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Journal: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology


Adult neurogenesis in the hippocampal subgranular zone (SGZ) and the anterior subventricular zone (SVZ) is regulated by multiple factors, including neurotransmitters, hormones, stress, aging, voluntary exercise, environmental enrichment, learning, and ischemia. Chronic treatment with selective serotonin reuptake inhibitors (SSRIs) modulates adult neurogenesis in the SGZ, the neuronal area that is hypothesized to mediate the antidepressant effects of these substances. Layer 1 inhibitory neuron progenitor cells (L1-INP cells) were recently identified in the adult cortex, but it remains unclear what factors other than ischemia affect the neurogenesis of L1-INP cells. Here, we show that chronic treatment with an SSRI, fluoxetine (FLX), stimulated the neurogenesis of gamma-aminobutyric acid (GABA)ergic interneurons from L1-INP cells in the cortex of adult mice. Immunofluorescence and genetic analyses revealed that FLX treatment increased the number of L1-INP cells in all examined cortical regions in a dose-dependent manner. Furthermore, enhanced Venus reporter expression driven by the synapsin I promoter demonstrated that GABAergic interneurons were derived from retrovirally labeled L1-INP cells. In order to assess if these new GABAergic interneurons possess physiological function, we examined the their effect on apoptosis surrounding areas following ischemia. Intriguingly, the number of neurons expressing the apoptotic marker, active caspase-3, was significantly lower in adult mice pretreated with FLX. Our findings indicate that FLX stimulates the neurogenesis of cortical GABAergic interneurons, which might have, at least, some functions, including a suppressive effect on apoptosis induced by ischemia.Neuropsychopharmacology accepted article preview online, 4 January 2013; doi:10.1038/npp.2013.2.

Concepts: Nervous system, Neuron, Hippocampus, Neurogenesis, Serotonin, Antidepressant, Selective serotonin reuptake inhibitor, Subgranular zone


Impulsivity, defined as impaired decision making, is associated with many psychiatric and behavioral disorders such as attention-deficit/hyperactivity disorder as well as eating disorders. Recent data indicate that there is a strong positive correlation between food reward behavior and impulsivity, but the mechanisms behind this relationship remain unknown. Here we hypothesize that ghrelin, an orexigenic hormone produced by the stomach and known to increase food reward behavior, also increases impulsivity. In order to assess the impact of ghrelin on impulsivity, rats were trained in three complementary tests of impulsive behavior and choice: differential-reinforcement-of-low-rate (DRL), go/no-go, and delay discounting. Ghrelin injection into the lateral ventricle increased impulsive behavior, as indicated by reduced efficiency of performance in the DRL test, and increased lever pressing during the no-go periods of the go/no-go test. Central ghrelin stimulation also increased impulsive choice, as evidenced by the reduced choice for large rewards when delivered with a delay in the delay discounting test. In order to determine whether signaling at the central ghrelin receptors is necessary for maintenance of normal levels of impulsive behavior, DRL performance was assessed following ghrelin receptor blockade with central infusion of a ghrelin receptor antagonist. Central ghrelin receptor blockade reduced impulsive behavior, as reflected by increased efficiency of performance in the DRL task. To further investigate the neurobiological substrate underlying the impulsivity effect of ghrelin we microinjected ghrelin into the ventral tegmental area, an area harboring dopaminergic cell bodies. Ghrelin receptor stimulation within the VTA was sufficient to increase impulsive behavior. We further evaluated the impact of ghrelin on dopamine-related gene expression and dopamine turnover in brain areas key in impulsive behavior control. This study provides the first demonstration that the stomach-produced hormone, ghrelin, increases impulsivity and also indicates that ghrelin can change two major components of impulsivity-motor and choice impulsivity.Neuropsychopharmacology accepted article preview online, 01 October 2015. doi:10.1038/npp.2015.297.

Concepts: Hormone, Receptor, Ligand, Receptor antagonist, Inverse agonist, Dopamine, Reward system, Ghrelin


Cannabidiol (CBD), the major non-psychoactive constituent of Cannabis sativa, has received attention for therapeutic potential in treating neurologic and psychiatric disorders. Recently, CBD has also been explored for potential in treating drug addiction. Substance use disorders are chronically relapsing conditions and relapse risk persists for multiple reasons including craving induced by drug contexts, susceptibility to stress, elevated anxiety, and impaired impulse control. Here, we evaluated the “anti-relapse” potential of a transdermal CBD preparation in animal models of drug seeking, anxiety and impulsivity. Rats with alcohol or cocaine self-administration histories received transdermal CBD at 24 h intervals for 7 days and were tested for context and stress-induced reinstatement, as well as experimental anxiety on the elevated plus maze. Effects on impulsive behavior were established using a delay-discounting task following recovery from a 7-day dependence-inducing alcohol intoxication regimen. CBD attenuated context-induced and stress-induced drug seeking without tolerance, sedative effects, or interference with normal motivated behavior. Following treatment termination, reinstatement remained attenuated up to ≈5 months although plasma and brain CBD levels remained detectable only for 3 days. CBD also reduced experimental anxiety and prevented the development of high impulsivity in rats with an alcohol dependence history. The results provide proof of principle supporting potential of CBD in relapse prevention along two dimensions: beneficial actions across several vulnerability states and long-lasting effects with only brief treatment. The findings also inform the ongoing medical marijuana debate concerning medical benefits of non-psychoactive cannabinoids and their promise for development and use as therapeutics.


