ore than 2 million Americans have an opioid use disorder (OUD), and in 2016, more than 42 000 Americans died of opioid overdoses. 1,2 Although in the first years of the opioid crisis, most overdose-associated deaths were caused by misuse of prescription analgesics, heroin and synthetic opioids (fentanyl and its analogues) currently account for most of the fatalities, a scenario that reflects the changing nature of the opioid crisis (Figure 1). We reviewed the pharmacology of opioids because it is relevant to their rewarding and analgesic effects that lead to their misuse, the epidemiology of the crisis and its transformations in the past 2 decades, and the interventions to treat and prevent OUD that must be implemented to overcome the current crisis and prevent it from happening again. Opioid PharmacologyOpioid drugs-prescription analgesics and illicit drugs-exert their pharmacologic effects by engaging the endogenous opioid system, where they act as agonists at the μ-opioid receptor (MOR). The agonist action at the MOR is responsible for the rewarding effects of opioids and analgesia. In the brain, these receptors are highly concentrated in regions that are part of the pain and reward networks. They are also located in regions that regulate emotions, which is why long-term opioid exposure is frequently associated with depression and anxiety. 4 In addition, MORs are located in brainstem regions that regulate breathing; there, IMPORTANCE More than 42 000 Americans died of opioid overdoses in 2016, and the fatalities continue to increase. This review analyzes the factors that triggered the opioid crisis and its further evolution, along with the interventions to manage and prevent opioid use disorder (OUD), which are fundamental for curtailing the opioid crisis.OBSERVATIONS Opioid drugs are among the most powerful analgesics but also among the most addictive. The current opioid crisis, initially triggered by overprescription of opioid analgesics, which facilitated their diversion and misuse, has now expanded to heroin and illicit synthetic opioids (fentanyl and its analogues), the potency of which further increases their addictiveness and lethality. Although there are effective medications to treat OUD (methadone hydrochloride, buprenorphine, and naltrexone hydrochloride), these medications are underused, and the risk of relapse is still high. Strategies to expand medication use and treatment retention include greater involvement of health care professionals (including psychiatrists) and approaches to address comorbidities. In particular, the high prevalence of depression and suicidality among patients with OUD, if untreated, contributes to relapse and increases the risk of overdose fatalities. Prevention interventions include screening and early detection of psychiatric disorders, which increase the risk of substance use disorders, including OUD. CONCLUSIONS AND RELEVANCEAlthough overprescription of opioid medications triggered the opioid crisis, improving opioid prescription practices for pain management, althoug...

Drug overdose deaths are at unprecedented levels in the United States. 1 Prescription opioids have been the most common drug involved in overdose deaths, but heroin and synthetic opioids (primarily illicit fentanyl) are increasingly implicated in overdoses. 2 In addition, synthetic opioids are increasingly found in illicit drug supplies of heroin, cocaine, methamphetamine, and counterfeit pills. 3 To date, the involvement of synthetic opioids in overdose deaths involving other drugs is not well characterized, limiting the ability to implement effective clinical and public health strategies. Using 2010-2016 mortality data, we describe recent trends for synthetic opioid involvement in drug overdose deaths.

IMPORTANCE Mortality associated with methamphetamine use has increased markedly in the US. Understanding patterns of methamphetamine use may help inform related prevention and treatment. OBJECTIVE To assess the national trends in and correlates of past-year methamphetamine use, methamphetamine use disorder (MUD), injection, frequent use, and associated overdose mortality from 2015 to 2019.

Most neurons possess a single, nonmotile cilium that projects out from the cell surface. These microtubule-based organelles are important in brain development and neurogenesis; however, their function in mature neurons is unknown. Cilia express a complement of proteins distinct from other neuronal compartments, one of which is the somatostatin receptor subtype SST 3 . We show here that SST 3 is critical for object recognition memory in mice. sst3 knock-out mice are severely impaired in discriminating novel objects, whereas they retain normal memory for object location. Further, systemic injection of an SST 3 antagonist (ACQ090) disrupts recall of familiar objects in wild-type mice. To examine mechanisms of SST 3 , we tested synaptic plasticity in CA1 hippocampus. Electrically evoked long-term potentiation (LTP) was normal in sst3 knock-out mice, while adenylyl cyclase/cAMP-mediated LTP was impaired. The SST 3 antagonist also disrupted cAMP-mediated LTP. Basal cAMP levels in hippocampal lysate were reduced in sst3 knock-out mice compared with wild-type mice, while the forskolin-induced increase in cAMP levels was normal. The SST 3 antagonist inhibited forskolin-stimulated cAMP increases, whereas the SST 3 agonist L-796,778 increased basal cAMP levels in hippocampal slices but not hippocampal lysate. Our results show that somatostatin signaling in neuronal cilia is critical for recognition memory and suggest that the cAMP pathway is a conserved signaling motif in cilia. Neuronal cilia therefore represent a novel nonsynaptic compartment crucial for signaling involved in a specific form of synaptic plasticity and in novelty detection.