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STUDY OBJECTIVES: Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, is approved in the United States and European Union for excessive daytime sleepiness in adults with narcolepsy (75–150 mg/day) or obstructive sleep apnea (OSA; 37.5–150 mg/day). In 12-week studies, solriamfetol was associated with improvements in quality of life in participants with narcolepsy or OSA. These analyses evaluated the long-term effects of solriamfetol on quality of life. METHODS: Participants with narcolepsy or OSA who completed previous solriamfetol studies were eligible. A 2-week titration was followed by a maintenance phase ≤ 50 weeks (stable doses: 75, 150, or 300 mg/day). Quality of life assessments included Functional Outcomes of Sleep Questionnaire short version, Work Productivity and Activity Impairment Questionnaire: Specific Health Problem, and 36-Item Short Form Health Survey version 2. Mean (standard deviation) changes from baseline to end of study were evaluated. Data were summarized descriptively. Adverse events were assessed. RESULTS: Safety population comprised 643 participants (417 OSA, 226 narcolepsy). Solriamfetol improved Functional Outcomes of Sleep Questionnaire short version Total scores (mean change [standard deviation], 3.7 [3.0]) and 36-Item Short Form Health Survey version 2 Physical and Mental Component Summary scores (3.1 [6.9] and 4.3 [8.4], respectively); improvements were sustained throughout treatment. On Work Productivity and Activity Impairment Questionnaire: Specific Health Problem, solriamfetol reduced (improved) % presenteeism, % overall work impairment, and % activity impairment by a minimum of 25%. Common adverse events (≥ 5%): headache, nausea, nasopharyngitis, insomnia, dry mouth, anxiety, decreased appetite, and upper respiratory tract infection. CONCLUSIONS: Long-term solriamfetol treatment was associated with clinically meaningful, sustained improvements in functional status, work productivity, and quality of life for up to 52 weeks. Adverse events were similar between narcolepsy and OSA. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: A Long-Term Safety Study of JZP-110 in the Treatment of Excessive Sleepiness in Subjects with Narcolepsy or OSA; Identifier: NCT02348632; URL: https://clinicaltrials.gov/ct2/show/NCT02348632 CITATION: Weaver TE, Pepin J-L, Schwab R, et al. Long-term effects of solriamfetol on quality of life and work productivity in participants with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea. J Clin Sleep Med. 2021;17(10):1995–2007.

Objectives: This analysis characterized changes in weight in participants with obstructive sleep apnea (OSA) or narcolepsy treated with solriamfetol (SunosiTM) 37.5 (OSA only), 75, 150, or 300 mg/d. Methods: In two 12-week, randomized, placebo-controlled trials and one 1-year open-label extension study, changes in weight were evaluated from baseline to end of study (week 12 or week 40 of the open -label extension [after up to 52 weeks of solriamfetol treatment]) in participants with OSA or narcolepsy. Results: After 12 weeks of solriamfetol treatment, median percent change in weight from baseline across all solriamfetol doses was-0.84%, compared with 0.54% for placebo, in participants with OSA; and-0.07%, compared with 3.08% for placebo, in participants with narcolepsy. After up to 52 weeks of solriamfetol treatment, overall median percent change in weight from baseline was-1.76%, which showed a dose-dependent pattern (75 mg, 0.57%; 150 mg,-1.2%; 300 mg,-2.5%).Results were similar in subgroups of participants with OSA or narcolepsy, with overall median percent changes in weight of-2.2% and-1.1%, respectively. After up to 52 weeks of solriamfetol treatment, the percentage of participants with weight loss >= 5% relative to baseline was 25.7% overall and increased in a dose -dependent manner (75 mg, 4.5%; 150 mg, 17.3%; 300 mg, 32.4%). Results were similar among sub-groups of participants with OSA or narcolepsy, with 26.4% and 24.2% of participants experiencing weight loss >= 5%, respectively. No weight-related treatment-emergent adverse events were serious. Conclusions: Solriamfetol treatment was associated with decreases in body weight in a dose-related manner.(c) 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background Solriamfetol, a dopamine-norepinephrine reuptake inhibitor, is approved in the United States to improve wakefulness in adults with excessive daytime sleepiness (EDS) associated with OSA (37.5-150 mg/d). Research Question Does solriamfetol have differential effects on EDS based on adherence to primary OSA therapy and does solriamfetol affect primary OSA therapy use? Study Design and Methods Participants were randomized to 12 weeks of placebo or solriamfetol 37.5, 75, 150, or 300 mg/d (stratified by primary OSA therapy adherence). Coprimary end points were week 12 change from baseline in 40-min Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) in the modified intention-to-treat population. Primary OSA therapy use (hours per night, % nights) and safety were evaluated. Results At baseline, 324 participants (70.6%) adhered to OSA therapy (positive airway pressure use ≥ 4 h/night on ≥ 70% nights, surgical intervention, or oral appliance use on ≥ 70% nights) and 135 participants (29.4%) did not adhere. Least squares (LS) mean differences from placebo in MWT sleep latency (minutes) in the 37.5-, 75-, 150-, and 300-mg/d groups among adherent participants were 4.8 (95% CI, 0.6-9.0), 8.4 (95% CI, 4.3-12.5), 10.2 (95% CI, 6.8-13.6), and 12.5 (95% CI, 9.0-15.9) and among nonadherent participants were 3.7 (95% CI, –2.0 to 9.4), 9.9 (95% CI, 4.4-15.4), 11.9 (95% CI, 7.5-16.3), and 13.5 (95% CI, 8.8-18.3). On ESS, LS mean differences from placebo in the 37.5-, 75-, 150-, and 300-mg/d groups among adherent participants were –2.4 (95% CI, –4.2 to –0.5), –1.3 (95% CI, –3.1 to 0.5), –4.2 (95% CI, –5.7 to –2.7), and –4.7 (95% CI, –6.1 to –3.2) and among nonadherent participants were –0.7 (95% CI, –3.5 to 2.1), –2.6 (95% CI, –5.4 to 0.1), –5.0 (95% CI, –7.2 to –2.9), and –4.6 (95% CI, –7.0 to –2.3). Common adverse events included headache, nausea, anxiety, decreased appetite, nasopharyngitis, and diarrhea. No clinically meaningful changes were seen in primary OSA therapy use with solriamfetol. Interpretation Solriamfetol improved EDS in OSA regardless of primary OSA therapy adherence. Primary OSA therapy use was unaffected with solriamfetol. Trial Registry ClinicalTrials.gov; No.: NCT02348606; URL: www.clinicaltrials.gov; EU Clinical Trials Register; No.: EudraCT2014-005514-31; URL: www.clinicaltrialsregister.eu, Graphical abstract

