Psilocybin pulse regimen reduces cluster headache attack frequency in the blinded extension phase of a randomized controlled trial.

BACKGROUND: In a recent randomized, double-blind, placebo-controlled study, we observed a nonsignificant reduction of attack frequency in cluster headache after pulse administration of psilocybin (10 mg/70 kg, 3 doses, 5 days apart each). We carried out a blinded extension phase to consider the safety and efficacy of repeating the pulse regimen. METHODS: Eligible participants returned to receive a psilocybin pulse at least 6 months after their first round of study participation. Participants kept headache diaries starting two weeks before and continuing through eight weeks after the first drug session. Ten participants completed the extension phase and all ten were included in the final analysis. RESULTS: In the three weeks after the start of the pulse, cluster attack frequency was significantly reduced from baseline (18.4 [95% confidence interval 8.4 to 28.4] to 9.8 [4.3 to 15.2] attacks/week; p = 0.013, d' = 0.97). A reduction of approximately 50% was seen regardless of individual response to psilocybin in the first round. Psilocybin was well-tolerated without any unexpected or serious adverse events. DISCUSSION: This study shows a significant reduction in cluster attack frequency in a repeat round of pulse psilocybin administration and suggests that prior response may not predict the effect of repeated treatment. To gauge the full potential of psilocybin as a viable medicine in cluster headache, future work should investigate the safety and therapeutic efficacy in larger, more representative samples over a longer time period, including repeating the treatment. CLINICAL TRIALS REGISTRATION: NCT02981173.

Exploratory investigation of a patient-informed low-dose psilocybin pulse regimen in the suppression of cluster headache: Results from a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Using a patient-informed regimen, we conducted an exploratory randomized, double-blind, placebo-controlled study to systematically investigate the effects of psilocybin in cluster headache. BACKGROUND: Sustained reductions in cluster headache burden after limited quantities of psilocybin-containing mushrooms are anecdotally reported, although to date there are no controlled studies investigating these effects. METHODS: Participants were randomized to receive psilocybin (0.143 mg/kg) or placebo (microcrystalline cellulose) in a pulse of three doses, each ~5 days apart. Participants maintained headache diaries starting 2 weeks before and continuing through 8 weeks after the first drug session. A total of 16 participants were randomized to receive experimental drug and 14 were included in the final analysis. RESULTS: In the 3 weeks after the start of the pulse regimen, the change in cluster attack frequency was 0.03 (95% confidence interval [CI] -2.6 to 2.6) attacks/week with placebo (baseline 8.9 [95% CI 3.8 to 14.0]) and -3.2 (95% CI -8.3 to 1.9) attacks/week with psilocybin (baseline 9.6 [95% CI 5.6 to 13.6]; p = 0.251). Group difference in change from baseline had a moderate effect size (d = 0.69). The effect size was small in episodic participants (d = 0.35) but large in chronic participants (d = 1.25), which remained over the entire 8-week period measured (d = 0.81). Changes in cluster attack frequency were not correlated with the intensity of acute psychotropic effects during psilocybin administration. Psilocybin was well-tolerated without any unexpected or serious adverse events. CONCLUSIONS: Findings from this initial, exploratory study provide valuable information for the development of larger, more definitive studies. Efficacy outcomes were negative, owing in part to the small number of participants. The separation of acute psychotropic effects and lasting therapeutic effects underscores the need for further investigation into the mechanism(s) of action of psilocybin in headache disorders.

Ethnic and racial comparisons of weight-loss treatment utilization history and outcomes in patients with obesity and binge-eating disorder.

BACKGROUND: This study examined ethnic/racial differences in reported utilization of weight-loss methods/treatments and weight loss among adults with binge-eating disorder (BED) with co-existing obesity. METHODS: Participants were 400 adults (non-Hispanic Black: n = 99, Hispanic: n = 38, non-Hispanic White: n = 263) seeking treatment for BED in Connecticut from 2007 to 2012. Participants were asked about prior weight-loss methods/treatments and resulting weight losses. RESULTS: Overall, self-help diets were utilized most; mental-health services were utilized least. While non-significant differences for most methods/treatments were observed by ethnicity/race, significant differences emerged for self-help diets and supervised programs with non-Hispanic Whites, in general, utilizing these diets more frequently and losing more weight on these types of diets. CONCLUSIONS: Among treatment-seeking patients with BED and obesity, non-Hispanic White patients reported histories of greater weight-loss treatment utilization and weight loss than non-White patients for supervised and self-help diets. Findings highlight the need for greater understanding of treatment utilization and outcomes among minority patients with obesity and BED.

