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Opioid addiction is a relapsing disorder marked by uncontrolled drug use and reduced interest in normally rewarding activities. The current study investigated the impact of spontaneous withdrawal from chronic morphine exposure on emotional, motivational and cognitive processes involved in regulating the pursuit and consumption of food rewards in male rats. In Experiment 1, rats experiencing acute morphine withdrawal lost weight and displayed somatic signs of drug dependence. However, hedonically driven sucrose consumption was significantly elevated, suggesting intact and potentially heightened reward processing. In Experiment 2, rats undergoing acute morphine withdrawal displayed reduced motivation when performing an effortful response for palatable food reward. Subsequent reward devaluation testing revealed that acute withdrawal disrupted their ability to exert flexible goal-directed control over reward seeking. Specifically, morphine-withdrawn rats were impaired in using current reward value to select actions both when relying on prior action-outcome learning and when given direct feedback about the consequences of their actions. In Experiment 3, rats tested after prolonged morphine withdrawal displayed heightened rather than diminished motivation for food rewards and retained their ability to engage in flexible goal-directed action selection. However, brief re-exposure to morphine was sufficient to impair motivation and disrupt goal-directed action selection, though in this case, rats were only impaired in using reward value to select actions in the presence of morphine-paired context cues and in the absence of response-contingent feedback. We suggest that these opioid-withdrawal induced deficits in motivation and goal-directed control may contribute to addiction by interfering with the pursuit of adaptive alternatives to drug use.

BACKGROUND: Buprenorphine is an effective treatment for opioid use disorder (OUD); however, buprenorphine initiation can be complicated by withdrawal symptoms including precipitated withdrawal. There has been increasing interest in using low dose initiation (LDI) strategies to reduce this withdrawal risk. As there are limited data on withdrawal symptoms during LDI, we characterize withdrawal symptoms in people with daily fentanyl use who underwent initiation using these strategies as outpatients. METHODS: We conducted a retrospective chart review of patients with OUD using daily fentanyl who were prescribed 7-day or 4-day LDI at 2 substance use disorder treatment clinics in San Francisco. Two addiction medicine experts assessed extracted chart documentation for withdrawal severity and precipitated withdrawal, defined as acute worsening of withdrawal symptoms immediately after taking buprenorphine. A third expert adjudicated disagreements. Data were analyzed using descriptive statistics. RESULTS: There were 175 initiations in 126 patients. The mean age was 37 (SD 10 years). 71% were men, 26% women, and 2% non-binary. 21% identified as Black, 16% Latine, and 52% white. 60% were unstably housed and 75% had Medicaid insurance. Substance co-use included 74% who used amphetamines, 29% cocaine, 22% benzodiazepines, and 19% alcohol. Follow up was available for 118 (67%) initiations. There was deviation from protocol instructions in 22% of these initiations with follow up. 31% had any withdrawal, including 21% with mild symptoms, 8% moderate and 2% severe. Precipitated withdrawal occurred in 10 cases, or 8% of initiations with follow up. Of these, 7 had deviation from protocol instructions; thus, there were 3 cases with follow up (3%) in which precipitated withdrawal occurred without protocol deviation. CONCLUSIONS: Withdrawal was relatively common in our cohort but was mostly mild, and precipitated withdrawal was rare. Deviation from instructions, structural barriers, and v

Tobacco smoking imposes a staggering burden on public health, underscoring the urgency of developing a deeper understanding of the processes that maintain addiction. Clinical and experience-sampling data highlight the importance of anxious withdrawal symptoms, but the underlying neurobiology has remained elusive. Mechanistic work in animals implicates the central extended amygdala (EAc)-including the central nucleus of the amygdala and the neighboring bed nucleus of the stria terminalis-but the translational relevance of these discoveries remains unexplored. Here we leveraged a randomized trial design, well-established threat-anticipation paradigm, and multidimensional battery of assessments to understand the consequences of 24-hour nicotine abstinence. The threat-anticipation paradigm had the expected consequences, amplifying subjective distress and arousal, and recruiting the canonical threat-anticipation network. Abstinence increased smoking urges and withdrawal symptoms, and potentiated threat-evoked distress, but had negligible consequences for EAc threat reactivity, raising questions about the translational relevance of prominent animal and human models of addiction. These observations provide a framework for conceptualizing nicotine abstinence and withdrawal, with implications for basic, translational, and clinical science.

Chronic nicotine results in dependence with withdrawal symptoms on discontinuation of use, through desensitization of nicotinic acetylcholine receptors and altered cholinergic neurotransmission. Nicotine withdrawal is associated with increased whole-brain functional connectivity and decreased network modularity; however, the role of cholinergic neurons in those changes is unknown. To identify the contribution of nicotinic receptors and cholinergic regions to changes in the functional network, we analyzed the contribution of the main cholinergic regions to brain-wide activation of the immediate early-gene Fos during withdrawal in male mice and correlated these changes with the expression of nicotinic receptor mRNA throughout the brain. We show that the main functional connectivity modules included the main long-range cholinergic regions, which were highly synchronized with the rest of the brain. However, despite this hyperconnectivity, they were organized into two anticorrelated networks that were separated into basal forebrain-projecting and brainstem-thalamic-projecting cholinergic regions, validating a long-standing hypothesis of the organization of the brain cholinergic systems. Moreover, baseline (without nicotine) expression of Chrna2, Chrna3, Chrna10, and Chrnd mRNA of each brain region correlated with withdrawal-induced changes in Fos expression. Finally, by mining the Allen Brain mRNA expression database, we were able to identify 1755 gene candidates and three pathways (Sox2-Oct4-Nanog, JAK-STAT, and MeCP2-GABA) that may contribute to nicotine withdrawal-induced Fos expression. These results identify the dual contribution of the basal forebrain and brainstem-thalamic cholinergic systems to whole-brain functional connectivity during withdrawal; and identify nicotinic receptors and novel cellular pathways that may be critical for the transition to nicotine dependence.

BackgroundBenzodiazepines are commonly used among older adults, despite well-known risks. Clinical pharmacists can lead tapering efforts, leveraging their clinical expertise and relieving time-pressured primary care providers.ObjectivesThe objective of this study is to describe the design, implementation, and evaluation of an outpatient pharmacist-led benzodiazepine-tapering clinic.Practice descriptionThe clinic is based within a community medical group associated with a large academic health system in Los Angeles, California.Practice innovationThe clinic is staffed by clinical pharmacists and supervised by a psychiatrist. The initial visit consists of patient education, design of patient-driven tapering schedule, and medical history review. Follow-up phone/video visits are used to monitor withdrawal symptoms and provide support.Evaluation methodsWe used chart review to assess tapering status among those enrolled in the tapering clinic versus those who did not enroll. We compared outcomes across the 2 groups using bivariate statistics.ResultsFrom March 2017 to May 2019, 176 patients were referred to the clinic; 17 were deemed ineligible. Of the 159 patients contacted, 62 patients enrolled in the clinic; 97 patients did not enroll. Among patients in the clinic, 13 (27%) of patients were tapered down, 29 (60%) completely tapered off, 6 (13%) were unable to taper, and 14 (23%) were in the process of tapering. In contrast, among patients who did not enroll, 3 (4%) of patients were tapered down, 15 (20%) completely tapered off, 57 (76%) were unable to taper, and 22 (22%) were in the process of tapering. Ninety percent of patients had at least some benzodiazepine tapering when enrolled in the clinic compared to 41% among not enrolled in the clinic (P<0.001).ConclusionA pharmacist-led benzodiazepine-tapering clinic can be an effective way to engage patients motivated to taper down. Lessons learned include the importance of ensuring referring providers adequately counsel

Recent controversies have arisen regarding claims of uncritical positive regard and hype surrounding psychedelic drugs and their therapeutic potential. Criticisms have included that study designs and reporting styles bias positive over negative outcomes. The present study was motivated by a desire to address this alleged bias by intentionally focusing exclusively on negative outcomes, defined as self-perceived negative psychological responses lasting for at least 72 h after psychedelic use. A strong justification for this selective focus was that it might improve our ability to capture otherwise missed cases of negative response, enabling us to validate their existence and better examine their nature, as well as possible causes, which could inspire risk-mitigation strategies. Via advertisements posted on social media, individuals were recruited who reported experiencing negative psychological responses to psychedelics (defined as classic psychedelics plus MDMA) lasting for greater than 72 h since using. Volunteers were directed to an online questionnaire requiring quantitative and qualitative input. A key second phase of this study involved reviewing all of the submitted cases, identifying the most severe-e.g., where new psychiatric diagnoses were made or pre-existing symptoms made worse post psychedelic-use-and inviting these individuals to participate in a semi-structured interview with two members of our research team, during which participant experiences and backgrounds were examined in greater depth. Based on the content of these interviews, a brief summary of each case was compiled, and an explorative thematic analysis was used to identify salient and consistent themes and infer common causes. 32 individuals fully completed an onboarding questionnaire (56% male, 53% < age 25); 37.5% of completers had a psychiatric diagnosis that emerged after their psychedelic experience, and anxiety symptoms arose or worsened in 87%. Twenty of the seemingly sever