STUDY OBJECTIVES: Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, is approved in the United States and European Union to treat excessive daytime sleepiness in patients with obstructive sleep apnea (OSA) (37.5–150 mg/day) and narcolepsy (75–150 mg/day). This analysis evaluated solriamfetol’s efficacy in subgroups of participants with OSA who were adherent or nonadherent to primary OSA therapy at baseline and examined whether solriamfetol affected the use of primary therapy in an open-label extension trial. METHODS: Participants with OSA who completed prior solriamfetol studies received solriamfetol 75, 150, or 300 mg/day for ≤ 52 weeks. The main efficacy outcome was the Epworth Sleepiness Scale score. Primary therapy use was summarized as the percentage of nights, the number of hours/night, and the percentage of nights with use ≥ 50%/night (%). Efficacy and primary therapy use are reported for participants who directly enrolled from a previous 12-week study and had ≤ 40 weeks of open-label treatment (n = 333). Safety data are reported for all participants (n = 417). RESULTS: Mean ESS scores in adherent (n = 255) and nonadherent (n = 78) subgroups, respectively, were 15.0 and 15.8 at baseline (of 12-week study) and 6.5 and 6.8 at week 40. For participants using an airway therapy, mean use at baseline was 90% of nights, 6.6 hours/night, and use ≥ 50%/night on 90% of nights; changes from baseline to week 40 were minimal (0.9%, −0.8 hours, and 6.5%, respectively). Common adverse events (both subgroups) included headache, nasopharyngitis, insomnia, dry mouth, nausea, anxiety, and upper respiratory tract infection. CONCLUSIONS: Long-term efficacy and safety of solriamfetol were similar regardless of adherence to primary OSA therapy. Solriamfetol did not affect primary therapy use. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: A Long-Term Safety Study of JZP-110 in the Treatment of Excessive Sleepiness in Subjects with Narcolepsy or OSA; URL: https://clinicaltrials.gov/ct2/show/NCT02348632; Identifier: NCT02348632 and Registry: EU Clinical Trials Register; Identifier: 2014-005489-31; URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-005489-31.. CITATION: Schweitzer PK, Strohl KP, Mayer G, et al. Effects of solriamfetol in a long-term trial of participants with obstructive sleep apnea who are adherent or nonadherent to airway therapy. J Clin Sleep Med. 2021;17(4):659–668.

