Impact of the COVID-19 Pandemic on HIV Test Uptake Among People Who Inject Drugs in the Context of an HIV Outbreak.

Glasgow, Scotland's largest city, has been experiencing an HIV outbreak among people who inject drugs (PWID) since 2015. A key focus of the public health response has been to increase HIV testing among those at risk of infection. Our aim was to assess the impact of COVID-19 on HIV testing among PWID in Glasgow. HIV test uptake in the last 12 months was quantified among: (1) PWID recruited in six Needle Exchange Surveillance Initiative (NESI) surveys (n = 6110); linked laboratory data for (2) people prescribed opioid agonist therapy (OAT) (n = 14,527) and (3) people hospitalised for an injecting-related hospital admission (IRHA) (n = 12,621) across four time periods: pre-outbreak (2010-2014); early-outbreak (2015-2016); ongoing-outbreak (2017-2019); and COVID-19 (2020-June 21). From the pre to ongoing period, HIV testing increased: the highest among people recruited in NESI (from 28% to 56%) and on OAT (from 17% to 54%) while the lowest was among people with an IRHA (from 15% to 42%). From the ongoing to the COVID-19 period, HIV testing decreased markedly among people prescribed OAT, from 54% to 37% (aOR 0.50, 95% CI 0.48-0.53), but increased marginally among people with an IRHA from 42% to 47% (aOR 1.19, 95% CI 1.08-1.31). In conclusion, progress in increasing testing in response to the HIV outbreak has been eroded by COVID-19. Adoption of a linked data approach could be warranted in other settings to inform efforts to eliminate HIV transmission.

Examination of the effects of cannabidiol on menstrual-related symptoms.

Some individuals attempt to alleviate menstrual-related symptoms (MRS) by using cannabis and report having expectations that cannabis can improve MRS; however, no study has examined the effect of cannabinoids on MRS. The present study is a pre-post, randomized, open-label trial that aimed to examine the effects of oral cannabidiol (CBD) isolate for alleviating MRS. Participants were assigned randomly to one of two open-label dosing groups of CBD softgels (160 mg twice a day, BID, n = 17; 320 mg BID, n = 16) and completed a 1-month baseline period. Following baseline, participants were instructed to consume CBD starting the first day they believed they experienced symptoms each month and to take their assigned dose daily for 5 consecutive days for three CBD-consumption months. We examined differences in MRS and related outcomes between baseline and 3 months of CBD consumption. Results revealed reductions (in both dosing groups) in MRS, irritability, anxiety, global impression of change, stress, and subjective severity scores when comparing baseline to all 3 months of CBD consumption. Depression scores did not change in either dosing group. Findings suggest that CBD may have the potential for managing MRS. Importantly, changes in symptoms appeared in the first month of CBD consumption and persisted over the 3 consumption months. Further research is warranted comparing the effects of CBD to placebo (a limitation of the study) and examining the potential to optimize CBD consumption for reducing MRS (e.g., combining CBD with terpenes; varying routes and timing of administration). (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A randomized, double-blind, placebo-controlled, repeated-dose pilot study of the safety, tolerability, and preliminary effects of a cannabidiol (CBD)- and cannabigerol (CBG)-based beverage powder to support recovery from delayed onset muscle soreness (DOMS).

BACKGROUND: Cannabinoid-containing products are marketed to athletes as promoting recovery, in spite of a lack of data on their safety and effects. This randomized, double-blind, placebo-controlled, repeated-dose pilot study tested the safety, tolerability, and preliminary effects on recovery of a formulation containing cannabidiol (CBD; 35 mg), cannabigerol (CBG; 50 mg), beta caryophyllene (BCP; 25 mg), branched-chain amino acids (BCAAs; 3.8 g), and magnesium citrate (420 mg). METHODS: Exercise-trained individuals (N = 40) underwent an experimental induction of delayed onset muscle soreness (DOMS) and completed follow-up visits 24-, 48-, and 72-hours post-DOMS. Participants were randomized to active or placebo formulation, and consumed the formulation twice per day for 3.5 days. RESULTS: There was one adverse event (AE) in the active group (diarrhea) and two AEs in placebo (dry mouth; eye rash/swollen eye). There was 100% self-reported compliance with formulation consumption across the two groups. For the primary outcome of interest, the estimate of effect for ratings of average soreness/discomfort 72 hours post-DOMS between active and placebo groups was -1.33 (85% confidence interval = -2.55, -0.10), suggesting moderate evidence of a treatment difference. The estimate of effect for the outcome of ratings of interference of soreness, discomfort, or stiffness on daily activities at work or home 48 hours post-DOMS was -1.82 (95% confidence interval = -3.64, -0.01), indicating a treatment difference of potential clinical importance. There was no significant effect between active and placebo groups on objective measures of recovery, sleep quality, or mood disturbance. CONCLUSIONS: The tested formulation reduced interference of DOMS on daily activities, demonstrating its improvement on a functional aspect of recovery.

