Contact
Biomedical Research Center251 Bayview Boulevard
Suite 200
Room 01B606
Baltimore, MD 21224
Email: mehdi.farokhnia@nih.gov
Research Interests
Mehdi received his Medical Degree from Tehran University and completed a Postdoctoral Fellowship in Dr. Leggio’s lab at the NIH Clinical Center when he was also a Fellow at the NIH Center on Compulsive Behaviors (CCB). He earned a Master of Public Health from Johns Hopkins University (with a Graduate Certificate in Public Mental Health Research and another one in Pharmacoepidemiology and Drug Safety) where he currently holds an adjunct faculty position in the Department of Mental Health. Mehdi’s research has been focused on understanding the neurobiology of addictive behaviors and identifying novel therapeutic targets for alcohol and other substance use disorders, with a particular focus on neuroendocrine pathways. He has led several clinical trials and uses a combination of behavioral, pharmacological, genetic, and neuroimaging methods. Beyond specific pharmacological targets and medications, Mehdi is interested in utilizing big data to understand the biobehavioral correlates of addiction and to examine alternative/improved outcomes for substance use disorder clinical trials. He is also interested in investigating innovative human laboratory approaches and large-scale epidemiological methods to facilitate the crosstalk between preclinical, clinical, and population-based research.
Publications
Selected Publications
2024
Faulkner, Monica L; Farokhnia, Mehdi; Lee, Mary R; Farinelli, Lisa; Browning, Brittney D; Abshire, Kelly; Daurio, Allison M; Munjal, Vikas; Deschaine, Sara L; Boukabara, Selim R; Fortney, Christopher; Sherman, Garrick; Schwandt, Melanie; Akhlaghi, Fatemeh; Momenan, Reza; Ross, Thomas J; Persky, Susan; Leggio, Lorenzo
A randomized, double-blind, placebo-controlled study of a GHSR blocker in people with alcohol use disorder Journal Article
In: JCI Insight, vol. 9, no. 24, 2024, ISSN: 2379-3708.
@article{pmid39704175,
title = {A randomized, double-blind, placebo-controlled study of a GHSR blocker in people with alcohol use disorder},
author = {Monica L Faulkner and Mehdi Farokhnia and Mary R Lee and Lisa Farinelli and Brittney D Browning and Kelly Abshire and Allison M Daurio and Vikas Munjal and Sara L Deschaine and Selim R Boukabara and Christopher Fortney and Garrick Sherman and Melanie Schwandt and Fatemeh Akhlaghi and Reza Momenan and Thomas J Ross and Susan Persky and Lorenzo Leggio},
url = {https://pubmed.ncbi.nlm.nih.gov/39704175/},
doi = {10.1172/jci.insight.182331},
issn = {2379-3708},
year = {2024},
date = {2024-12-01},
urldate = {2024-12-01},
journal = {JCI Insight},
volume = {9},
number = {24},
abstract = {BACKGROUNDStudies have demonstrated the role of ghrelin in alcohol-related behaviors and consumption. Blockade of the growth hormone secretagogue receptor (GHSR), which is the ghrelin receptor, has been shown to decrease alcohol drinking and reward-related behaviors across several animal models. We previously conducted a human study testing a GHSR inverse agonist/competitive antagonist, PF-5190457, in individuals who are heavy drinkers and showed its safety when coadministered with alcohol. Here, we conducted a phase IIa experimental medicine study in patients with alcohol use disorder (AUD) to investigate the effects of PF-5190457 on alcohol- and food-related outcomes.METHODSForty-two individuals with AUD (n = 29 completers) participated in a randomized, double-blind, placebo-controlled study where they received PF-5190457 100mg b.i.d. (or placebo) in 2 counterbalanced, within-subject stages. Participants completed an alcohol cue-reactivity (CR) experiment in a bar-like laboratory and a virtual food choice experiment in a cafeteria-like virtual reality (VR) environment. A subset of participants (n = 12) performed a CR task during a brain functional MRI (fMRI) experiment.RESULTSPF-5190457 did not reduce cue-elicited alcohol craving. PF-5190457 reduced virtual calories selected (P = 0.04) in the VR environment. PF-5190457 did not influence neural activation during CR task in the fMRI experiment.CONCLUSIONThis study provides human evidence of the role of GHSR blockade in behaviors related to food selection and highlights the need for future investigations into targeting the ghrelin system in AUD.TRIAL REGISTRATIONClinicalTrials.gov (accession no. NCT02707055).FUNDINGNIDA and NIAAA ZIA-DA000635; National Center for Advancing Translational Sciences UH2/UH3-TR000963.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUNDStudies have demonstrated the role of ghrelin in alcohol-related behaviors and consumption. Blockade of the growth hormone secretagogue receptor (GHSR), which is the ghrelin receptor, has been shown to decrease alcohol drinking and reward-related behaviors across several animal models. We previously conducted a human study testing a GHSR inverse agonist/competitive antagonist, PF-5190457, in individuals who are heavy drinkers and showed its safety when coadministered with alcohol. Here, we conducted a phase IIa experimental medicine study in patients with alcohol use disorder (AUD) to investigate the effects of PF-5190457 on alcohol- and food-related outcomes.METHODSForty-two individuals with AUD (n = 29 completers) participated in a randomized, double-blind, placebo-controlled study where they received PF-5190457 100mg b.i.d. (or placebo) in 2 counterbalanced, within-subject stages. Participants completed an alcohol cue-reactivity (CR) experiment in a bar-like laboratory and a virtual food choice experiment in a cafeteria-like virtual reality (VR) environment. A subset of participants (n = 12) performed a CR task during a brain functional MRI (fMRI) experiment.RESULTSPF-5190457 did not reduce cue-elicited alcohol craving. PF-5190457 reduced virtual calories selected (P = 0.04) in the VR environment. PF-5190457 did not influence neural activation during CR task in the fMRI experiment.CONCLUSIONThis study provides human evidence of the role of GHSR blockade in behaviors related to food selection and highlights the need for future investigations into targeting the ghrelin system in AUD.TRIAL REGISTRATIONClinicalTrials.gov (accession no. NCT02707055).FUNDINGNIDA and NIAAA ZIA-DA000635; National Center for Advancing Translational Sciences UH2/UH3-TR000963.