Introduction Treatment with sodium oxybate (SXB) has been associated with weight loss in patients with narcolepsy. Lower-sodium oxybate (LXB) contains the same active moiety as SXB, with 92% less sodium, and is approved in the United States for the treatment of idiopathic hypersomnia in adults. This analysis assessed weight changes during LXB treatment in a phase 3 clinical study (NCT03533114). Methods Participants 18–75 years of age with idiopathic hypersomnia (treatment naive or taking an alerting agent [with or without SXB] at study entry) began LXB treatment in a 10- to 14-week, open-label, optimized treatment and titration period. After a 2-week stable-dose period (SDP) on their optimized dose of LXB, participants were randomized (1:1) to LXB or placebo for a 2-week, double-blind, randomized withdrawal period, followed by a 24-week open-label extension (OLE). Results Study participants (N=154) had a mean (SD) age of 40.3 (13.7) years; baseline mean (SD) weight was 76.9 (18.6) kg, and baseline mean (SD) body mass index (BMI) was 27.1 (5.9) kg/m2. At baseline, 1.3% (2/154) of participants were underweight (BMI Conclusion In this phase 3 clinical trial, adults with idiopathic hypersomnia treated with LXB experienced weight loss, including weight loss ≥5% in 28.7% of participants. Mean weight loss was greater in participants with a higher baseline BMI. Support (If Any) Jazz Pharmaceuticals.

Introduction Idiopathic hypersomnia (IH) is a rare central hypersomnolence disorder. In a randomized, controlled study of lower-sodium oxybate (LXB; Xywav™) in adults with IH (NCT03533114), significant differences for LXB compared with placebo were observed in Epworth Sleepiness Scale (ESS; primary efficacy endpoint), self-reported Patient Global Impression of Change (PGIc), and IH Severity Scale (IHSS; key secondary endpoints). In this clinical study, investigators were permitted to initiate LXB dosing on a once-nightly or twice-nightly regimen. Methods Eligible participants aged 18–75 years began LXB treatment, administered once or twice nightly during an open-label treatment/titration and optimization period (OLTTOP; 10–14 weeks); dose amount/regimen could be adjusted during this period. Participants next entered a 2-week, open-label, stable-dose period (SDP), then were randomized to placebo or to continue LXB treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). P values are nominal for this exploratory analysis. Results Of 154 enrolled participants, 40 (26%) initiated LXB treatment on a once-nightly regimen. In the efficacy population (n=115), 27 participants were on a once-nightly regimen during SDP (48.1% of whom initiated treatment once nightly during OLTTOP) and 88 participants were on a twice-nightly regimen during SDP (86.4% of whom initiated treatment twice nightly during OLTTOP). During SDP, median (min, max) LXB total dose was 4.5 (2.5, 6) g/night (once-nightly group) and 7.5 (4.5, 9) g/night (twice-nightly group). ESS scores worsened in participants randomized to placebo vs those continuing LXB in the once-nightly group (n=11 and n=15, respectively; LS mean difference [95% CI]: −4.93 [−7.41, −2.46]; P=0.0004) and twice-nightly group (n=47 and n=41, respectively; LS mean difference [95% CI]: −7.44 [−9.15, −5.72]; P Conclusion The efficacy and safety of LXB in IH were demonstrated for both once-nightly and twice-nightly regimens. The majority of participants initiated and remained on a twice-nightly regimen. Support (if any) Jazz Pharmaceuticals

Introduction Solriamfetol (formerly JZP-110), a dopamine and norepinephrine reuptake inhibitor, has been approved in the United States to improve wakefulness in adults with excessive daytime sleepiness (EDS) associated with narcolepsy (75–150 mg) or obstructive sleep apnoea (OSA; 37.5–150 mg). A Marketing Authorisation Application for these indications is under review with the European Medicines Agency. This study evaluated the long-term safety and efficacy of solriamfetol. Methods Participants with EDS associated with narcolepsy or OSA who completed prior solriamfetol studies initiated open-label treatment with a 2-week titration phase followed by a maintenance phase of ≤50 weeks. A 2-week, placebo-controlled, randomised withdrawal (RW) phase was conducted after 6 months. Change from beginning to end of the RW phase in Epworth Sleepiness Scale (ESS) was the primary endpoint; Patient and Clinician Global Impression of Change (PGI-C and CGI-C, respectively) were secondary endpoints. Results Safety population comprised 643 participants (226 narcolepsy; 417 OSA); 280 participants (141 placebo; 139 solriamfetol) comprised the RW modified intent-to-treat population. A total of 458 participants (71%) completed the study. Maintenance of efficacy in this 1-year study was demonstrated on the ESS, PGI-C, and CGI-C. Least squares mean change from the beginning to the end of the RW phase in ESS score was 5.3 versus 1.6 in participants randomised to placebo or solriamfetol, respectively (P Discussion These results demonstrate the long-term efficacy of solriamfetol for EDS in participants with narcolepsy or OSA. Safety profile following long-term administration was consistent with prior solriamfetol studies. Support Jazz Pharmaceuticals.

