Lorenzo Leggio, M.D., Ph.D.

@article{pmid35064236,

title = {Involvement of the ghrelin system in the maintenance of oxycodone self-administration: converging evidence from endocrine, pharmacologic and transgenic approaches},

author = {Zhi-Bing You and Eliot L Gardner and Ewa Galaj and Allamar R Moore and Tristram Buck and Chloe J Jordan and Bree A Humburg and Guo-Hua Bi and Zheng-Xiong Xi and Lorenzo Leggio},

url = {https://pubmed.ncbi.nlm.nih.gov/35064236/},

doi = {10.1038/s41380-022-01438-5},

issn = {1476-5578},

year  = {2022},

date = {2022-01-01},

urldate = {2022-01-01},

journal = {Mol Psychiatry},

abstract = {Ghrelin, an orexigenic hormone, has emerged as a critical biological substrate implicated in drug reward. However, the response of the ghrelin system to opioid-motivated behaviors and the role of ghrelin in oxycodone self-administration remain to be studied. Here, we investigated the reciprocal interactions between the endogenous ghrelin system and oxycodone self-administration behaviors in rats and the role of the ghrelin system in brain stimulation reward (BSR) driven by optogenetic stimulation of midbrain reward circuits in mice. Oxycodone self-administration significantly elevated plasma ghrelin, des-acyl ghrelin and growth hormone and showed no effect on plasma LEAP2, a newly identified endogenous ghrelin receptor (GHS-R1a) antagonist. Oxycodone self-administration produced significant decreases in plasma gastric inhibitory polypeptide and insulin. Acquisition of oxycodone self-administration significantly upregulated GHS-R1a mRNA levels in dopamine neurons in the ventral tegmental area (VTA), a brain region critical in drug reward. Pretreatment with JMV2959, a selective GHS-R1a antagonist, dose-dependently reduced oxycodone self-administration and decreased the breakpoint for oxycodone under a progressive ratio reinforcement in Long-Evans rats. The inhibitory effects of JMV2959 on oxycodone self-administration is selectively mediated by GHS-R1a as JMV2959 showed a similar effect in Wistar wildtype but not in GHS-R knockout rats. JMV2959 pretreatment significantly inhibited BSR driven by selective stimulation of VTA dopamine neurons, but not by stimulation of striatal GABA neurons projecting to the VTA in mice. These findings suggest that elevation of ghrelin signaling by oxycodone or oxycodone-associated stimuli is a causal process by which oxycodone motivates oxycodone drug-taking and targeting the ghrelin system may be a viable treatment approach for opioid use disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34853299,

title = {Gut microbiome and metabolome in a non-human primate model of chronic excessive alcohol drinking},

author = {Daria Piacentino and Silvia Grant-Beurmann and Carlotta Vizioli and Xiaobai Li and Catherine F Moore and Victor Ruiz-Rodado and Mary R Lee and Paule V Joseph and Claire M Fraser and Elise M Weerts and Lorenzo Leggio},