A double-blind, randomized, placebo-controlled study of the safety and effects of CBN with and without CBD on sleep quality.

The present study sought to determine the effects of cannabinol (CBN) alone and in combination with cannabidiol (CBD) on sleep quality. This was a double-blind, randomized, placebo-controlled study conducted between May and November 2022. Participants were randomized to receive either (a) placebo, (b) 20 mg CBN, (c) 20 mg CBN + 10 mg CBD, (d) 20 mg CBN + 20 mg CBD, or (e) 20 mg CBN + 100 mg CBD for seven consecutive nights. Participants were 18-55 years of age who self-rated sleep quality as "very poor" or "poor." The primary endpoint was sleep quality, while secondary endpoints included sleep onset latency, number of awakenings, wake after sleep onset (WASO), overall sleep disturbance, and daytime fatigue. In a modified intent-to-treat analyses (N = 293), compared to placebo, 20 mg CBN demonstrated a nonsignificant but potentially meaningful effect on sleep quality (OR [95% CI] = 2.26 [0.93, 5.52], p = .082) and significantly reduced number of awakenings (95% CI [-0.96, -0.05], p = .025) and overall sleep disturbance (95% CI [-2.59, -0.14], p = .023). There was no difference from placebo among any group for sleep onset latency, WASO, or daytime fatigue (all p > .05). Individuals receiving 20 mg CBN demonstrated reduced nighttime awakenings and overall sleep disturbance relative to placebo, with no impact on daytime fatigue. The addition of CBD did not positively augment CBN treatment effects. No differences were observed for latency to sleep onset or WASO. Findings suggest 20 mg of CBN taken nightly may be helpful for improving overall sleep disturbance, including the number of times one wakes up throughout the night, without impacting daytime fatigue. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A Two-Phase, Dose-Ranging, Placebo-Controlled Study of the Safety and Preliminary Test of Acute Effects of Oral Δ8-Tetrahydrocannabivarin in Healthy Participants.

Introduction: Tetrahydrocannabivarin (THCV) is an understudied cannabinoid that appears to have effects that vary as a function of dose. No human study has evaluated the safety and nature of effects in a wide range of THCV doses. Methods: This was a two-phase, dose-ranging, placebo-controlled trial of the Δ8 isomer of oral THCV in healthy adults. Phase 1 utilized an unblinded, single-ascending dose design (n=3). Phase 2 used a double-blind, randomized, within-participant crossover design (n=18). Participants received single acute doses of placebo and 12.5, 25, 50, 100, and 200 mg of THCV. Safety measures and subjective and cognitive effects were assessed predose and up to 8 h postdose. Results: Most adverse events (AEs; 55/60) were mild. Euphoric mood was the most common AE. The 12.5, 25, and 200 mg doses produced significantly lower minimum times to complete the digit vigilance test (ps=0.01). The 25 mg dose showed elevations on mean ratings of "energetic" at 1-, 2-, and 4-h postdose, but the maximum postdose rating for this dose did not achieve statistical significance relative to placebo ([95% confidence interval]=3.2 [-0.5 to 6.9], p=0.116). The 100 and 200 mg doses showed elevations on ratings of "feel a drug effect" and "like the drug effect." Almost all urine drug screens (78/79) at 8 h postdose in the active THCV conditions tested positive for tetrahydrocannabinol (THC). Conclusion: All THCV doses displayed a favorable safety profile. Several THCV doses showed a preliminary signal for improved sustained attention, but the effect was not dose dependent. Though mild and not associated with impairment, THC-like effects were observed at higher THCV doses. Oral THCV-containing products could lead to positive urine drug screens for THC. ClinicalTrials.gov ID: NCT05210634.