Study Objectives To evaluate long-term safety and maintenance of efficacy of solriamfetol treatment for excessive daytime sleepiness in narcolepsy and obstructive sleep apnea (OSA). Methods Participants with narcolepsy or OSA who completed a prior solriamfetol study were eligible. A 2-week titration period was followed by a maintenance phase (up to 50 weeks). Efficacy was assessed by Epworth Sleepiness Scale (ESS) and Patient and Clinical Global Impression of Change (PGI-C and CGI-C, respectively). After approximately 6 months of treatment, a subgroup entered a 2-week placebo-controlled randomized withdrawal (RW) phase. Change in ESS from beginning to end of the RW phase was the primary endpoint; PGI-C and CGI-C were secondary endpoints. Safety was assessed throughout the study. Results In the maintenance phase, solriamfetol-treated participants demonstrated clinically meaningful improvements on ESS, PGI-C, and CGI-C. In the RW phase, least squares mean change on ESS was 1.6 in participants continuing solriamfetol versus 5.3 in participants switched to placebo (p < .0001). For both secondary endpoints, higher percentages of participants receiving placebo were reported as worse at the end of the RW phase versus solriamfetol (p < .0001). Common treatment-emergent adverse events (TEAEs) with solriamfetol were headache, nausea, nasopharyngitis, insomnia, dry mouth, anxiety, decreased appetite, and upper respiratory tract infection; 27 (4.2%) participants experienced at least one serious TEAE, and 61 (9.5%) withdrew because of TEAEs. Conclusions This study demonstrated long-term maintenance of efficacy of solriamfetol under open-label and double-blind, placebo-controlled conditions. Safety profile of solriamfetol was consistent with previous 12-week studies; no new safety concerns were identified. Trial Registration NCT02348632

Introduction Idiopathic hypersomnia (IH) is a rare central hypersomnolence disorder with no approved treatment, characterized by excessive daytime sleepiness, prolonged sleep time, and sleep inertia. The Idiopathic Hypersomnia Severity Scale (IHSS) is a 14-item, self-reported questionnaire that assesses severity of IH symptoms, including symptoms related to night/inertia (component I) and day/performance (component II). Individual IHSS items measure symptom frequency, intensity, and consequences using 3- or 4-point Likert scales, yielding a total score (range, 0–50), comprising component I (range, 0–16) and component II (range, 0–34). Higher scores indicate worse symptoms. In a recent clinical trial of the efficacy and safety of lower-sodium oxybate (LXB; Xywav™) for the treatment of IH, the IHSS was a key efficacy measure. Methods Eligible participants 18–75 years of age with IH began LXB treatment with an open-label treatment titration and optimization period (OLTTOP; 10–14 weeks), followed by a 2-week stable-dose period (SDP). Participants were randomized to placebo or continued LXB treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). The IHSS was completed at baseline, during OLTTOP (weeks 1, 4, and 8), and at the end of OLTTOP, SDP, and DBRWP. Change in IHSS total score from SDP to DBRWP was a key secondary endpoint. Results The efficacy population included 115 participants (mean±SD age, 41±14 years; 71% female). At baseline and the end of SDP, respectively, mean±SD IHSS scores were 31.6±8.3 and 15.3±8.5 for total score, 10.3±3.6 and 5.4±2.8 for component I (night/inertia), and 21.2±5.8 and 9.9±6.5 for component II (day/performance). Worsening from SDP to DBRWP was observed in patients randomized to placebo compared with LXB in IHSS total scores (estimated median difference [95% CI], −12.0 [−15.0, −8.0]; significant P Conclusion These results support the efficacy of LXB for the treatment of IH symptoms, as assessed with the IHSS. Support (if any) Jazz Pharmaceuticals

Introduction The Idiopathic Hypersomnia Severity Scale (IHSS) is a 14-item, self-reported questionnaire that assesses core Idiopathic Hypersomnia (IH) symptom severity. The relationship between IHSS scores and other IH symptom measures, such as the Epworth Sleepiness Scale (ESS; measures daytime sleepiness), sleep inertia visual analog scale (VAS-SI; measures sleep inertia), and Patient Global Impression of Change (PGIc; measures patients’ self-assessed change in symptoms), has not been established. This post hoc analysis analyzed correlations between the IHSS and ESS, VAS-SI, and PGIc using data from a clinical trial (NCT03533114) evaluating lower-sodium oxybate (LXB; Xywav™) for the treatment of IH. Methods During a clinical trial, the IHSS (0–50 score range) and ESS (0–24 score range) were completed at baseline; the IHSS, ESS, and PGIc (ordinal, 7 categories) were completed during an open-label treatment titration and optimization period (OLTTOP), after the OLTTOP, after a stable-dose period (SDP), and after a double-blind, randomized withdrawal period (DBRWP). The VAS-SI (0–100 score range) was completed during screening, SDP, and DBRWP. Correlation coefficients (rs) for IHSS vs ESS and VAS-SI were estimated from the within-subject variance matrix using a repeated-measures linear mixed model (LMM). The correlation between changes in IHSS score and PGIc was assessed using a Kruskal-Wallis test. Results IHSS scores correlated positively with ESS scores (rs [95% CI], 0.77 [0.73, 0.81]) and VAS-SI scores (0.69 [0.63, 0.75]). IHSS total score change was correlated with PGIc rank (chi-square with 6 degrees of freedom = 595.8, nominal P Conclusion IHSS scores or score changes strongly correlated with individual instruments assessing excessive daytime sleepiness, sleep inertia, and self-reported global symptoms, suggesting that the IHSS is a reliable, comprehensive measure of these symptoms of IH. Support (if any) Jazz Pharmaceuticals