12 Months later: Motivational interviewing plus nutrition psychoeducation for weight loss in primary care.

PURPOSE: Motivational interviewing (MI) weight-loss interventions have garnered much attention, particularly in primary care. Few studies, however, have examined long-term outcomes of MI for weight loss in primary care. This study sought to examine the longer-term outcomes of a combination approach comprising MI and nutrition psychoeducation (MINP) with a publically available web-support component (i.e., livestrong.com). METHODS: Thirty-one adults with overweight/obesity were enrolled in a 3-month MINP treatment delivered in primary care by medical assistants. Weight, blood pressure, and depression (beck depression inventory) were assessed at baseline and 1-year following treatment cessation (i.e., 15 months total). RESULTS: Participants' average BMI was significantly lower 12-months following treatment. Approximately one-third of participants (34.8%) maintained 5% or more weight loss. Participants also experienced significant decreases in diastolic blood pressure, resting heart rate, and depression symptoms, but not systolic blood pressure or waist circumference. CONCLUSION: The scalable (2.5 h total) MINP intervention delivered in primary care by medical assistants resulted in significant weight (medium effect size) and psychological improvements 12 months later. These findings complement previous RCT findings that MI or nutrition psychoeducation interventions, delivered separately, resulted in small weight loss effects after 12 months, with 5% and 17% of participants, respectively, maintaining 5% weight loss. It remains unclear, however, if implementing MI in primary care for weight loss is cost effective beyond providing nutrition psychoeducation alone. CLINICAL TRIAL REGISTRATION: The clinical trial registration number is NCT02578199. LEVEL OF EVIDENCE: IV, uncontrolled trial.

Immigration, Criminal Involvement, and Violence in the U.S.: Results from the National Epidemiologic Survey on Alcohol and Related Conditions-III.

Topics of immigration and crime often receive national attention, despite evidence of the "immigrant paradox," in which immigrants have lower than expected crime and violence given their extreme social disadvantage. Research examining the immigrant paradox using an expanded set of crime outcomes and the latest available population data is needed. Using the National Epidemiologic Survey on Alcohol and Related Conditions Wave III data (2012-2013; n = 36,309), we analyzed the association between first-generation immigrant status alongside violence (i.e., other-directed, self-directed, victimization) and criminal involvement (i.e., crime, legal problems, incarceration) outcomes. Immigrants self-reported lower rates of all outcomes compared to U.S.-born adults, providing continued support for the immigrant paradox. Future research considering later generations of immigrants, as well as differential mechanisms through which immigrants and U.S.-born adults engage in violence and crime, is needed.

Exploratory Controlled Study of the Migraine-Suppressing Effects of Psilocybin.

While anecdotal evidence suggests that select 5-hydroxytryptamine 2A (5-HT2A) receptor ligands, including psilocybin, may have long-lasting therapeutic effects after limited dosing in headache disorders, controlled investigations are lacking. In an exploratory double-blind, placebo-controlled, cross-over study, adults with migraine received oral placebo and psilocybin (0.143 mg/kg) in 2 test sessions spaced 2 weeks apart. Subjects maintained headache diaries starting 2 weeks before the first session until 2 weeks after the second session. Physiological and psychological drug effects were monitored during sessions and several follow-up contacts with subjects were carried out to assure safety of study procedures. Ten subjects were included in the final analysis. Over the 2-week period measured after single administration, the reduction in weekly migraine days from baseline was significantly greater after psilocybin (mean, - 1.65 (95% CI: - 2.53 to - 0.77) days/week) than after placebo (- 0.15 (- 1.13 to 0.83) days/week; p = 0.003, t(9) = 4.11). Changes in migraine frequency in the 2 weeks after psilocybin were not correlated with the intensity of acute psychotropic effects during drug administration. Psilocybin was well-tolerated; there were no unexpected or serious adverse events or withdrawals due to adverse events. This exploratory study suggests there is an enduring therapeutic effect in migraine headache after a single administration of psilocybin. The separation of acute psychotropic effects and lasting therapeutic effects is an important finding, urging further investigation into the mechanism underlying the clinical effects of select 5-HT2A receptor compounds in migraine, as well as other neuropsychiatric conditions. Clinicaltrials.gov : NCT03341689.

