Mehdi Farokhnia, M.D., M.P.H.

@article{pmid34214881,

title = {A population-based investigation of the association between alcohol intake and serum total ghrelin concentrations among cigarette-smoking, non-alcohol-dependent male individuals},

author = {Mehdi Farokhnia and Gwen Murphy and Stephanie J Weinstein and Navan N Shah and Dominick Parisi and Demetrius Albanes and Lorenzo Leggio},

url = {https://pubmed.ncbi.nlm.nih.gov/34214881/},

doi = {10.1016/j.drugalcdep.2021.108835},

issn = {1879-0046},

year  = {2021},

date = {2021-11-02},

urldate = {2021-09-01},

journal = {Drug Alcohol Depend},

volume = {226},

pages = {108835},

abstract = {BACKGROUND: Ghrelin plays significant roles in regulating appetite, food intake, and metabolism. Furthermore, the ghrelin system is increasingly being studied in relation to alcohol seeking behaviors. To this end, it is important to understand the possible effects of alcohol intake on the ghrelin system. The aim of the present study was to investigate the association between alcohol drinking and circulating ghrelin levels in a large sample of cigarette-smoking, non-alcohol-dependent male individuals.



METHODS: We utilized data from two nested case-control studies (study A, n = 807; study B, n = 976) based within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) trial. Data on alcohol consumption (grams of pure alcohol consumed per day) were obtained via a food frequency questionnaire. Blood samples were also collected (after 12 h of fasting), and serum concentrations of total ghrelin were measured by radioimmunoassay.



RESULTS: Dichotomous comparison between alcohol drinkers (>0 g/day of alcohol intake) and non-drinkers (0 g/day of alcohol intake) found higher total ghrelin levels among individuals who drank alcohol than those who did not, with statistically significant results in study A [F (1, 798) = 4.32, P = 0.03] and less robust results in study B [F (1, 966) = 2.62, P = 0.10], controlling for a list of factors that may influence ghrelin levels and/or differ between drinkers and non-drinkers. Bivariate correlational analysis among drinkers found no association between the quantity of daily alcohol intake and blood total ghrelin concentrations.



CONCLUSION: These results indicate elevated ghrelin levels among alcohol drinkers and provide additional/relevant information on the complex interaction between alcohol use and the ghrelin system.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34341493,

title = {Effectiveness of spironolactone dispensation in reducing weekly alcohol use: a retrospective high-dimensional propensity score-matched cohort study},

author = {Vanessa A Palzes and Mehdi Farokhnia and Andrea H Kline-Simon and Joseph Elson and Stacy Sterling and Lorenzo Leggio and Constance Weisner and Felicia W Chi},

url = {https://pubmed.ncbi.nlm.nih.gov/34341493/},

doi = {10.1038/s41386-021-01117-z},

issn = {1740-634X},

year  = {2021},

date = {2021-11-01},

urldate = {2021-01-01},

journal = {Neuropsychopharmacology},

volume = {46},

number = {12},

pages = {2140--2147},

abstract = {There is a need to increase the armamentarium of pharmacotherapies for alcohol use disorder (AUD). Recent research suggests that mineralocorticoid receptor (MR) antagonism via spironolactone may represent a novel pharmacological treatment for AUD. We conducted a pharmacoepidemiologic retrospective cohort study (June 1, 2014 to May 31, 2018) to examine whether spironolactone dispensation (≥90 continuous days), for any indication, is associated with changes in weekly alcohol use about 6 months later. We compared 523 spironolactone-treated adults and 2305 untreated adults, matched on high-dimensional propensity scores created from a set of predefined (sociodemographic and health characteristics, diagnoses, and service utilization) and empirical electronic health record-derived covariates. The sample was 57% female and 27% non-White with a mean age of 59.2 years (SD = 19.3). Treated patients reduced their weekly alcohol use by 3.50 drinks (95% CI = -4.22, -2.79), while untreated patients reduced by 2.74 drinks (95% CI = -3.22, -2.26), yielding a significant difference of 0.76 fewer drinks (95% CI = -1.43, -0.11). Among those who drank >7 drinks/week at baseline, treated patients, compared to untreated patients, reported a greater reduction in weekly alcohol use by 4.18 drinks (95% CI = -5.38, -2.97), while there was no significant difference among those who drank less. There was a significant dose-response relationship between spironolactone dosage and change in drinks/week. Pending additional evidence on its safety and efficacy in individuals with AUD, spironolactone (and MR blockade, at large) may hold promise as a pharmacotherapy for AUD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33560411,