Introduction Idiopathic hypersomnia (IH) is a rare central hypersomnolence disorder characterized by excessive daytime sleepiness, prolonged nighttime sleep, and sleep inertia. No US/EU medication is approved for treatment of IH. Lower-sodium oxybate (LXB; Xywav™; previously designated JZP-258) is a novel oxybate treatment with 92% less sodium than sodium oxybate (Xyrem®). The efficacy and safety of LXB was evaluated in adults with IH. Methods Eligible participants aged 18–75 years with IH began once- or twice-nightly LXB treatment entering an open-label titration and optimization period (10–14 weeks), followed by a 2-week, open-label, stable-dose period (SDP); they were then randomized to placebo or to continue LXB treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). The primary efficacy endpoint was change in Epworth Sleepiness Scale (ESS) score; key secondary endpoints were proportion of participants who reported worsening (minimally/much/very much worse) on Patient Global Impression of Change (PGIc) and change in Idiopathic Hypersomnia Severity Scale (IHSS) score, all from end of SDP to end of DBRWP. Results The study enrolled 154 participants (mean±SD age, 40±14 years; 68% female; mean±SD ESS, 16±3.6); mean±SD dose was 6.0±1.6 g/night. Mean±SD ESS score (n=115) decreased over open-label titration/optimization (15.7±3.8 at baseline, 9.8±4.5 at week 4, and 6.1±4.0 at the end of the SDP). At the end of the DBRWP, significant worsening was observed in participants randomized to placebo, compared with maintenance of improvement in participants randomized to continue LXB, in ESS scores (n=115; LS mean difference [95% CI] in change from SDP, −6.51 [−7.99, −5.03]; P Conclusion In participants with IH, LXB demonstrated a clinically meaningful effect on excessive daytime sleepiness, self-reported global change, and overall IH symptom severity. The overall safety profile was consistent with that of LXB in narcolepsy. Support (if any) Jazz Pharmaceuticals

MicroRNAs (miRNAs) released into the peripheral circulation upon cellular injury have shown a promise as a new class of tissue-specific biomarkers. We were first to demonstrate that next-generation sequencing analysis of serum from human subjects with acetaminophen-induced liver injury revealed a specific signature of circulating miRNAs. We consequently hypothesized that different types of hepatic liver impairments might feature distinct signatures of circulating miRNAs and that this approach might be useful as minimally invasive diagnostic "liquid biopsies" enabling the interrogation of underlying molecular mechanisms of injury in distant tissues. Therefore we examined serum circulating miRNAs in a total of 72 serum samples from a group of 53 subjects that included patients with accidental acetaminophen overdose, hepatitis B infection, liver cirrhosis and type 2 diabetes as well as gender-and age-matched healthy subjects with no evidence of liver disease. The miRNA signatures were identified using next-generation sequencing that provided analysis for the whole miRNome, including miRNA isoforms. Compared to the healthy subjects, a total of 179 miRNAs showed altered serum levels across the diseased subjects. Although many subjects have elevated alanine aminotransferase suggesting liver impairments, we identified distinct miRNA signatures for different impairments with minimum overlap. Furthermore, the bioinformatics analysis of miRNA signatures revealed relevant molecular pathways associated with the mechanisms of toxicity and or pathogenesis of disease. Interestingly, the high proportion of miRNA isoforms present in the respective signatures indicated a new level of complexity in cellular response to stress or disease. Our study demonstrates for the first time that signatures of circulating miRNAs show specificity for liver injury phenotypes and, once validated, might become useful for diagnosis of organ pathologies as "liquid biopsies".