The Prevalence of Substance Use Disorders among Community-based Adults with Legal Problems in the U.S.

BACKGROUND: Current national prevalence estimates of DSM-5 diagnosed substance use disorders (SUDs) among adults with justice system involvement are lacking. METHODS: This study drew from NESARC-III data (n = 36,309; 2012-2013), a nationally representative U.S. sample, to examine current and lifetime alcohol use disorder (AUD) and drug use disorder (DUD) diagnoses among adults reporting current or prior drug-related, alcohol-related, and general legal problems. RESULTS: Adults reporting current alcohol-related legal problems were 22 times more likely to have a current AUD diagnosis (AOR = 22.0, 95% CI = 12.1; 40.1) and 15 times more likely to have had a lifetime AUD diagnosis (AOR = 15.2, 95% CI = 7.5; 30.9) than adults without alcohol-related legal problems. Adults with lifetime drug-related legal problems were 3-5 times more likely to have a current (AOR = 2.6, 95% CI = 2.1; 3.2) and lifetime (AOR = 5.1, 95% CI = 4.3; 6.1) DUD diagnosis, with stimulant use disorder being the most prevalent (AOR = 5.4, 95% CI = 4.5; 6.5). Adults with general legal problems were around 3 times more likely to have a current AUD (AOR = 3.2, 95% CI = 2.6; 4.0) or DUD (AOR = 3.5, 95% CI = 2.8; 4.4). Women with any type of legal problem were more likely to have SUD diagnoses than men. CONCLUSIONS: SUD diagnoses are prevalent among adults reporting legal problems, particularly those involving alcohol. There is a continued need for community-based addiction prevention and intervention efforts, especially for women with justice system involvement.

In an exploratory randomized, double-blind, placebo-controlled, cross-over study, psychoactive doses of intravenous delta-9-tetrahydrocannabinol fail to produce antinociceptive effects in healthy human volunteers.

RATIONALE: Animal studies and anecdotal human reports suggest that cannabinoids have antinociceptive effects. Controlled human studies have produced mixed results. OBJECTIVES: We sought to reduce existing variability by investigating the effects of intravenous delta-9-tetrahydrocannabinol (THC) in several pain paradigms within the same human subjects, addressing some of the limitations to the published literature. METHODS: In this exploratory randomized, double-blind, placebo-controlled, cross-over study, healthy human subjects received 0.01 mg/kg or 0.03 mg/kg intravenous THC or placebo (ethanol vehicle) infused over 10 min on three test days, each separated by at least 72 h. Capsaicin (250 µg) was injected intradermally to induce chemical pain and hyperalgesia. Four other forms of acute pain were induced: mechanical (von Frey filament), hot and cold (thermode), and electrical (pulse generator). Pain ratings were obtained before drug administration, at peak drug effects, and 2 h after drug administration and included both objective and subjective measures. THC drug effects and vital signs were also collected during experimental sessions. Nonparametric analysis with repeated measures was performed. RESULTS: THC induced euphoria, perceptual and cognitive alterations, and tachycardia in a dose-related manner, but failed to have significant effects in experimentally induced acute chemical, mechanical, thermal, or electrical pain and capsaicin-induced hyperalgesia. CONCLUSIONS: In this exploratory controlled study, intravenous THC lacked significant antinociceptive properties in experimental models of acute pain and capsaicin-induced hyperalgesia in healthy human subjects. Continued study of THC and other cannabinoids through high-quality, controlled studies in both healthy volunteers and patients with pain conditions is warranted to inform the growing demand for the clinical application of cannabinoids in pain management.

Co-occurring opioid and sedative use disorder: Gender differences in use patterns and psychiatric co-morbidities in the United States.