title = {Neuroendocrine Response to Exogenous Ghrelin Administration, Combined With Alcohol, in Heavy-Drinking Individuals: Findings From a Randomized, Double-Blind, Placebo-Controlled Human Laboratory Study},

author = {Mehdi Farokhnia and Kelly M Abshire and Aaron Hammer and Sara L Deschaine and Anitha Saravanakumar and Enoch Cobbina and Zhi-Bing You and Carolina L Haass-Koffler and Mary R Lee and Fatemeh Akhlaghi and Lorenzo Leggio},

url = {https://pubmed.ncbi.nlm.nih.gov/33560411/},

doi = {10.1093/ijnp/pyab004},

issn = {1469-5111},

year  = {2021},

date = {2021-07-22},

urldate = {2021-07-14},

journal = {Int J Neuropsychopharmacol},

volume = {24},

number = {6},

pages = {464--476},

abstract = {BACKGROUND: Accumulating evidence has established a role for the orexigenic hormone ghrelin in alcohol-seeking behaviors. Accordingly, the ghrelin system may represent a potential pharmacotherapeutic target for alcohol use disorder. Ghrelin modulates several neuroendocrine pathways, such as appetitive, metabolic, and stress-related hormones, which are particularly relevant in the context of alcohol use. The goal of the present study was to provide a comprehensive assessment of neuroendocrine response to exogenous ghrelin administration, combined with alcohol, in heavy-drinking individuals.



METHODS: This was a randomized, crossover, double-blind, placebo-controlled human laboratory study, which included 2 experimental alcohol administration paradigms: i.v. alcohol self-administration and i.v. alcohol clamp. Each paradigm consisted of 2 counterbalanced sessions of i.v. ghrelin or placebo administration. Repeated blood samples were collected during each session, and peripheral concentrations of the following hormones were measured: leptin, glucagon-like peptide-1, pancreatic polypeptide, gastric inhibitory peptide, insulin, insulin-like growth factor-1, cortisol, prolactin, and aldosterone.



RESULTS: Despite some statistical differences, findings were consistent across the 2 alcohol administration paradigms: i.v. ghrelin, compared to placebo, increased blood concentrations of glucagon-like peptide-1, pancreatic polypeptide, cortisol, and prolactin, both acutely and during the whole session. Lower levels of leptin and higher levels of aldosterone were also found during the ghrelin vs placebo session.



CONCLUSION: These findings, gathered from a clinically relevant sample of heavy-drinking individuals with alcohol use disorder, provide a deeper insight into the complex interplay between ghrelin and appetitive, metabolic, and stress-related neuroendocrine pathways in the context of alcohol use.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33908131b,

title = {A closer look at alcohol-induced changes in the ghrelin system: novel insights from preclinical and clinical data},

author = {Sara L Deschaine and Mehdi Farokhnia and Adriana Gregory-Flores and Lia J Zallar and Zhi-Bing You and Hui Sun and Deon M Harvey and Renata C N Marchette and Brendan J Tunstall and Bharath K Mani and Jacob E Moose and Mary R Lee and Eliot Gardner and Fatemeh Akhlaghi and Marisa Roberto and James L Hougland and Jeffrey M Zigman and George F Koob and Leandro F Vendruscolo and Lorenzo Leggio},