OBJECTIVES: Rising rates of hospitalization for patients with opioid use disorder (OUD) result in high rates of patient-directed discharge (PDD, also called "discharge against medical advice") and 30-day readmissions. Interdisciplinary addiction consult services are an emerging criterion standard to improve care for these patients, but these services are resource- and expertise-intensive. A set of withdrawal guidelines was developed to guide generalists in caring for patients with opioid withdrawal at a hospital without an addiction consult service. METHODS: Retrospective chart review was performed to determine PDD, 30-day readmission, and psychiatry consult rates for hospitalized patients with OUD during periods before (July 1, 2017, to March 31, 2018) and after (January 1, 2019, to July 31, 2019) the withdrawal guidelines were implemented. Information on the provision of opioid agonist therapy (OAT) was also obtained. RESULTS: Use of OAT in patients with OUD increased significantly after guideline introduction, from 23.3% to 64.8% ( P < 0.001). Patient-directed discharge did not change, remaining at 14% before and after. Thirty-day readmissions increased 12.4% to 15.7% ( P = 0.05065). Receiving any OAT was associated with increased PDD and readmission, but only within the postintervention cohort. CONCLUSIONS: A guideline to facilitate generalist management of opioid withdrawal in hospitalized patients improved the process of care, increasing the use of OAT and decreasing workload on the psychiatry consult services. Although increased inpatient OAT has been previously shown to decrease PDD, in this study PDD and readmission rates did not improve. Guidelines may be insufficient to impact these outcomes.

It is estimated that a majority of people who use psychostimulants, particularly methamphetamine (MA) and cocaine, experience withdrawal upon abstinence from sustained use. This review of clinical research reports the evidence regarding biomedical and behavioral treatments for psychostimulant withdrawal symptoms. It provides a framework for clinicians and scientists to increase impact on attenuating MA and cocaine withdrawal during initial and sustained abstinence. Articles reviewed included reports of controlled clinical trials (randomized or non-randomized) reporting at least one withdrawal symptom among the outcomes or specifically studying patients in withdrawal. Potential efficacy for MA withdrawal is noted for a few medications (mirtazapine, naltrexone, bupropion) and repetitive transcranial magnetic stimulation during acute (first week), early protracted (weeks 2-4) and late protracted (> 4 weeks) withdrawal phases. Topiramate shows mixed evidence of efficacy for cocaine withdrawal. In general, there is inconsistent signal for biomedical and behavioral treatments on MA and cocaine withdrawal.

IntroductionPhenobarbital has been successfully used in the emergency department (ED) to manage symptoms of alcohol withdrawal, but few studies have reported outcomes for ED patients who receive phenobarbital and are discharged. We compared return encounter rates in discharged ED patients with alcohol withdrawal who were treated with benzodiazepines and phenobarbital.MethodsThis is a retrospective cohort study conducted at a single academic medical center utilizing chart review of discharged ED patients with alcohol withdrawal from July 1, 2016, to June 30, 2019. Patients were stratified according to ED management with benzodiazepines, phenobarbital, or a combination of both agents. The primary outcome was return ED encounter within three days of the index ED encounter. Multivariate logistic regression identified significant covariates of an ED return encounter.ResultsOf 470 patients who were discharged with the diagnosis of alcohol withdrawal, 235 were treated with benzodiazepines, 133 with phenobarbital, and 102 with a combination of both. Baseline characteristics were similar among the groups. However, patients who received phenobarbital were provided significantly more lorazepam equivalents compared to patients who received benzodiazepines alone. Treatment with phenobarbital, alone or in combination with benzodiazepines, was associated with significantly lower odds of a return ED visit within three days compared with benzodiazepines alone [AOR 0.45 (95% CI 0.23, 0.88) p = 0.02 and AOR 0.33 (95% CI 0.15, 0.74) p = 0.007].ConclusionsPatients who received phenobarbital for alcohol withdrawal were less likely to return to the ED within three days of the index encounter. Despite similar baseline characteristics, patients who received phenobarbital, with or without benzodiazepines, were provided greater lorazepam equivalents the ED.

Alcohol use disorder (AUD) is a major health problem that causes millions of deaths annually world-wide. AUD is considered to be a chronic pain disorder, that is exacerbated by alcohol withdrawal, contributing to a high (∼80%) relapse rate. Chronic alcohol consumption has a marked impact on the gut microbiome, recognized to have a significant effect on chronic pain. We tested the hypothesis that modulating gut microbiota through feeding rats with probiotics can attenuate alcohol-induced muscle mechanical hyperalgesia. To test this hypothesis, rats were fed alcohol (6.5%, 4 days on 3 days off) for 3 weeks, which induced skeletal muscle mechanical hyperalgesia. Following alcohol feeding, at which time nociceptive thresholds were ∼37% below pre-alcohol levels, rats received probiotics in their drinking water, either Lactobacillus Rhamnosus GG (Culturelle) or De Simone Formulation (a mixture of 8 bacterial species) for 8 days; control rats received plain water to drink. When muscle mechanical nociceptive threshold was evaluated 1 day after beginning probiotic feeding, nociceptive thresholds were significantly higher than rats not receiving probiotics. Mechanical nociceptive thresholds continued to increase during probiotic feeding, with thresholds approaching pre-alcohol levels 5 days after starting probiotics; nociceptive threshold in rats not receiving probiotics remained low. After probiotics were removed from the drinking water, nociceptive thresholds gradually decreased in these two groups, although they remained higher than the group not treated with probiotic (21 days after ending alcohol feeding). These observations suggest that modification of gut microbiota through probiotic feeding has a marked effect on chronic alcohol-induced muscle mechanical hyperalgesia. Our results suggest that administration of probiotics to individuals with AUD may reduce pain associated with alcohol consumption and withdrawal, and may be a novel therapeutic intervention to reduce the

A growing body of research has reported on the potential opioid-sparing effects of cannabis and cannabinoids, but less is known about specific mechanisms. The present research examines cannabis-related posts in two large online communities on the Reddit platform ("subreddits") to compare mentions of naturalistic cannabis use by persons self-identifying as actively using opioids versus persons in recovery. We extracted all posts mentioning cannabis-related keywords (e.g., "weed", "cannabis", "marijuana") from December 2015 through August 2019 from an opioid use subreddit and an opioid recovery subreddit. To investigate how cannabis is discussed at-scale, we identified and compared the most frequent phrases in cannabis-related posts in each subreddit using term-frequency-inverse document frequency (TF-IDF) weighting. To contextualize these findings, we also conducted a qualitative content analysis of 200 random posts (100 from each subreddit). Cannabis-related posts were about twice as prevalent in the recovery subreddit (n = 908; 5.4% of 16,791 posts) than in the active opioid use subreddit (n = 4,224; 2.6% of 159,994 posts, p < .001). The most frequent phrases from the recovery subreddit referred to time without using opioids and the possibility of using cannabis as a "treatment." The most frequent phrases from the opioid subreddit referred to concurrent use of cannabis and opioids. The most common motivations for using cannabis were to manage opioid withdrawal symptoms in the recovery subreddit, often in conjunction with anti-anxiety and GI-distress "comfort meds," and to enhance the "high" when used in combination with opioids in the opioid subreddit. Despite limitations in generalizability from pseudonymous online posts, this examination of reports of naturalistic cannabis use in relation to opioid use identified withdrawal symptom management as a common motivation. Future research is warranted with more structured assessments that examines the role of cannabi

Research on nicotine metabolism has primarily focused on white adults. This study examined associations between nicotine metabolism, tobacco use, and demographic characteristics among Alaska Native adults who smoke cigarettes. Participants (N = 244) were Alaska Native adults who smoked and who provided a plasma sample at baseline (70.1%) or follow-up (29.9%) of a randomized controlled trial of a cardiovascular risk behavior intervention. At baseline, participants self-reported age, sex, Alaska Native heritage, cigarettes per day, time to first cigarette upon wakening, menthol use, perceived difficulty staying quit, tobacco withdrawal symptoms, and past-month tobacco product use, binge drinking, and cannabis use. At 3-, 6-, 12-, and 18-month follow-ups, participants self-reported 7-day point prevalence abstinence from smoking. Height and weight were measured to calculate body mass index (BMI). Participants' nicotine metabolite ratio (NMR), calculated as the ratio of plasma cotinine and trans-3' hydroxycotinine, was log-transformed. The sample (52.0% male, age M = 47.0 years [SD = 13.8], 60.3% of Inupiaq heritage) averaged 12.5 cigarettes per day (SD = 10.5); 64.0% smoked within 30 min of wakening. NMR was not significantly associated with age, sex, Alaska Native heritage, BMI, cigarettes per day, time to first cigarette upon wakening, menthol use, perceived difficulty staying quit, past-month dual tobacco product use, withdrawal symptoms, past-month binge drinking, past-month cannabis use, or abstinence from smoking (all p-values > .050). Characteristics that relate to NMR in Alaska Native adults may differ from those typically identified among white adults. Specifically, results may suggest that Alaska Native adults with slower nicotine metabolism do not titrate their nicotine intake when smoking. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

