Sedative-Hypnotic Agents That Impact Gamma-Aminobutyric Acid Receptors: Focus on Flunitrazepam, Gamma-Hydroxybutyric Acid, Phenibut, and Selank.

There are many nonopioid central nervous system depressant substances that share a gamma-aminobutyric acid (GABA) receptor-related mechanism of action. These sedatives-hypnotics can be indicated to treat anxiety, seizures, depression, and insomnia but are also used as substances of abuse and used to facilitate sexual assault. Barbiturates, methaqualone, and glutethimide were among the first type A GABA receptor-mediated sedative-hypnotics. Their clinical use was limited for most indications by serious adverse events and strong abuse potential but continue to be used illicitly around the world. The benzodiazepines supplanted barbiturates for most indications because they were less likely to cause severe adverse events in monotherapy. Flunitrazepam is a newer benzodiazepine that is preferentially used recreationally and to facilitate sexual assault. Flunitrazepam has greater potency and higher affinity for the type A GABA receptor than most benzodiazepines. Gamma-hydroxybutyric acid is sought illicitly for its hypnotic, euphoric and anabolic effects as well as to facilitate sexual assault. When any of these GABAergic drugs are used in high doses or with other sedative hypnotic agents, respiratory depression, coma, and death have occurred. Chronic use of these GABAergic drugs can lead to significant withdrawal syndromes. Phenibut and selank are poorly studied Russian drugs with GABAergic mechanisms that are inexplicably sold to US consumers as dietary supplements. Poison control center calls regarding phenibut have increased substantially over the past 5 years. Desired euphoriant effects account for the recreational and illicit use of many GABA-modulating agents. However, illicit use can lead to significant toxicities related to abuse, dependence, and subsequent withdrawal syndromes. Significant evaluation of developing agents with GABA properties should be conducted to determine abuse potential before public access ensues.

Alcohol withdrawal syndrome: improving outcomes in the emergency department with aggressive management strategies.

Alcohol use disorder is a prevalent medical and psychiatric disease, and consequently, alcohol withdrawal is encountered frequently in the emergency department. Patients commonly manifest hyperadrenergic signs and symptoms, necessitating admission to the intensive care unit, administration of intravenous sedatives, and frequently, adjunctive pharmacotherapy. This issue reviews the pathophysiology of alcohol withdrawal syndrome, describes the manifestations of alcohol withdrawal, and examines the available evidence for optimal treatment of alcohol withdrawal. An aggressive frontloading approach with benzodiazepines is presented, and the management of benzodiazepine-resistant disease is addressed.

Reduced thalamic resting-state functional connectivity and impaired cognition in acute abstinent heroin users.

As a critical component of cortico-striato-thalamo-cortical loop in addiction, our understanding of the thalamus in impaired cognition of heroin users (HU) has been limited. Due to the complex thalamic connection with cortical and subcortical regions, thalamus was divided into prefrontal (PFC), occipital (OC), premotor, primary motor, sensory, temporal, and posterior parietal association subregions according to white matter tractography. We adopted seven subregions of bilateral thalamus as regions of interest to systematically study the implications of distinct thalamic nuclei in acute abstinent HU. The volume and resting-state functional connectivity (RSFC) differences of the thalamus were investigated between age-, gender-, and alcohol-matched 37 HU and 33 healthy controls (HCs). Trail making test-A (TMT-A) was adopted to assess cognitive function deficits, which were then correlated with neuroimaging findings. Although no significant different volumes were found, HU group showed decreased RSFC between left PFC_thalamus and middle temporal gyrus as well as between left OC_thalamus and inferior frontal gyrus and supplementary motor area relative to HCs. Meanwhile, the higher TMT-A scores in HU were negatively correlated with PFC_thalamic RSFC with inferior temporal gyrus, fusiform, and precuneus. Craving scores were negatively correlated with OC_thalamic RSFC with accumbens, hippocampus, and insula. Opiate Withdrawal Scale scores were negatively correlated with left PFC/OC_thalamic RSFC with orbitofrontal cortex and medial PFC. We indicated two thalamus subregions separately involvement in cognitive control and craving to reveal the implications of thalamic subnucleus in pathology of acute abstinent HU.

Resting state hypothalamic and dorsomedial prefrontal cortical connectivity of the periaqueductal gray in cocaine addiction.