Oral Cannabidiol Treatment in Two Postmenopausal Women with Osteopenia: A Case Series.

Introduction: Cannabidiol (CBD), a nonintoxicating cannabinoid, may be involved in bone remodeling, but human studies are limited. In this case series, we explored the effects of oral CBD administration on bone turnover. Materials and Methods: Two postmenopausal women with osteopenia (T-score=-1 to -2.5) were randomized to receive 100 or 300 mg CBD daily (oral, bis in die [twice per day]) for 12 weeks. Serum markers of bone resorption (carboxyl-terminal collagen crosslinks [CTx]) and bone formation (procollagen type 1 N-terminal propeptide [P1NP], bone-specific alkaline phosphatase [BSAP], and osteocalcin [OC]); safety measures; plasma concentrations of CBD and metabolites; sleep disturbance; symptoms of depression, anxiety, and stress; and quality of life, were assessed. Results: CBD was well tolerated, with no clinically significant change in vital signs, hematology, chemistry, or urinalysis, and no adverse events reported. Reductions (% change vs. baseline) in CTx (-8.5%, -28.1%), P1NP (-9.9%, -39.5%), BSAP (-12.7%, -74.8%), and OC (-16.0%, -6.7%) were observed after 12 weeks of oral administration of 100 or 300 mg CBD daily, respectively. The two participants self-reported consuming 95.3% and 98.8% of CBD doses, respectively. CBD and select metabolites were measurable in plasma after 4 and 12 weeks of CBD treatment. No notable changes in sleep disturbance, depression, anxiety, stress, or quality of life were observed. Conclusions: CBD was well tolerated after 12 weeks of twice-daily oral administration and was associated with reduction in measured markers of bone turnover. Compliance with CBD treatment was good. Large-scale randomized clinical trials into the bone protective effects of CBD in postmenopausal women are warranted.

Sex Differences in the Safety and Subjective Effects of Two Oral Δ9-Tetrahydrocannabinol-Containing Cannabis Products over Multiple Doses Among Healthy Adults.

Introduction: A growing number of females report consuming cannabis products. There is a paucity of data on sex differences in safety and subjective effects after repeated use of varying oral doses of Δ9-tetrahydrocannabinol (THC; the primary psychoactive constituent of cannabis). Materials and Methods: Data were from two randomized, double-blind, placebo-controlled, multiple-dose, between-subject trials of two THC-containing oral cannabis products. Healthy adults received placebo, low-dose THC (∼2.5 or ∼5 mg per dose), or high-dose THC (∼7.5 or ∼10 mg per dose) twice daily for 7 days. There were 38 males (8 placebo, 17 low-dose THC, 13 high-dose THC) and 46 females (8 placebo, 17 low-dose THC, 21 high-dose THC). Analyses compared adverse events (AEs) and subjective effects between males and females, by THC dose. Results: In the placebo and low-dose THC groups, there were no sex differences in the relative rate of AEs. In the high-dose THC group, females versus males reported 3.08 (95% confidence interval [CI]=1.31-8.33) times as many AEs. There were no significant interactions of sex×low-dose THC group for any subjective effect. In the high-dose THC group, females versus males reported greater "relaxed" ratings (b=15.14, 95% CI=1.44-28.84, p=0.027), whereas in the placebo group, males versus females reported greater ratings of "liking the effect" (b=-30.01, 95% CI=2.77-57.26, p=0.028). Although analyses were underpowered to assess the sex×THC dose×day interaction, the initial sex disparity in AEs and some subjective effects in the high-dose THC group appeared to shrink after the first day. Conclusions: In this exploratory analysis, sex differences in some responses to oral THC were nuanced. Females appeared more sensitive than males to AEs and some subjective effects at higher but not lower doses. Males reported higher ratings than females on some subjective effects in response to placebo. Initial sex differences in response to higher doses of oral THC tended to diminish over 7 days of dosing. If replicated, findings could help inform sex-specific dosing strategies of medical cannabis products and could help educate medical cannabis patients on any temporality of effects.

Sex Differences in the Pharmacokinetics of Cannabidiol and Metabolites Following Oral Administration of a Cannabidiol-Dominant Cannabis Oil in Healthy Adults.