Lysergic acid diethylamide (LSD) is used recreationally and has been evaluated as an adjunct to psychotherapy to treat anxiety in patients with life-threatening illness. LSD is well-known to induce perceptual alterations, but unknown is whether LSD alters emotional processing in ways that can support psychotherapy. We investigated the acute effects of LSD on emotional processing using the Face Emotion Recognition Task (FERT) and Multifaceted Empathy Test (MET). The effects of LSD on social behavior were tested using the Social Value Orientation (SVO) test. Two similar placebo-controlled, double-blind, random-order, cross-over studies were conducted using 100 μg LSD in 24 subjects and 200 μg LSD in 16 subjects. All of the subjects were healthy and mostly hallucinogen-naive 25- to 65-year-old volunteers (20 men, 20 women). LSD produced feelings of happiness, trust, closeness to others, enhanced explicit and implicit emotional empathy on the MET, and impaired the recognition of sad and fearful faces on the FERT. LSD enhanced the participants' desire to be with other people and increased their prosocial behavior on the SVO test. These effects of LSD on emotion processing and sociality may be useful for LSD-assisted psychotherapy.Neuropsychopharmacology accepted article preview online, 01 June 2016. doi:10.1038/npp.2016.82.

Concepts: Psychology, Empathy, Emotion, Fear, Lysergic acid diethylamide, Lysergic acid, Ergot, Multidisciplinary Association for Psychedelic Studies


Although the brains of patients with schizophrenia and bipolar disorder exhibit decreased brain pH relative to those of healthy controls upon postmortem examination, it remains controversial whether this finding reflects a primary feature of the diseases or is a result of confounding factors such as medication and agonal state. To date, systematic investigation of brain pH has not been undertaken using animal models, which can be studied without confounds inherent in human studies. In the present study, we first reevaluated the pH of the postmortem brains of patients with schizophrenia and bipolar disorder by conducting a meta-analysis of existing datasets from ten studies. We then measured pH, lactate levels, and related metabolite levels in brain homogenates from five neurodevelopmental mouse models of psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorders. All mice were drug-naïve with the same agonal state, postmortem interval, and age within each strain. Our meta-analysis revealed that brain pH was significantly lower in patients with schizophrenia and bipolar disorder than in control participants, even when a few potential confounding factors (postmortem interval, age, and history of antipsychotic use) were considered. In animal experiments, we observed significantly lower pH and higher lactate levels in the brains of model mice relative to controls, as well as a significant negative correlation between pH and lactate levels. Our findings suggest that lower pH associated with increased lactate levels is not a mere artifact, but rather implicated in the underlying pathophysiology of schizophrenia and bipolar disorder.Neuropsychopharmacology accepted article preview online, 04 August 2017. doi:10.1038/npp.2017.167.

Concepts: Autism, Mental disorder, Antipsychotic, Schizophrenia, Psychosis, Bipolar disorder, Suicide, Schizoaffective disorder


The role of omega-3 polyunsaturated fatty acids (omega-3 or n-3 PUFAs) in the pathogenesis and treatment of children and adolescents with attention deficit hyperactivity disorder (ADHD) is unclear. A systematic review followed by meta-analysis was conducted on: (1) randomized controlled trials (RCTs) assessing the effects of n-3 PUFAs on clinical symptoms and cognition in children and adolescent with ADHD; and (2) case-control studies assessing the levels of n-3 PUFAs in blood and buccal tissues of children and adolescents with ADHD. In seven RCTs, totalling n=534 randomised youth with ADHD, n-3 PUFAs supplementation improves ADHD clinical symptom scores (g=0.38, p<0.0001); and in three RCTs, totalling n=214 randomised youth with ADHD, n-3 PUFAs supplementation improves cognitive measures associated with attention (g=1.09, p=0.001). Moreover, children and adolescents with ADHD have lower levels of DHA (seven studies, n=412, g=-0.76, p=0.0002), EPA (seven studies, n=468, g=-0.38, p=0.0008), and total n-3 PUFAs (six studies, n=396, g=-0.58, p=0.0001). In summary, there is evidence that n-3 PUFAs supplementation monotherapy improves clinical symptoms and cognitive performances in children and adolescents with ADHD, and that these youth have a deficiency in n-3 PUFAs levels. Our findings provide further support to the rationale for using n-3 PUFAs as a treatment option for ADHD.Neuropsychopharmacology accepted article preview online, 25 July 2017. doi:10.1038/npp.2017.160.