IntroductionPhenobarbital has been successfully used in the emergency department (ED) to manage symptoms of alcohol withdrawal, but few studies have reported outcomes for ED patients who receive phenobarbital and are discharged. We compared return encounter rates in discharged ED patients with alcohol withdrawal who were treated with benzodiazepines and phenobarbital.MethodsThis is a retrospective cohort study conducted at a single academic medical center utilizing chart review of discharged ED patients with alcohol withdrawal from July 1, 2016, to June 30, 2019. Patients were stratified according to ED management with benzodiazepines, phenobarbital, or a combination of both agents. The primary outcome was return ED encounter within three days of the index ED encounter. Multivariate logistic regression identified significant covariates of an ED return encounter.ResultsOf 470 patients who were discharged with the diagnosis of alcohol withdrawal, 235 were treated with benzodiazepines, 133 with phenobarbital, and 102 with a combination of both. Baseline characteristics were similar among the groups. However, patients who received phenobarbital were provided significantly more lorazepam equivalents compared to patients who received benzodiazepines alone. Treatment with phenobarbital, alone or in combination with benzodiazepines, was associated with significantly lower odds of a return ED visit within three days compared with benzodiazepines alone [AOR 0.45 (95% CI 0.23, 0.88) p = 0.02 and AOR 0.33 (95% CI 0.15, 0.74) p = 0.007].ConclusionsPatients who received phenobarbital for alcohol withdrawal were less likely to return to the ED within three days of the index encounter. Despite similar baseline characteristics, patients who received phenobarbital, with or without benzodiazepines, were provided greater lorazepam equivalents the ED.

BackgroundCigarette smoking urges, withdrawal, and smoking reinstatement may be especially relevant to people with elevated depression symptoms who smoke. This laboratory study aimed to assess relations between depression symptom level and smoking urges for reward and relief, cigarette withdrawal, and smoking reinstatement in people who smoke cigarettes daily during acute abstinence and while smoking as usual.MethodsParticipants with low (n = 51) or elevated (n = 29) baseline depression symptoms underwent two counterbalanced laboratory sessions (i.e., abstinent, non-abstinent). At each session, they completed subjective measures of smoking urges for reward and relief, and withdrawal. They also completed a laboratory smoking reinstatement task measuring whether they would delay smoking and the number of cigarettes smoked.ResultsThe elevated depression symptom group reported significantly higher withdrawal (p = .01) and smoked more cigarettes than the low depression symptoms group during the smoking reinstatement task self-administration period at the abstinent session (p = .04). Smoking urges for reward and relief were not significantly different by depression symptom group. There were no significant interactions of depression and abstinence with any outcomes.ConclusionsAs outcomes were measured at both an abstinent and non-abstinent session, findings identify factors for people with elevated depression symptoms who smoke which may drive smoking behavior and impede smoking cessation efforts. This study provides evidence that people with elevated depression symptoms who smoke may need additional/more pharmacological or behavioral smoking cessation aids targeted at reducing withdrawal and number of cigarettes smoked.

Alcohol use disorder (AUD) is a major health problem that causes millions of deaths annually world-wide. AUD is considered to be a chronic pain disorder, that is exacerbated by alcohol withdrawal, contributing to a high (∼80%) relapse rate. Chronic alcohol consumption has a marked impact on the gut microbiome, recognized to have a significant effect on chronic pain. We tested the hypothesis that modulating gut microbiota through feeding rats with probiotics can attenuate alcohol-induced muscle mechanical hyperalgesia. To test this hypothesis, rats were fed alcohol (6.5%, 4 days on 3 days off) for 3 weeks, which induced skeletal muscle mechanical hyperalgesia. Following alcohol feeding, at which time nociceptive thresholds were ∼37% below pre-alcohol levels, rats received probiotics in their drinking water, either Lactobacillus Rhamnosus GG (Culturelle) or De Simone Formulation (a mixture of 8 bacterial species) for 8 days; control rats received plain water to drink. When muscle mechanical nociceptive threshold was evaluated 1 day after beginning probiotic feeding, nociceptive thresholds were significantly higher than rats not receiving probiotics. Mechanical nociceptive thresholds continued to increase during probiotic feeding, with thresholds approaching pre-alcohol levels 5 days after starting probiotics; nociceptive threshold in rats not receiving probiotics remained low. After probiotics were removed from the drinking water, nociceptive thresholds gradually decreased in these two groups, although they remained higher than the group not treated with probiotic (21 days after ending alcohol feeding). These observations suggest that modification of gut microbiota through probiotic feeding has a marked effect on chronic alcohol-induced muscle mechanical hyperalgesia. Our results suggest that administration of probiotics to individuals with AUD may reduce pain associated with alcohol consumption and withdrawal, and may be a novel therapeutic intervention to reduce the

We previously found that human heroin addicts and mice chronically exposed to morphine exhibit a significant increase in the number of detected hypocretin/orexin (Hcrt)-producing neurons. However, it remains unknown how this increase affects target areas of the hypocretin system involved in opioid withdrawal, including norepinephrine containing structures locus coeruleus (LC) and A1/A2 medullary regions. Using a combination of immunohistochemical, biochemical, imaging, and behavioral techniques, we now show that the increase in detected hypocretin cell number translates into a significant increase in hypocretin innervation and tyrosine hydroxylase (TH) levels in the LC without affecting norepinephrine-containing neuronal cell number. We show that the increase in TH is completely dependent on Hcrt innervation. The A1/A2 regions were unaffected by morphine treatment. Manipulation of the Hcrt system may affect opioid addiction and withdrawal.SIGNIFICANCE STATEMENT Previously, we have shown that the hypothalamic hypocretin system undergoes profound anatomic changes in human heroin addicts and in mice exposed to morphine, suggesting a role of this system in the development of addictive behaviors. The locus coeruleus plays a key role in opioid addiction. Here we report that the hypothalamic hypocretin innervation of the locus coeruleus increases dramatically with morphine administration to mice. This increase is correlated with a massive increase in tyrosine hydroxylase expression in locus coeruleus. Elimination of hypocretin neurons prevents the tyrosine hydroxylase increase in locus coeruleus and dampens the somatic and affective components of opioid withdrawal.

Extending from the triple wave epidemic of opioid-related overdose deaths, a fourth wave of high mortality involving methamphetamine and cocaine use has been gathering force. This article provides a review of the published literature on stimulants including epidemiology, pharmacology, neurobiology, medical and psychiatric consequences, withdrawal management, and medical and behavioral treatments.

Alcohol use disorder is a constellation of symptoms and behaviours related to dependence and abuse. It is present in 11.0% of US adults and is a leading cause of death and healthcare expenditures in the USA. Medication-assisted treatment (MAT) is medication to reduce cravings, decrease rewards or limit withdrawal symptoms in combination with behavioural therapy.A review of all patients with an alcohol-related condition admitted to internal medicine teams at an academic medical centre over a 7-month period (N=583) identified that only 1.4% (n=8) were discharged with an MAT prescription. Quality improvement methods were used to increase the proportion of patients discharged with an MAT prescription.Implementing educational interventions and embedding a recommendation for MAT into the order sets used to treat alcohol withdrawal increased the percentage of patients with an alcohol-related condition that were discharged with an MAT prescription to 11.2%.MAT remains an underused intervention for the treatment of alcohol use disorder. However, combining educational and structural interventions, including just-in-time teaching, can successfully increase the percentage of patients who receive an MAT prescription.

Introduction: Among adolescents and young adults, cannabis use is prevalent. Prior studies characterizing withdrawal effects in this age range have primarily included treatment seeking or comorbid psychiatric samples; these studies have identified several affected domains, especially sleep, mood, and anxiety. The present study compared a community (i.e., nontreatment seeking) sample of cannabis-using and control participants on mood, anxiety, sleep, and withdrawal inventories during the course of a monitored 3-week cannabis abstinence period. Materials and Methods: Seventy-nine adolescent and young adult participants (cannabis-using group=37 and control group=42) were recruited from the community to undergo 3 weeks of confirmed abstinence (i.e., urine and sweat patch toxicology) and completion of Cannabis Withdrawal Symptom Criteria, State-Trait Anxiety Inventory, Becks Depression Inventory, and Pittsburgh Sleep Quality Index across the study period. Repeated measures and cross-sectional regressions were used to examine main effects of group and interactions with time (where appropriate), while accounting for recent alcohol use and cotinine levels. Results: Cannabis-using participants reported higher mood (p=0.006), overall withdrawal (p=0.009), and sleep-related withdrawal (p<0.001) symptoms across abstinence compared to controls. Overall withdrawal severity (p=0.04) and sleep-related withdrawal symptoms (p=0.02) demonstrated a quadratic trajectory across the monitored abstinence periods, with an increase from baseline and subsequent decreases in symptom severity. No differences of anxiety scores (p=0.07) or trajectories (p=0.18) were observed. By study completion, groups did not differ among sleep quality components (all ps>.05). Conclusions: These findings revealed that nontreatment-seeking cannabis-using adolescents and young adults reported heightened total withdrawal symptoms during a 3-week sustained abstinence period relative to controls. Cannabis-usin