url = {https://pubmed.ncbi.nlm.nih.gov/34853299/},

doi = {10.1038/s41398-021-01728-6},

issn = {2158-3188},

year  = {2021},

date = {2021-01-01},

urldate = {2021-01-01},

journal = {Transl Psychiatry},

volume = {11},

number = {1},

pages = {609},

abstract = {A relationship between the gut microbiome and alcohol use disorder has been suggested. Excessive alcohol use produces changes in the fecal microbiome and metabolome in both rodents and humans. Yet, these changes can be observed only in a subgroup of the studied populations, and reversal does not always occur after abstinence. We aimed to analyze fecal microbial composition and function in a translationally relevant baboon model of chronic heavy drinking that also meets binge criteria (drinking too much, too fast, and too often), i.e., alcohol ~1 g/kg and blood alcohol levels (BALs) ≥ 0.08 g/dL in a 2-hour period, daily, for years. We compared three groups of male baboons (Papio anubis): L = Long-term alcohol drinking group (12.1 years); S = Short-term alcohol drinking group (2.7 years); and C = Control group, drinking a non-alcoholic reinforcer (Tang®) (8.2 years). Fecal collection took place during 3 days of Drinking (D), followed by a short period (3 days) of Abstinence (A). Fecal microbial alpha- and beta-diversity were significantly lower in L vs. S and C (p's < 0.05). Members of the commensal families Lachnospiraceae and Prevotellaceae showed a relative decrease, whereas the opportunistic pathogen Streptococcus genus showed a relative increase in L vs. S and C (p's < 0.05). Microbiota-related metabolites of aromatic amino acids, tricarboxylic acid cycle, and pentose increased in L vs. S and C (FDR-corrected p < 0.01), with the latter two suggesting high energy metabolism and enhanced glycolysis in the gut lumen in response to alcohol. Consistent with the long-term alcohol exposure, mucosal damage and oxidative stress markers (N-acetylated amino acids, 2-hydroxybutyrate, and metabolites of the methionine cycle) increased in L vs. S and C (FDR-corrected p < 0.01). Overall, S showed few differences vs. C, possibly due to the long-term, chronic alcohol exposure needed to alter the normal gut microbiota. In the three groups, the fecal microbiome barely differed between conditions D and A, whereas the metabolome shifted in the transition from condition D to A. In conclusion, changes in the fecal microbiome and metabolome occur after significant long-term excessive drinking and are only partially affected by acute forced abstinence from alcohol. These results provide novel information on the relationship between the fecal microbiome and metabolome in a controlled experimental setting and using a unique non-human primate model of chronic excessive alcohol drinking.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33646717,

title = {Cardiovascular Consequences of Excessive Alcohol Drinking via Electrocardiogram: A Systematic Review},

author = {Lisa A Farinelli and Daria Piacentino and Brittney D Browning and Barbara B Brewer and Lorenzo Leggio},

url = {https://pubmed.ncbi.nlm.nih.gov/33646717/},

doi = {10.1097/JAN.0000000000000384},

issn = {1548-7148},

year  = {2021},

date = {2021-01-01},

journal = {J Addict Nurs},

volume = {32},

number = {1},

pages = {39--45},

abstract = {ABSTRACT: There is a link between excessive alcohol drinking and an increased risk to develop cardiovascular disease, including alcoholic cardiomyopathy. This association warrants further research on the potential utility for the electrocardiogram (ECG) in the participatory management of the chronic consequences of alcohol use disorder (AUD). Our goal is to enhance understanding about the pernicious role alcohol plays on cardiac health using the ECG, an accessible, cost-effective, validated tool to inform novel targeted treatments for AUD. In this systematic review of human studies, we examine the relationship between abnormal clinically significant changes to ECG variables and excessive alcohol drinking with the goal of identifying key patterns specific to quantity of alcohol consumed. Three independent reviewers and one consensus reviewer, adhering to the PRISMA guidelines, conducted an initial review on studies published from database inception to April 19, 2019, using PubMed, Embase, CINAHL and COCHRANE databases. The initial search generated 2,225 articles. The final selected number included 153 original articles. This systematic review provides evidence of patterns of clinically significant changes to ECG variables as a consequence of excessive alcohol consumption. Future directions include investigating whether a real-time assessment, such as the ECG, in conjunction with other key behavioral and cardiac measures, can help clinicians and patients realize the progressive and insidious cardiac damage because of excessive alcohol consumption. This theory-guided nurse science review supports the development of personalized symptom monitoring to deliver tailored feedback that illuminate risk factors as a potentially transformative approach in the management of AUD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Lee:2018aa,

title = {The novel ghrelin receptor inverse agonist PF-5190457 administered with alcohol: preclinical safety experiments and a phase 1b human laboratory study.},

author = {Mary R Lee and Jenica D Tapocik and Mwlod Ghareeb and Melanie L Schwandt and Alexandra A Dias and April N Le and Enoch Cobbina and Lisa A Farinelli and Sofia Bouhlal and Mehdi Farokhnia and Markus Heilig and Fatemeh Akhlaghi and Lorenzo Leggio},