The opportunity to engage in scientific research is an important, but often neglected, component of undergraduate training in biology. We describe the curriculum for an innovative, course‐based undergraduate research experience (CURE) appropriate for a large, introductory cell and molecular biology laboratory class that leverages students′ high level of interest in cancer. The course is highly collaborative and emphasizes the analysis and interpretation of original scientific data. During the course, students work in teams to characterize a collection of mutations in the human p53 tumor suppressor gene via expression and analysis in yeast. Initially, student pairs use both qualitative and quantitative assays to assess the ability of their p53 mutant to activate expression of reporter genes, and they localize their mutation within the p53 structure. Through facilitated discussion, students suggest possible molecular explanations for the transactivation defects displayed by their p53 mutants and propose experiments to test these hypotheses that they execute during the second part of the course. They use a western blot to determine whether mutant p53 levels are reduced, a DNA‐binding assay to test whether recognition of any of three p53 target sequences is compromised, and fluorescence microscopy to assay nuclear localization. Students studying the same p53 mutant periodically convene to discuss and interpret their combined data. The course culminates in a poster session during which students present their findings to peers, instructors, and the greater biosciences community. Based on our experience, we provide recommendations for the development of similar large introductory lab courses. © 2016 by The International Union of Biochemistry and Molecular Biology, 45(2):161–178, 2017.

The different clinical trajectories of cocaine-dependent men and women may be a consequence of distinct neurobiological substrates. Hypoperfusion of the orbitofrontal cortex (OFC) has previously been reported in individuals addicted to cocaine and has been posited as a biological mediator of relapse due to impulsivity or impaired decision making.This study assessed regional cerebral blood flow (rCBF) between abstinent cocaine-dependent men and women and sex-matched healthy controls.Cocaine-dependent subjects were abstinent from cocaine for 11 to 28 days and had no other major mental health or substance use disorders. rCBF was assessed with single photon emission computed tomography after administration of a placebo saline infusion. A resting scan was also obtained in a subset of cocaine-dependent and control men.In the 35 cocaine-dependent and 37 healthy control subjects examined, a sex-by-group effect was observed for the left lateral (P=0.001), right lateral (P=0.002), and medial (P0.02) OFC. Cocaine-dependent men demonstrated significantly lower right and left lateral, but not medial, OFC rCBF compared with sex-matched healthy controls after placebo infusion (Por=0.001). Similar bilateral OFC decreases were observed in male cocaine-dependent subjects at rest. In contrast, cocaine-dependent women showed lower rCBF in the medial, but not lateral, OFC relative to sex-matched healthy controls after placebo infusion (P0.01). Male cocaine-dependent subjects also showed decreased rCBF (P0.01) in the bilateral anterolateral temporal cortex and anterior cingulate, whereas decreased rCBF was observed in female cocaine-dependent subjects in the bilateral superior frontal gyri. Large and diffuse areas of increased rCBF were observed after placebo infusion in cocaine-dependent men, but not in women, relative to sex-matched healthy controls.rCBF appears to be reduced in the bilateral OFC in cocaine-dependent men and in the medial OFC in cocaine-dependent women. Sex differences in the medial and lateral OFC rCBF may be relevant to understanding relapse characteristics differentiating men and women addicted to cocaine.