BACKGROUND: Benzodiazepines, Z-drugs, pregabalin, and melatonin (BZPMs) have been associated with a higher risk of traffic accidents, but the evidence is inconsistent, and lacking for newer drugs.AIM: To examine the association of BZPMs with risk of traffic accidents.METHODS: All Danish adults (n = 3,823,588) were followed for redeemed prescriptions of BZPM and for incident traffic accidents registered in Danish registers from 2002 through 2018. Associations were examined in cohort and case-crossover designs using Cox proportional hazard and conditional logistic regression with adjustment for co-variables.RESULTS: A total of 19.3% (n = 738,019) of all participants initiated treatment with BZPMs. During the mean follow-up of 10.3 years, 595,173(15.5%) of participants were involved in a traffic accident. In the cohort analysis, all BZPMs besides pregabalin were associated with a higher risk of traffic accidents in adults below 70 years, with chlordiazepoxide showing the strongest association (hazard ratio (HR)age 18-49 = 1.76, 95% confidence interval (CI): 1.67-1.86 and HRage 50-69 = 1.84, 95% CI: 1.70-2.00). In the older age groups, the specific BZPM medications were associated with lower or no risk of traffic accidents. However, in case-time-crossover analysis with inherited control for confounders, no BZPM medication was positively associated with traffic accidents, except for chlordiazepoxide, which had a higher odds ratio in middle-aged group (1.62, 95% CI: 1.15-2.29).CONCLUSIONS: This study does not fully support that BZPM use is a risk factor for traffic accidents. However, a positive association was found for chlordiazepoxide, which is approved for treatment of acute alcohol withdrawal.

OBJECTIVES: Fear and risk of precipitated withdrawal are barriers for initiating buprenorphine in individuals with opioid use disorder, particularly among those using fentanyl. A buprenorphine rapid overlap initiation (ROI) protocol (also knownas rapidmicro-dosing) utilizing small, escalating doses of buprenorphine can overcome this barrier, reaching therapeutic doses in 3 to 4 days. We sought to demonstrate the feasibility of implementing a buprenorphine ROI protocol for buprenorphine initiation in the outpatient setting. METHODS: We conducted a retrospective chart review of patients prescribed an outpatient ROI protocol at the Office-based Buprenorphine Induction Clinic from October to December 2020. The ROI protocol utilizes divided doses of sublingual buprenorphine tablets and blister packaging for easier dosing. Patients were not required to stop other opioid use and were advised to follow up on day 4 of initiation. RESULTS: Twelve patients were included, of whom eleven (92%) were using fentanyl at intake. Eleven patients picked up their prescription. Seven patients returned for follow-up (58%), and all 7 completed the ROI protocol. One patient reported any withdrawal symptoms, which were mild. At 30 days, 7 patients (58%) were retained in care, and 5 (42%) were still receiving buprenorphine treatment, 4 (33%) of whom had been abstinent from nonprescribed opioid use for ≥2 weeks. CONCLUSIONS: The ROI protocol was successful in initiating buprenorphine treatment for patients in our outpatient clinic, many of whom were using fentanyl. The ROI protocol may offer a safe alternative to traditional buprenorphine initiation and warrants further study.

RationaleCannabidiol (CBD) reduces craving in animal models of alcohol and cocaine use and is known to modulate nicotinic receptor function, suggesting that it may alleviate symptoms of nicotine withdrawal. However, preclinical evaluation of its efficacy is still lacking.ObjectivesThe goal of this study was to test the preclinical efficacy of a chronic CBD treatment in reducing nicotine dependence using measures of withdrawal symptoms including somatic signs, hyperalgesia, and weight gain during acute and protracted abstinence.MethodsMale and female Wistar rats were made dependent on nicotine using osmotic minipumps (3.15 mg/kg/day) for 2 weeks, after which minipumps were removed to induce spontaneous withdrawal. Three groups received CBD injections at doses of 7.5, 15, and 30 mg/kg/day for 2 weeks, starting 1 week into chronic nicotine infusion. The control groups included rats with nicotine minipumps that received vehicle injections of sesame oil instead of CBD; rats implanted with saline minipumps received sesame oil injections (double vehicle) or the highest dose of CBD 30 mg/kg/day. Throughout the experiment, serum was collected for determination of CBD and nicotine concentrations, mechanical sensitivity threshold and withdrawal scores were measured, and body weight was recorded.ResultsCBD prevented rats from exhibiting somatic signs of withdrawal and hyperalgesia during acute and protracted abstinence. There was no dose-response observed for CBD, suggesting a ceiling effect at the doses used and the potential for lower effective doses of CBD. The saline minipump group did not show either somatic signs of withdrawal or hyperalgesia during acute and protracted abstinence, and the highest dose of CBD used (30 mg/kg/day) did not alter these results.ConclusionsThis preclinical study suggests that using CBD as a strategy to alleviate the withdrawal symptoms upon nicotine cessation may be beneficial.

Cue-elicited drug-craving is a cardinal feature of addiction that intensifies (incubates) during protracted withdrawal. In a rat model, these addiction-related behavioral pathologies are mediated, respectively, by time-dependent increases in PI3K/Akt1 signaling and reduced Group 1 metabotropic glutamate receptor (mGlu) expression, within the ventromedial prefrontal cortex (vmPFC). Herein, we examined the capacity of single oral dosing with everolimus, an FDA-approved inhibitor of the PI3K/Akt effector mTOR, to reduce incubated cocaine-craving and reverse incubation-associated changes in vmPFC kinase activity and mGlu expression. Rats were trained to lever-press for intravenous infusions of cocaine or delivery of sucrose pellets and then subjected to tests for cue-reinforced responding during early (3 days) or late (30-46 days) withdrawal. Rats were gavage-infused with everolimus (0-1.0 mg/kg), either prior to testing to examine for effects upon reinforcer-seeking behavior, or immediately following testing to probe effects upon the consolidation of extinction learning. Single oral dosing with everolimus dose-dependently blocked cocaine-seeking during late withdrawal and the effect lasted at least 24 h. No everolimus effects were observed for cue-elicited sucrose-seeking or cocaine-seeking in early withdrawal. In addition, everolimus treatment, following initial cue-testing, reduced subsequent cue hyper-responsivity exhibited observed during late withdrawal, arguing a facilitation of extinction memory consolidation. everolimus' "anti-incubation" effect was associated with a reversal of withdrawal-induced changes in indices of PI3K/Akt1/mTOR activity, as well as Homer protein and mGlu1/5 expression, within the prelimbic (PL) subregion of the prefrontal cortex. Our results indicate mTOR inhibition as a viable strategy for interrupting heightened cocaine-craving and facilitating addiction recovery during protracted withdrawal.

RationaleCannabidiol (CBD) reduces craving in animal models of alcohol and cocaine use and is known to modulate nicotinic receptor function, suggesting that it may alleviate symptoms of nicotine withdrawal. However, preclinical evaluation of its efficacy is still lacking.ObjectivesThe goal of this study was to test the preclinical efficacy of a chronic CBD treatment in reducing nicotine dependence using measures of withdrawal symptoms including somatic signs, hyperalgesia, and weight gain during acute and protracted abstinence.MethodsMale and female Wistar rats were made dependent on nicotine using osmotic minipumps (3.15 mg/kg/day) for 2 weeks, after which minipumps were removed to induce spontaneous withdrawal. Three groups received CBD injections at doses of 7.5, 15, and 30 mg/kg/day for 2 weeks, starting 1 week into chronic nicotine infusion. The control groups included rats with nicotine minipumps that received vehicle injections of sesame oil instead of CBD; rats implanted with saline minipumps received sesame oil injections (double vehicle) or the highest dose of CBD 30 mg/kg/day. Throughout the experiment, serum was collected for determination of CBD and nicotine concentrations, mechanical sensitivity threshold and withdrawal scores were measured, and body weight was recorded.ResultsCBD prevented rats from exhibiting somatic signs of withdrawal and hyperalgesia during acute and protracted abstinence. There was no dose-response observed for CBD, suggesting a ceiling effect at the doses used and the potential for lower effective doses of CBD. The saline minipump group did not show either somatic signs of withdrawal or hyperalgesia during acute and protracted abstinence, and the highest dose of CBD used (30 mg/kg/day) did not alter these results.ConclusionsThis preclinical study suggests that using CBD as a strategy to alleviate the withdrawal symptoms upon nicotine cessation may be beneficial.

Numerous brain regions have been identified as contributing to withdrawal behaviors, but it is unclear the way in which these brain regions as a whole lead to withdrawal. The search for a final common brain pathway that is involved in withdrawal remains elusive. To address this question, we implanted osmotic minipumps containing either saline, nicotine (24 mg/kg/d), cocaine (60 mg/kg/d), or methamphetamine (4 mg/kg/d) for one week in male C57BL/6J mice. After one week, the minipumps were removed and brains collected 8 h (saline, nicotine, and cocaine) or 12 h (methamphetamine) after removal. We then performed single-cell whole-brain imaging of neural activity during the withdrawal period when brains were collected. We used hierarchical clustering and graph theory to identify similarities and differences in brain functional architecture. Although methamphetamine and cocaine shared some network similarities, the main common neuroadaptation between these psychostimulant drugs was a dramatic decrease in modularity, with a shift from a cortical-driven to subcortical-driven network, including a decrease in total hub brain regions. These results demonstrate that psychostimulant withdrawal produces the drug-dependent remodeling of functional architecture of the brain and suggest that the decreased modularity of brain functional networks and not a specific set of brain regions may represent the final common pathway associated with withdrawal.

