About

Daniel D. Langleben, MD, is an Emeritus Professor and Chair of Psychiatry at the University of Pennsylvania's Perelman School of Medicine. He serves as an Attending Psychiatrist at Penn Medicine and is a Staff Physician at the Philadelphia VA Medical Center. Dr. Langleben is a member of the Mahoney Institute for Neurological Sciences and a Distinguished Fellow at the Annenberg Public Policy Center, both at the University of Pennsylvania. His professional focus includes the use of brain imaging for lie detection, as well as research on brain responses related to addiction, emotional processing, and cognitive functions. His work has contributed to understanding the neural mechanisms underlying deception, addiction, and emotional stimuli, and he has published extensively on these topics.

Research topics

• Computer Science
• Internal medicine
• Neuroscience
• Psychology
• Medicine

Selected publications

• Emotional arousal of graphic cigarette warning labels loses its beneficial effects on craving reduction after repeated exposure – A longitudinal neuroimaging study

  Drug and Alcohol Dependence · 2026-01-29

  articleOpen access

  Graphic warning labels (GWLs) on cigarette packaging have been implemented in many countries. In the U.S., however, GWLs have faced legal challenges based on concerns that their aversive imagery elicits excessive emotional arousal without sufficient data to support its beneficial impact. This longitudinal study examined how GWLs’ level of arousal affects cigarette craving and neural responses related to emotional processing. A total of 158 adults who smoked cigarettes were exposed to either high-arousal (n=79) or low-arousal (n=79) GWLs attached to their cigarette packs for 4 weeks. Cigarette craving and brain responses to GWLs were measured using functional magnetic resonance imaging before and after the exposure period. The amygdala, a key region involved in emotional processing, was the brain region of interest. At baseline, high-arousal GWLs elicited a greater reduction in craving and stronger amygdala activation than low-arousal GWLs. However, by week 4, the differences in craving reduction and amygdala response between groups were no longer significant. Amygdala activity mediated the effect of GWLs on craving reduction, with the mediation effect being more pronounced in the high-arousal group than the low-arousal group at baseline but not at week 4. The impact of GWL-induced arousal on cigarette craving appears to diminish over time, likely due to habituation in amygdala reactivity. High-arousal GWLs do not provide sustained advantages over low-arousal ones. Low-arousal GWLs may represent a more practical and legally defensible approach to tobacco control in the U.S. • We tested the effects of cigarette GWLs evoking high vs. low emotional arousal. • High-arousal GWLs initially activated amygdala and reduced craving more strongly. • Differences between high- and low-arousal GWLs disappeared after 4-week exposure. • Amygdala habituation may underlie the diminishing effect of arousal over time. • High-arousal imagery in GWLs may not offer long-term benefits.

  PublisherDOI

• Effects of emotional arousal on amygdala neural response and cigarette craving reduction during repeated exposure to graphic warning labels

  medRxiv · 2025-03-28

  preprintOpen access

  Graphic warning labels (GWLs) have been implemented on cigarette packaging worldwide. In the U.S., GWLs have encountered legal obstacles based on the tobacco industry arguments that their aversive imagery unnecessarily triggers strong emotional arousal. This longitudinal study evaluated the effect of the high-arousal GWLs on cigarette craving and the neural substrates of emotional processing. 158 adult smokers were exposed to either high-arousal (n=79) or low-arousal (n=79) GWLs that were attached to their own cigarette packs for 4 weeks. Craving and brain activity in response to GWLs and control stimuli were measured using functional magnetic resonance imaging before and after the 4-week exposure. The amygdala, which plays a key role in emotional processing, served as the a priori region of interest. Results indicate that, at baseline, high-arousal GWLs elicited a larger reduction in craving and stronger amygdala neural response compared to low-arousal GWLs; however, at week 4, GWL-induced craving reduction and amygdala response became comparable between the high-arousal and low-arousal groups. Amygdala response mediated GWLs' effects on craving reduction, which was moderated by arousal and time in such a way that the amygdala's mediating role was more pronounced for high-arousal than low-arousal GWLs at baseline but did not differ between groups at week 4. Together, the results suggest that the impact of emotional arousal on cigarette cravings decreases over time, potentially due to the amygdala's diminishing responsivity to repeated presentations of high-arousal imagery. Low-arousal GWLs may represent a more feasible approach for tobacco control efforts in the U.S.