Concepts: Epidemiology, Attention, Randomized controlled trial, Educational psychology, Attention-deficit hyperactivity disorder, Hyperactivity


This review provides an overview of the changing U.S. epidemiology of cannabis use and associated problems. Adults and adolescents increasingly view cannabis as harmless, and some can use cannabis without harm. However, potential problems include harms from pre-natal exposure and unintentional childhood exposure; decline in educational or occupational functioning after early adolescent use, and in adulthood, impaired driving and vehicle crashes; cannabis use disorders (CUD), cannabis withdrawal, and psychiatric comorbidity. Evidence suggests national increases in cannabis potency, prenatal and unintentional childhood exposure; and in adults, increased use, CUD, cannabis-related emergency room visits and fatal vehicle crashes. Twenty-nine states have medical marijuana laws (MML) and of these, 8 have recreational marijuana laws (RML). Many studies indicate that MML or their specific provisions did not increase adolescent cannabis use. However, the more limited literature suggests that MML have led to increased cannabis potency, unintentional childhood exposures, adult cannabis use, and adult CUD. Ecological-level studies suggest that MML have led to substitution of cannabis for opioids, and also possibly for psychiatric medications. Much remains to be determined about cannabis trends and the role of MML and RML in these trends. The public, health professionals and policy makers would benefit from education about the risks of cannabis use, the increases in such risks, and the role of marijuana laws in these increases.Neuropsychopharmacology accepted article preview online, 30 August 2017. doi:10.1038/npp.2017.198.

Concepts: Cannabis, Legality of cannabis by country


Attention Deficit/ Hyperactivity Disorder (ADHD) is one of the most common child psychiatric disorders, and is often treated with stimulant medication. Non-pharmacological treatments include dietary supplementation with omega-3 fatty acids, although their effectiveness remains to be shown conclusively. In this study, we investigated the effects of dietary omega-3 fatty acid supplementation on ADHD symptoms and cognitive control in young boys with and without ADHD.Neuropsychopharmacology accepted article preview online, 19 March 2015. doi:10.1038/npp.2015.73.

Concepts: Nutrition, Fatty acid, Triglyceride, Essential fatty acid, Omega-3 fatty acid, Attention-deficit hyperactivity disorder, Hyperactivity, Omega-6 fatty acid


Given the known vascular effects of cannabis, this study examined the neurophysiological factors that may impact studies of brain activity in cannabis users. We conducted a systematic evaluation in 72-hour abstinent, chronic cannabis users (N=74) and non-using controls (N=101) to determine the association between prolonged cannabis use and the following neurophysiological indicators: (1) global and regional resting cerebral blood flow (CBF), (2) oxygen extraction fraction (OEF), and (3) cerebral metabolic rate of oxygen (CMRO2). We found that cannabis users had greater global OEF and CMRO2 compared to non-users. Regionally, we found higher CBF in in the right pallidum/putamen of the cannabis users compared to non-users. Global resting CBF and regional CBF of right superior frontal cortex correlated positively with creatinine-normalized Δ9-tetrahydrocannabinol (THC) levels. These findings demonstrate residual effects of cannabis use whereby global and regional brain metabolism are altered in those with prolonged cannabis exposure. These neurophysiological alterations should be considered in both research and clinical applications.Neuropsychopharmacology accepted article preview online, 27 February 2017. doi:10.1038/npp.2017.44.

Concepts: Protein, Metabolism, Cerebral cortex, Cerebrum, Cannabinoid receptor, Tetrahydrocannabinol, Frontal lobe, Cannabis


All modern clinical studies using the classic hallucinogen lysergic acid diethylamide (LSD) in healthy subjects or patients in the last 25 years are reviewed herein. There were five recent studies in healthy participants and one in patients. In a controlled setting, LSD acutely induced bliss, audiovisual synesthesia, altered meaning of perceptions, derealization, depersonalization, and mystical experiences. These subjective effects of LSD were mediated by the 5-HT2A receptor. LSD increased feelings of closeness to others, openness, trust, and suggestibility. LSD impaired the recognition of sad and fearful faces, reduced left amygdala reactivity to fearful faces, and enhanced emotional empathy. LSD increased the emotional response to music and the meaning of music. LSD acutely produced deficits in sensorimotor gating, similar to observations in schizophrenia. LSD had weak autonomic stimulant effects and elevated plasma cortisol, prolactin, and oxytocin levels. Resting state functional magnetic resonance studies showed that LSD acutely reduced the integrity of functional brain networks and increased connectivity between networks that normally are more dissociated. LSD increased functional thalamocortical connectivity and functional connectivity of the primary visual cortex with other brain areas. The latter effect was correlated with subjective hallucinations. LSD acutely induced global increases in brain entropy that were associated with greater trait openness 14 day later. In patients with anxiety associated with life-threatening disease, anxiety was reduced for 2 months after two doses of LSD. In medical settings, no complications of LSD administration were observed. These data should contribute to further investigations of the therapeutic potential of LSD in psychiatry.Neuropsychopharmacology accepted article preview online, 27 April 2017. doi:10.1038/npp.2017.86.

Concepts: Medicine, Clinical trial, Brain, Visual perception, Meaning of life, Lysergic acid diethylamide, Lysergic acid, Ergot