Cocaine-dependent (CD) individuals demonstrate significant anxiety and dysphoria during withdrawal, a negative emotional state that may perpetuate drug seeking and consumption. An extensive body of work has focused on characterizing reward circuit dysfunction, but relatively little is known about the pain circuit during cocaine withdrawal. In an earlier study, we highlighted how cue-elicited functional connectivity between the periaqueductal gray (PAG), a subcortical hub of the pain circuit, and ventromedial prefrontal cortex supports tonic craving in recently abstinent CD. The functional organization of the brain can be characterized by intrinsic connectivities, and it is highly likely that the resting state functional connectivity (rsFC) of the PAG may also be altered in association with cocaine use variables. Here, we examined this issue in 52 CD and 52 healthy control (HC) participants. Imaging data were processed with published routines, and the findings were evaluated with a corrected threshold. In a covariance analysis, CD as compared with HC showed higher PAG rsFC with the hypothalamus, dorsomedial prefrontal, and inferior parietal cortices. Further, these connectivities were correlated negatively with tonic cocaine craving and recent cocaine use, respectively. Higher hypothalamic and frontoparietal rsFC with the PAG may reflect a compensatory process to regulate craving and compulsive drug use. The findings provide additional evidence in humans implicating the PAG circuit and may help research of the role of negative reinforcement in sustaining habitual drug use in cocaine addiction.

The effects of mindfulness-based yogic breathing on craving, affect, and smoking behavior.

Breathing practices are often incorporated into treatments for tobacco dependence, but there is little direct research testing the efficacy of breathing practices. This study examined the effects of a mindfulness-based yogic breathing (MB) intervention versus active treatment (cognitive strategy [CS]) and no-treatment (NT) control groups on craving, affect, withdrawal, and smoking behavior. Smokers (N = 60; 50% female; 83% African American) were randomized to receive 20 min of MB, CS, or NT. Participants completed self-report measures before and after the manipulation and then took part in a 50-min smoking choice procedure. Afterward, participants were advised to use the techniques they learned and self-monitor smoking for 24 hr. They received 3 reminder text messages and returned to the lab the following day. MB and CS were more effective than NT in decreasing craving to smoke and perceived nicotine withdrawal. MB, but not CS, was more effective than NT in reducing negative affect. MB reduced the risk of smoking by more than twofold relative to both CS and NT during the smoking choice procedure. Participants in the MB condition smoked fewer cigarettes than those in the CS and NT conditions in the 24 hr following the manipulation. There were no differential effects of the manipulations on state mindfulness or positive affect. Mindful yogic breathing appears to be particularly effective in alleviating the acute negative effects of smoking abstinence and decreasing smoking behavior. Mindful breathing techniques are safe, simple, and cost-effective strategies that deserve additional research attention, especially among underserved populations of smokers. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Acute naloxone-precipitated morphine withdrawal elicits nausea-like somatic behaviors in rats in a manner suppressed by N-oleoylglycine.

RATIONALE: Acute naloxone-precipitated morphine withdrawal (MWD) produces a conditioned place aversion (CPA) in rats even after one or two exposures to high-dose (20 mg/kg, sc) morphine followed 24-h later by naloxone (1 mg/kg, sc). However, the somatic withdrawal reactions produced by acute naloxone-precipitated MWD in rats have not been investigated. A recently discovered fatty acid amide, N-oleoylglycine (OlGly), which has been suggested to act as a fatty acid amide hydrolase (FAAH) inhibitor and as a peroxisome proliferator-activated receptor alpha (PPARα) agonist, was previously shown to interfere with a naloxone-precipitated MWD-induced CPA in rats. OBJECTIVES: The aims of these studies were to examine the somatic withdrawal responses produced by acute naloxone-precipitated MWD and determine whether OlGly can also interfere with these responses. RESULTS: Here, we report that following two exposures to morphine (20 mg/kg, sc) each followed by naloxone (1 mg/kg, sc) 24 h later, rats display nausea-like somatic reactions of lying flattened on belly, abdominal contractions and diarrhea, and display increased mouthing movements and loss of body weight. OlGly (5 mg/kg, ip) interfered with naloxone-precipitated MWD-induced abdominal contractions, lying on belly, diarrhea and mouthing movements in male Sprague-Dawley rats, by both a cannabinoid 1 (CB1) and a PPARα mechanism of action. Since these withdrawal reactions are symptomatic of nausea, we evaluated the potential of OlGly to interfere with lithium chloride (LiCl)-induced and MWD-induced conditioned gaping in rats, a selective measure of nausea; the suppression of MWD-induced gaping reactions by OlGly was both CB1 and PPARα mediated. CONCLUSION: These results suggest that the aversive effects of acute naloxone-precipitated MWD reflect nausea, which is suppressed by OlGly.

Heroin addiction engages negative emotional learning brain circuits in rats.

Opioid use disorder (OUD) is associated with the emergence of persistent negative emotional states during drug abstinence that drive compulsive drug taking and seeking. Functional magnetic resonance imaging (fMRI) in rats identified neurocircuits that were activated by stimuli that were previously paired with heroin withdrawal. The activation of amygdala and hypothalamic circuits was related to the degree of heroin dependence, supporting the significance of conditioned negative affect in sustaining compulsive-like heroin seeking and taking and providing neurobiological insights into the drivers of the current opioid crisis.

Guanfacine decreases symptoms of cannabis withdrawal in daily cannabis smokers.