Introduction: Oral cannabidiol (CBD) product use is increasingly growing among women; however, there is a lack of data on sex differences in the pharmacokinetics (PKs) of CBD and its primary metabolites, 7-hydroxy-CBD (7-OH-CBD) and 7-carboxy-CBD (7-COOH-CBD), after repeated doses. Materials and Methods: The present study is a secondary analysis of data from a randomized, double-blind, placebo-controlled multiple-dose trial of a commercially available, CBD-dominant oral cannabis product. Healthy participants (n=17 males and 15 females) were randomized to receive 120 to 480 mg of CBD daily for 7 days. Dosing groups were pooled for all analyses due to sample size limitations. Analyses compared plasma PK parameters by sex, day, and sex×day. Results: For raw PK parameters for CBD and metabolites, there were no statistically significant effects of sex×day or sex (all p-values >0.05). For metabolite-to-parent ratios (MPRs) of AUC0-t, there were significant effects of the sex×day interactions for 7-OH-CBD (F=6.89, p=0.016) and 7-COOH-CBD (F=5.96, p=0.021). For 7-OH-CBD, follow-up analyses showed significant simple effects of day within females (t=4.13, p<0.001), but not within males (t=0.34, p=0.73), such that 7-OH-CBD MPRs increased significantly from day 1 to 7 for females, but not for males. For 7-COOH-CBD, follow-up analyses revealed significant simple effects of day within females (t=8.24, p<0.001) and males (t=5.20, p<0.001), therefore 7-COOH-CBD MPRs increased significantly from day 1 to 7 in both sexes, but the increase was significantly greater among females than among males. Within dosing days, there were no statistically significant simple effects of sex on MPRs of 7-OH-CBD or 7-COOH-CBD. Conclusions: Females exhibited greater relative exposure to CBD metabolites in plasma over time, which may reflect sex differences in CBD metabolism or elimination. Further research assessing the safety implications of higher relative exposure to CBD metabolites over longer periods of time is warranted to mirror typical consumer use patterns.

Cannabidiol Reduces Nicotine Withdrawal Severity and State Anxiety During an Acute E-cigarette Abstinence Period: A Novel, Open-Label Study.

Introduction: Despite efforts to curb nicotine use, 8.1 million adults in the United States use e-cigarettes. Notably, the majority of nicotine-containing e-cigarette users report wanting to quit in the near future, yet there is a dearth of research surrounding intervention efforts. Cannabidiol (CBD) has potential to facilitate e-cigarette quit attempts by decreasing withdrawal symptom intensity and anxiety during nicotine e-cigarette abstinence. Methods: This study employed an open-label, crossover design (n=20) to test the hypothesis that among daily nicotine-containing e-cigarette users, oral administration of 320 mg CBD would reduce self-reported nicotine withdrawal severity and state anxiety following a 4-h e-cigarette abstinence period compared to withdrawal and anxiety reported after abstinence in the absence of CBD. Results: After controlling for participants' positive CBD expectancies, results were consistent with hypotheses, suggesting CBD reduced both nicotine withdrawal symptom severity and state anxiety during e-cigarette abstinence. Conclusion: These preliminary findings suggest testing the impact of CBD on e-cigarette cessation attempts is warranted.

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).

Effect of very low nicotine content cigarettes on alcohol drinking and smoking among adult smokers who are at-risk alcohol drinkers.

Alcohol and tobacco use are interrelated. This study examined response to very low nicotine content (VLNC) and moderate nicotine content (MNC) cigarettes by problematic drinking. We utilized a double-blind, randomized, within-subjects crossover design of VLNC and MNC cigarettes in two groups of adult cigarette smokers: with at-risk drinking (ARD; n = 23) and without ARD (n = 24). Participants smoked only their assigned experimental cigarette in their home environment for 7 days, and completed laboratory visits, including ad libitum smoking of the assigned experimental cigarette, at the beginning and end of each experimental week. Participants smoked their usual cigarettes for 7 days between conditions. Participants provided daily reports of alcohol and cigarette consumption. Current Diagnostic and Statistical Manual of Mental Disorders-5th edition (DSM-5) alcohol use disorder (AUD) was assessed at baseline and the end of each experimental week. Compliance with smoking of experimental cigarettes was good. Adjusting for baseline drinking, there was no significant effect of experimental cigarette or ARD group on drinks per day or alcohol urges. There was no effect of experimental cigarette or ARD group on cigarettes per day, or on any puff topography outcome or postsmoking exhaled carbon monoxide during laboratory smoking. No participant had a change in AUD status or AUD severity. After 7 days of exposure to VLNC cigarettes, adult cigarette smokers with ARD did not show compensatory drinking or compensatory smoking behavior. A future policy change in the United States to reduce nicotine content in cigarettes may not produce unintended compensatory drinking or smoking among this vulnerable and prevalent population of smokers. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Serum Markers of Bone Turnover Following Controlled Administration of Two Medical Cannabis Products in Healthy Adults.

