IMPORTANCE Historical shifts are occurring in marijuana policy. The effect of legalizing marijuana for recreational use on rates of adolescent marijuana use is a topic of considerable debate.OBJECTIVE To examine the association between the legalization of recreational marijuana use in Washington and Colorado in 2012 and the subsequent perceived harmfulness and use of marijuana by adolescents. DESIGN, SETTING, AND PARTICIPANTSWe used data of 253 902 students in eighth, 10th, and 12th grades from 2010 to 2015 from Monitoring the Future, a national, annual, cross-sectional survey of students in secondary schools in the contiguous United States. Difference-indifference estimates compared changes in perceived harmfulness of marijuana use and in past-month marijuana use in Washington and Colorado prior to recreational marijuana legalization (2010-2012) with postlegalization (2013-2015) vs the contemporaneous trends in other states that did not legalize recreational marijuana use in this period. MAIN OUTCOMES AND MEASURESPerceived harmfulness of marijuana use (great or moderate risk to health from smoking marijuana occasionally) and marijuana use (past 30 days). RESULTSOf the 253 902 participants, 120 590 of 245 065(49.2%) were male, and the mean (SD) age was 15.6 (1.7) years. In Washington, perceived harmfulness declined 14.2% and 16.1% among eighth and 10th graders, respectively, while marijuana use increased 2.0% and 4.1% from 2010-2012 to 2013-2015. In contrast, among states that did not legalize recreational marijuana use, perceived harmfulness decreased by 4.9% and 7.2% among eighth and 10th graders, respectively, and marijuana use decreased by 1.3% and 0.9% over the same period. Difference-in-difference estimates comparing Washington vs states that did not legalize recreational drug use indicated that these differences were significant for perceived harmfulness (eighth

Background Adolescent marijuana use is associated with adverse later-life consequences, so identifying factors underlying adolescent use is of substantial public health importance. The relationship of U.S. state medical marijuana laws (MML) to adolescent marijuana use has been controversial. Such laws could convey a message about marijuana acceptability that increases marijuana use soon after passage, even if implementation is delayed or the law narrowly limits use. We used 24 years of U.S. national data to examine the relationship between state MML and adolescent marijuana use. Methods Data came from 1,098,270 U.S. adolescents in 8th, 10th, and 12th grade in the national Monitoring the Future annual surveys conducted between 1991–2014. The main outcome was any marijuana use in the prior 30 days. Using multilevel regression modeling, we examined marijuana use in adolescents nested within states, including whether marijuana use was higher overall in states that ever passed a MML up to 2014, and whether the risk of use changed after state MML were passed. Individual-, school- and state-level covariates were controlled. Findings Overall, marijuana use was more prevalent in states that enacted MML up to 2014 than in other states (AOR=1.27, 95%CI=1.07–1.51). Pre- and post-MML risk did not differ in the full sample (AOR=0.92, 95%CI=0.82–1.04). A significant interaction (p<0.001) indicated differential post-MML risk by grade. In 8th graders, post-MML use decreased (AOR=0.73, 95%CI=0.63–0.84), while no significant change occurred in 10th or 12th graders. Results were generally robust across sensitivity analyses. Interpretation Previous evidence and this study show that MML passage does not result in increased adolescent marijuana use. However, overall, adolescent use is higher in states that ever enacted MML than in other states. State-level risk factors other than MML may contribute to both marijuana use and MML, warranting investigation. An observed 8th-grade post-MML decrease also merits further study. Funding U.S. National Institute on Drug Abuse, Columbia University Mailman School of Public Health, New York State Psychiatric Institute.

The finding that oxygenase-catalyzed protein hydroxylation regulates animal transcription raises questions as to whether the translation machinery and prokaryotic proteins are analogously modified. Escherichia coli ycfD is a growth-regulating 2-oxoglutarate oxygenase catalyzing arginyl hydroxylation of the ribosomal protein Rpl16. Human ycfD homologs, Myc-induced nuclear antigen (MINA53) and NO66, are also linked to growth and catalyze histidyl hydroxylation of Rpl27a and Rpl8, respectively. This work reveals new therapeutic possibilities via oxygenase inhibition and by targeting modified over unmodified ribosomes.

Serotonin reuptake inhibitors (SRIs), the first-line pharmacological treatment for obsessive-compulsive disorder (OCD), have two limitations: incomplete symptom relief and 2-3 months lag time before clinically meaningful improvement. New medications with faster onset are needed. As converging evidence suggests a role for the glutamate system in the pathophysiology of OCD, we tested whether a single dose of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, could achieve rapid antiobsessional effects. In a randomized, double-blind, placebo-controlled, crossover design, drug-free OCD adults (n ¼ 15) with nearconstant obsessions received two 40-min intravenous infusions, one of saline and one of ketamine (0.5 mg/kg), spaced at least 1-week apart. The OCD visual analog scale (OCD-VAS) and the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) were used to assess OCD symptoms. Unexpectedly, ketamine's effects within the crossover design showed significant (po0.005) carryover effects (ie, lasting longer than 1 week). As a result, only the first-phase data were used in additional analyses. Specifically, those receiving ketamine (n ¼ 8) reported significant improvement in obsessions (measured by OCD-VAS) during the infusion compared with subjects receiving placebo (n ¼ 7). One-week post-infusion, 50% of those receiving ketamine (n ¼ 8) met criteria for treatment response (X35% Y-BOCS reduction) vs 0% of those receiving placebo (n ¼ 7). Rapid anti-OCD effects from a single intravenous dose of ketamine can persist for at least 1 week in some OCD patients with constant intrusive thoughts. This is the first randomized, controlled trial to demonstrate that a drug affecting glutamate neurotransmission can reduce OCD symptoms without the presence of an SRI and is consistent with a glutamatergic hypothesis of OCD.