url = {https://www.ncbi.nlm.nih.gov/pubmed/29728704},

doi = {10.1038/s41380-018-0064-y},

issn = {1476-5578 (Electronic); 1359-4184 (Linking)},

year  = {2020},

date = {2020-05-04},

urldate = {2020-05-04},

journal = {Mol Psychiatry},

address = {Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA.},

abstract = {Rodent studies indicate that ghrelin receptor blockade reduces alcohol consumption. However, no ghrelin receptor blockers have been administered to heavy alcohol drinking individuals. Therefore, we evaluated the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD) and behavioral effects of a novel ghrelin receptor inverse agonist, PF-5190457, when co-administered with alcohol. We tested the effects of PF-5190457 combined with alcohol on locomotor activity, loss-of-righting reflex (a measure of alcohol sedative actions), and on blood PF-5190457 concentrations in rats. Then, we performed a single-blind, placebo-controlled, within-subject human study with PF-5190457 (placebo/0 mg b.i.d., 50 mg b.i.d., 100 mg b.i.d.). Twelve heavy drinkers during three identical visits completed an alcohol administration session, subjective assessments, and an alcohol cue-reactivity procedure, and gave blood samples for PK/PD testing. In rats, PF-5190457 did not interact with the effects of alcohol on locomotor activity or loss-of-righting reflex. Alcohol did not affect blood PF-5190457 concentrations. In humans, all adverse events were mild or moderate and did not require discontinuation or dose reductions. Drug dose did not alter alcohol concentration or elimination, alcohol-induced stimulation or sedation, or mood during alcohol administration. Potential PD markers of PF-5190457 were acyl-to-total ghrelin ratio and insulin-like growth factor-1. PF-5190457 (100 mg b.i.d.) reduced alcohol craving during the cue-reactivity procedure. This study provides the first translational evidence of safety and tolerability of the ghrelin receptor inverse agonist PF-5190457 when co-administered with alcohol. PK/PD/behavioral findings support continued research of PF-5190457 as a potential pharmacological agent to treat alcohol use disorder.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32494001,

title = {Labeled oxytocin administered via the intranasal route reaches the brain in rhesus macaques},

author = {M R Lee and T A Shnitko and S W Blue and A V Kaucher and A J Winchell and D W Erikson and K A Grant and L Leggio},

url = {https://pubmed.ncbi.nlm.nih.gov/32494001/},

doi = {10.1038/s41467-020-15942-1},

issn = {2041-1723},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Nat Commun},

volume = {11},

number = {1},

pages = {2783},

abstract = {Oxytocin may have promise as a treatment for neuropsychiatric disorders. Its therapeutic effect may depend on its ability to enter the brain and bind to the oxytocin receptor. To date, the brain tissue penetrance of intranasal oxytocin has not been demonstrated. In this nonhuman primate study, we administer deuterated oxytocin intranasally and intravenously to rhesus macaques and measure, with mass spectrometry, concentrations of labeled (exogenously administered) and endogenous oxytocin in 12 brain regions two hours after oxytocin administration. Labeled oxytocin is quantified after intranasal (not intravenous) administration in brain regions (orbitofrontal cortex, striatum, brainstem, and thalamus) that lie in the trajectories of the olfactory and trigeminal nerves. These results suggest that intranasal administration bypasses the blood-brain barrier, delivering oxytocin to specific brain regions, such as the striatum, where oxytocin acts to impact motivated behaviors. Further, high concentrations of endogenous oxytocin are in regions that overlap with projection fields of oxytocinergic neurons.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Farokhnia:2020aa,

title = {Effects of oral, smoked, and vaporized cannabis on endocrine pathways related to appetite and metabolism: a randomized, double-blind, placebo-controlled, human laboratory study},

author = {Mehdi Farokhnia and Gray R McDiarmid and Matthew N Newmeyer and Vikas Munjal and Osama A Abulseoud and Marilyn A Huestis and Lorenzo Leggio},

url = {https://pubmed.ncbi.nlm.nih.gov/32075958/},

doi = {10.1038/s41398-020-0756-3},

isbn = {2158-3188},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Translational Psychiatry},

volume = {10},

number = {1},

pages = {71},

abstract = {As perspectives on cannabis continue to shift, understanding the physiological and behavioral effects of cannabis use is of paramount importance. Previous data suggest that cannabis use influences food intake, appetite, and metabolism, yet human research in this regard remains scant. The present study investigated the effects of cannabis administration, via different routes, on peripheral concentrations of appetitive and metabolic hormones in a sample of cannabis users. This was a randomized, crossover, double-blind, placebo-controlled study. Twenty participants underwent four experimental sessions during which oral cannabis, smoked cannabis, vaporized cannabis, or placebo was administered. Active compounds contained 6.9 $pm$0.95% (~50.6 mg) ∆9-tetrahydrocannabinol (THC). Repeated blood samples were obtained, and the following endocrine markers were measured: total ghrelin, acyl-ghrelin, leptin, glucagon-like peptide-1 (GLP-1), and insulin. Results showed a significant drug main effect (p = 0.001), as well as a significant drug ×time-point interaction effect (p = 0.01) on insulin. The spike in blood insulin concentrations observed under the placebo condition (probably due to the intake of brownie) was blunted by cannabis administration. A significant drug main effect (p = 0.001), as well as a trend-level drug ×time-point interaction effect (p = 0.08) was also detected for GLP-1, suggesting that GLP-1 concentrations were lower under cannabis, compared to the placebo condition. Finally, a significant drug main effect (p = 0.01) was found for total ghrelin, suggesting that total ghrelin concentrations during the oral cannabis session were higher than the smoked and vaporized cannabis sessions. In conclusion, cannabis administration in this study modulated blood concentrations of some appetitive and metabolic hormones, chiefly insulin, in cannabis users. Understanding the mechanisms underpinning these effects may provide additional information on the cross-talk between cannabinoids and physiological pathways related to appetite and metabolism.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Agabio:2018aa,