url = {https://pubmed.ncbi.nlm.nih.gov/33908131/},

doi = {10.1111/adb.13033},

issn = {1369-1600},

year  = {2021},

date = {2021-07-20},

urldate = {2021-04-27},

journal = {Addict Biol},

volume = {27},

number = {1},

pages = {e13033},

abstract = {Ghrelin is a gastric-derived peptide hormone with demonstrated impact on alcohol intake and craving, but the reverse side of this bidirectional link, that is, the effects of alcohol on the ghrelin system, remains to be fully established. To further characterize this relationship, we examined (1) ghrelin levels via secondary analysis of human laboratory alcohol administration experiments with heavy-drinking participants; (2) expression of ghrelin, ghrelin receptor, and ghrelin-O-acyltransferase (GOAT) genes (GHRL, GHSR, and MBOAT4, respectively) in post-mortem brain tissue from individuals with alcohol use disorder (AUD) versus controls; (3) ghrelin levels in Ghsr knockout and wild-type rats following intraperitoneal (i.p.) alcohol administration; (4) effect of alcohol on ghrelin secretion from gastric mucosa cells ex vivo and GOAT enzymatic activity in vitro; and (5) ghrelin levels in rats following i.p. alcohol administration versus a calorically equivalent non-alcoholic sucrose solution. Acyl- and total-ghrelin levels decreased following acute alcohol administration in humans, but AUD was not associated with changes in central expression of ghrelin system genes in post-mortem tissue. In rats, alcohol decreased acyl-ghrelin, but not des-acyl-ghrelin, in both Ghsr knockout and wild-type rats. No dose-dependent effects of alcohol were observed on acyl-ghrelin secretion from gastric mucosa cells or on GOAT acylation activity. Lastly, alcohol and sucrose produced distinct effects on ghrelin in rats despite equivalent caloric value. Our findings suggest that alcohol acutely decreases peripheral ghrelin concentrations in vivo, but not in proportion to alcohol's caloric value or through direct interaction with ghrelin-secreting gastric mucosal cells, the ghrelin receptor, or the GOAT enzyme.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34086845,

title = {Racial Differences in the Association Between Alcohol Drinking and Cigarette Smoking: Preliminary Findings From an Alcohol Research Program},

author = {Julia C Harris and Ethan H Mereish and Monica L Faulkner and Shervin Assari and Kelvin Choi and Lorenzo Leggio and Mehdi Farokhnia},

url = {https://pubmed.ncbi.nlm.nih.gov/34086845/},

doi = {10.1093/alcalc/agab038},

issn = {1464-3502},

year  = {2021},

date = {2021-07-18},

urldate = {2021-06-04},

journal = {Alcohol Alcohol},

abstract = {AIMS: Important differences have been shown in alcohol drinking and cigarette smoking prevalence, patterns and consequences among individuals from different racial backgrounds. Alcohol and nicotine are often co-used, and the association between drinking and smoking may differ between racial groups-a question explored in the present study.



METHODS: Data from the NIAAA natural history and screening protocols were utilized; non-Hispanic Black and non-Hispanic White individuals were included in the analyses [N = 1692; 65.2% male; 58.3% met criteria for current alcohol use disorder (AUD); 37.8% were current cigarette smokers]. Bivariate associations between assessments related to alcohol drinking and cigarette smoking were examined, and the strength and direction of these associations were compared between the two groups.



RESULTS: The sample included 796 Black and 896 White individuals. Black participants had higher frequency (P < 0.0001) and severity (P = 0.007) of AUD, as well as higher frequency (P < 0.0001) of cigarette smoking. Bivariate analyses showed that the expected positive associations between alcohol drinking and cigarette smoking, observed among White individuals, were blunted or absent among Black individuals [age at first cigarette-AUD identification test (AUDIT) score: F(1, 292) = 7.60, P = 0.006; cigarette pack years-AUDIT score: F(1, 1111) = 10.97, P = 0.001].