Mojtabai, Ramin; Susukida, Ryoko; Farokhnia, Mehdi; Nguyen, Trang Quynh; Dunn, Kelly E; Amin-Esmaeili, Masoumeh
Trajectories of craving in the course of pharmacotherapy trials for methamphetamine use disorder Journal Article
In: Addiction, vol. 119, no. 10, pp. 1803–1812, 2024, ISSN: 1360-0443.
@article{pmid38984671,
title = {Trajectories of craving in the course of pharmacotherapy trials for methamphetamine use disorder},
author = {Ramin Mojtabai and Ryoko Susukida and Mehdi Farokhnia and Trang Quynh Nguyen and Kelly E Dunn and Masoumeh Amin-Esmaeili},
url = {https://pubmed.ncbi.nlm.nih.gov/38984671/},
doi = {10.1111/add.16610},
issn = {1360-0443},
year = {2024},
date = {2024-10-01},
urldate = {2024-10-01},
journal = {Addiction},
volume = {119},
number = {10},
pages = {1803--1812},
abstract = {AIMS: The aim of this study was to measure trajectories of craving for methamphetamine during the course of pharmacotherapy trials for methamphetamine use disorder.nnDESIGN, SETTING AND PARTICIPANTS: Craving trajectories were identified using Group-Based Trajectory Modeling. The association of craving trajectories with drug use trajectories was examined using a dual trajectory model. Association of craving trajectories with other health and social outcomes was also examined. The study used pooled data from five randomized controlled pharmacotherapy trials for methamphetamine use disorder. A total of 866 adults with methamphetamine use disorder participated in randomized controlled pharmacotherapy trials.nnMEASUREMENT: Craving was assessed weekly using the Brief Substance Craving Scale. Drug use was assessed using urine toxicology. Alcohol- and drug-related problems, as well as psychiatric, medical, legal, employment and relationship problems, were measured using the Addiction Severity Index.nnFINDINGS: A three-trajectory model with high, medium and low craving trajectories was selected as the most parsimonious model. Craving trajectories were associated with methamphetamine use trajectories in the course of trial; 88.4% of those in the high craving trajectory group had a consistently high frequency of methamphetamine use compared with 18.7% of those in the low craving group. High craving was also associated with less improvement in most other outcomes and higher rate of dropout from treatment. In turn, low craving was associated with a rapidly decreasing frequency of methamphetamine use, greater improvement in most other outcomes and a lower rate of dropout. Participants on modafinil daily and ondansetron 1 mg twice daily were less likely to be in the high craving group compared with those on placebo.nnCONCLUSIONS: Trajectories of methamphetamine craving in the course of clinical trials for methamphetamine use disorder appear to be both highly variable and strongly associated with greater frequency of drug use, other drug-related outcomes and dropout from trials. Two medications, modafinil daily and ondansetron at a dose of 1 mg two times daily, appear to be associated with greater reduction in craving in the course of treatment compared with placebo. A decrease in methamphetamine craving shows promise as an early indicator of recovery from methamphetamine use disorder.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
AIMS: The aim of this study was to measure trajectories of craving for methamphetamine during the course of pharmacotherapy trials for methamphetamine use disorder.nnDESIGN, SETTING AND PARTICIPANTS: Craving trajectories were identified using Group-Based Trajectory Modeling. The association of craving trajectories with drug use trajectories was examined using a dual trajectory model. Association of craving trajectories with other health and social outcomes was also examined. The study used pooled data from five randomized controlled pharmacotherapy trials for methamphetamine use disorder. A total of 866 adults with methamphetamine use disorder participated in randomized controlled pharmacotherapy trials.nnMEASUREMENT: Craving was assessed weekly using the Brief Substance Craving Scale. Drug use was assessed using urine toxicology. Alcohol- and drug-related problems, as well as psychiatric, medical, legal, employment and relationship problems, were measured using the Addiction Severity Index.nnFINDINGS: A three-trajectory model with high, medium and low craving trajectories was selected as the most parsimonious model. Craving trajectories were associated with methamphetamine use trajectories in the course of trial; 88.4% of those in the high craving trajectory group had a consistently high frequency of methamphetamine use compared with 18.7% of those in the low craving group. High craving was also associated with less improvement in most other outcomes and higher rate of dropout from treatment. In turn, low craving was associated with a rapidly decreasing frequency of methamphetamine use, greater improvement in most other outcomes and a lower rate of dropout. Participants on modafinil daily and ondansetron 1 mg twice daily were less likely to be in the high craving group compared with those on placebo.nnCONCLUSIONS: Trajectories of methamphetamine craving in the course of clinical trials for methamphetamine use disorder appear to be both highly variable and strongly associated with greater frequency of drug use, other drug-related outcomes and dropout from trials. Two medications, modafinil daily and ondansetron at a dose of 1 mg two times daily, appear to be associated with greater reduction in craving in the course of treatment compared with placebo. A decrease in methamphetamine craving shows promise as an early indicator of recovery from methamphetamine use disorder.
Amin-Esmaeili, Masoumeh; Farokhnia, Mehdi; Susukida, Ryoko; Leggio, Lorenzo; Johnson, Renee M; Crum, Rosa M; Mojtabai, Ramin
In: Addiction, vol. 119, no. 5, pp. 833–843, 2024, ISSN: 1360-0443.