BackgroundIn the United States, the criminalization and stigmatization of drug use and sex work contribute to infectious disease transmission and healthcare disengagement. People who inject drugs (PWID) and engage in sex work experience exacerbated HIV risk. In the context of the ongoing HIV and overdose epidemics little research describes why PWID engage in sex work and its relative HIV risk. To inform intervention needs, we aimed to create a typology of sex work among PWID with a focus on HIV risk and healthcare utilization behaviours.MethodsWe drew from in-depth interviews conducted across Massachusetts and Rhode Island from 2016-2019. Participants were ≥18 years old and self-reported past-month injection drug use and HIV-negative status. Using data from individuals reporting sex work experience (n=33/78), we utilized the framework method to develop a typology of perspectives on sex work engagement and attributes pertaining to HIV risk and healthcare utilization behaviours.ResultsWe uncovered varying perspectives on sex work and associated HIV risks and prevention needs. A typology included three groups who viewed their sex work engagement as a (1) consistent job, (2) income supplement, or (3) survival method to abate withdrawal symptoms. The first group described more consistent sexual and injection behaviours to mitigate HIV risk than the second group. The third group appeared particularly vulnerable to HIV, describing inconsistent condom use and frequent sharing of injection equipment, low healthcare utilization, and limited disclosure of sex work and injection drug use to healthcare providers.ConclusionFindings highlight distinct perspectives on sex work among PWID involved in it and corresponding perceptions of HIV risk and healthcare utilization behaviours. Understanding the nuances in sex work engagement among PWID can inform interventions to prevent infectious disease transmission, including efforts to further connect this marginalized population to harm

Currently available therapies for smoking cessation have limited efficacy, and potential treatments that target specific brain regions are under evaluation, with a focus on the insula. The ventral and dorsal anterior subregions of the insula serve distinct functional networks, yet our understanding of how these subregions contribute to smoking behavior is unclear. Resting-state functional connectivity (RSFC) provides a window into network-level function associated with smoking-related internal states. The goal of this study was to determine potentially distinct relationships of ventral and dorsal anterior insula RSFC with cigarette withdrawal after brief abstinence from smoking. Forty-seven participants (24 women; 18-45 years old), who smoked cigarettes daily and were abstinent from smoking overnight (~12 h), provided self-reports of withdrawal and underwent resting-state fMRI before and after smoking the first cigarette of the day. Correlations between withdrawal and RSFC were computed separately for ventral and dorsal anterior insula seed regions in whole-brain voxel-wise analyses. Withdrawal was positively correlated with RSFC of the right ventral anterior insula and dorsal anterior cingulate cortex (dACC) before but not after smoking. The correlation was mainly due to a composite effect of craving and physical symptoms of withdrawal. These results suggest a role of right ventral anterior insula-dACC connectivity in the internal states that maintain smoking behavior (e.g., withdrawal) and present a specific neural target for brain-based therapies seeking to attenuate withdrawal symptoms in the critical early stages of smoking cessation.

Background and aimsRelative pharmacological effects of e-cigarettes and cigarettes during 24 hours of ad-libitum use have not been described. In this study, 24-hour blood plasma nicotine concentrations and 48-hour subjective effects with use of cigarettes and e-cigarettes were measured among dual users.DesignTwo-arm within-subject cross-over design with preferred e-cigarette or cigarette ad-libitum use over 48 hours.SettingHospital research ward in San Francisco, California, USA.ParticipantsThirty-six healthy dual users of e-cigarettes and cigarettes (n = 8, 25% females).MeasurementsTwenty-four-hour blood plasma nicotine and cotinine concentrations and 48-hour self-reported nicotine withdrawal symptoms and rewarding effects.FindingsAnalyses used analysis of variance (ANOVA)-based mixed models with order of product (e-cigarette or cigarette) and product type (combustible cigarette or type of e-cigarette) as fixed effects, and subject as a repeated effect. During a 24-hour period, e-cigarettes produced lower nicotine exposure than cigarettes for the majority of users, although 25% received more nicotine from e-cigarettes, which was predicted by more frequent e-cigarette use or greater dependence. Compared to cigarette smoking, nicotine exposure for variable-power tank users was similar, while cig-a-like (t(30)  = 2.71, P = 0.011, d = 0.745) and fixed-power tank users (t(30)  = 3.37, P = 0.002, d = 0.993) were exposed to less nicotine. Cigarettes were rated higher than e-cigarettes on some desirable subjective effects (e.g. psychological reward, t(322)  = 7.24 P < 0.001, d = 0.432), but withdrawal symptom reduction was comparable. No differences were found between e-cigarette types, but Bayes factors indicate that these measures were insensitive.ConclusionsDuring a 24-hour period in a hospital setting in the United States, nicotine exposure for dual users of

Caffeine is the most widely consumed psychoactive substance in the world. However, there is controversy about whether becoming addicted to caffeine is possible and a lack of well-established animal models to examine caffeine consumption. The present study sought to establish a model of caffeine consumption in Wistar rats, identify different rat populations based on caffeine preference, and determine whether extended voluntary caffeine consumption produces compulsive-like caffeine intake and withdrawal symptoms. Male Wistar rats were used throughout the experiment. The optimal concentration of caffeine to maximize caffeine consumption and caffeine preference was determined. Rats were then given continuous access to caffeine, followed by intermittent access. Rats were tested for signs of withdrawal-like behavior by measuring mechanical nociception and irritability-like behavior. Rats were further examined for compulsive-like caffeine consumption using quinine adulteration. Dose-response testing indicated an optimal caffeine concentration of 0.3 mg/mL. During intermittent access to caffeine, the rats did not escalate their caffeine intake and instead exhibited a decrease in intake over sessions. Three groups of rats were identified based on caffeine preference (high, medium, and low) across continuous and intermittent access. These three groups of rats matched low (1 cup), medium (2 cups), and high (4 cups) levels of daily coffee consumption in humans. Caffeine-consuming rats did not exhibit differences in mechanical nociception or irritability-like behavior compared with controls. In high caffeine-preferring rats but not in medium or low caffeine-preferring rats, compulsive-like caffeine consumption was observed. The present study established a rodent model of caffeine consumption that resulted in large individual differences in caffeine intake, similar to humans. Compulsive-like caffeine consumption in high caffeine-preferring rats and differences in caffeine pr

Recent evidence implicates endogenous pituitary adenylyl cyclase activating polypeptide (PACAP) in the aversive effect of nicotine. In the present study, we assessed if nicotine-induced conditioned place preference (CPP) or affective signs of nicotine withdrawal would be altered in the absence of PACAP and if there were any sex-related differences in these responses. Male and female mice lacking PACAP and their wild-type controls were tested for baseline place preference on day 1, received conditioning with saline or nicotine (1 mg/kg) on alternate days for 6 days and were then tested for CPP the next day. Mice were then exposed to four additional conditioning and were tested again for nicotine-induced CPP 24 hr later. Controls were conditioned with saline in both chambers and tested similarly. All mice were then, 96 hr later, challenged with mecamylamine (3 mg/kg), and tested for anxiety-like behaviors 30 min later. Mice were then, 2 hr later, forced to swim for 15 min and then tested for depression-like behaviors 24 hr later. Our results showed that male but not female mice lacking PACAP expressed a significant CPP that was comparable to their wild-type controls. In contrast, male but not female mice lacking PACAP exhibited reduced anxiety- and depression-like behaviors compared to their wild-type controls following the mecamylamine challenge. These results suggest that endogenous PACAP is involved in affective signs of nicotine withdrawal, but there is a sex-related difference in this response.

RationaleOver the last decade, oxycodone has become one of the most widely abused drugs in the USA. Oxycodone use disorder (OUD) is a serious health problem that has prompted a need to develop animal models of OUD that have both face and predictive validity. Oxycodone use in humans is more prevalent in women and leads to pronounced hyperalgesia and irritability during withdrawal. However, unclear is whether current animal models of oxycodone self-administration recapitulate these characteristics in humans.ObjectivesWe assessed the face validity of a model of extended-access oxycodone self-administration in rats by examining the escalation of oxycodone intake and behavioral symptoms of withdrawal, including irritability-like behavior and mechanical nociception, in male and female Wistar rats.ResultsBoth male and female rats escalated their oxycodone intake over fourteen 12-h self-administration sessions. After escalation, female rats administered more drug than male rats. No differences in plasma oxycodone levels were identified, but males had a significantly higher level of oxycodone in the brain at 30 min. Extended access to oxycodone significantly decreased aggressive-like behavior and increased defensive-like behaviors when tested immediately after a 12-h self-administration session, followed by a rebound increase in aggressive-like behavior 12 h into withdrawal. Tests of mechanical nociception thresholds during withdrawal indicated pronounced hyperalgesia. No sex differences in irritability-like behavior or pain sensitivity were observed.ConclusionsThe present study demonstrated the face validity of the extended access model of oxycodone self-administration by identifying sex differences in the escalation of oxycodone intake and pronounced changes in pain and affective states.

