Background: There is a substantial and unmet clinical need for pharmacological treatment of cannabis use disorders. Cannabidiol (CBD) could offer a novel treatment but it is unclear which doses might be effective or safe.Methods: Participants meeting DSM-5 cannabis use disorder criteria were allocated to four-week treatment with oral CBD at 200mg, 400mg, 800mg or placebo during a cessation attempt using a double-blinded block randomisation sequence. All received a brief psychological intervention of motivational interviewing. An adaptive Bayesian dose-finding design was used to identify effective/ineffective doses at a priori interim and final analysis stages. The primary objective was to identify the Most Effective Dose (MED) of CBD for reducing cannabis use. The primary endpoint was lower urinary THC-COOH:creatinine concentrations and/or increased days per week abstinent from cannabis during treatment, evidenced by posterior probabilities exceeding Pr=0.9 for CBD versus placebo. All analyses were intention-to-treat.Outcomes: Participants were initially randomised to placebo, 200mg, 400mg and 800mg CBD (n=48; 1:1:1:1). At interim analysis 200mg CBD was eliminated from the trial as an ineffective dose.Randomisation continued to 400mg CBD, 800mg CBD, and placebo (n=34; 1:1:1). At final analysis, both 400mg CBD and 800mg CBD exceeded primary endpoint criteria (Pr=0.9) for both primary outcomes: urinary THC-COOH:creatinine (Pr(400mg=MED │Data)=0.9995; Pr(800mg=MED │Data)=0.9965), days per week abstinent from cannabis (Pr(400mg=MED │Data)=0.9966; Pr(800mg=MED │Data)=0.9247). Compared to placebo, 400mg CBD decreased THC-COOH:creatinine concentrations by -94.21 ng/ml (95% Interval ) and increased abstinence from cannabis by 0.48 days per week (95% Interval Estimate=0.15, 0.82). Compared to placebo, 800mg CBD decreased THC-COOH:creatinine concentrations by -72.02 ng/ml (95% Interval Estimate= -135.47, -19.52) and increased abstinence from cannabis by 0.27 days per week (95% Interval Estimate= -0.09, 0.64). CBD was well tolerated with no severe adverse events and 94% completed treatment.Interpretation: In the first randomised clinical trial of CBD for cannabis use disorder, 400mg and 800mg CBD were safe and more effective than placebo at reducing cannabis use.

Background and aims Cannabis products with high delta‐9‐tetrahydrocannabinol (THC) concentrations carry an increased risk of addiction and mental health disorders, while it has been suggested that cannabidiol (CBD) may moderate the effects of THC. This study aimed to systematically review and meta‐analyse changes in THC and CBD concentrations in cannabis over time (PROSPERO registration: CRD42019130055). Design Embase, MEDLINE® and Epub Ahead of Print, In‐Process and Other Non‐Indexed Citations and Daily, Global Health, PsycINFO and Scopus were searched from inception to 27/03/2019 for observational studies reporting changes in mean THC and/or CBD concentration in cannabis over at least three annual time points. Searches and extraction were conducted by two independent reviewers. Random effects meta‐regression models estimated annual changes in THC and CBD for each product within each study; these estimates were pooled across studies in random effects models. Results We identified 12 eligible studies from the USA, UK, Netherlands, France, Denmark, Italy and New Zealand. For all herbal cannabis, THC concentrations increased by 0.29% each year (95% CI: 0.11, 0.47), P < 0.001 based on 66 747 cannabis samples from eight studies, 1970–2017. For cannabis resin, THC concentrations increased by 0.57% each year (95% CI: 0.10, 1.03), P = 0.017 based on 17 371 samples from eight studies, 1975–2017. There was no evidence for changes in CBD in herbal cannabis [−0.01% (95% CI: −0.02, 0.01), P = 0.280; 49 434 samples from five studies, 1995–2017] or cannabis resin [0.03% (95% CI: −0.11, 0.18), P = 0.651; 11 382 samples from six studies, 1992–2017]. Risk of bias was low apart from non‐random sampling in most studies. There was evidence of moderate to substantial heterogeneity. Conclusions Concentrations of delta‐9‐tetrahydrocannabinol (THC) in international cannabis markets increased from 1970 to 2017 while cannabidiol (CBD) remained stable. Increases in THC were greater in cannabis resin than herbal cannabis. Rising THC in herbal cannabis was attributable to an increased market share of high‐THC sinsemilla relative to low‐THC traditional herbal cannabis.

SUMMARY Plasmodium infection begins with the bite of an anopheline mosquito, when sporozoites along with saliva are injected into a vertebrate host. The role of the host responses to mosquito saliva components in malaria remains unclear. We observed that antisera against Anopheles gambiae salivary glands partially protected mice from mosquito-borne Plasmodium infection. Specifically, antibodies to A. gambiae TRIO (AgTRIO), a mosquito salivary gland antigen, contributed to the protection. Mice administered AgTRIO antiserum showed lower Plasmodium liver burden and decreased parasitemia when exposed to infected mosquitoes. Active immunization with AgTRIO was also partially protective against Plasmodium berghei infection. A combination of AgTRIO antiserum and antibodies against Plasmodium circumsporozoite protein, a vaccine candidate, further decreased P. berghei infection. In humanized mice, AgTRIO antiserum afforded some protection against mosquito-transmitted Plasmodium falciparum. AgTRIO antiserum reduced the movement of sporozoites in the murine dermis. AgTRIO may serve as an arthropod-based target against Plasmodium to combat malaria.