CONCLUSIONS: Some decoupling in the association between alcohol drinking and cigarette smoking was found among Black compared to White individuals. The sample was drawn from a specific population enrolled in alcohol research protocols, which is a limitation of the present study. These preliminary findings highlight the importance of considering racial/ethnic background in preventive and therapeutic strategies for comorbid alcohol and nicotine use.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34304121,

title = {Patterns of reduced use and abstinence in multi-site randomized controlled trials of pharmacotherapies for cocaine and methamphetamine use disorders},

author = {Masoumeh Amin-Esmaeili and Ryoko Susukida and Renee M Johnson and Mehdi Farokhnia and Rosa M Crum and Johannes Thrul and Ramin Mojtabai},

url = {https://pubmed.ncbi.nlm.nih.gov/34304121/},

doi = {10.1016/j.drugalcdep.2021.108904},

issn = {1879-0046},

year  = {2021},

date = {2021-07-15},

urldate = {2021-07-21},

journal = {Drug Alcohol Depend},

volume = {226},

pages = {108904},

abstract = {BACKGROUND: Many individuals with cocaine or methamphetamine use disorders who enter treatment do not achieve abstinence but reduce their use of the target drug. We aimed to compare change in pattern of drug use (i.e., achieving "abstinence", "reduced use" or no reduction in use) among participants in randomized controlled trials (RCTs) of treatment of cocaine and methamphetamine use disorder, irrespective of the type of treatment.



METHODS: The data were drawn from 10 multi-site pharmacotherapy RCTs of cocaine (n = 1,134) and methamphetamine (n = 555) use disorders. The outcome patterns and their sociodemographic and clinical correlates were compared in cocaine and methamphetamine RCTs, using multinomial logistic regression models. Analyses were adjusted for missing data, clustering within RCTs, socio-demographic and baseline clinical characteristics, and treatment arms.



RESULTS: Those in cocaine RCTs were more likely to experience reduced use compared to participants in methamphetamine RCTs (20.6% vs. 13.2%, respectively), but less likely to experience "abstinence" (7.6% vs. 20.3%; Chi-squared = 14.20, df = 2, P < 0.001). Differences in "abstinence" persisted after adjustment for baseline covariates. Association of sociodemographic and clinical correlates with outcomes differed in cocaine and methamphetamine RCTs.



CONCLUSION: A sizeable proportion of individuals in RCTs of pharmacological treatment for stimulant use disorder who do not attain "abstinence" nevertheless reduce their use. The outcome patterns of drug use are different for cocaine and methamphetamine use disorders and reliance on abstinence as the sole outcome may obscure these differences.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32339499,

title = {Effects of exogenous ghrelin administration and ghrelin receptor blockade, in combination with alcohol, on peripheral inflammatory markers in heavy-drinking individuals: Results from two human laboratory studies},

author = {Mehdi Farokhnia and Jeanelle Portelli and Mary R Lee and Gray R McDiarmid and Vikas Munjal and Kelly M Abshire and Jillian T Battista and Brittney D Browning and Sara L Deschaine and Fatemeh Akhlaghi and Lorenzo Leggio},