Randomized controlled trials' ability to produce evidence useful for people to decide whether to take, continue taking, or stop taking psychotropic drugs has been intensely critiqued, along with the trials' commercial, ideological, and regulatory contexts. This article applies the critique to the topic of withdrawal effects confounding the outcomes of relapse-prevention trials where prescribed psychotropic drugs are discontinued. Until recently, the complexity and reach of withdrawal and post-withdrawal effects were neglected by mainstream psychiatry, but not by lay users of prescribed psychotropics. This article discusses withdrawal effects as part of the pharmacology of psychotropic drugs but shaped by psychosocial factors, and possibly shaping the presentation of psychological distress generally. It outlines biases and misconceptions in assumptions, design, and reporting of general efficacy trials and findings from a recent review of 80 discontinuation trials. In theory, relapse-prevention trials are tautological and exaggerate efficacy. In publications, they pay little attention to the central feature of their design, favor abrupt or rapid discontinuations, do not attend to environmental factors, and provide insufficient data to allow re-analyses. Thus, relapse-prevention RCTs likely confound the detection of their main outcome of interest: "relapse." Using slower tapers, active placebo controls, and specific covariates in analyses would reduce the risk of withdrawal confounding, and better reporting would reduce the opaqueness of trials. The crisis in psychopharmacology is fueled partly by the disconnect between claims of therapeutic efficacy from so-called best-evidence methods despite unchanging population-level indicators of psychiatric sickness. Only by "stacking the deck" against trial sponsors' hoped-for outcomes can psychopharmacology trials regain scientific credibility.

Caffeine is the most widely consumed psychoactive substance in the world. However, there is controversy about whether becoming addicted to caffeine is possible and a lack of well-established animal models to examine caffeine consumption. The present study sought to establish a model of caffeine consumption in Wistar rats, identify different rat populations based on caffeine preference, and determine whether extended voluntary caffeine consumption produces compulsive-like caffeine intake and withdrawal symptoms. Male Wistar rats were used throughout the experiment. The optimal concentration of caffeine to maximize caffeine consumption and caffeine preference was determined. Rats were then given continuous access to caffeine, followed by intermittent access. Rats were tested for signs of withdrawal-like behavior by measuring mechanical nociception and irritability-like behavior. Rats were further examined for compulsive-like caffeine consumption using quinine adulteration. Dose-response testing indicated an optimal caffeine concentration of 0.3 mg/mL. During intermittent access to caffeine, the rats did not escalate their caffeine intake and instead exhibited a decrease in intake over sessions. Three groups of rats were identified based on caffeine preference (high, medium, and low) across continuous and intermittent access. These three groups of rats matched low (1 cup), medium (2 cups), and high (4 cups) levels of daily coffee consumption in humans. Caffeine-consuming rats did not exhibit differences in mechanical nociception or irritability-like behavior compared with controls. In high caffeine-preferring rats but not in medium or low caffeine-preferring rats, compulsive-like caffeine consumption was observed. The present study established a rodent model of caffeine consumption that resulted in large individual differences in caffeine intake, similar to humans. Compulsive-like caffeine consumption in high caffeine-preferring rats and differences in caffeine pr

Recent evidence implicates endogenous pituitary adenylyl cyclase activating polypeptide (PACAP) in the aversive effect of nicotine. In the present study, we assessed if nicotine-induced conditioned place preference (CPP) or affective signs of nicotine withdrawal would be altered in the absence of PACAP and if there were any sex-related differences in these responses. Male and female mice lacking PACAP and their wild-type controls were tested for baseline place preference on day 1, received conditioning with saline or nicotine (1 mg/kg) on alternate days for 6 days and were then tested for CPP the next day. Mice were then exposed to four additional conditioning and were tested again for nicotine-induced CPP 24 hr later. Controls were conditioned with saline in both chambers and tested similarly. All mice were then, 96 hr later, challenged with mecamylamine (3 mg/kg), and tested for anxiety-like behaviors 30 min later. Mice were then, 2 hr later, forced to swim for 15 min and then tested for depression-like behaviors 24 hr later. Our results showed that male but not female mice lacking PACAP expressed a significant CPP that was comparable to their wild-type controls. In contrast, male but not female mice lacking PACAP exhibited reduced anxiety- and depression-like behaviors compared to their wild-type controls following the mecamylamine challenge. These results suggest that endogenous PACAP is involved in affective signs of nicotine withdrawal, but there is a sex-related difference in this response.

The attenuated inhibitory control of smokers is a stumbling block for treating nicotine dependence. Unfortunately, smokers are often exposed to cigarette-related salient cues, which may violate homeostasis, override self-control, and lead to relapse. To understand the mechanisms underlying these associations, we investigate the cognitive and neural processes of inhibitory control (including proactive and reactive inhibition) of smoking cues in abstinent smokers. Twenty-six smokers completed cue-reactivity and stop signal tasks during functional magnetic resonance imaging scans, on two separate sessions, 2-3 weeks apart: one involved a neutral cue reactivity task, and the other a smoking cue reactivity task. Findings pointed to no significant subjective craving changes, or behavioral influences of smoking cues on proactive and reactive inhibition. However, abstinent smokers exhibited hyperactive brain reactivity in response to smoking versus neutral stimuli, in regions including the insula, amygdala, anterior cingulate cortex (ACC), and putamen. They also had hypoactive bilateral rostral ACC (rACC) and hyperactive right pre-supplementary motor area during reactive inhibition in smoking versus neutral conditions. Support vector regression analysis showed that activation of these regions predicted and correlated with reactive inhibition index (i.e., SSRT), alluding to the possibility of their involvement in the reactive inhibition. Subjective craving scores were predicted by and correlated with activation of bilateral dorsal and rostral ACC, supporting the ideas of their possible involvement in subjective craving. These findings suggest that smoking cues evoke hyperactive brain reactivity; this may interfere with normal performance monitoring and rapid reactive inhibition. These findings have important implication for treating smoking dependence.

AimTo describe systemic nicotine exposure and subjective effects of electronic cigarettes (e-cigarettes) in people who use both e-cigarettes and cigarettes (dual users), including within-subject comparisons of e-cigarette and cigarette use.DesignTwo-arm, counterbalanced cross-over study. Participants used their usual brand of e-cigarette or cigarette during a standardized session in a 2-week study.SettingHospital research ward, San Francisco, CA, USA.ParticipantsThirty-six healthy (eight women, 28 men) participants.MeasurementsPlasma nicotine was analyzed by gas chromatography-tandem mass spectrometry; nicotine withdrawal, urge to smoke and vape, affective states, craving, satisfaction and psychological reward were measured by standardized questionnaires.FindingsCompared with cigarettes, average maximum plasma nicotine concentration (Cmax ) was lower with e-cigarettes [6.1 ± 5.5 ng/ml, mean ± standard deviation (SD) versus 20.2 ± 11.1 ng/ml, P < 0.001] and time of maximal concentration (Tmax ) was longer (6.5 ± 5.4 versus 2.7 ± 2.4 minutes, P < 0.001). Use of both products resulted in a reduction in the severity of withdrawal symptoms, negative affect and urge to use either product. E-cigarettes were less rewarding and satisfying and reduced craving to a lesser degree than cigarettes. We were not able to detect any differences in withdrawal symptoms, affective states and urge to smoke cigarettes between e-cigarette and cigarette use.ConclusionSystemic nicotine exposure was, on average, lower with single use of e-cigarettes compared with cigarettes, and e-cigarettes were judged to be less satisfying and rewarding and reduced craving less than cigarettes.