Disruption of Hypothalamic-Pituitary-Adrenal (HPA) axis activity is recognized as a pathophysiological alteration during the intoxicating, withdrawal, and abstinence phases of alcoholism. A number of studies have documented the increase in cortisol secretion during intoxication (Adinoff et al., 2003; Mendelson et al., 1971; Stokes, 1973) and withdrawal (Adinoff et al., 1991; Iranmanesh et al., 1989; Keedwell et al., 2001; Mendelson et al., 1971), occasionally resulting in a hypercortisolemic state mimicking the clinical and biochemical characteristics of Cushing syndrome (Jeffcoate, 1993; Veldman and Meinders, 1996). Concurrent with and after the resolution of this hypercortisolemic state, however, several investigators have observed an attenuation of the axis to pharmacological and psychological stressors. Although the increase in glucocorticoid secretion associated with intoxication and withdrawal resolves within a few days after the cessation of alcohol ingestion (Adinoff et al., 1991), suppression of HPA axis functioning seems to persist for at least the first several weeks of abstinence. Attenuated responsiveness of the HPA axis has been revealed at each level of the axis in both drinking and abstinent alcohol-dependent patients. Central stimuli, including alcohol (Merry and Marks, 1972), operative trauma (Margraf et al., 1967), cold pressor (Errico et al., 1993), insulin-induced hypoglycemia (Chalmers et al., 1978; Costa et al., 1996), nicotine (Coiro and Vescovi, 1999), public speaking (Lovallo et al., 2000), m-chlorophenylpiperazine (Krystal et al., 1996), and hyperthermia (Vescovi et al., 1997) produce a blunted corticotropin and/or cortisol response in alcohol-dependent patients compared with healthy controls. Alcohol-dependent patients also have a muted corticotropin response to naloxone (Inder et al., 1995), an opioid antagonist that blocks the tonic inhibition of endogenous opioids on the hypothalamus. Pituitary stimulation by ovine or human CRH induces a blunted corticotropin and/or cortisol response for at least 3 weeks after drinking cessation (Adinoff et al., 1990; Costa et al., 1996; Ehrenreich et al., 1997). Finally, direct stimulation of the adrenal cortex by exogenously administered adrenocorticotropinα1–24 (cosyntropin) results in a markedly decreased cortisol response in alcohol-dependent individuals (Knudsen et al., 1987; Margraf et al., 1967; Wand and Dobs, 1991). This impressive and consistent literature, however, offers only suggestive clues as to which specific levels of the axis are critical for the hyporesponsive state. Because of both positive and negative organizational loops, interactions between the various components of the HPA axis confound the interpretation of any specific stressor on a given hormonal unit. In addition, increases or decreases in endogenous hormone secretion could alter organ sensitivity to a given stimulus. Finally, many of the studies referenced above have significant confounders that make interpretation of their findings problematic. For example, chronic medical and/or psychiatric conditions (i.e., post–traumatic stress disorder [PTSD], depression) may interfere with HPA axis functioning. To clarify the specific alterations in HPA axis functioning that occur after chronic and excessive use of alcohol, we designed a series of studies to explore basal pulsatile characteristics of corticotropin and cortisol, adrenocortical sensitivity to exogenous stimulation in the presence or absence of endogenous stimulation, and pituitary glucocorticoid sensitivity in 1-month-abstinent alcohol-dependent patients. Secretory characteristics of corticotropin and cortisol were determined by obtaining frequent sampling of plasma corticotropin and cortisol from 2000 to 0800 hr. Adrenocortical sensitivity to an exogenous stimulus was assessed by administering cosyntropin, a corticotropin analog (corticotropinα1–24). To avoid a maximal glucocorticoid response, or ceiling effect, that could obscure potential group differences, we assessed adrenocortical sensitivity with a very low dose (0.01 μg/kg) of cosyntropin. This is approximately 0.3% of the clinically recommended dose (250 μg) used in the cosyntropin stimulation test in the diagnosis of endocrine disorders. In a second test, we isolated the adrenal cortex from its major endogenous input (pituitary corticotropin) by first administering high-dose dexamethasone before the cosyntropin administration. We also determined hypothalamic-pituitary glucocorticoid sensitivity by measuring the corticotropin response to dexamethasone administration. Finally, to assess potential disruptions in adrenosteroid synthesis, we assessed glucocorticoid, minerocorticoid, and androgen hormones (in addition to cortisol) after cosyntropin administration. It was hypothesized that cortisol secretion in response to cosyntropin would be significantly attenuated in alcohol-dependent participants both with and without dexamethasone pretreatment.