Non-medical use of both opioids and sedatives increases risk of overdose or accident. The purpose of the present study was to describe rates of co-use, to examine baseline characteristics and psychiatric conditions potentially associated with meeting criteria for co-occurring opioid use disorder and sedative use disorder, and to examine whether these relationships varied by gender. Participants were 330 individuals from the NESARC-III who met criteria for current opioid use disorder. Gender-stratified logistic regression analyses, accounting for the survey design, were used to identify psychiatric conditions associated with meeting criteria for co-occurring sedative use disorder. Results indicated that 16.4% of the sample also met criteria for sedative use disorder. Notably, 55.6% of the sample attained opioids through their own prescription. Of those with co-occurring sedative use disorder, 47.2% attained sedatives through their own prescription. Posttraumatic stress disorder (OR = 3.02, 95% CI = 1.40-6.51) and antisocial personality disorder (OR = 2.72, 95% CI = 1.37-5.41) were associated with co-occurring sedative use disorder among both men and women with opioid use disorder. Depressive disorders (OR = 2.12, 95% CI = 1.01-4.42) and schizotypal personality disorder (OR = 5.78, 95% CI = 2.48-13.49) were associated with co-occurring sedative use disorder in women only. Results of the present study highlight the importance of prescription monitoring, further research into gender-informed treatments, and implementation of treatments for substance use and co-occurring symptoms.

Associations Between Nicotine Metabolite Ratio and Gender With Transitions in Cigarette Smoking Status and E-Cigarette Use: Findings Across Waves 1 and 2 of the Population Assessment of Tobacco and Health (PATH) Study.

INTRODUCTION: Nicotine metabolite ratio (NMR), the ratio of trans 3'-hydroxycotinine to cotinine, is a biomarker of nicotine metabolism. Discrepant findings among clinical trials and population-based studies warrant replication on whether higher NMR, or faster nicotine metabolism, is associated with quitting cigarette smoking. Associations of NMR and e-cigarette use are largely unknown, as well as the relationship between NMR and gender on quitting cigarette smoking or e-cigarette use. METHODS: The Population Assessment of Tobacco and Health (PATH) Study is a nationally representative, longitudinal cohort study assessing tobacco use in the US population. In the current study, the PATH (waves 1 and 2; adult interviews) was used to evaluate longitudinal predictions in relationships among NMR and gender and their association with transitions (quit vs. current stable) in cigarette smoking status and e-cigarette use status across waves 1 and 2 of the PATH study. RESULTS: NMR and gender were not significantly associated with quit behavior for combustible cigarettes. Regarding e-cigarettes, a significant two-way interaction demonstrated that women with higher NMR were less likely to quit e-cigarette use compared to women with lower NMR (odds ratio [OR] = 0.10, 95% confidence interval [CI] = 0.02-0.57; p = .01). CONCLUSIONS: Findings identify that women with faster nicotine metabolism were 10 times less likely to quit e-cigarettes compared to women with slower nicotine metabolism across waves 1 and 2 of the PATH study. Results suggest that NMR may be used as a biomarker for transitions in e-cigarette quit behavior for women. IMPLICATIONS: Findings identify that women with faster nicotine metabolism were 10 times less likely to quit e-cigarettes compared to women with slower nicotine metabolism. Results suggest that NMR may be used as a biomarker for transitions in e-cigarette quit behavior for women. Establishing parameters for NMR collection and for the use of NMR as a biomarker for cigarette smoking behavior and e-cigarette use is an important next step, and may have implications for early intervention and treatment for cessation.

Craving to Quit: A Randomized Controlled Trial of Smartphone App-Based Mindfulness Training for Smoking Cessation.

INTRODUCTION: Mindfulness training may reduce smoking rates and lessen the association between craving and smoking. This trial tested the efficacy of mindfulness training via smartphone app to reduce smoking. Experience sampling (ES) was used to measure real-time craving, smoking, and mindfulness. METHODS: A researcher-blind, parallel randomized controlled trial compared the efficacy of mobile mindfulness training with experience sampling (MMT-ES; Craving to Quit) versus experience sampling only (ES) to (1) increase 1-week point-prevalence abstinence rates at 6 months, and (2) lessen the association between craving and smoking. A modified intent-to-treat approach was used for treatment starters (MMT-ES n = 143; ES n = 182; 72% female, 81% white, age 41 ± 12 year). RESULTS: No group difference was found in smoking abstinence at 6 months (overall, 11.1%; MMT-ES, 9.8%; ES, 12.1%; χ2(1) = 0.43, p = .51). From baseline to 6 months, both groups showed a reduction in cigarettes per day (p < .0001), craving strength (p < .0001) and frequency (p < .0001), and an increase in mindfulness (p < .05). Using ES data, a craving by group interaction was observed (F(1,3785) = 3.71, p = .05) driven by a stronger positive association between craving and cigarettes per day for ES (t = 4.96, p < .0001) versus MMT-ES (t = 2.03, p = .04). Within MMT-ES, the relationship between craving and cigarettes per day decreased as treatment completion increased (F(1,104) = 4.44, p = .04). CONCLUSIONS: Although mindfulness training via smartphone app did not lead to reduced smoking rates compared with control, our findings provide preliminary evidence that mindfulness training via smartphone app may help lessen the association between craving and smoking, an effect that may be meaningful to support quitting in the longer term. IMPLICATIONS: This is the first reported full-scale randomized controlled trial of any smartphone app for smoking cessation. Findings provide preliminary evidence that smartphone app-based MMT-ES may lessen the association between craving and smoking. TRIAL REGISTRATION: Clinicaltrials.gov NCT02134509.