title = {Baclofen for the treatment of alcohol use disorder: the Cagliari Statement.},

author = {Roberta Agabio and Julia Ma Sinclair and Giovanni Addolorato and Henri-Jean Aubin and Esther M Beraha and Fabio Caputo and Jonathan D Chick and Patrick de La Selle and Nicolas Franchitto and James C Garbutt and Paul S Haber and Mathis Heydtmann and Philippe Jaury and Anne R Lingford-Hughes and Kirsten C Morley and Christian A Muller and Lynn Owens and Adam Pastor and Louise M Paterson and Fanny Pelissier and Benjamin Rolland and Amanda Stafford and Andrew Thompson and Wim van den Brink and Renaud de Beaurepaire and Lorenzo Leggio},

url = {https://www.ncbi.nlm.nih.gov/pubmed/30413394},

doi = {10.1016/S2215-0366(18)30303-1},

issn = {2215-0374 (Electronic); 2215-0366 (Linking)},

year  = {2018},

date = {2018-12-05},

urldate = {2018-12-05},

journal = {Lancet Psychiatry},

volume = {5},

number = {12},

pages = {957--960},

address = {Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cittadella Universitaria, I-09042 Monserrato, Italy. Electronic address: agabio@unica.it.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Farokhnia:2017aab,

title = {Exogenous ghrelin administration increases alcohol self-administration and modulates brain functional activity in heavy-drinking alcohol-dependent individuals.},

author = {M Farokhnia and E N Grodin and M R Lee and E N Oot and A N Blackburn and B L Stangl and M L Schwandt and L A Farinelli and R Momenan and V A Ramchandani and L Leggio},

url = {https://www.ncbi.nlm.nih.gov/pubmed/29133954},

doi = {10.1038/mp.2017.226},

issn = {1476-5578 (Electronic); 1359-4184 (Linking)},

year  = {2017},

date = {2017-11-14},

urldate = {2017-11-14},

journal = {Mol Psychiatry},

address = {Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA.},

abstract = {Preclinical evidence suggests that ghrelin, a peptide synthesized by endocrine cells of the stomach and a key component of the gut-brain axis, is involved in alcohol seeking as it modulates both central reward and stress pathways. However, whether and how ghrelin administration may impact alcohol intake in humans is not clear. For, we believe, the first time, this was investigated in the present randomized, crossover, double-blind, placebo-controlled, human laboratory study. Participants were non-treatment-seeking alcohol-dependent heavy-drinking individuals. A 10-min loading dose of intravenous ghrelin/placebo (3 mcg kg(-1)) followed by a continuous ghrelin/placebo infusion (16.9 ng/kg/min) was administered. During a progressive-ratio alcohol self-administration experiment, participants could press a button to receive intravenous alcohol using the Computerized Alcohol Infusion System. In another experiment, brain functional magnetic resonance imaging was conducted while participants performed a task to gain points for alcohol, food or no reward. Results showed that intravenous ghrelin, compared to placebo, significantly increased the number of alcohol infusions self-administered (percent change: 24.97+/-10.65},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Leggio2014,

title = {Intravenous ghrelin administration increases alcohol craving in alcohol-dependent heavy drinkers: a preliminary investigation.},

author = {Leggio, Lorenzo and Zywiak, William H and Fricchione, Samuel R and Edwards, Steven M and de la Monte, Suzanne M and Swift, Robert M and Kenna, George A},