url = { https://pubmed.ncbi.nlm.nih.gov/32339499/},

doi = {10.1016/j.brainres.2020.146851},

issn = {1872-6240},

year  = {2020},

date = {2020-08-01},

urldate = {2020-01-01},

journal = {Brain Res},

volume = {1740},

pages = {146851},

abstract = {The ghrelin system has been garnering interest for its role in different neuropsychiatric disorders, including alcohol use disorder (AUD). Accordingly, targeting the ghrelin system is under investigation as a potential novel therapeutic approach. While alcohol provokes the immune system and inflammatory responses, ghrelin has potent immunomodulatory and anti-inflammatory properties. The present study aimed to shed light on the "crosstalk" between ghrelin and inflammation by examining the effects of exogenous ghrelin administration and ghrelin receptor blockade on peripheral inflammatory markers in the context of two human laboratory studies with alcohol administration. Non-treatment-seeking, heavy-drinking individuals with alcohol dependence, the majority of whom were African American males, were enrolled. In the first randomized, crossover, double-blind, placebo-controlled human laboratory study, participants underwent two experimental paradigms - an intravenous alcohol self-administration (IV-ASA) and an intravenous alcohol clamp (IV-AC) - each consisting of two counterbalanced sessions (ghrelin, placebo). A loading dose of intravenous ghrelin (3 mcg/kg) or placebo, followed by a continuous ghrelin (16.9 ng/kg/min) or placebo infusion was administered. In the second dose-escalating, single-blind, placebo-controlled human laboratory phase 1b study, participants were dosed with an oral ghrelin receptor blocker (PF-5190457) and underwent an oral alcohol challenge. Repeated blood samples were collected, and plasma concentrations of the following inflammatory markers were measured: C-reactive protein (CRP), interleukin (IL)-6, IL-10, IL-18, and tumor necrosis factor alpha (TNF-α). During the IV-ASA experiment, significant drug × time interaction effects were observed for IL-6 (F = 3.345, p = 0.030) and IL-10 (F = 4.638, p = 0.006), indicating that ghrelin, compared to placebo, significantly reduced blood concentrations of the proinflammatory cytokine IL-6, while increasing blood concentrations of the anti-inflammatory cytokine IL-10. No significant drug × time interaction effects were observed during the IV-AC experiment, possibly because of its much shorter duration and/or smaller sample. Treatment with PF-5190457, compared to placebo, had no significant effect on the inflammatory markers investigated. In conclusion, a supraphysiologic pharmacological challenge with exogenous ghrelin in heavy-drinking individuals produced anti-inflammatory effects in the context of intravenous alcohol administration. On the contrary, ghrelin receptor blockade did not lead to any change in the inflammatory markers included in this study. Mechanistic studies are required to better understand the interaction between ghrelin, alcohol, and inflammatory processes.},

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{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{Assari:2019aa,

title = {Substance Use among Economically Disadvantaged African American Older Adults; Objective and Subjective Socioeconomic Status.},

author = {Shervin Assari and James Smith and Ritesh Mistry and Mehdi Farokhnia and Mohsen Bazargan},

url = {https://pubmed.ncbi.nlm.nih.gov/31126049/},

doi = {10.3390/ijerph16101826},

year  = {2019},

date = {2019-05-23},

journal = {Int J Environ Res Public Health},

volume = {16},

number = {10},

abstract = {Purpose. This study investigated the effects of objective and subjective socioeconomic status (SES) indicators on two health behaviors, cigarette smoking and alcohol drinking, among African American older adults. Methods. This community-based study recruited 619 economically disadvantaged African American older adults (age ≥ 65 years) residing in South Los Angeles. Structured face-to-face interviews were conducted to collect data. Data on demographic factors (age and gender), subjective SES (financial difficulties), objective SES (educational attainment), living arrangement, marital status, healthcare access (insurance), and health (number of chronic medical conditions, self-rated health, sick days, depression, and chronic pain) and health behaviors (cigarette smoking and alcohol drinking) were collected from participants. Logistic regressions were used to analyze the data. Results. High financial difficulties were associated with higher odds of smoking cigarettes and drinking alcohol, independent of covariates. Educational attainment did not correlate with our outcomes. Similar patterns emerged for cigarette smoking and alcohol drinking. Conclusion. Subjective SES indicators such as financial difficulties may be more relevant than objective SES indicators such as educational attainment to health risk behaviors such as cigarette smoking and alcohol drinking among African American older adults in economically constrain urban environments. Smoking and drinking may serve as coping mechanisms with financial difficulty, especially among African American older adults. In line with the minorities' diminished returns (MDR) theory, and probably due to discrimination against racial minorities, educational attainment has a smaller protective effect among economically disadvantaged African American individuals against health risk behaviors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{FAROKHNIA201949,

title = {Ghrelin: From a gut hormone to a potential therapeutic target for alcohol use disorder},

author = {Mehdi Farokhnia and Monica L Faulkner and Daria Piacentino and Mary R Lee and Lorenzo Leggio},