Relationships between drinking quantity and frequency and behavioral and hippocampal BOLD responses during working memory performance involving allocentric spatial navigation in college students.

BACKGROUND: Quantity and frequency of drinking may be used to effectively quantify the severity of alcohol-use. Drinking-severity has been related to neurocognitive impairments in such domains as spatial working memory (SWM). Youth drinking has been associated with altered neurofunctional underpinnings of SWM. The current study examined the relationship between drinking-severity and SWM processing. METHODS: One-hundred-and-seventy college drinkers reported the maximum number of drinks in a 24 -h period in the last six-months (quantity) and average number of drinking weeks in the last six-months (frequency). All participants performed a virtual Morris Water Task during fMRI which included trials where the target platform was visible or hidden. RESULTS: Greater quantity was associated with reduced SWM-related activity in the dorsolateral prefrontal cortex (F(1, 167) = 4.15, p = .04). Greater frequency was associated with reduced SWM-related activity in the hippocampus (F(1, 167) = 4.34, p = 0.039). Greater quantity was associated with longer search times (r = 0.21, p = .005) and greater platforms found (r = 0.19, p = .01) in VISIBLE trials. We did not find a relationship between drinking quantity or frequency and gender on SWM-related activity, although men found more platforms in both HIDDEN (F(1, 168) = 11.7, p = 0.0008) and VISIBLE (F(1, 168) = 23.0, p < .0001) trials compared to women. CONCLUSIONS: Altered SWM-related hippocampal function relating to alcohol use in young adults raises questions regarding the impact on young adult health and the nature of the findings. Future studies should examine whether these differences may lead to cognitive deficits later in life.

Psychiatric Disorders and Crime in the US Population: Results From the National Epidemiologic Survey on Alcohol and Related Conditions Wave III.

OBJECTIVE: Current knowledge regarding the intersection of psychiatric disorders and crime in the United States is limited to psychiatric, forensic, and youth samples. This study presents nationally representative data on the relationship of DSM-5 psychiatric disorders, comorbid substance and mental health disorders, and multimorbidity (number of disorders) with criminal behavior and justice involvement among non-institutionalized US adults. METHODS: Data were drawn from the National Epidemiologic Survey on Alcohol and Related Conditions Wave III (NESARC-III; 2012-2013; N = 36,309). Logistic regressions were used to examine the association of specific disorders (eg, mood, anxiety, eating, posttraumatic stress, substance use), comorbid substance use and mental health disorders, and multimorbidity with lifetime criminal behavior, incarceration experience, and past-12-month general, alcohol-related, and drug-related legal problems. RESULTS: Overall, 28.5% of participants reported a history of criminal behavior, 11.4% reported a history of incarceration, 1.8% reported current general legal problems, 0.8% reported current alcohol-related legal problems, and 2.7% reported current drug-related legal problems. The presence of any disorder was associated with a 4 to 5 times increased risk of crime outcomes. Drug use disorders were associated with the highest risk of lifetime crime (adjusted odds ratio [AOR] = 6.8; 95% CI, 6.1-7.6) and incarceration (AOR = 4.7; 95% CI, 4.1-5.3) and current legal problems (AOR = 3.3; 95% CI, 2.6-4.2). Multimorbidity and comorbid substance use and mental health disorders were associated with additional risk. Controlling for antisocial personality disorder did not change the findings. CONCLUSIONS: Community adults with substance use disorders, comorbid substance use and mental health disorders, and increasing multimorbidity are most at risk of crime and justice involvement, highlighting the importance of community-based addiction treatment.