@article{pmid38197836,
title = {Reduced drug use as an alternative valid outcome in individuals with stimulant use disorders: Findings from 13 multisite randomized clinical trials},
author = {Masoumeh Amin-Esmaeili and Mehdi Farokhnia and Ryoko Susukida and Lorenzo Leggio and Renee M Johnson and Rosa M Crum and Ramin Mojtabai},
url = {https://pubmed.ncbi.nlm.nih.gov/38197836/},
doi = {10.1111/add.16409},
issn = {1360-0443},
year = {2024},
date = {2024-05-01},
urldate = {2024-05-01},
journal = {Addiction},
volume = {119},
number = {5},
pages = {833--843},
abstract = {BACKGROUND AND AIMS: Total abstinence has historically been the goal of treatment for substance use disorders; however, there is a growing recognition of the health benefits associated with reduced use as a harm reduction measure in stimulant use disorders treatment. We aimed to assess the validity of reduced stimulant use as an outcome measure in randomized controlled trials (RCTs) of pharmacological interventions for stimulant use disorder.nnDESIGN: We conducted a secondary analysis of a pooled dataset of 13 RCTs.nnSETTING AND PARTICIPANTS: Participants were individuals seeking treatment for cocaine or methamphetamine use disorders (N = 2062) in a wide range of treatment facilities in the United States.nnMEASUREMENTS: We validated reduced stimulant use against a set of clinical indicators drawn from harmonized measurements, including severity of problems caused by drug use, comorbid depression, global severity of substance use and improvement, severity of drug-seeking behavior, craving and high-risk behaviors, all assessed at the end of the trial, as well as follow-up urine toxicology. A series of mixed effect regression models was conducted to validate reduction in frequency of use against no reduction in use and abstinence.nnFINDINGS: More participants reduced frequency of primary drug use than achieved abstinence (18.0% vs. 14.2%, respectively). Reduced use was significantly associated with decreases in craving for the primary drug [60.1%, 95% confidence interval (CI) = 54.3%-64.7%], drug seeking behaviors (41.0%, 95% CI = 36.6%-45.7%), depression severity (39.9%, 95% CI = 30.9%-48.3%), as well as multiple measures of global improvement in psychosocial functioning and severity of drug-related problems, albeit less strongly so than abstinence. Moreover, reduced use was associated with sustained clinical benefit at follow-up, as confirmed by negative urine tests (adjusted odds ratio compared with those with no reduction in use: 0.50, 95% CI = 0.35-0.71).nnCONCLUSION: Reduced frequency of stimulant use appears to be associated with meaningful improvement in various clinical indicators of recovery. Assessment of reduced use, in addition to abstinence, could broaden the scope of outcomes measured in randomized controlled trials of stimulant use disorders and facilitate the development of more diverse treatment approaches.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND AND AIMS: Total abstinence has historically been the goal of treatment for substance use disorders; however, there is a growing recognition of the health benefits associated with reduced use as a harm reduction measure in stimulant use disorders treatment. We aimed to assess the validity of reduced stimulant use as an outcome measure in randomized controlled trials (RCTs) of pharmacological interventions for stimulant use disorder.nnDESIGN: We conducted a secondary analysis of a pooled dataset of 13 RCTs.nnSETTING AND PARTICIPANTS: Participants were individuals seeking treatment for cocaine or methamphetamine use disorders (N = 2062) in a wide range of treatment facilities in the United States.nnMEASUREMENTS: We validated reduced stimulant use against a set of clinical indicators drawn from harmonized measurements, including severity of problems caused by drug use, comorbid depression, global severity of substance use and improvement, severity of drug-seeking behavior, craving and high-risk behaviors, all assessed at the end of the trial, as well as follow-up urine toxicology. A series of mixed effect regression models was conducted to validate reduction in frequency of use against no reduction in use and abstinence.nnFINDINGS: More participants reduced frequency of primary drug use than achieved abstinence (18.0% vs. 14.2%, respectively). Reduced use was significantly associated with decreases in craving for the primary drug [60.1%, 95% confidence interval (CI) = 54.3%-64.7%], drug seeking behaviors (41.0%, 95% CI = 36.6%-45.7%), depression severity (39.9%, 95% CI = 30.9%-48.3%), as well as multiple measures of global improvement in psychosocial functioning and severity of drug-related problems, albeit less strongly so than abstinence. Moreover, reduced use was associated with sustained clinical benefit at follow-up, as confirmed by negative urine tests (adjusted odds ratio compared with those with no reduction in use: 0.50, 95% CI = 0.35-0.71).nnCONCLUSION: Reduced frequency of stimulant use appears to be associated with meaningful improvement in various clinical indicators of recovery. Assessment of reduced use, in addition to abstinence, could broaden the scope of outcomes measured in randomized controlled trials of stimulant use disorders and facilitate the development of more diverse treatment approaches.
2023
Leggio, Lorenzo; Hendershot, Christian S; Farokhnia, Mehdi; Fink-Jensen, Anders; Klausen, Mette Kruse; Schacht, Joseph P; Simmons, W Kyle
GLP-1 receptor agonists are promising but unproven treatments for alcohol and substance use disorders Journal Article
In: Nat Med, vol. 29, no. 12, pp. 2993–2995, 2023, ISSN: 1546-170X.
@article{pmid38001271,
title = {GLP-1 receptor agonists are promising but unproven treatments for alcohol and substance use disorders},
author = {Lorenzo Leggio and Christian S Hendershot and Mehdi Farokhnia and Anders Fink-Jensen and Mette Kruse Klausen and Joseph P Schacht and W Kyle Simmons},
url = {https://pubmed.ncbi.nlm.nih.gov/38001271/},
doi = {10.1038/s41591-023-02634-8},
issn = {1546-170X},
year = {2023},
date = {2023-12-01},
urldate = {2023-12-01},
journal = {Nat Med},
volume = {29},
number = {12},
pages = {2993--2995},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Chuong, Vicky; Farokhnia, Mehdi; Khom, Sophia; Pince, Claire L; Elvig, Sophie K; Vlkolinsky, Roman; Marchette, Renata Cn; Koob, George F; Roberto, Marisa; Vendruscolo, Leandro F; Leggio, Lorenzo
The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission Journal Article
In: JCI Insight, vol. 8, no. 12, 2023, ISSN: 2379-3708.