url = {https://pubmed.ncbi.nlm.nih.gov/30738971/},

doi = {https://doi.org/10.1016/j.physbeh.2019.02.008},

issn = {0031-9384},

year  = {2019},

date = {2019-01-01},

journal = {Physiology & Behavior},

volume = {204},

pages = {49 - 57},

abstract = {Alcohol use disorder (AUD) is a leading cause of morbidity and mortality worldwide. However, treatment options, including pharmacotherapies, are limited in number and efficacy. Accumulating evidence suggests that elements of the gut-brain axis, such as neuroendocrine pathways and gut microbiome, are involved in the pathophysiology of AUD and, therefore, may be investigated as potential therapeutic targets. One pathway that has begun to be examined in this regard is the ghrelin system. Here, we review preclinical and clinical data on the relationship between ghrelin and alcohol-related outcomes, with a special focus on the role of the ghrelin system as a treatment target for AUD. Observational studies indicate that endogenous ghrelin levels are positively associated with craving for alcohol, subjective responses to alcohol, and brain activity in response to alcohol cues. Knockout rodent models suggest that deletion of the ghrelin peptide or receptor gene leads to reduction of alcohol intake and other alcohol-related outcomes. Different research groups have found that ghrelin administration increases, while ghrelin receptor (GHS-R1a) blockade reduces alcohol intake and other alcohol-related outcomes in rodents. Ghrelin administration in heavy-drinking individuals increases alcohol craving and self-administration and modulates brain activity in response to alcohol reward anticipation. PF-5190457, a GHS-R1a blocker, has been shown to be safe and tolerable when co-administered with alcohol. Furthermore, preliminary results suggest that this compound may reduce cue-elicited craving for alcohol in heavy-drinking individuals – a finding in need of replication. Collectively, the existing literature supports further examination of the ghrelin system as a therapeutic target for AUD. More research is also needed to understand the biobehavioral and molecular mechanisms underlying ghrelin's functions and to examine different interventional approaches to target the ghrelin system for AUD treatment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{cite-keyb,

title = {Prospects for pharmacotherapies to treat alcohol use disorder: an update on recent human studies},

author = {Mehdi Farokhnia and Brittney D Browning and Lorenzo Leggio},

url = {https://pubmed.ncbi.nlm.nih.gov/31107292/},

doi = {10.1097/YCO.0000000000000519},

isbn = {0951-7367},

year  = {2019},

date = {2019-01-01},

journal = {Current Opinion in Psychiatry},

volume = {32},

number = {4},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Farokhnia:2018aab,

title = {A deeper insight into how GABA-B receptor agonism via baclofen may affect alcohol seeking and consumption: lessons learned from a human laboratory investigation.},

author = {Mehdi Farokhnia and Sara L Deschaine and Armin Sadighi and Lisa A Farinelli and Mary R Lee and Fatemeh Akhlaghi and Lorenzo Leggio},

url = {https://www.ncbi.nlm.nih.gov/pubmed/30382188},

doi = {10.1038/s41380-018-0287-y},

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

year  = {2018},

date = {2018-10-31},

urldate = {2018-10-31},

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 = {Previous studies suggest that GABA-B receptor agonism may represent an effective pharmacological approach to treat addictive disorders. Baclofen is a selective GABA-B receptor agonist which has been investigated as a potential treatment for alcohol use disorder. However, research is needed to understand the biobehavioral mechanisms underlying baclofen's effect on alcohol use. In the present randomized, double-blind, placebo-controlled study, thirty-four alcohol-dependent individuals were randomized to receive baclofen (30 mg/d) or placebo for a week, and then participated in a laboratory experiment consisting of three procedures: alcohol cue-reactivity, priming, and self-administration. During the experiment, craving and other subjective responses to alcohol were assessed, and blood samples were collected for pharmacokinetic measurements. The effects of baclofen on the relationships between different alcohol-related laboratory parameters were investigated. Baclofen pharmacokinetic parameters and their correlations with behavioral measures were also examined. Results showed that baclofen disrupted the link between alcohol priming and self-administration, as indicated by significant interaction effects between drug condition (baclofen vs. placebo) and some of the priming variables (alcohol craving: F3},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{FAROKHNIA2018230,