High Risk of Alcohol-Impaired Driving in Adults With Comorbid Alcohol and Substance Use Disorders in the U.S. Population.

OBJECTIVE: Alcohol-impaired driving is a significant source of injury and morbidity in the United States. People with alcohol use disorder (AUD) are more likely to drive while impaired by alcohol than their nonclinical counterparts. Less is known about rates of impaired driving in people with AUD and a comorbid substance use disorder (SUD). The current study examined the association among AUD, other SUDs, and alcohol-impaired driving in a nationally representative sample of adults in the United States. METHOD: Data were from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC-III; n = 36,309). AUD and SUD diagnoses according to DSM-5 criteria were determined using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-5. We compared rates of past-year alcohol-impaired driving in people with AUD, another SUD (i.e., cannabis use disorder, stimulant use disorder, opioid use disorder), or AUD comorbid with another SUD against those with no past-year AUD or SUD diagnoses. RESULTS: People with AUD had increased odds (adjusted odds ratios [AORs] = 15.85-28.27) of past-year alcohol-impaired driving behavior compared with past-year drinkers with no AUD or SUD. Although other SUDs per se were not consistently associated with increased odds of these behaviors (AORs = 0.28-4.07), people with AUD comorbid with SUD showed comparatively higher odds of these behaviors (AORs = 30.46-93.97). These effects held even when alcohol use quantity/frequency and AUD severity were controlled for. CONCLUSIONS: People with AUD and a comorbid SUD are at high risk for alcohol-impaired driving. More research is needed to understand the factors mediating increased odds of driving while impaired in people with substance use comorbidities, especially considering societal movement toward cannabis legalization.

Intersection of E-Cigarette Use and Gender on Transitions in Cigarette Smoking Status: Findings Across Waves 1 and 2 of the Population Assessment of Tobacco and Health Study.

INTRODUCTION: Cigarette smokers report using electronic cigarettes (e-cigarettes) to reduce or quit smoking, but findings are mixed regarding the benefit and risk of e-cigarettes in this population, and effects of gender are unknown. METHODS: The Population Assessment of Tobacco and Health (PATH; waves 1 and 2; adult interviews) was used to evaluate relationships among wave 1 e-cigarette use (daily, nondaily, never) and gender and their association with transitions (quit vs. current; relapse vs. former) in cigarette smoking status across waves 1 and 2 of the PATH study. RESULTS: Daily e-cigarette users had higher odds of quitting smoking (odds ratio [OR] = 1.56, 95% confidence interval [CI] = 1.12 to 2.18) compared with never e-cigarette users. Conversely, daily and nondaily e-cigarette users were at greater risk of smoking relapse (OR = 1.84, 95% CI = 1.15 to 2.94 and OR = 1.85, 95% CI = 0.99 to 3.46, respectively) compared with never e-cigarette users. Women were less likely to quit smoking compared with men independent of e-cigarette use (OR = 0.76, 95% CI = 0.59 to 0.99). In stratified analyses, daily or nondaily e-cigarette use did not increase the likelihood of quitting or relapse in women. In men, daily and nondaily e-cigarette users were at greater risk of smoking relapse (OR = 2.96, 95% CI = 1.49 to 5.86 and OR = 3.05, 95% CI = 1.29 to 7.17, respectively) compared with men who were never e-cigarette users. CONCLUSIONS: Findings identify e-cigarettes as a potential aid for smoking cessation but also as a potential risk for smoking relapse in men only. Overall, women were less likely to quit smoking, and e-cigarette use did not impact their ability to quit or to stay quit. IMPLICATIONS: Cigarette smokers report using e-cigarettes to reduce or quit smoking, but findings are mixed regarding the benefit and risk of e-cigarettes in this population. Using data from the newly available PATH (waves 1 and 2; adult interviews), our findings identify e-cigarettes as a potential aid for smoking cessation but also identify e-cigarettes as a potential risk for smoking relapse in men only. These findings may have implications for the regulation of e-cigarettes by the Food and Drug Administration and the benefit-cost ratio of e-cigarette use in smokers.

Survey Analysis of the Use, Effectiveness, and Patient-Reported Tolerability of Inhaled Oxygen Compared With Injectable Sumatriptan for the Acute Treatment of Cluster Headache.

