a variety of documented medical conditions were assessed prior to initiating MMJ treatment and after 3 months of treatment as part of a larger longitudinal study. In order to examine the effect of MMJ treatment on task-related brain activation, MMJ patients completed the Multi-Source Interference Test (MSIT) while undergoing functional magnetic resonance imaging (fMRI). We also collected data regarding conventional medication use, clinical state, and health-related measures at each visit. Following 3 months of treatment, MMJ patients demonstrated improved task performance accompanied by changes in brain activation patterns within the cingulate cortex and frontal regions. Interestingly, after MMJ treatment, brain activation patterns appeared more similar to those exhibited by healthy controls from previous studies than at pre-treatment, suggestive of a potential normalization of brain function relative to baseline. These findings suggest that MMJ use may result in different effects relative to recreational marijuana (MJ) use, as recreational consumers have been shown to exhibit decrements in task performance accompanied by altered brain activation. Moreover, patients in the current study also reported improvements in clinical state and health-related measures as well as notable decreases in prescription medication use, particularly opioids and benzodiapezines after 3 months of treatment. Further research is needed to clarify the specific neurobiologic impact, clinical efficacy, and unique effects of MMJ for a range of indications and how it compares to recreational MJ use.

Citicoline Treatment Improves Measures of Impulsivity and Task Performance in Chronic Marijuana Smokers: A Pilot BOLD fMRI Study.

OBJECTIVE: Citicoline is an endogenous nucleotide that has historically been used to treat stroke, traumatic brain injury, and cognitive dysfunction. Research has also shown that citicoline treatment is associated with improved cognitive performance in substance-abusing populations. We hypothesized that marijuana (MJ) smokers who received citicoline would demonstrate improvement in cognitive performance as well as increased neural efficiency during tasks of cognitive control relative to those who received placebo. METHOD: The current study tested this hypothesis by examining the effects of citicoline in treatment-seeking chronic MJ smokers. In an 8-week double-blind, placebo-controlled study, 19 MJ smokers were randomly assigned via a double-blind procedure to the citicoline (8 Males, 2 Females) or placebo group (9 Males, 0 Females). All participants completed fMRI scanning at baseline and after 8 weeks of treatment during two cognitive measures of inhibitory processing, the Multi Source Interference Test (MSIT) and Stroop Color Word Test, and also completed the Barratt Impulsiveness Scale (BIS-11), a self-report measure of impulsivity. RESULTS: Following the 8 week trial, MJ smokers treated with citicoline demonstrated significantly lower levels of behavioral impulsivity, improved task accuracy on both the MSIT and Stroop tasks, and exhibited significantly different patterns of brain activation relative to baseline levels and relative to those who received placebo. CONCLUSIONS: Findings suggest that citicoline may facilitate the treatment of MJ use disorders by improving the cognitive skills necessary to fully engage in comprehensive treatment programs.

Activation in dorsolateral prefrontal cortex in response to maternal criticism and praise in recovered depressed and healthy control participants.

BACKGROUND: High family levels of expressed emotion reliably predict relapse in patients with schizophrenia and mood disorders; however, the neural mechanisms linking expressed emotion and relapse are unexplored. Dysfunctional activity in the dorsolateral prefrontal cortex (DLPFC) has been implicated in the pathophysiology of depression. Functional magnetic resonance imaging (fMRI) was used to assess focal activation changes in DLPFC in response to a novel psychosocial challenge stimulus developed from the expressed emotion construct. METHODS: Healthy control subjects and fully remitted unipolar depressed participants completed blood oxygen level-dependent fMRI while they heard their own mothers making critical and praising comments about them. RESULTS: Relative to control subjects, participants with a history of depression failed to activate DLPFC when they heard critical remarks. There were no differences between the two groups in their DLPFC responses to maternal praise. CONCLUSIONS: Even if fully well at the time of testing, participants with a known vulnerability to depression respond differently to the psychosocial challenge of being criticized. These findings might have implications for our understanding of vulnerability to depression and to depressive relapse.

Frontal lobe GABA levels in cocaine dependence: a two-dimensional, J-resolved magnetic resonance spectroscopy study.

Non-invasive measures of brain gamma-aminobutyric acid (GABA) concentrations may be especially useful in the identification of cocaine-related changes in brain chemistry that can be used to guide the development of future treatments for cocaine-dependent persons. This study assessed whether brain GABA levels in cocaine-dependent subjects with and without an alcohol disorder differ from GABA levels in healthy comparison subjects. Two-dimensional, proton magnetic resonance spectroscopy was used to determine GABA levels in the left prefrontal lobe of cocaine-dependent subjects (N=35) recruited from a National Institute on Drug Abuse (NIDA)-sponsored treatment trial of cocaine dependence and a comparison group (N=20). At treatment baseline, mean GABA concentrations were 0.93+/-0.27 mM/kg in cocaine-dependent subjects and 1.32+/-0.44 mM/kg in the comparison sample (t [d.f.=53]=3.65, P<0.001). Cocaine-dependent subjects with a history of a co-morbid alcohol disorder (N=23) had significantly lower baseline GABA levels (0.87 mM/kg) (t [d.f.=41]=4.31, P<0.001) than the comparison group. However, cocaine-dependent subjects without an alcohol disorder (N=12) also had lower GABA levels (1.04 mM/kg) than the comparison subjects (t [d.f.=30]=2.09, P=0.045), suggesting that cocaine dependence alone can decrease GABA levels.