Hypercortisolemia is experienced during both chronic alcohol ingestion (Adinoff et al., 2003; Mendelson and Stein, 1966; Stokes, 1973) and repeated bouts of alcohol withdrawal (Adinoff et al., 1991; Iranmanesh et al., 1989; Keedwell et al., 2001). The prolonged state of glucocorticoid excess in heavy, daily drinkers (Adinoff et al., 2003; Mendelson and Stein, 1966) seems to induce pituitary and adrenocortical hyporesponsiveness that persists after cessation of drinking. Pharmacologic interventions that restore equilibrium to the hypothalamic-pituitary-adrenal (HPA) axis may have potential in the treatment of alcohol dependence. Therefore, isolating the specific level of axis disruption, the degree of physiological hyposensitivity at each organ level, and the persistence of these alterations upon abstinence assumes increasing importance. Such an understanding would allow a targeted, dose-appropriate pharmacologic intervention upon the critical axis disruption during a temporally relevant period of biological vulnerability. The HPA cascade begins with central activation of hypothalamic corticotropin-releasing hormone (CRH), primarily in response to fearful or anxiety-inducing stressors. CRH then induces the synthesis and secretion of corticotropin from the anterior pituitary gland, which in turn stimulates the production of glucocorticoids from the adrenal cortex. The glucocorticoids (primarily cortisol in humans) have a negative feedback effect on both hypothalamic CRH and pituitary corticotropin secretion. As noted, the HPA axis exhibits diminished responsiveness during early abstinence. For example, cerebrospinal fluid measures of CRH are reduced in abstinent alcohol-dependent individuals (Geracioti et al., 1994), suggesting a decrease in CRH hypothalamic release. In response to naloxone, which blocks opioid tonic inhibition of CRH secretion, Inder et al. (1995) observed a blunted corticotropin response in alcohol-dependent men who were 10 days to 6 weeks abstinent. This report suggested a down-regulation of hypothalamic CRH and/or pituitary corticotroph receptors. A number of investigators (Adinoff et al., 1990; Bardeleben et al., 1989; Costa et al., 1996; Ehrenreich et al., 1997; Loosen et al., 1991) have reported a similar blunting of the corticotropin response to ovine corticotropin-releasing hormone (oCRH), which directly stimulates pituitary corticotrophs. Adinoff et al. (1990) demonstrated that the corticotropin suppression seems to gradually resolve after 3 weeks of abstinence, although others have shown that this response persists for at least 12 weeks of abstinence (Ehrenreich et al., 1997). The pituitary corticotropin response has also been shown to be suppressed after nicotine (Coiro and Vescovi, 1999), hyperthermia (Vescovi et al., 1997), and insulin-induced hypoglycemia (Costa et al., 1996). Downstream adrenocortical secretion is suppressed after an alcohol challenge (Merry and Marks, 1972), insulin-induced hypoglycemia (Costa et al., 1996), operative trauma (Margraf et al., 1967), nicotine (Coiro and Vescovi, 1999), CRH stimulation (Bailly et al., 1989), cosyntropin stimulation (Wand and Dobs, 1991), hyperthermia (Vescovi et al., 1997), cold pressor (Errico et al., 1993), mental arithmetic (Errico et al., 1993), and public speaking (Lovallo et al., 2000) (for review, see Adinoff et al., 1998). These cumulative studies implicate a similarly muted response at each level of the HPA axis for several days, if not weeks, after cessation of drinking in alcohol-dependent individuals. The relative consistency of this literature, however, does not define the relative contribution of each axis component. Previous studies, for example, have typically used only a single provocative measure of HPA axis reactivity, limiting concurrent assessments of the hierarchical levels of HPA axis functioning. Hypothalamic, pituitary, and adrenal sensitivity to both exogenous and endogenous stimulation also remains uncertain because high doses of biological stimuli have typically been used to assess the system. Such severe activation may produce a ceiling response, particularly of the adrenocortical response, thus masking more subtle disruptions. In addition, the resolution or persistence of axis disruption with more extended periods of abstinence remains uncertain. Most studies have assessed HPA axis functioning in a patient cohort exhibiting varied abstinence intervals, leaving the time frame of HPA persistence or recovery unanswered. Finally, many studies of HPA axis responsiveness include patients with psychiatric and/or other substance use disorders. Because disruptions in HPA axis alterations have been documented in other substance use disorders (for review, see Kreek and Koob, 1998; Sinha, 2001) and psychiatric disorders (Gold and Chrousos, 2002; Yehuda, 2001), it is critical to separate out the pathophysiology induced by chronic alcohol ingestion as opposed to concomitant disease processes. In a series of studies, we assessed hypothalamic, pituitary, and adrenal responsiveness in 1-month alcohol-dependent men. Because of restrictions on the volume of blood withdrawal and the importance of obtaining all studies during a similar period of abstinence, two distinct groups of alcohol-dependent participants were compared with healthy control participants. In part 1 of the study (Adinoff et al., 2005), corticotropin and cortisol pulsatile characteristics were obtained from 2000 to 0800 hr, adrenocortical sensitivity was assessed in both the presence and the relative absence of endogenous pituitary corticotropin, and the pituitary corticotropin response to dexamethasone inhibition was obtained. In the current study (part 2), hypothalamic, pituitary, and adrenal activation was assessed with low doses of both oCRH and naloxone. In addition, corticotropin and cortisol pulsatility were determined from 0800 to 2000 hr. We hypothesized (1) that the net integrated corticotropin and cortisol responses to oCRH stimulation would be suppressed in the alcohol-dependent group compared with the healthy controls, indicating decreased pituitary responsiveness and (2) that the net integrated corticotropin and cortisol responses to naloxone stimulation would also be suppressed in the alcohol-dependent population compared with healthy controls, reflecting altered endogenous opioid activity at the hypothalamic level.

Limbic system functioning is integral to the control and modulation of affect, motivation, reward, and memory. Neuropsychiatric disturbances involving disruptions in these cognitive and emotional dimensions exhibit different prevalence rates for men and women. Gender-specific differences in this integrated brain area may therefore be important in understanding both normal behavioral functioning and the etiologic underpinnings of neuropsychiatric disorders. To further explore such differences in limbic system function, we assessed regional cerebral blood flow, by SPECT, in men and women following the administration of procaine. Procaine is a local anesthetic that preferentially stimulates limbic structures. Psychiatrically and medically healthy, age-matched women (n = 15, 33.2 +/- 6.9 years) and men (n = 15, 32.8 +/- 6.9 years) were administered 1.38 mg/kg procaine or saline intravenously in two separate sessions. Using voxel-based analyses (P < 0.001), males significantly activated the bilateral insular cortex following procaine, whereas females more strongly activated the bilateral anterior and mesial temporal cortex. Both groups demonstrated significant anterior cingulate activation. Subjective responses to procaine did not significantly differ between the men and women. To our knowledge, this is the first report demonstrating gender-specific responses in limbic activation following a pharmacologic challenge. These findings suggest that men and women can activate different limbic structures following the same provocative pharmacologic stimulus, despite sharing a similar subjective experience. Studies assessing pharmacologic challenges of limbic system structures should consider gender as a critical variable in assessing biologic responsiveness.