Background and aimsRelative pharmacological effects of e-cigarettes and cigarettes during 24 hours of ad-libitum use have not been described. In this study, 24-hour blood plasma nicotine concentrations and 48-hour subjective effects with use of cigarettes and e-cigarettes were measured among dual users.DesignTwo-arm within-subject cross-over design with preferred e-cigarette or cigarette ad-libitum use over 48 hours.SettingHospital research ward in San Francisco, California, USA.ParticipantsThirty-six healthy dual users of e-cigarettes and cigarettes (n = 8, 25% females).MeasurementsTwenty-four-hour blood plasma nicotine and cotinine concentrations and 48-hour self-reported nicotine withdrawal symptoms and rewarding effects.FindingsAnalyses used analysis of variance (ANOVA)-based mixed models with order of product (e-cigarette or cigarette) and product type (combustible cigarette or type of e-cigarette) as fixed effects, and subject as a repeated effect. During a 24-hour period, e-cigarettes produced lower nicotine exposure than cigarettes for the majority of users, although 25% received more nicotine from e-cigarettes, which was predicted by more frequent e-cigarette use or greater dependence. Compared to cigarette smoking, nicotine exposure for variable-power tank users was similar, while cig-a-like (t(30)  = 2.71, P = 0.011, d = 0.745) and fixed-power tank users (t(30)  = 3.37, P = 0.002, d = 0.993) were exposed to less nicotine. Cigarettes were rated higher than e-cigarettes on some desirable subjective effects (e.g. psychological reward, t(322)  = 7.24 P < 0.001, d = 0.432), but withdrawal symptom reduction was comparable. No differences were found between e-cigarette types, but Bayes factors indicate that these measures were insensitive.ConclusionsDuring a 24-hour period in a hospital setting in the United States, nicotine exposure for dual users of

Behavioral and clinical studies suggest a critical role of substance P (SP)/neurokinin-1 receptor (NK-1R) signaling in alcohol dependence. Here, we examined regulation of GABA transmission in the medial subdivision of the central amygdala (CeM) by the SP/NK-1R system, and its neuroadaptation following chronic alcohol exposure. In naïve rats, SP increased action potential-dependent GABA release, and the selective NK-1R antagonist L822429 decreased it, demonstrating SP regulation of CeM activity under basal conditions. SP induced a larger GABA release in alcohol-dependent rats accompanied by decreased NK-1R expression compared to naïve controls, suggesting NK-1R hypersensitivity which persisted during protracted alcohol withdrawal. The NK-1R antagonist blocked acute alcohol-induced GABA release in alcohol-dependent and withdrawn but not in naïve rats, indicating that dependence engages the SP/NK-1R system to mediate acute effects of alcohol. Collectively, we report long-lasting CeA NK-1R hypersensitivity corroborating that NK-1Rs are promising targets for the treatment of alcohol use disorder.

Randomized controlled trials' ability to produce evidence useful for people to decide whether to take, continue taking, or stop taking psychotropic drugs has been intensely critiqued, along with the trials' commercial, ideological, and regulatory contexts. This article applies the critique to the topic of withdrawal effects confounding the outcomes of relapse-prevention trials where prescribed psychotropic drugs are discontinued. Until recently, the complexity and reach of withdrawal and post-withdrawal effects were neglected by mainstream psychiatry, but not by lay users of prescribed psychotropics. This article discusses withdrawal effects as part of the pharmacology of psychotropic drugs but shaped by psychosocial factors, and possibly shaping the presentation of psychological distress generally. It outlines biases and misconceptions in assumptions, design, and reporting of general efficacy trials and findings from a recent review of 80 discontinuation trials. In theory, relapse-prevention trials are tautological and exaggerate efficacy. In publications, they pay little attention to the central feature of their design, favor abrupt or rapid discontinuations, do not attend to environmental factors, and provide insufficient data to allow re-analyses. Thus, relapse-prevention RCTs likely confound the detection of their main outcome of interest: "relapse." Using slower tapers, active placebo controls, and specific covariates in analyses would reduce the risk of withdrawal confounding, and better reporting would reduce the opaqueness of trials. The crisis in psychopharmacology is fueled partly by the disconnect between claims of therapeutic efficacy from so-called best-evidence methods despite unchanging population-level indicators of psychiatric sickness. Only by "stacking the deck" against trial sponsors' hoped-for outcomes can psychopharmacology trials regain scientific credibility.

Recent evidence implicates endogenous pituitary adenylyl cyclase activating polypeptide (PACAP) in the aversive effect of nicotine. In the present study, we assessed if nicotine-induced conditioned place preference (CPP) or affective signs of nicotine withdrawal would be altered in the absence of PACAP and if there were any sex-related differences in these responses. Male and female mice lacking PACAP and their wild-type controls were tested for baseline place preference on day 1, received conditioning with saline or nicotine (1 mg/kg) on alternate days for 6 days and were then tested for CPP the next day. Mice were then exposed to four additional conditioning and were tested again for nicotine-induced CPP 24 hr later. Controls were conditioned with saline in both chambers and tested similarly. All mice were then, 96 hr later, challenged with mecamylamine (3 mg/kg), and tested for anxiety-like behaviors 30 min later. Mice were then, 2 hr later, forced to swim for 15 min and then tested for depression-like behaviors 24 hr later. Our results showed that male but not female mice lacking PACAP expressed a significant CPP that was comparable to their wild-type controls. In contrast, male but not female mice lacking PACAP exhibited reduced anxiety- and depression-like behaviors compared to their wild-type controls following the mecamylamine challenge. These results suggest that endogenous PACAP is involved in affective signs of nicotine withdrawal, but there is a sex-related difference in this response.

RationaleOver the last decade, oxycodone has become one of the most widely abused drugs in the USA. Oxycodone use disorder (OUD) is a serious health problem that has prompted a need to develop animal models of OUD that have both face and predictive validity. Oxycodone use in humans is more prevalent in women and leads to pronounced hyperalgesia and irritability during withdrawal. However, unclear is whether current animal models of oxycodone self-administration recapitulate these characteristics in humans.ObjectivesWe assessed the face validity of a model of extended-access oxycodone self-administration in rats by examining the escalation of oxycodone intake and behavioral symptoms of withdrawal, including irritability-like behavior and mechanical nociception, in male and female Wistar rats.ResultsBoth male and female rats escalated their oxycodone intake over fourteen 12-h self-administration sessions. After escalation, female rats administered more drug than male rats. No differences in plasma oxycodone levels were identified, but males had a significantly higher level of oxycodone in the brain at 30 min. Extended access to oxycodone significantly decreased aggressive-like behavior and increased defensive-like behaviors when tested immediately after a 12-h self-administration session, followed by a rebound increase in aggressive-like behavior 12 h into withdrawal. Tests of mechanical nociception thresholds during withdrawal indicated pronounced hyperalgesia. No sex differences in irritability-like behavior or pain sensitivity were observed.ConclusionsThe present study demonstrated the face validity of the extended access model of oxycodone self-administration by identifying sex differences in the escalation of oxycodone intake and pronounced changes in pain and affective states.

Caffeine is the most widely consumed psychoactive substance in the world. However, there is controversy about whether becoming addicted to caffeine is possible and a lack of well-established animal models to examine caffeine consumption. The present study sought to establish a model of caffeine consumption in Wistar rats, identify different rat populations based on caffeine preference, and determine whether extended voluntary caffeine consumption produces compulsive-like caffeine intake and withdrawal symptoms. Male Wistar rats were used throughout the experiment. The optimal concentration of caffeine to maximize caffeine consumption and caffeine preference was determined. Rats were then given continuous access to caffeine, followed by intermittent access. Rats were tested for signs of withdrawal-like behavior by measuring mechanical nociception and irritability-like behavior. Rats were further examined for compulsive-like caffeine consumption using quinine adulteration. Dose-response testing indicated an optimal caffeine concentration of 0.3 mg/mL. During intermittent access to caffeine, the rats did not escalate their caffeine intake and instead exhibited a decrease in intake over sessions. Three groups of rats were identified based on caffeine preference (high, medium, and low) across continuous and intermittent access. These three groups of rats matched low (1 cup), medium (2 cups), and high (4 cups) levels of daily coffee consumption in humans. Caffeine-consuming rats did not exhibit differences in mechanical nociception or irritability-like behavior compared with controls. In high caffeine-preferring rats but not in medium or low caffeine-preferring rats, compulsive-like caffeine consumption was observed. The present study established a rodent model of caffeine consumption that resulted in large individual differences in caffeine intake, similar to humans. Compulsive-like caffeine consumption in high caffeine-preferring rats and differences in caffeine pr

ObjectiveTo examine whether sustained minimal manifestation status (MMS) with complete withdrawal of prednisone is better achieved in thymectomized patients with myasthenia gravis (MG).MethodsThis study is a post hoc analysis of data from a randomized trial of thymectomy in MG (Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy [MGTX]). MGTX was a multicenter, randomized, rater-blinded 3-year trial that was followed by a voluntary 2-year extension for patients with acetylcholine receptor (AChR) antibody-positive MG without thymoma. Patients were randomized 1:1 to thymectomy plus prednisone vs prednisone alone. Participants were age 18-65 years at enrollment with disease duration less than 5 years. All patients received oral prednisone titrated up to 100 mg on alternate days until they achieved MMS, which prompted a standardized prednisone taper as long as MMS was maintained. The achievement rate of sustained MMS (no symptoms of MG for 6 months) with complete withdrawal of prednisone was compared between the thymectomy plus prednisone and prednisone alone groups.ResultsPatients with MG in the thymectomy plus prednisone group achieved sustained MMS with complete withdrawal of prednisone more frequently (64% vs 38%) and quickly compared to the prednisone alone group (median time 30 months vs no median time achieved, p < 0.001) over the 5-year study period. Prednisone-associated adverse symptoms were more frequent in the prednisone alone group and distress level increased with higher doses of prednisone.ConclusionsThymectomy benefits patients with MG by increasing the likelihood of achieving sustained MMS with complete withdrawal of prednisone.Clinicaltrialsgov identifierNCT00294658.Classification of evidenceThis study provides Class II evidence that for patients with generalized MG with AChR antibody, those receiving thymectomy plus prednisone are more likely to attain sustained MMS and complete prednisone withdrawal than tho

Adolescence is a time of major plasticity of brain systems that regulate motivated behavior and cognition, and is also the age of peak onset of nicotine use. Although there has been a decline in teen use of cigarettes in recent years, there has been a huge increase in nicotine vaping. It is therefore critically important to understand the impact of nicotine on this critical phase of brain development. Animal studies have shown that nicotine has unique effects on adolescent brain. The goal of this review is therefore to systematically evaluate age- and sex-differences in the effects of nicotine on brain and behavior. Both acute and chronic effects of nicotine on brain biochemistry and behavior, particularly drug reward, aversion, cognition and emotion, are evaluated. Gaps in our current knowledge that need to be addressed are also highlighted. This review compares and integrates human and animals findings. Although there can be no experimental studies in humans to confirm similar behavioral effects of teen nicotine exposure, an emerging observational literature suggests similarities across species. Given the substantial evidence for long-term negative impact of adolescent nicotine exposure on brain and behavior, further longitudinal assessment of health outcomes in teen and young adult e-cigarette users is warranted.