@article{pmid37192005b,
title = {The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission},
author = {Vicky Chuong and Mehdi Farokhnia and Sophia Khom and Claire L Pince and Sophie K Elvig and Roman Vlkolinsky and Renata Cn Marchette and George F Koob and Marisa Roberto and Leandro F Vendruscolo and Lorenzo Leggio},
url = {https://pubmed.ncbi.nlm.nih.gov/37192005/},
doi = {10.1172/jci.insight.170671},
issn = {2379-3708},
year = {2023},
date = {2023-06-01},
urldate = {2023-06-01},
journal = {JCI Insight},
volume = {8},
number = {12},
abstract = {Growing evidence indicates that the glucagon-like peptide-1 (GLP-1) system is involved in the neurobiology of addictive behaviors, and GLP-1 analogues may be used for the treatment of alcohol use disorder (AUD). Here, we examined the effects of semaglutide, a long-acting GLP-1 analogue, on biobehavioral correlates of alcohol use in rodents. A drinking-in-the-dark procedure was used to test the effects of semaglutide on binge-like drinking in male and female mice. We also tested the effects of semaglutide on binge-like and dependence-induced alcohol drinking in male and female rats, as well as acute effects of semaglutide on spontaneous inhibitory postsynaptic currents (sIPSCs) from central amygdala (CeA) and infralimbic cortex (ILC) neurons. Semaglutide dose-dependently reduced binge-like alcohol drinking in mice; a similar effect was observed on the intake of other caloric/noncaloric solutions. Semaglutide also reduced binge-like and dependence-induced alcohol drinking in rats. Semaglutide increased sIPSC frequency in CeA and ILC neurons from alcohol-naive rats, suggesting enhanced GABA release, but had no overall effect on GABA transmission in alcohol-dependent rats. In conclusion, the GLP-1 analogue semaglutide decreased alcohol intake across different drinking models and species and modulated central GABA neurotransmission, providing support for clinical testing of semaglutide as a potentially novel pharmacotherapy for AUD.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Growing evidence indicates that the glucagon-like peptide-1 (GLP-1) system is involved in the neurobiology of addictive behaviors, and GLP-1 analogues may be used for the treatment of alcohol use disorder (AUD). Here, we examined the effects of semaglutide, a long-acting GLP-1 analogue, on biobehavioral correlates of alcohol use in rodents. A drinking-in-the-dark procedure was used to test the effects of semaglutide on binge-like drinking in male and female mice. We also tested the effects of semaglutide on binge-like and dependence-induced alcohol drinking in male and female rats, as well as acute effects of semaglutide on spontaneous inhibitory postsynaptic currents (sIPSCs) from central amygdala (CeA) and infralimbic cortex (ILC) neurons. Semaglutide dose-dependently reduced binge-like alcohol drinking in mice; a similar effect was observed on the intake of other caloric/noncaloric solutions. Semaglutide also reduced binge-like and dependence-induced alcohol drinking in rats. Semaglutide increased sIPSC frequency in CeA and ILC neurons from alcohol-naive rats, suggesting enhanced GABA release, but had no overall effect on GABA transmission in alcohol-dependent rats. In conclusion, the GLP-1 analogue semaglutide decreased alcohol intake across different drinking models and species and modulated central GABA neurotransmission, providing support for clinical testing of semaglutide as a potentially novel pharmacotherapy for AUD.
Farokhnia, Mehdi; Wang, Tammy; Jourdan, Tony; Godlewski, Grzegorz; Farinelli, Lisa A; Kunos, George; Leggio, Lorenzo
In: Drug Alcohol Depend, vol. 245, pp. 109809, 2023, ISSN: 1879-0046.
@article{pmid36822122,
title = {A human laboratory study on the link between alcohol administration and circulating fibroblast growth factor 21 (FGF21) in individuals with alcohol use disorder},
author = {Mehdi Farokhnia and Tammy Wang and Tony Jourdan and Grzegorz Godlewski and Lisa A Farinelli and George Kunos and Lorenzo Leggio},
url = {https://pubmed.ncbi.nlm.nih.gov/36822122/},
doi = {10.1016/j.drugalcdep.2023.109809},
issn = {1879-0046},
year = {2023},
date = {2023-04-01},
urldate = {2023-04-01},
journal = {Drug Alcohol Depend},
volume = {245},
pages = {109809},
abstract = {Growing evidence indicates that the crosstalk between the central nervous system and the periphery plays an important role in the pathophysiology of neuropsychiatric conditions, including addictive disorders. Fibroblast growth factor 21 (FGF21) is part of the liver-brain axis and regulates energy homeostasis, metabolism, and macronutrient intake. In addition, FGF21 signaling modulates alcohol intake and preference, and changes in FGF21 levels are observed following alcohol consumption. To further elucidate the relationship between alcohol use and FGF21, we assessed serum FGF21 concentrations in 16 non-treatment seeking individuals with alcohol use disorder (AUD) in a naturalistic outpatient setting, as well as a controlled laboratory experiment that included alcohol cue-reactivity, alcohol priming, and alcohol self-administration in a bar-like setting. FGF21 levels were stable during the outpatient phase when participants received placebo and had no significant lifestyle changes. During the bar-like laboratory experiment, a robust increase in serum FGF21 concentrations was found after the 2-hr alcohol self-administration session (F = 23.39, p < 0.001). Percent change in FGF21 levels positively correlated with the amount of alcohol self-administered but did not reach statistical significance. No significant changes in FGF21 levels were found after exposure to alcohol cues or consuming the priming drink. Given the bidirectional link between FGF21 and alcohol, targeting the FGF21 system may be further examined as a potential pharmacotherapy for AUD.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Growing evidence indicates that the crosstalk between the central nervous system and the periphery plays an important role in the pathophysiology of neuropsychiatric conditions, including addictive disorders. Fibroblast growth factor 21 (FGF21) is part of the liver-brain axis and regulates energy homeostasis, metabolism, and macronutrient intake. In addition, FGF21 signaling modulates alcohol intake and preference, and changes in FGF21 levels are observed following alcohol consumption. To further elucidate the relationship between alcohol use and FGF21, we assessed serum FGF21 concentrations in 16 non-treatment seeking individuals with alcohol use disorder (AUD) in a naturalistic outpatient setting, as well as a controlled laboratory experiment that included alcohol cue-reactivity, alcohol priming, and alcohol self-administration in a bar-like setting. FGF21 levels were stable during the outpatient phase when participants received placebo and had no significant lifestyle changes. During the bar-like laboratory experiment, a robust increase in serum FGF21 concentrations was found after the 2-hr alcohol self-administration session (F = 23.39, p < 0.001). Percent change in FGF21 levels positively correlated with the amount of alcohol self-administered but did not reach statistical significance. No significant changes in FGF21 levels were found after exposure to alcohol cues or consuming the priming drink. Given the bidirectional link between FGF21 and alcohol, targeting the FGF21 system may be further examined as a potential pharmacotherapy for AUD.