Introduction: Cannabidiol (CBD) has been shown to maintain bone integrity in pre-clinical models, but little is known about the effects of delta-9-tetrahydrocannabinol (THC) on bone turnover. In this study we explored the effects of two oral medical cannabis products on normal bone homeostasis through evaluation of markers of bone resorption (carboxyl-terminal collagen crosslinks, CTx) and bone formation (procollagen type 1 N-terminal propeptide, P1NP; alkaline phosphatase, ALP). Methods: This study is an analysis of secondary data from two Phase 1 double-blind, placebo-controlled trials of Spectrum Yellow (0.9 mg THC, 20 mg CBD/mL of oil) and Spectrum Red (2.5 mg THC, 0.3 mg CBD/softgel). Healthy participants (n=38 men, 45 women) were randomized to receive 5-20 mg THC (CBD levels varied as a function of administered product) or placebo daily (BID) for 7 days. Bone markers were assessed at baseline, upon completion of product administration (day 8), and after a 5-day washout (day 13). Results: All bone markers were significantly higher in men at baseline (p≤0.008). For CTx, there was a significant day×group interaction (F=3.23, p=0.04); CTx levels were significantly lower in participants treated with Spectrum Red (b=-164.28; 95% confidence interval [CI], -328 to -0.29; p=0.04) and marginally lower in participants treated with Spectrum Yellow (b=-157.31; 95% CI, -323 to 8.68; p=0.06) versus placebo on day 8. For P1NP and ALP, there were no significant differences between treatments across study days. Bone marker values outside the reference range (RR) were observed; CTx > RR (n=71) was predominantly (85.9%) observed in male participants, whereas P1NP > RR (n=100) was more evenly distributed between sexes (53.0% in men). These were not considered clinically significant and did not differ between treatment groups. Conclusions: These are the first interventional human data on the effect of cannabinoids on biomarkers of bone turnover. Short-term treatment with CBD- or THC-dominant medical cannabis products resulted in attenuation of a marker of bone resorption. Although the attenuation was not clinically significant, this finding may be indicative of protective properties of cannabinoids in bone. Further research over longer dosing durations in individuals exhibiting bone-specific conditions (e.g., osteoporosis) is warranted. ClinicalTrials.gov IDs: ACTRN12619001723178 and ACTRN12619001450101.

Medical cannabis authorization patterns, safety, and associated effects in older adults.

BACKGROUND: Use of medical cannabis is increasing among older adults. However, few investigations have examined cannabis use in this population. METHODS: We assessed the authorization patterns, safety, and effects of medical cannabis in a sub-analysis of 201 older adults (aged ≥ 65 years) who completed a 3-month follow-up during this observational study of patients who were legally authorized a medical cannabis product (N = 67). Cannabis authorization patterns, adverse events (AEs), Edmonton Symptom Assessment Scale-revised (ESAS-r), and Brief Pain Inventory Short Form (BPI-SF) data were collected. RESULTS: The most common symptoms for which medical cannabis was authorized were pain (159, 85.0%) and insomnia (9, 4.8%). At baseline and at the 3-month follow-up, cannabidiol (CBD)-dominant products were authorized most frequently (99, 54%), followed by balanced products (76, 42%), and then delta-9-tetrahydrocannabinol (THC)-dominant products (8, 4.4%). The most frequent AEs were dizziness (18.2%), nausea (9.1%), dry mouth (9.1%), and tinnitus (9.1%). Significant reductions in ESAS-r scores were observed over time in the domains of drowsiness (p = .013) and tiredness (p = .031), but not pain (p = .106) or well-being (p = .274). Significant reductions in BPI-SF scores over time were observed for worst pain (p = .010), average pain (p = .012), and overall pain severity (p = 0.009), but not pain right now (p = .052) or least pain (p = .141). CONCLUSIONS: Overall, results suggest medical cannabis was safe, well-tolerated, and associated with clinically meaningful reductions in pain in this sample of older adults. However, the potential bias introduced by the high subject attrition rate means that all findings should be interpreted cautiously and confirmed by more rigorous studies.