  PublisherOA PDFDOI

• MEDIAL PREFRONTAL NEUROPLASTICITY DURING EXTENDED-RELEASE NALTREXONE TREATMENT OF OPIOID USE DISORDER – A LONGITUDINAL STRUCTURAL MAGNETIC RESONANCE IMAGING STUDY

  The International Journal of Neuropsychopharmacology · 2025-02-01

  articleOpen access

  Abstract Background Opioid use disorder (OUD) has been linked to macroscopic structural alterations in the brain [1]. The monthly injectable, extended-release formulation of μ-opioid antagonist naltrexone (XR-NTX) is highly effective in reducing opioid craving and preventing opioid relapse [2,3]. Aims & Objectives We aimed to investigate the neuroanatomical effects of XR-NTX by examining the changes in cortical thickness during treatment for OUD. Method Forty-seven OUD patients underwent structural magnetic resonance imaging (sMRI) and were assessed for opioid craving on two sessions: less than 1 day before the first XR-NTX injection (i.e., pre- treatment session); and an average of 11 days after the first injection (i.e., on-treatment session). A sample of fifty-six non-OUD individuals who completed a single imaging session served as a comparison group. sMRI images were analyzed using the volume-based cortical thickness pipeline implemented in the Advanced Normalization Tools. A publicly available [11C]Carfentanil positron emission tomography (PET) dataset was used to assess the relationship between cortical thickness change and mu-opioid receptor (MOR) binding potential across brain regions. Results The thickness of the medial prefrontal and anterior cingulate cortices (mPFC/aCC) was comparable between the non-OUD individuals and the OUD patients at pre-treatment, but showed a significant reduction among the OUD patients from pre-treatment to on-treatment (whole-brain familywise error-corrected p<0.05) (see Figure 1A &1B). Patients with greater reduction in mPFC/aCC thickness also showed greater reduction in opioid craving from pre-treatment to on-treatment (R2=0.19, p=0.002) (see Figure 1C). Analysis with the [11C]Carfentanil PET data indicated that, across brain regions, there was a positive association between MOR binding potential and cortical thickness reduction in regions with relatively high MOR binding potential (R2=0.29, p<0.001) (see Figure 1D). Discussion & Conclusion XR-NTX treatment for OUD is associated with reduced cortical thickness in the mPFC and aCC regions. The reduction does not appear to indicate a restoration to the non-OUD level but rather reflects XR-NTX’ s distinct therapeutic impact on an MOR-rich brain structure. Our findings highlight the neuroplastic effects of XR-NTX that may inform the development of novel OUD interventions. References [1]Shi Z, Li X, Byanyima JI, O’ Brien CP, Childress AR, Lynch KG, et al. Effects of current smoking severity on brain gray matter volume in opioid use disorder– a voxel-based morphometry study. American Journal of Drug and Alcohol Abuse. 2023;49(2):180-9. [2]Krupitsky E, Nunes EV, Ling W, Illeperuma A, Gastfriend DR, Silverman BL. Injectable extended- release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomised trial. Lancet. 2011;377(9776):1506-13. [3]Shi Z, Wang A-L, Jagannathan K, Fairchild VP, O’ Brien CP, Childress AR, et al. Effects of extended- release naltrexone on the brain response to drug-related stimuli in patients with opioid use disorder. Journal of Psychiatry and Neuroscience. 2018;43(4):254-61.