2022
Farokhnia, Mehdi; Rentsch, Christopher T; Chuong, Vicky; McGinn, M Adrienne; Elvig, Sophie K; Douglass, Eliza A; Gonzalez, Luis A; Sanfilippo, Jenna E; Marchette, Renata C N; Tunstall, Brendan J; Fiellin, David A; Koob, George F; Justice, Amy C; Leggio, Lorenzo; Vendruscolo, Leandro F
Spironolactone as a potential new pharmacotherapy for alcohol use disorder: convergent evidence from rodent and human studies Journal Article
In: Mol Psychiatry, vol. 27, no. 11, pp. 4642–4652, 2022, ISSN: 1476-5578.
@article{pmid36123420,
title = {Spironolactone as a potential new pharmacotherapy for alcohol use disorder: convergent evidence from rodent and human studies},
author = {Mehdi Farokhnia and Christopher T Rentsch and Vicky Chuong and M Adrienne McGinn and Sophie K Elvig and Eliza A Douglass and Luis A Gonzalez and Jenna E Sanfilippo and Renata C N Marchette and Brendan J Tunstall and David A Fiellin and George F Koob and Amy C Justice and Lorenzo Leggio and Leandro F Vendruscolo},
url = {https://pubmed.ncbi.nlm.nih.gov/36123420/},
doi = {10.1038/s41380-022-01736-y},
issn = {1476-5578},
year = {2022},
date = {2022-11-01},
urldate = {2022-11-01},
journal = {Mol Psychiatry},
volume = {27},
number = {11},
pages = {4642--4652},
abstract = {Evidence suggests that spironolactone, a nonselective mineralocorticoid receptor (MR) antagonist, modulates alcohol seeking and consumption. Therefore, spironolactone may represent a novel pharmacotherapy for alcohol use disorder (AUD). In this study, we tested the effects of spironolactone in a mouse model of alcohol drinking (drinking-in-the-dark) and in a rat model of alcohol dependence (vapor exposure). We also investigated the association between spironolactone receipt for at least 60 continuous days and change in self-reported alcohol consumption, using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), in a pharmacoepidemiologic cohort study in the largest integrated healthcare system in the US. Spironolactone dose-dependently reduced the intake of sweetened or unsweetened alcohol solutions in male and female mice. No effects of spironolactone were observed on drinking of a sweet solution without alcohol, food or water intake, motor coordination, alcohol-induced ataxia, or blood alcohol levels. Spironolactone dose-dependently reduced operant alcohol self-administration in dependent and nondependent male and female rats. In humans, a greater reduction in alcohol consumption was observed among those who received spironolactone, compared to propensity score-matched individuals who did not receive spironolactone. The largest effects were among those who reported hazardous/heavy episodic alcohol consumption at baseline (AUDIT-C ≥ 8) and those exposed to ≥ 50 mg/day of spironolactone. These convergent findings across rodent and human studies demonstrate that spironolactone reduces alcohol use and support the hypothesis that this medication may be further studied as a novel pharmacotherapy for AUD.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Evidence suggests that spironolactone, a nonselective mineralocorticoid receptor (MR) antagonist, modulates alcohol seeking and consumption. Therefore, spironolactone may represent a novel pharmacotherapy for alcohol use disorder (AUD). In this study, we tested the effects of spironolactone in a mouse model of alcohol drinking (drinking-in-the-dark) and in a rat model of alcohol dependence (vapor exposure). We also investigated the association between spironolactone receipt for at least 60 continuous days and change in self-reported alcohol consumption, using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), in a pharmacoepidemiologic cohort study in the largest integrated healthcare system in the US. Spironolactone dose-dependently reduced the intake of sweetened or unsweetened alcohol solutions in male and female mice. No effects of spironolactone were observed on drinking of a sweet solution without alcohol, food or water intake, motor coordination, alcohol-induced ataxia, or blood alcohol levels. Spironolactone dose-dependently reduced operant alcohol self-administration in dependent and nondependent male and female rats. In humans, a greater reduction in alcohol consumption was observed among those who received spironolactone, compared to propensity score-matched individuals who did not receive spironolactone. The largest effects were among those who reported hazardous/heavy episodic alcohol consumption at baseline (AUDIT-C ≥ 8) and those exposed to ≥ 50 mg/day of spironolactone. These convergent findings across rodent and human studies demonstrate that spironolactone reduces alcohol use and support the hypothesis that this medication may be further studied as a novel pharmacotherapy for AUD.