Characterisation of a Hepatitis C Virus Subtype 2a Cluster in Scottish PWID with a Suboptimal Response to Glecaprevir/Pibrentasvir Treatment.

Direct-acting antivirals (DAAs) have revolutionised the treatment of Hepatitis C virus (HCV), allowing the World Health Organisation (WHO) to set a target of eliminating HCV by 2030. In this study we aimed to investigate glecaprevir and pibrentasvir (GP) treatment outcomes in a cohort of patients with genotype 2a infection. METHODS: Clinical data and plasma samples were collected in NHS Greater Glasgow & Clyde. Next generation whole genome sequencing and replicon assays were carried out at the MRC-University of Glasgow Centre for Virus Research. RESULTS: 132 cases infected with genotype 2a HCV were identified. The SVR rate for this group was 91% (112/123) following treatment with GP. An NS5A polymorphism, L31M, was detected in all cases of g2a infection, and L31M+R353K in individuals that failed treatment. The results showed that R353K was present in 90% of individuals in the Glasgow genotype 2a phylogenetic cluster but in less than 5% of all HCV subtype 2a published sequences. In vitro efficacy of pibrentasvir against sub-genomic replicon constructs containing these mutations showed a 2-fold increase in IC50 compared to wildtype. CONCLUSION: This study describes a cluster of HCV genotype 2a infection associated with a lower-than-expected SVR rate following GP treatment in association with the NS5A mutations L31M+R353K.

Pharmacokinetics of cannabichromene in a medical cannabis product also containing cannabidiol and Δ9-tetrahydrocannabinol: a pilot study.

PURPOSE: Cannabichromene (CBC) is a phytocannabinoid commonly found in cannabis, yet its acute post-dose pharmacokinetics (PK) have not been examined in humans. This is a secondary data analysis from a trial investigating Spectrum Yellow oil, an oral cannabis product used for medical purposes that contained 20 mg cannabidiol (CBD), 0.9 mg Δ9-tetrahydrocannabinol (THC), and 1.1 mg CBC, per 1 mL of oil. METHODS: Participants (N = 43) were randomized to one of 5 groups: 120 mg CBD, 5.4 mg THC, and 6.6 mg CBC daily; 240 mg CBD, 10.8 mg THC, and 13.2 mg CBC daily; 360 mg CBD, 16.2 mg THC, and 19.8 mg CBC daily; 480 mg CBD, 21.6 mg THC, and 26.4 mg CBC daily; or placebo. Study medication was administered every 12 h for 7 days. Plasma CBC concentrations were analyzed by a validated two-dimensional high-performance liquid chromatography-tandem mass spectrometry assay. RESULTS: After a single dose and after the final dose, the Cmax of CBC increased by 1.3-1.8-fold for each twofold increase in dose; the tmax range was 1.6-4.3 h. Based on the ratio of administered CBD, THC, and CBC to the plasma concentration, the dose of CBD was 18 times higher than the dose of CBC, yet the AUC0-t of CBD was only 6.6-9.8-fold higher than the AUC0-t of CBC; the dose of THC was similar to the dose of CBC, yet THC was quantifiable in fewer plasma samples than was CBC. CONCLUSIONS: CBC may have preferential absorption over CBD and THC when administered together. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry #ACTRN12619001450101, registered 18 October 2019.

Safety, Pharmacokinetics and Pharmacodynamics of Spectrum Red Softgels in Healthy Participants.