OBJECTIVE: In this secondary analysis of the Clusterbusters® Medication Use survey, the use, effectiveness, and tolerability of inhaled oxygen were investigated and compared with injectable sumatriptan. We also sought to understand the predictors of medication response. BACKGROUND: Inhaled oxygen is a mainstay abortive intervention in cluster headache but is not approved by the Food and Drug Administration (FDA). Unlike injectable sumatriptan, the only FDA-approved pharmacologic intervention for cluster headache, oxygen can be used multiple times a day, which is highly relevant for a condition with numerous daily attacks. In addition to obstacles in obtaining oxygen therapy, optimal oxygen delivery (ie, mask, flow rate) is not uniformly employed in cluster headache. These factors lead to underuse and imprecise therapeutic response rates. METHODS: A secondary analysis was conducted using deidentified data from the Clusterbusters® Medication Use survey, which was modeled after previously published surveys and available online. Subjects were recruited from headache clinics and cluster headache websites. Most responses were chosen from a list; others were free-texted. The final analysis included responses from 493 adult participants with a validated diagnosis of cluster headache. This analysis of deidentified data from the Clusterbusters® Medication Use survey received institutional approval. RESULTS: The most commonly used delivery system used by subjects was a non-rebreather-type mask. The use of oxygen flow rates >10 L/min was a positive predictor of medication response (OR = 2.36, P = .016). Among those who used flow rates >10 L/min, both inhaled oxygen (81.5%) and injectable sumatriptan (80.5%) were efficacious and did not differ significantly from each other in any specific group examined. At flow rates >10 L/min, positive predictors of oxygen response were male gender (OR = 2.07, P = .031) and cigarette smoking (current or historical; OR = 2.25, P = .017). Among the groups examined, there were no predictors of sumatriptan response. Most comments about side effects and concerns were directed at triptans. CONCLUSION: Therapeutic response to inhaled oxygen at sufficiently high flow rates (>10 L/min) had comparable efficacy to that of injectable sumatriptan for the acute treatment of cluster headache. Other factors in oxygen delivery (ie, flow rate changes) should be explored for optimization of therapy. The reasons for improved oxygen response in males and those with a cigarette smoking history require further exploration. While both oxygen and sumatriptan can be effective in the management of cluster headache, patient-reported side effects and concerns were more commonly directed at triptan medications. Current restrictions on access to inhaled oxygen, which exist at many levels, limit the therapeutic options available for patients with cluster headache, thereby doing a disservice to this patient population and the providers who deliver their care.

The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects.

The ability of ketamine administration to activate prefrontal glutamate neurotransmission is thought to be a key mechanism contributing to its transient psychotomimetic effects and its delayed and sustained antidepressant effects. Rodent studies employing carbon-13 magnetic resonance spectroscopy (13C MRS) methods have shown ketamine and other N-methyl-D-aspartate (NMDA) receptor antagonists to transiently increase measures reflecting glutamate-glutamine cycling and glutamate neurotransmission in the frontal cortex. However, there are not yet direct measures of glutamate neurotransmission in vivo in humans to support these hypotheses. The current first-level pilot study employed a novel prefrontal 13C MRS approach similar to that used in the rodent studies for direct measurement of ketamine effects on glutamate-glutamine cycling. Twenty-one participants (14 healthy and 7 depressed) completed two 13C MRS scans during infusion of normal saline or subanesthetic doses of ketamine. Compared to placebo, ketamine increased prefrontal glutamate-glutamine cycling, as indicated by a 13% increase in 13C glutamine enrichment (t = 2.4, p = 0.02). We found no evidence of ketamine effects on oxidative energy production, as reflected by 13C glutamate enrichment. During ketamine infusion, the ratio of 13C glutamate/glutamine enrichments, a putative measure of neurotransmission strength, was correlated with the Clinician-Administered Dissociative States Scale (r = -0.54, p = 0.048). These findings provide the most direct evidence in humans to date that ketamine increases glutamate release in the prefrontal cortex, a mechanism previously linked to schizophrenia pathophysiology and implicated in the induction of rapid antidepressant effects.

Cannabinoid receptor-mediated disruption of sensory gating and neural oscillations: A translational study in rats and humans.