title = {Neuroendocrine response to GABA-B receptor agonism in alcohol-dependent individuals: Results from a combined outpatient and human laboratory experiment},

author = {Mehdi Farokhnia and Mikela B Sheskier and Mary R Lee and April N Le and Erick Singley and Sofia Bouhlal and Timmy Ton and Zhen Zhao and Lorenzo Leggio},

url = {https://pubmed.ncbi.nlm.nih.gov/29665351/},

doi = {https://doi.org/10.1016/j.neuropharm.2018.04.011},

issn = {0028-3908},

year  = {2018},

date = {2018-01-01},

journal = {Neuropharmacology},

volume = {137},

pages = {230 - 239},

abstract = {Gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the nervous system, plays an important role in biobehavioral processes that regulate alcohol seeking, food intake, and stress response. The metabotropic GABA-B receptor has been investigated as a potential therapeutic target for alcohol use disorder, by using orthosteric agonists (e.g., baclofen) and positive allosteric modulators. Whether and how pharmacological manipulation of the GABA-B receptor, in combination with alcohol intake, may affect feeding- and stress-related neuroendocrine pathways remains unknown. In the present randomized, double-blind, placebo-controlled study, thirty-four alcohol-dependent individuals received baclofen (30 mg/day) or placebo in a naturalistic outpatient setting for one week, and then performed a controlled laboratory experiment which included alcohol cue-reactivity, fixed-dose priming, and self-administration procedures. Blood samples were collected, and the following neuroendocrine markers were measured: ghrelin, leptin, amylin, glucagon-like peptide-1 (GLP-1), insulin, prolactin, thyroid-stimulating hormone, growth hormone, cortisol, and adrenocorticotropic hormone (ACTH). During the outpatient phase, baclofen significantly increased blood concentrations of acyl-ghrelin (p = 0.01), leptin (p = 0.01), amylin (p = 0.004), and GLP-1 (p = 0.02). Significant drug × time-point interaction effects for amylin (p = 0.001) and insulin (p = 0.03), and trend-level interaction effects for GLP-1 (p = 0.06) and ACTH (p = 0.10) were found during the laboratory experiment. Baclofen, compared to placebo, had no effect on alcohol drinking in this study (p's ≥ 0.05). Together with previous studies, these findings shed light on the role of the GABAergic system and GABA-B receptors in the shared neurobiology of alcohol-, feeding-, and stress-related behaviors.},

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{Farokhnia:2017aab,

title = {Biobehavioral effects of baclofen in anxious alcohol-dependent individuals: a randomized, double-blind, placebo-controlled, laboratory study},

author = {M Farokhnia and M L Schwandt and M R Lee and J W Bollinger and L A Farinelli and J P Amodio and L Sewell and T A Lionetti and D E Spero and L Leggio},

url = {https://www.nature.com/articles/tp201771},

doi = {10.1038/tp.2017.71},

isbn = {2158-3188},

year  = {2017},

date = {2017-01-01},

journal = {Translational Psychiatry},

volume = {7},

number = {4},

pages = {e1108--e1108},

abstract = {Baclofen has been suggested as a potential pharmacotherapy for alcohol use disorder, but the clinical data are conflicting. Here we investigated the biobehavioral effects of baclofen in a sample of anxious alcohol-dependent individuals. This was a randomized, double-blind, placebo-controlled, human laboratory study in non-treatment seeking alcohol-dependent individuals with high trait anxiety (N=34). Participants received baclofen (30 mg per day) or placebo for at least 8 days, then performed an experimental session consisting of alcohol cue-reactivity followed by alcohol administration procedure (alcohol priming, then alcohol self-administration). Total amount of alcohol self-administered was the primary outcome; alcohol craving, subjective/physiological responses and mood/anxiety symptoms were also evaluated. There was no significant medication effect on the total amount of alcohol consumed during the alcohol self-administration (P=0.76). Baclofen blunted the positive association between maximum breath alcohol concentration during priming and the amount of alcohol consumption (significant interaction},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Farokhnia:2014aa,