Farokhnia, Mehdi; Browning, Brittney D; Crozier, Madeline E; Sun, Hui; Akhlaghi, Fatemeh; Leggio, Lorenzo
In: Addict Biol, vol. 27, no. 5, pp. e13211, 2022, ISSN: 1369-1600.
@article{pmid36001436,
title = {The glucagon-like peptide-1 system is modulated by acute and chronic alcohol exposure: Findings from human laboratory experiments and a post-mortem brain study},
author = {Mehdi Farokhnia and Brittney D Browning and Madeline E Crozier and Hui Sun and Fatemeh Akhlaghi and Lorenzo Leggio},
url = {https://pubmed.ncbi.nlm.nih.gov/36001436/},
doi = {10.1111/adb.13211},
issn = {1369-1600},
year = {2022},
date = {2022-09-01},
urldate = {2022-09-01},
journal = {Addict Biol},
volume = {27},
number = {5},
pages = {e13211},
abstract = {Growing evidence suggests that the glucagon-like peptide-1 (GLP-1) system modulates alcohol seeking and consumption, and GLP-1 analogues may represent novel pharmacotherapies for alcohol use disorder (AUD). Accordingly, it is important to understand the potential effects of alcohol on the endogenous GLP-1 system. In a series of secondary analyses of previous human laboratory experiments, we first examined the effects of alcohol administration, with different doses and routes of administration, on peripheral active GLP-1 concentrations in heavy-drinking individuals with AUD enrolled in placebo-controlled pharmacological studies (only placebo conditions were analysed here). Alcohol administration resulted in a significant reduction of GLP-1 levels across the four experiments (oral alcohol, variable dose: F = 6.52, p = 0.002; oral alcohol, fixed dose: F = 5.08, p < 0.001; intravenous alcohol, variable dose: F = 20.72, p < 0.001; intravenous alcohol, fixed dose: F = 10.44, p < 0.001). Next, central expression of the GLP-1 receptor (GLP-1R) in post-mortem brain tissues (amygdala, ventral tegmental area, nucleus accumbens, hippocampus and prefrontal cortex) was compared between individuals with AUD and controls. Fold change of GLP-1R mRNA in the hippocampus was significantly higher in individuals with AUD, compared to controls (F = 6.80, p = 0.01). A trend-level effect with the same direction was also found in the prefrontal cortex (F = 3.07, p = 0.09). Exploratory analyses showed that GLP-1R gene expression levels were correlated with behavioural measures of alcohol drinking (hippocampus) and cigarette smoking (hippocampus and prefrontal cortex). Collectively, these data provide novel information on the crosstalk between alcohol and GLP-1 in a clinically relevant sample. Further studies are needed to understand the underlying mechanisms of this link.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Growing evidence suggests that the glucagon-like peptide-1 (GLP-1) system modulates alcohol seeking and consumption, and GLP-1 analogues may represent novel pharmacotherapies for alcohol use disorder (AUD). Accordingly, it is important to understand the potential effects of alcohol on the endogenous GLP-1 system. In a series of secondary analyses of previous human laboratory experiments, we first examined the effects of alcohol administration, with different doses and routes of administration, on peripheral active GLP-1 concentrations in heavy-drinking individuals with AUD enrolled in placebo-controlled pharmacological studies (only placebo conditions were analysed here). Alcohol administration resulted in a significant reduction of GLP-1 levels across the four experiments (oral alcohol, variable dose: F = 6.52, p = 0.002; oral alcohol, fixed dose: F = 5.08, p < 0.001; intravenous alcohol, variable dose: F = 20.72, p < 0.001; intravenous alcohol, fixed dose: F = 10.44, p < 0.001). Next, central expression of the GLP-1 receptor (GLP-1R) in post-mortem brain tissues (amygdala, ventral tegmental area, nucleus accumbens, hippocampus and prefrontal cortex) was compared between individuals with AUD and controls. Fold change of GLP-1R mRNA in the hippocampus was significantly higher in individuals with AUD, compared to controls (F = 6.80, p = 0.01). A trend-level effect with the same direction was also found in the prefrontal cortex (F = 3.07, p = 0.09). Exploratory analyses showed that GLP-1R gene expression levels were correlated with behavioural measures of alcohol drinking (hippocampus) and cigarette smoking (hippocampus and prefrontal cortex). Collectively, these data provide novel information on the crosstalk between alcohol and GLP-1 in a clinically relevant sample. Further studies are needed to understand the underlying mechanisms of this link.
Farokhnia, Mehdi; Fede, Samantha J; Grodin, Erica N; Browning, Brittney D; Crozier, Madeline E; Schwandt, Melanie L; Hodgkinson, Colin A; Momenan, Reza; Leggio, Lorenzo
Differential association between the GLP1R gene variants and brain functional connectivity according to the severity of alcohol use Journal Article
In: Sci Rep, vol. 12, no. 1, pp. 13027, 2022, ISSN: 2045-2322.