  PublisherOA PDFDOI

• Drug Use Severity is Linked to Reduced Brain Network Segregation in Opioid Use Disorder

  Drug and Alcohol Dependence · 2025-02-01

  article
  PublisherDOI

• Long-acting naltrexone restores network connectivity in subjects with co-morbid cannabis and opioid use disorder

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-19

  preprintOpen access

  Comorbid substance use disorders (SUDs) are common but difficult to study due to the complex, interacting and overlapping mechanisms through which they affect brain networks. Many datasets collected to investigate a specific SUD include participants with comorbid SUDs. Although most studies treat comorbid SUDs as covariates of no interest, these covariates also contain untapped information. This is particularly relevant as cannabis use disorder (CanUD) has become increasingly prevalent and comorbid with other SUDs that have been more thoroughly studied. While pharmacotherapies have been established for multiple SUDs, none have been approved for CanUD, although naltrexone (NTX) has been associated with reduced use. Here, we conducted a retrospective secondary analysis of functional magnetic resonance imaging (fMRI) data from individuals with primary opioid use disorder (OUD-only, N = 25 pre-NTX, N = 20 on-NTX) with comorbid CanUD (N = 10), alcohol use disorder (AUD, N = 6) or cocaine use disorder (CocUD, N = 7). All participants underwent imaging prior to receiving a therapeutic dose of long-acting intramuscular NTX (Vivitrol), an approved treatment for OUD and AUD but not for CocUD, and again 2 weeks postadministration. At baseline, OUD individuals with comorbid CanUD, AUD or CocUD exhibited distinct functional connectivity (FC) alterations compared to those with OUD-only. These differences were greater in younger participants and primarily involved the default mode network. Following NTX administration, FC differences between the comorbid CanUD and OUD-only groups globally diminished. A similar FC response to NTX was observed in the comorbid AUD group, whereas little change in FC was observed in comorbid CocUD. These findings, combined with prior evidence that NTX reduces cannabis use by dampening reward, suggest NTX may hold promise as a treatment for CanUD.

  PublisherOA PDFDOI

• Brain network segregation is associated with drug use severity in individuals with opioid use disorder

  Drug and Alcohol Dependence · 2025-09-04

  articleOpen access
  PublisherOA PDFDOI

• The effect of pre-release treatment with injectable naltrexone on criminal justice and substance use outcomes: Results from a randomized controlled trial

  Journal of Experimental Criminology · 2025-01-30

  articleOpen accessSenior author

  Abstract Objectives Evaluate the impact of extended-release naltrexone (XR-NTX) on postrelease criminal justice contact and substance use among individuals with opioid use disorder in correctional settings. Methods A randomized waitlist-controlled trial was conducted. The treatment group ( n = 47) received XR-NTX shortly before release, and the comparison group ( n = 47) was put on a waitlist for treatment at six months post-release. Outcomes were measured at 3 and 6 months post-release and included new arrests, parole revocations, reincarceration, and positive drug tests. Data were analyzed using t -tests and Kaplan–Meier survival estimates. Results At 3 months post-release, the treatment group had marginally fewer parole revocations. At 6 months, there were no significant differences in criminal justice or substance use outcomes, though the treatment group had fewer positive drug tests and a longer time to first positive drug test. Conclusions There is limited evidence that XR-NTX reduces poor criminal justice and substance use outcomes.

  PublisherOA PDFDOI

• Delayed Effects of Cigarette Graphic Warning Labels on Smoking Behavior

  American Journal of Health Promotion · 2025-07-16 · 1 citations

  articleOpen accessSenior author

  Purpose Graphic warning labels (GWLs) are widely employed to communicate smoking-related health risks. Most GWLs elicit a high level of emotional reaction (ER). Our recent study showed poorer efficacy of high-ER GWLs vs low-ER ones during a month-long naturalistic exposure. Here, we aimed to examine whether GWL effects persist after discontinuing the exposure. Design A secondary analysis investigated the delayed GWL effects on smoking severity. Setting Philadelphia Metropolitan Area, United States. Subjects 96 adult smokers who completed a month-long exposure to high-ER or low-ER GWLs. Measures The number of cigarettes smoked per day (CPD) was measured immediately and 4 weeks after the end of GWL exposure. Participants also indicated their subjective feeling of being relieved from having to see the GWLs. Analysis Generalized estimating equations examined the change in CPD across time and its association with sense of relief. Results We found a significant reduction in CPD from the immediate to the 4-week post-exposure timepoint (11.69 vs 10.30, P = 0.001). There was no difference between the high-ER and low-ER groups in CPD reduction ( P = 0.74). Higher sense of relief was associated with greater CPD reduction in the high-ER group (z = −2.14, P = 0.033). Conclusion Our study suggests lasting impact of GWLs on smoking behavior. The findings may be particularly important to high-ER GWLs, which appear less effective in reducing smoking during active exposure.