Opioid use disorder (OUD) is a public health crisis. Differences in opioid withdrawal severity that predict treatment outcome could facilitate the process of matching patients to treatments. This is a secondary analysis of a randomized controlled trial (RCT) that enrolled treatment seeking heroin-users (N = 89, males = 78) into a residential study. Participants maintained on morphine (30 mg, subcutaneous, four-times daily) underwent a naloxone (0.4 mg, IM = intramuscular) challenge session to precipitate withdrawal. Area-under-the-curve (AUC) values from self-reported withdrawal ratings during the challenge session were analyzed using K-means clustering, revealing two phenotype groups. Withdrawal and retention from the subsequent 14-day double-blind, double-dummy RCT comparing three study medications (clonidine, tramadol-ER, and buprenorphine) were evaluated as a function of phenotype. Cluster analyses suggested HIGH (N = 37; mean [SD] subjective opiate withdrawal scale [SOWS]-AUC 123.7 [65.8]) and LOW (N = 52; SOWS-AUC 68.0 [47.7]) withdrawal phenotype groups. HIGH participants were significantly more female and had lower body mass indices than LOW participants; no drug-use variables were significant. Regarding RCT outcomes, HIGH phenotype participants were less likely to be retained in the study (P = 0.02) and had higher mean self-reported withdrawal (P = 0.05) than LOW phenotype participants. A significant interaction in RCT retention was observed between phenotype (P = 0.02) and study medication (P < 0.01). Self-reported withdrawal was significant for phenotype (P = 0.02); study medication trended towards significance (P = 0.07). Results suggest patients have meaningfully different experiences of opioid withdrawal that may predict differential response to opioid pharmacotherapies during supervised withdrawal. Additional prospective research to replicate and more thorough

BACKGROUND AND AIMS: Relative pharmacological effects of e-cigarettes and cigarettes during 24 hours of ad-libitum use have not been described. In this study, 24-hour blood plasma nicotine concentrations and 48-hour subjective effects with use of cigarettes and e-cigarettes were measured among dual users. DESIGN: Two-arm within-subject cross-over design with preferred e-cigarette or cigarette ad-libitum use over 48 hours. SETTING: Hospital research ward in San Francisco, California, USA. PARTICIPANTS: Thirty-six healthy dual users of e-cigarettes and cigarettes (n = 8, 25% females). MEASUREMENTS: Twenty-four-hour blood plasma nicotine and cotinine concentrations and 48-hour self-reported nicotine withdrawal symptoms and rewarding effects. FINDINGS: Analyses used analysis of variance (ANOVA)-based mixed models with order of product (e-cigarette or cigarette) and product type (combustible cigarette or type of e-cigarette) as fixed effects, and subject as a repeated effect. During a 24-hour period, e-cigarettes produced lower nicotine exposure than cigarettes for the majority of users, although 25% received more nicotine from e-cigarettes, which was predicted by more frequent e-cigarette use or greater dependence. Compared to cigarette smoking, nicotine exposure for variable-power tank users was similar, while cig-a-like (t(30)  = 2.71, P = 0.011, d = 0.745) and fixed-power tank users (t(30)  = 3.37, P = 0.002, d = 0.993) were exposed to less nicotine. Cigarettes were rated higher than e-cigarettes on some desirable subjective effects (e.g. psychological reward, t(322)  = 7.24 P < 0.001, d = 0.432), but withdrawal symptom reduction was comparable. No differences were found between e-cigarette types, but Bayes factors indicate that these measures were insensitive. CONCLUSIONS: During a 24-hour period in a hospital setting in the United States, nicotine exposu

OBJECTIVE: To examine whether sustained minimal manifestation status (MMS) with complete withdrawal of prednisone is better achieved in thymectomized patients with myasthenia gravis (MG). METHODS: This study is a post hoc analysis of data from a randomized trial of thymectomy in MG (Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy [MGTX]). MGTX was a multicenter, randomized, rater-blinded 3-year trial that was followed by a voluntary 2-year extension for patients with acetylcholine receptor (AChR) antibody-positive MG without thymoma. Patients were randomized 1:1 to thymectomy plus prednisone vs prednisone alone. Participants were age 18-65 years at enrollment with disease duration less than 5 years. All patients received oral prednisone titrated up to 100 mg on alternate days until they achieved MMS, which prompted a standardized prednisone taper as long as MMS was maintained. The achievement rate of sustained MMS (no symptoms of MG for 6 months) with complete withdrawal of prednisone was compared between the thymectomy plus prednisone and prednisone alone groups. RESULTS: Patients with MG in the thymectomy plus prednisone group achieved sustained MMS with complete withdrawal of prednisone more frequently (64% vs 38%) and quickly compared to the prednisone alone group (median time 30 months vs no median time achieved, p < 0.001) over the 5-year study period. Prednisone-associated adverse symptoms were more frequent in the prednisone alone group and distress level increased with higher doses of prednisone. CONCLUSIONS: Thymectomy benefits patients with MG by increasing the likelihood of achieving sustained MMS with complete withdrawal of prednisone. CLINICALTRIALSGOV IDENTIFIER: NCT00294658. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with generalized MG with AChR antibody, those receiving thymectomy plus prednisone are more likely to attain sustained MMS and complete prednisone wi

RationaleOver the last decade, oxycodone has become one of the most widely abused drugs in the USA. Oxycodone use disorder (OUD) is a serious health problem that has prompted a need to develop animal models of OUD that have both face and predictive validity. Oxycodone use in humans is more prevalent in women and leads to pronounced hyperalgesia and irritability during withdrawal. However, unclear is whether current animal models of oxycodone self-administration recapitulate these characteristics in humans.ObjectivesWe assessed the face validity of a model of extended-access oxycodone self-administration in rats by examining the escalation of oxycodone intake and behavioral symptoms of withdrawal, including irritability-like behavior and mechanical nociception, in male and female Wistar rats.ResultsBoth male and female rats escalated their oxycodone intake over fourteen 12-h self-administration sessions. After escalation, female rats administered more drug than male rats. No differences in plasma oxycodone levels were identified, but males had a significantly higher level of oxycodone in the brain at 30 min. Extended access to oxycodone significantly decreased aggressive-like behavior and increased defensive-like behaviors when tested immediately after a 12-h self-administration session, followed by a rebound increase in aggressive-like behavior 12 h into withdrawal. Tests of mechanical nociception thresholds during withdrawal indicated pronounced hyperalgesia. No sex differences in irritability-like behavior or pain sensitivity were observed.ConclusionsThe present study demonstrated the face validity of the extended access model of oxycodone self-administration by identifying sex differences in the escalation of oxycodone intake and pronounced changes in pain and affective states.

Caffeine is the most widely consumed psychoactive substance in the world. However, there is controversy about whether becoming addicted to caffeine is possible and a lack of well-established animal models to examine caffeine consumption. The present study sought to establish a model of caffeine consumption in Wistar rats, identify different rat populations based on caffeine preference, and determine whether extended voluntary caffeine consumption produces compulsive-like caffeine intake and withdrawal symptoms. Male Wistar rats were used throughout the experiment. The optimal concentration of caffeine to maximize caffeine consumption and caffeine preference was determined. Rats were then given continuous access to caffeine, followed by intermittent access. Rats were tested for signs of withdrawal-like behavior by measuring mechanical nociception and irritability-like behavior. Rats were further examined for compulsive-like caffeine consumption using quinine adulteration. Dose-response testing indicated an optimal caffeine concentration of 0.3 mg/mL. During intermittent access to caffeine, the rats did not escalate their caffeine intake and instead exhibited a decrease in intake over sessions. Three groups of rats were identified based on caffeine preference (high, medium, and low) across continuous and intermittent access. These three groups of rats matched low (1 cup), medium (2 cups), and high (4 cups) levels of daily coffee consumption in humans. Caffeine-consuming rats did not exhibit differences in mechanical nociception or irritability-like behavior compared with controls. In high caffeine-preferring rats but not in medium or low caffeine-preferring rats, compulsive-like caffeine consumption was observed. The present study established a rodent model of caffeine consumption that resulted in large individual differences in caffeine intake, similar to humans. Compulsive-like caffeine consumption in high caffeine-preferring rats and differences in caffeine pr