@article{pmid35906358,
title = {Differential association between the GLP1R gene variants and brain functional connectivity according to the severity of alcohol use},
author = {Mehdi Farokhnia and Samantha J Fede and Erica N Grodin and Brittney D Browning and Madeline E Crozier and Melanie L Schwandt and Colin A Hodgkinson and Reza Momenan and Lorenzo Leggio},
url = {https://pubmed.ncbi.nlm.nih.gov/35906358/},
doi = {10.1038/s41598-022-17190-3},
issn = {2045-2322},
year = {2022},
date = {2022-07-01},
urldate = {2022-07-01},
journal = {Sci Rep},
volume = {12},
number = {1},
pages = {13027},
abstract = {Growing evidence suggests that the glucagon-like peptide-1 (GLP-1) system is involved in mechanisms underlying alcohol seeking and consumption. Accordingly, the GLP-1 receptor (GLP-1R) has begun to be studied as a potential pharmacotherapeutic target for alcohol use disorder (AUD). The aim of this study was to investigate the association between genetic variation at the GLP-1R and brain functional connectivity, according to the severity of alcohol use. Participants were 181 individuals categorized as high-risk (n = 96) and low-risk (n = 85) alcohol use, according to their AUD identification test (AUDIT) score. Two uncommon single nucleotide polymorphisms (SNPs), rs6923761 and rs1042044, were selected a priori for this study because they encode amino-acid substitutions with putative functional consequences on GLP-1R activity. Genotype groups were based on the presence of the variant allele for each of the two GLP-1R SNPs of interest [rs6923761: AA + AG (n = 65), GG (n = 116); rs1042044: AA + AC (n = 114), CC (n = 67)]. Resting-state functional MRI data were acquired for 10 min and independent component (IC) analysis was conducted. Multivariate analyses of covariance (MANCOVA) examined the interaction between GLP-1R genotype group and AUDIT group on within- and between-network connectivity. For rs6923761, three ICs showed significant genotype × AUDIT interaction effects on within-network connectivity: two were mapped onto the anterior salience network and one was mapped onto the visuospatial network. For rs1042044, four ICs showed significant interaction effects on within-network connectivity: three were mapped onto the dorsal default mode network and one was mapped onto the basal ganglia network. For both SNPs, post-hoc analyses showed that in the group carrying the variant allele, high versus low AUDIT was associated with stronger within-network connectivity. No significant effects on between-network connectivity were found. In conclusion, genetic variation at the GLP-1R was differentially associated with brain functional connectivity in individuals with low versus high severity of alcohol use. Significant findings in the salience and default mode networks are particularly relevant, given their role in the neurobiology of AUD and addictive behaviors.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Growing evidence suggests that the glucagon-like peptide-1 (GLP-1) system is involved in mechanisms underlying alcohol seeking and consumption. Accordingly, the GLP-1 receptor (GLP-1R) has begun to be studied as a potential pharmacotherapeutic target for alcohol use disorder (AUD). The aim of this study was to investigate the association between genetic variation at the GLP-1R and brain functional connectivity, according to the severity of alcohol use. Participants were 181 individuals categorized as high-risk (n = 96) and low-risk (n = 85) alcohol use, according to their AUD identification test (AUDIT) score. Two uncommon single nucleotide polymorphisms (SNPs), rs6923761 and rs1042044, were selected a priori for this study because they encode amino-acid substitutions with putative functional consequences on GLP-1R activity. Genotype groups were based on the presence of the variant allele for each of the two GLP-1R SNPs of interest [rs6923761: AA + AG (n = 65), GG (n = 116); rs1042044: AA + AC (n = 114), CC (n = 67)]. Resting-state functional MRI data were acquired for 10 min and independent component (IC) analysis was conducted. Multivariate analyses of covariance (MANCOVA) examined the interaction between GLP-1R genotype group and AUDIT group on within- and between-network connectivity. For rs6923761, three ICs showed significant genotype × AUDIT interaction effects on within-network connectivity: two were mapped onto the anterior salience network and one was mapped onto the visuospatial network. For rs1042044, four ICs showed significant interaction effects on within-network connectivity: three were mapped onto the dorsal default mode network and one was mapped onto the basal ganglia network. For both SNPs, post-hoc analyses showed that in the group carrying the variant allele, high versus low AUDIT was associated with stronger within-network connectivity. No significant effects on between-network connectivity were found. In conclusion, genetic variation at the GLP-1R was differentially associated with brain functional connectivity in individuals with low versus high severity of alcohol use. Significant findings in the salience and default mode networks are particularly relevant, given their role in the neurobiology of AUD and addictive behaviors.
2021
Farokhnia, Mehdi; Murphy, Gwen; Weinstein, Stephanie J; Shah, Navan N; Parisi, Dominick; Albanes, Demetrius; Leggio, Lorenzo
In: Drug Alcohol Depend, vol. 226, pp. 108835, 2021, ISSN: 1879-0046.
@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}
}
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.
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.
Palzes, Vanessa A; Farokhnia, Mehdi; Kline-Simon, Andrea H; Elson, Joseph; Sterling, Stacy; Leggio, Lorenzo; Weisner, Constance; Chi, Felicia W
In: Neuropsychopharmacology, vol. 46, no. 12, pp. 2140–2147, 2021, ISSN: 1740-634X.
@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}
}
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.
Farokhnia, Mehdi; Abshire, Kelly M; Hammer, Aaron; Deschaine, Sara L; Saravanakumar, Anitha; Cobbina, Enoch; You, Zhi-Bing; Haass-Koffler, Carolina L; Lee, Mary R; Akhlaghi, Fatemeh; Leggio, Lorenzo
In: Int J Neuropsychopharmacol, vol. 24, no. 6, pp. 464–476, 2021, ISSN: 1469-5111.
@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}
}
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.
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.
Deschaine, Sara L; Farokhnia, Mehdi; Gregory-Flores, Adriana; Zallar, Lia J; You, Zhi-Bing; Sun, Hui; Harvey, Deon M; Marchette, Renata C N; Tunstall, Brendan J; Mani, Bharath K; Moose, Jacob E; Lee, Mary R; Gardner, Eliot; Akhlaghi, Fatemeh; Roberto, Marisa; Hougland, James L; Zigman, Jeffrey M; Koob, George F; Vendruscolo, Leandro F; Leggio, Lorenzo
A closer look at alcohol-induced changes in the ghrelin system: novel insights from preclinical and clinical data Journal Article
In: Addict Biol, vol. 27, no. 1, pp. e13033, 2021, ISSN: 1369-1600.
@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}
}
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.
Amin-Esmaeili, Masoumeh; Susukida, Ryoko; Johnson, Renee M; Farokhnia, Mehdi; Crum, Rosa M; Thrul, Johannes; Mojtabai, Ramin
In: Drug Alcohol Depend, vol. 226, pp. 108904, 2021, ISSN: 1879-0046.