Cannabis use has been associated with altered sensory gating and neural oscillations. However, it is unclear which constituent in cannabis is responsible for these effects, or whether these are cannabinoid receptor 1 (CB1R) mediated. Therefore, the present study in humans and rats examined whether cannabinoid administration would disrupt sensory gating and evoked oscillations utilizing electroencephalography (EEG) and local field potentials (LFPs), respectively. Human subjects (n = 15) completed four test days during which they received intravenous delta-9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD), Δ9-THC + CBD, or placebo. Subjects engaged in a dual-click paradigm, and outcome measures included P50 gating ratio (S2/S1) and evoked power to S1 and S2. In order to examine CB1R specificity, rats (n = 6) were administered the CB1R agonist CP-55940, CP-55940+AM-251 (a CB1R antagonist), or vehicle using the same paradigm. LFPs were recorded from CA3 and entorhinal cortex. Both Δ9-THC (p < 0.007) and Δ9-THC + CBD (p < 0.004) disrupted P50 gating ratio compared to placebo, while CBD alone had no effect. Δ9-THC (p < 0.048) and Δ9-THC + CBD (p < 0.035) decreased S1 evoked theta power, and in the Δ9-THC condition, S1 theta negatively correlated with gating ratios (r = -0.629, p < 0.012 (p < 0.048 adjusted)). In rats, CP-55940 disrupted gating in both brain regions (p < 0.0001), and this was reversed by AM-251. Further, CP-55940 decreased evoked theta (p < 0.0077) and gamma (p < 0.011) power to S1, which was partially blocked by AM-251. These convergent human/animal data suggest that CB1R agonists disrupt sensory gating by altering neural oscillations in the theta-band. Moreover, this suggests that the endocannabinoid system mediates theta oscillations relevant to perception and cognition.

Pilot investigation of the effect of carvedilol on stress-precipitated smoking-lapse behavior.

INTRODUCTION: Separate α1- and ß-adrenergic antagonists have shown efficacy in reducing nicotine-motivated behaviors in rodents and humans, supporting a role for the noradrenergic system in mediating the reinforcing properties of drugs of abuse. However, the effect of the combined α1- and ß-adrenergic antagonist, carvedilol, on stress-related smoking is unknown. METHODS: Using a well-established human laboratory model of stress-precipitated smoking-lapse behavior, we examined whether carvedilol (0 or 50 mg/day; between subject, n=17 per group), administered to steady-state, would attenuate the ability to resist smoking following stress imagery (vs. neutral imagery) and reduce subsequent smoking self-administration in nicotine-deprived smokers ( n = 34 total). Tobacco craving, withdrawal, and physiologic reactivity were also assessed. RESULTS: Latency to start smoking and number of cigarettes smoked during the self-administration period did not differ by medication condition. Counter to our hypothesis, tobacco craving demonstrated a medication × time effect, with greater craving in the carvedilol condition. Systolic blood pressure and heart rate demonstrated lower values in the carvedilol versus placebo group, consistent with known effects of carvedilol. CONCLUSION: While carvedilol attenuated physiologic reactivity consistent with its clinical indication, beneficial effects on smoking outcomes were absent in this preliminary investigation and may suggest possible worsening. Future work may benefit from discerning the single versus combined effects of α1- and ß-adrenergic antagonism on smoking outcomes.

Early weight loss predicts weight loss treatment response regardless of binge-eating disorder status and pretreatment weight change.

OBJECTIVE: Individuals seeking weight loss treatment have diverse pretreatment weight trajectories, and once enrolled, individuals' response to weight loss treatments also varies greatly and may be influenced by the presence of binge-eating disorder (BED). Reported average weight losses may obscure these considerable differences. This study examined whether BED status and different weight-related change variables are associated with successful weight loss treatment outcomes in a controlled treatment study. METHOD: Participants (N = 89) with overweight/obesity, with and without BED, participated in a 3-month weight loss trial in primary care with 3- and 12-month follow-ups. We tested the prognostic significance of four weight-related change variables (the last supper, early weight loss, pretreatment weight trajectory, weight suppression) on outcomes (weight loss-overall, weight loss-"subsequent," weight loss during second half of treatment). RESULTS: Early weight loss was positively associated with weight loss-overall at post-treatment, and at 3-month and 12-month follow-up. Early weight loss was positively associated with weight loss-subsequent at post-treatment only. No other weight-related variables were significantly associated with weight loss. Models including BED status and treatment condition were not significant. DISCUSSION: Participants with early weight loss were more likely to continue losing weight, regardless of BED status or treatment condition. The results highlight the importance of early dedication to weight loss treatment to increase the likelihood of positive outcomes.