Due to a lack of published pharmacokinetic (PK) and/or pharmacodynamic (PD) data, informed physician and patient decision-making surrounding appropriate dosing of cannabis for medical purposes is limited. This Phase 1, multiple-dose study evaluated the safety, tolerability, PK and PD of Spectrum Red softgels (2.5 mg Δ9-tetrahydrocannabinol (THC) and <0.25 mg cannabidiol (CBD)). Participants (n = 41) were randomized to one of five groups: 5 mg THC and 0.06 mg CBD daily (Treatment A), 10 mg THC and 0.12 mg CBD daily (Treatment B), 15 mg THC and 0.18 mg CBD daily (Treatment C), 20 mg THC and 0.24 mg CBD daily (Treatment D) or placebo. Study medication was administered in divided doses, every 12 h, ∼60 min after a standardized meal, for 7 consecutive days. All treatment-emergent adverse events (TEAEs) (65/65) were of mild-to-moderate severity; none was serious. The highest number of TEAEs (30/65) occurred on the first day of treatment. The most common TEAEs included somnolence, lethargy and headache (reported by eight, seven and five participants, respectively). On Day 7, maximum observed plasma concentration of 11-carboxy-THC increased by 2.0- and 2.5-fold as the dose doubled between Treatments A and B and between Treatments B and D, respectively. Mean peak post-treatment ratings of self-reported subjective effects of 'feel any effect' and 'dazed' differed between Treatment D and placebo on Days 1, 3 and 7. Over a week of twice-daily dosing of Spectrum Red softgels, daily doses of THC up to 20 mg and of CBD up to 0.24 mg were generally safe and became better tolerated after the first day of treatment. A prudent approach to improve tolerability with Spectrum Red softgels might involve initial daily doses no higher than 10 mg THC and 0.12 mg CBD in divided doses, with titration upward over time as needed based on tolerability.

Safety, Pharmacokinetics and Pharmacodynamics of Spectrum Yellow Oil in Healthy Participants.

Due to a lack of published pharmacokinetic (PK) and/or pharmacodynamic (PD) data, decision-making surrounding appropriate dosing of cannabis used for medical purposes is limited. This multiple-dose study evaluated the safety, tolerability, PK and PD of Spectrum Yellow oil [20 mg/mL cannabidiol (CBD)/<1 mg/mL ∆9-tetrahydrocannabinol (THC)]. Participants (n = 43) were randomized to one of five groups: 120 mg CBD and 5.4 mg THC daily, 240 mg CBD and 10.8 mg THC daily, 360 mg CBD and 16.2 mg THC daily, 480 mg CBD and 21.6 mg THC daily or placebo. Study medication was administered every 12 h for 7 consecutive days. Treatment-emergent adverse events (TEAEs); plasma and urine concentrations of THC, CBD and metabolites; and self-reported subjective effects were collected. Nearly all TEAEs (44/45) were of mild or moderate severity; none was serious. The highest incidence of TEAEs (67%) was in the two higher-dose treatment groups. The highest number of TEAEs (17/45) occurred on the first treatment day. Steady-state plasma CBD concentrations were reached by Day 7. On Day 7, CBD exposure showed dose proportionality (AUC0-t slope = 1.03 [0.70, 1.36], Cmax slope = 0.92 [0.53, 1.31]). Most plasma THC concentrations were below the limit of quantification. Across Days 1 and 7, there were no consistent differences in subjective effects between placebo and active study medication. A prudent approach to improve tolerability with Spectrum Yellow oil might involve initial doses no higher than 240 mg total CBD and 10.8 mg total THC daily in divided doses, with titration upward over time as needed based on tolerability.

Self-Assembled Peptide Amphiphile Nanofibers for Controlled Therapeutic Delivery to the Atherosclerotic Niche.

Atherosclerotic plaque remains the leading contributor to cardiovascular disease and requires invasive surgical procedures for its removal. Nanomedicine offers a minimally invasive approach to alleviate plaque burden by targeted therapeutic delivery. However, nanocarriers are limited without the ability to sense and respond to the diseased microenvironment. In this study, targeted self-assembled peptide amphiphile (PA) nanofibers were developed that cleave in response to biochemical cues expressed in atherosclerotic lesions-reactive oxygen species (ROS) and intracellular glutathione-to deliver a liver X receptor agonist (LXR) to enhance macrophage cholesterol efflux. The PAs released LXR in response to physiological levels of ROS and reducing agents and could be co-assembled with plaque-targeting PAs to form nanofibers. The resulting LXR PA nanofibers promoted cholesterol efflux from macrophages in vitro as well as LXR alone and with lower cytotoxicity. Further, the ApoA1-LXR PA nanofibers targeted plaque within an atherosclerotic mouse model in vivo and activated ATP-binding cassette A1 (ABCA1) expression as well as LXR alone with reduced liver toxicity. Taken together, these results demonstrate the potential of self-assembled PA nanofibers for controlled therapeutic delivery to the atherosclerotic niche.