@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}
}
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.
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.
2020
Farokhnia, Mehdi; Portelli, Jeanelle; Lee, Mary R; McDiarmid, Gray R; Munjal, Vikas; Abshire, Kelly M; Battista, Jillian T; Browning, Brittney D; Deschaine, Sara L; Akhlaghi, Fatemeh; Leggio, Lorenzo
In: Brain Res, vol. 1740, pp. 146851, 2020, ISSN: 1872-6240.
@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}
}
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.
Lee, Mary R; Tapocik, Jenica D; Ghareeb, Mwlod; Schwandt, Melanie L; Dias, Alexandra A; Le, April N; Cobbina, Enoch; Farinelli, Lisa A; Bouhlal, Sofia; Farokhnia, Mehdi; Heilig, Markus; Akhlaghi, Fatemeh; Leggio, Lorenzo
In: Mol Psychiatry, 2020, ISSN: 1476-5578 (Electronic); 1359-4184 (Linking).
@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}
}
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.
Farokhnia, Mehdi; McDiarmid, Gray R; Newmeyer, Matthew N; Munjal, Vikas; Abulseoud, Osama A; Huestis, Marilyn A; Leggio, Lorenzo
In: Translational Psychiatry, vol. 10, no. 1, pp. 71, 2020, ISBN: 2158-3188.
@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}
}
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.
2019
Assari, Shervin; Smith, James; Mistry, Ritesh; Farokhnia, Mehdi; Bazargan, Mohsen
Substance Use among Economically Disadvantaged African American Older Adults; Objective and Subjective Socioeconomic Status. Journal Article
In: Int J Environ Res Public Health, vol. 16, no. 10, 2019.
@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}
}
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.
Farokhnia, Mehdi; Browning, Brittney D; Leggio, Lorenzo
Prospects for pharmacotherapies to treat alcohol use disorder: an update on recent human studies Journal Article
In: Current Opinion in Psychiatry, vol. 32, no. 4, 2019, ISBN: 0951-7367.
@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}
}
Farokhnia, Mehdi; Faulkner, Monica L; Piacentino, Daria; Lee, Mary R; Leggio, Lorenzo
Ghrelin: From a gut hormone to a potential therapeutic target for alcohol use disorder Journal Article
In: Physiology & Behavior, vol. 204, pp. 49 - 57, 2019, ISSN: 0031-9384.
@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}
}
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.
2018
Farokhnia, Mehdi; Deschaine, Sara L; Sadighi, Armin; Farinelli, Lisa A; Lee, Mary R; Akhlaghi, Fatemeh; Leggio, Lorenzo
In: Mol Psychiatry, 2018, ISSN: 1476-5578 (Electronic); 1359-4184 (Linking).
@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}
}
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
Farokhnia, Mehdi; Sheskier, Mikela B; Lee, Mary R; Le, April N; Singley, Erick; Bouhlal, Sofia; Ton, Timmy; Zhao, Zhen; Leggio, Lorenzo
In: Neuropharmacology, vol. 137, pp. 230 - 239, 2018, ISSN: 0028-3908.
@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}
}
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.
2017
Farokhnia, M; Grodin, E N; Lee, M R; Oot, E N; Blackburn, A N; Stangl, B L; Schwandt, M L; Farinelli, L A; Momenan, R; Ramchandani, V A; Leggio, L
In: Mol Psychiatry, 2017, ISSN: 1476-5578 (Electronic); 1359-4184 (Linking).
@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}
}
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
Farokhnia, M; Schwandt, M L; Lee, M R; Bollinger, J W; Farinelli, L A; Amodio, J P; Sewell, L; Lionetti, T A; Spero, D E; Leggio, L
Biobehavioral effects of baclofen in anxious alcohol-dependent individuals: a randomized, double-blind, placebo-controlled, laboratory study Journal Article
In: Translational Psychiatry, vol. 7, no. 4, pp. e1108–e1108, 2017, ISBN: 2158-3188.
@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}
}
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
2014
Farokhnia, Mehdi; Sabzabadi, Maryam; Pourmahmoud, Hossein; Khodaie-Ardakani, Mohammad-Reza; Hosseini, Seyed-Mohammad-Reza; Yekehtaz, Habibeh; Tabrizi, Mina; Rezaei, Farzin; Salehi, Bahman; Akhondzadeh, Shahin
In: Psychopharmacology, vol. 231, no. 3, pp. 533–542, 2014, ISBN: 1432-2072.
@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}
}
Several recent studies have focused on glutamate modulating agents for symptoms relief in schizophrenia, especially negative symptoms which are resistant to conventional therapies.
2013
Farokhnia, Mehdi; Azarkolah, Anita; Adinehfar, Forod; Khodaie-Ardakani, Mohammad-Reza; Hosseini, Seyed-Mohammad-Reza; Yekehtaz, Habibeh; Tabrizi, Mina; Rezaei, Farzin; Salehi, Bahman; Sadeghi, Seyed-Mohammad-Hossein; Moghadam, Marzieh; Gharibi, Fardin; Mirshafiee, Omid; Akhondzadeh, Shahin
In: Clinical Neuropharmacology, vol. 36, no. 6, 2013, ISBN: 0362-5664.
@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}
}
2012
Khajavi, Danial; Farokhnia, Mehdi; Modabbernia, Amirhossein; Ashrafi, Mandana; Abbasi, Seyed-Hesammedin; Tabrizi, Mina; Akhondzadeh, Shahin
Oral scopolamine augmentation in moderate to severe major depressive disorder: a randomized, double-blind, placebo-controlled study. Journal Article
In: J Clin Psychiatry, vol. 73, no. 11, pp. 1428–1433, 2012, ISSN: 1555-2101 (Electronic); 0160-6689 (Linking).
@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}
}
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