title = {A double-blind, placebo controlled, randomized trial of riluzole as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia},

author = {Mehdi Farokhnia and Maryam Sabzabadi and Hossein Pourmahmoud and Mohammad-Reza Khodaie-Ardakani and Seyed-Mohammad-Reza Hosseini and Habibeh Yekehtaz and Mina Tabrizi and Farzin Rezaei and Bahman Salehi and Shahin Akhondzadeh},

url = {https://pubmed.ncbi.nlm.nih.gov/24013610/},

doi = {10.1007/s00213-013-3261-z},

isbn = {1432-2072},

year  = {2014},

date = {2014-01-01},

journal = {Psychopharmacology},

volume = {231},

number = {3},

pages = {533--542},

abstract = {Several recent studies have focused on glutamate modulating agents for symptoms relief in schizophrenia, especially negative symptoms which are resistant to conventional therapies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Farokhnia:2013aa,

title = {N-Acetylcysteine as an Adjunct to Risperidone for Treatment of Negative Symptoms in Patients With Chronic Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Study},

author = {Mehdi Farokhnia and Anita Azarkolah and Forod Adinehfar and Mohammad-Reza Khodaie-Ardakani and Seyed-Mohammad-Reza Hosseini and Habibeh Yekehtaz and Mina Tabrizi and Farzin Rezaei and Bahman Salehi and Seyed-Mohammad-Hossein Sadeghi and Marzieh Moghadam and Fardin Gharibi and Omid Mirshafiee and Shahin Akhondzadeh},

url = {https://journals.lww.com/clinicalneuropharm/Fulltext/2013/11000/N_Acetylcysteine_as_an_Adjunct_to_Risperidone_for.2.aspx},

isbn = {0362-5664},

year  = {2013},

date = {2013-01-01},

journal = {Clinical Neuropharmacology},

volume = {36},

number = {6},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Khajavi:2012aa,

title = {Oral scopolamine augmentation in moderate to severe major depressive disorder: a randomized, double-blind, placebo-controlled study.},

author = {Danial Khajavi and Mehdi Farokhnia and Amirhossein Modabbernia and Mandana Ashrafi and Seyed-Hesammedin Abbasi and Mina Tabrizi and Shahin Akhondzadeh},

url = {https://pubmed.ncbi.nlm.nih.gov/23146150/

https://pubmed.ncbi.nlm.nih.gov/24201233/},

doi = {10.4088/JCP.12m07706},

issn = {1555-2101 (Electronic); 0160-6689 (Linking)},

year  = {2012},

date = {2012-11-01},

journal = {J Clin Psychiatry},

volume = {73},

number = {11},

pages = {1428--1433},

abstract = {OBJECTIVE: To evaluate the antidepressant effect of oral scopolamine as an adjunct to citalopram. METHOD: In this randomized double-blind placebo-controlled study, patients were assessed in the outpatient clinics of 2 large hospitals from November 2011 to January 2012. Forty patients (18-55 years) with major depressive disorder (DSM-IV-TR criteria) and 17-Item Hamilton Depression Rating Scale (HDRS) score ≥ 22 were randomly assigned to scopolamine hydrobromide (1 mg/d) (n = 20) or placebo (n = 20) in addition to citalopram for 6 weeks. HDRS score was measured at baseline and days 4, 7, 14, 28, and 42. The primary outcome measure was HDRS score change from baseline to week 6 in the scopolamine group versus the placebo group. Response was defined as ≥ 50% decrease in HDRS score; remission, as HDRS score ≤ 7. RESULTS: Augmentation with scopolamine was significantly more effective than placebo (F(1,38) = 5.831},

keywords = {},

pubstate = {published},

tppubtype = {article}

}