  PublisherDOI

• Brain Network Segregation is Associated with Drug Use Severity in Individuals with Opioid Use Disorder

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-04 · 1 citations

  preprintOpen access

  Opioid use disorder (OUD) is associated with altered brain network connectivity, particularly in the fronto-parietal (FPN), default mode, and salience (SN) networks. At rest, brain networks that are distinct from each other but are partially connected can optimize neural efficiency and support cognitive performance. Previous research found lower network segregation in people with cognitive impairment, alcohol use disorder, and as people age. Here, we examined brain network segregation (a graph theory-based metric of the network integration/segregation balance) in individuals with OUD and hypothesized that recent drug use severity would be linked to reduced network segregation. Forty adults with OUD completed resting-state functional magnetic resonance imaging, the drug use severity subscale of the Addiction Severity Index, and measures of cognition (IQ and working memory), mood, and affect. We grouped 264 brain regions into 10 networks, categorized as association (higher-order cognition) or sensorimotor (sensory and motor) networks. Regression analyses showed that drug use severity predicted lower brain network segregation in the association networks, with the FPN and SN driving this effect. Age predicted lower brain network segregation in the sensorimotor networks, while an interaction with age showed that drug use severity only predicted lower sensorimotor network segregation in younger adults. Cognition did not relate to brain network segregation, but positive affect related to greater SN segregation. Brain network segregation remained stable across OUD treatment. These findings elucidate alterations in brain network segregation related to drug use severity in people with OUD, which may contribute to cognitive impairment and accelerated brain aging.

  PublisherOA PDFDOI

• Collateral Damage: Neurological Correlates of Non-Fatal Overdose in the Era of Fentanyl-Xylazine

  Neuroscience Insights · 2024-01-01 · 17 citations

  articleOpen access

  Non-fatal opioid overdoses are associated with significant morbidity. Hypoxic brain injury caused by opioid-induced respiratory depression is a key mechanism of such morbidity. For example, reports describe an amnestic syndrome in opioid users associated with acute injury to the hippocampus, a brain region that is highly susceptible to hypoxic injury. In our recent study we investigated the effects of non-fatal opioid overdose on the hippocampal volume in a well-characterized sample of opioid use disorder (OUD) patients with a history of overdose (OD) compared to those with no prior overdose (NOD). Using structural magnetic resonance imaging (MRI) and voxel-based morphometry, we observed lower hippocampal volume in patients with a history OD than in the NOD group. These findings support an association between non-fatal opioid overdose and hippocampal injury, which we hypothesize contributes to recently reported cases of OUD related amnestic syndrome. Here we review our study findings and the potential pathophysiological mechanisms underlying the acute and delayed hippocampal injury in nonfatal opioid overdose. We also discuss the implications for the risk of overdose and brain injury with the increased prevalence of fentanyl and xylazine contamination of the illicit opioid supply. Lastly, we highlight considerations for clinical management of the underappreciated neurological injury and cognitive dysfunction in OUD patients.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R21DA024419

  NIH · $1.5M · 2013

• Neurobiology of care giving in opioid dependent mothers

  NIH · $409k · 2017–2020

• Brain and behavioral effects of graphic cigarette warning labels

  NIH · $2.9M · 2013–2020

• Neuroimaging study of HIV-prevention public service announcements

  NIH · $320k · 2013–2018

• NIH Grant K23DA015746

  NIH · $902k · 2009

Frequent coauthors

• Anna Rose Childress

  California University of Pennsylvania

  52 shared

• Charles P. O’Brien

  49 shared

• Jesse J. Suh

  39 shared

• Ronald N. Ehrman

  Philadelphia VA Medical Center

  36 shared

• Igor Elman

  Cambridge Health Alliance

  34 shared

• Zhenhao Shi

  University of Pennsylvania

  31 shared

• Michael J. Gawrysiak

  West Chester University

  24 shared

• Kanchana Jagannathan

  22 shared

Labs

• Langleben LabPI

Awards & honors

• Distinguished Fellow, Annenberg Public Policy Center, Univer…