Evaluation of the scale-up of HIV testing among people who inject drugs in Scotland in the context of an ongoing HIV outbreak.

BACKGROUND: A large outbreak of HIV among people who inject drugs (PWID) has been ongoing in Glasgow city centre (GCC), Scotland since early 2015. The outbreak is associated with high levels of homelessness, cocaine injecting and injecting in public places. A key component of the public health response was the scale-up of HIV testing in a range of services engaged with PWID. Our aims were to: 1) evaluate the extent of and change in HIV testing over the course of the outbreak and 2) examine factors associated with reporting an HIV test. METHODS: Self-report of an HIV test in the last 12 months was collected for 15,081 PWID interviewed in six national cross-sectional bio-behavioural surveys during 2008-2018. Multi-variate logistic regression was undertaken to determine trends in HIV testing by region of recruitment (GCC; rest of Glasgow; other Scottish city centres (SCC); and rest of Scotland) and outbreak period (pre: 2008-14; early: 2015-16; ongoing: 2017-18). RESULTS: HIV testing increased across all regions and was most pronounced in GCC comparing the ongoing (67%) to the pre-outbreak period (33%) (aOR=4.68, 95% CI 3.23 to 6.77, p<0.001). However, compared to other SCCs pre-outbreak (with 46% reporting testing), those recruited in GCC had a lower odds of HIV testing early outbreak (aOR=0.37, 95% CI 0.27 to 0.54, p<0.001) and more modest increased odds in the ongoing outbreak period (aOR=1.41, 95% CI 0.97 to 2.05, p=0.069). Among PWID recruited in the whole of Glasgow in the ongoing phase, reporting an HIV test was associated with injecting cocaine or in public places (aOR=2.20, 95% CI 1.53 to 3.17, p<0.001), receipt of methadone (aOR=1.48, 95% CI 1.01 to 2.17, p=0.042) and incarceration in the last year (aOR=1.72, 95% CI 1.18 to 2.51, p=0.004). CONCLUSIONS: Relatively low levels of HIV testing pre- and early-outbreak likely hindered efforts to control the spread of infection among PWID in Glasgow. Uptake has since increased with expansion of testing across multiple settings, particularly among those at high risk of infection. Further effort is needed to ensure the vast majority of PWID are regularly tested, not just in the epicentre of the outbreak but in other areas with low population prevalence of infection.

Intravenous Delivery of Lung-Targeted Nanofibers for Pulmonary Hypertension in Mice.

Pulmonary hypertension is a highly morbid disease with no cure. Available treatments are limited by systemic adverse effects due to non-specific biodistribution. Self-assembled peptide amphiphile (PA) nanofibers are biocompatible nanomaterials that can be modified to recognize specific biological markers to provide targeted drug delivery and reduce off-target toxicity. Here, PA nanofibers that target the angiotensin I-converting enzyme and the receptor for advanced glycation end-products (RAGE) are developed, as both proteins are overexpressed in the lung with pulmonary hypertension. It is demonstrated that intravenous delivery of RAGE-targeted nanofibers containing the targeting epitope LVFFAED (LVFF) significantly accumulated within the lung in a chronic hypoxia-induced pulmonary hypertension mouse model. Using 3D light sheet fluorescence microscopy, it is shown that LVFF nanofiber localization is specific to the diseased pulmonary tissue with immunofluorescence analysis demonstrating colocalization of the targeted nanofiber to RAGE in the hypoxic lung. Furthermore, biodistribution studies show that significantly more LVFF nanofibers localized to the lung compared to major off-target organs. Targeted nanofibers are retained within the pulmonary tissue for 24 h after injection. Collectively, these data demonstrate the potential of a RAGE-targeted nanomaterial as a drug delivery platform to treat pulmonary hypertension.