url = {https://www.ncbi.nlm.nih.gov/pubmed/24775991},

doi = {10.1016/j.biopsych.2014.03.019},

issn = {1873-2402 (Electronic); 0006-3223 (Linking)},

year  = {2014},

date = {2014-11-01},

urldate = {2014-11-01},

journal = {Biol Psychiatry},

volume = {76},

number = {9},

pages = {734--741},

abstract = {BACKGROUND: There is a need to identify novel pharmacologic targets to treat alcoholism. Animal and human studies suggest a role for ghrelin in the neurobiology of alcohol dependence and craving. Here, we were the first to test the hypothesis that intravenous administration of exogenous ghrelin acutely increases alcohol craving. METHODS: This was a double-blind, placebo-controlled human laboratory proof-of-concept study. Nontreatment-seeking, alcohol-dependent, heavy-drinking individuals were randomized to receive intravenous ghrelin 1 mcg/kg, 3 mcg/kg or 0 mcg/kg (placebo), followed by a cue-reactivity procedure, during which participants were exposed to neutral (juice) and alcohol cues. The primary outcome variable was the increase in alcohol craving (also called urge) for alcohol, assessed by the Alcohol Visual Analogue Scale. RESULTS: Out of 103 screenings, 45 individuals received the study drug. Repeated measures of analysis of covariance revealed a group effect across ghrelin doses in increasing alcohol craving (p < .05). A dose-specific examination revealed a significant effect of ghrelin 3 mcg/kg versus placebo in increasing alcohol craving (p < .05) with a large effect size (d = .94). By contrast, no significant ghrelin effect was found in increasing either urge to drink juice or food craving (p = ns). No significant differences in side effects were found (p = ns). CONCLUSIONS: Intravenous administration of exogenous ghrelin increased alcohol craving in alcohol-dependent heavy-drinking individuals. Although the small sample requires confirmatory studies, these findings provide preliminary evidence that ghrelin may play a role in the neurobiology of alcohol craving, thus demonstrating a novel pharmacologic target for treatment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Addolorato2007,

title = {Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study.},

author = {Giovanni Addolorato and Lorenzo Leggio and Anna Ferrulli and Silvia Cardone and Luisa Vonghia and Antonio Mirijello and Ludovico Abenavoli and Cristina D'Angelo and Fabio Caputo and Antonella Zambon and Paul S Haber and Giovanni Gasbarrini},

url = {https://www.ncbi.nlm.nih.gov/pubmed/18068515},

doi = {10.1016/S0140-6736(07)61814-5},

issn = {1474-547X (Electronic); 0140-6736 (Linking)},

year  = {2007},

date = {2007-12-08},

urldate = {2007-12-08},

journal = {Lancet},

volume = {370},

number = {9603},

pages = {1915--1922},

address = {Institute of Internal Medicine, Catholic University of Rome, Rome, Italy. g.addolorato@rm.unicatt.it},

abstract = {BACKGROUND: Intervention to achieve alcohol abstinence represents the most effective treatment for alcohol-dependent patients with liver cirrhosis; however, anticraving drugs might worsen liver disease. We aimed to investigate the effectiveness and safety of baclofen in achieving and maintaining alcohol abstinence in patients with liver cirrhosis. METHODS: Between October, 2003, and November, 2006, 148 alcohol-dependent patients with liver cirrhosis were referred to the Institute of Internal Medicine, Rome, Italy. 84 were randomly allocated either oral baclofen or placebo for 12 weeks. Primary outcome was proportion of patients achieving and maintaining alcohol abstinence. Measures of this outcome were total alcohol abstinence and cumulative abstinence duration, which were assessed at outpatient visits. Relapse was defined as alcohol intake of more than four drinks per day or overall consumption of 14 or more drinks per week over a period of at least 4 weeks. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00525252. FINDINGS: Of 42 patients allocated baclofen, 30 (71%) achieved and maintained abstinence compared with 12 (29%) of 42 assigned placebo (odds ratio 6.3 [95% CI 2.4-16.1]; p=0.0001). The number of dropouts (termination of treatment) did not differ between the baclofen (6/42 [14%]) and placebo (13/42 [31%]) groups (p=0.12). Cumulative abstinence duration was about twofold higher in patients allocated baclofen than in those assigned placebo (mean 62.8 [SE 5.4] vs 30.8 [5.5] days; p=0.001). No hepatic side-effects were recorded. INTERPRETATION: Baclofen is effective at promoting alcohol abstinence in alcohol-dependent patients with liver cirrhosis. The drug is well tolerated and could have an important role in treatment of these individuals.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}