The α2a-adrenergic agonist, lofexidine, reduced cannabis withdrawal-related sleep disruption in the laboratory, but side effects (e.g. fatigue, hypotension) limit its utility as a treatment for cannabis use disorder. This study tested the potential efficacy and tolerability of a daily bedtime administration of the FDA-approved α2a-adrenergic agonist, guanfacine, in a human laboratory model of cannabis use disorder. Daily, nontreatment-seeking cannabis smokers (13M, 2F) completed a within-subject study comprising two 9-day inpatient study phases. Each phase tested the effects of daily placebo or immediate-release guanfacine (2 mg) on cannabis intoxication (5.6 percent THC; 2 days), withdrawal (4 days of abstinence) and subsequent 'relapse' (3 days of cannabis self-administration). Ratings of mood, sleep, cardiovascular effects, food intake, psychomotor performance and cannabis self-administration were assessed. An outpatient phase preceded each inpatient phase for medication clearance or dose induction. Under placebo medication conditions, cannabis abstinence produced significant withdrawal, including irritability, sleep disruption and anorexia. Guanfacine reduced ratings of irritability and improved objective measures of sleep during cannabis withdrawal relative to placebo but did not reduce cannabis self-administration. Guanfacine was well tolerated with little evidence of fatigue and only small decreases in blood pressure: no dose was held due to hypotension. Thus, a single daily administration of guanfacine at bedtime improved sleep and mood during cannabis withdrawal relative to placebo. This positive signal supports further studies varying the guanfacine dose, formulation or frequency of administration, or combining it with other medications to increase the likelihood of having an impact on cannabis use.

Varenicline and nabilone in tobacco and cannabis co-users: effects on tobacco abstinence, withdrawal and a laboratory model of cannabis relapse.

Tobacco and cannabis co-users (T+CUs) have poor cannabis cessation outcomes, but the mechanisms underlying this are not well understood. This laboratory study examined the effects of (1) the partial nicotinic agonist, varenicline, on tobacco cessation among T+CUs, and (2) varenicline, alone, and when combined with the cannabinoid agonist nabilone, on cannabis withdrawal and a laboratory model of cannabis relapse. Non-treatment-seeking T+CUs were randomized to active-varenicline or placebo-varenicline, and completed a 15-day outpatient phase; varenicline was titrated to 1 mg BID during days 1-8, and participants were instructed to abstain from tobacco during days 9-15. Participants then moved inpatient for 16 days, where they continued their outpatient medication and tobacco abstinence. Inpatient testing included two, 8-day medication periods, where active-nabilone and placebo-nabilone were administered in counterbalanced order, and measures of acute cannabis effects (days 1-2), withdrawal (days 4-5) and 'relapse' (days 6-8) were collected. Participants in the active-varenicline group were more likely to achieve cotinine-verified tobacco abstinence during the outpatient period versus placebo-varenicline group (46 percent versus 24 percent, respectively), and also reported less mood disturbance and cigarette craving while inpatient. Active-nabilone attenuated cannabis withdrawal in both groups but did not affect cannabis relapse. Regression analyses revealed that two tobacco-related variables, i.e. age of first cigarette use, and cigarette craving while inpatient, were independent predictors of cannabis relapse outcomes. Thus, varenicline holds promise in this population, as a tool to examine the effects of tobacco abstinence on cannabis use outcomes, and as a component of smoking cessation treatments targeting T+CUs.

[Reversible cerebral vasoconstriction syndrome following smoking cessation and treatment with bupropion]. / Sindrome de vasoconstriccion cerebral reversible tras abandono de habito tabaquico y tratamiento con bupropion.

TITLE: Sindrome de vasoconstriccion cerebral reversible tras abandono de habito tabaquico y tratamiento con bupropion.

Dispositional mindfulness, anticipation and abstinence symptoms related to hypnotic dependence among insomniac women who seek treatment: A cross-sectional study.

INTRODUCTION: Dispositional mindfulness can be described as the mental ability to pay attention to the present moment, non-judgmentally. There is evidence of inverse relation between dispositional mindfulness and insomnia and substance use, but as of yet, no studies evaluating the specific association between dispositional mindfulness and the components of hypnotic use disorder. OBJECTIVE: To evaluate the association between dispositional mindfulness and the components of dependence among female chronic hypnotic users. DESIGN AND METHOD: Seventy-six women, chronic users of hypnotics, who resorted to Mindfulness-Based Relapse Prevention for the cessation of hypnotic use were included in the study. The Five Facet Mindfulness Questionnaire (FFMQ) evaluated the levels and facets of mindfulness, and the subscales of the Benzodiazepine Dependence Questionnaire (BENDEP) assessed dependence on hypnotics. We also evaluated sociodemographic variables and symptoms of insomnia and anxiety. The associations between the FFMQ facets and the BENDEP subscales were evaluated with binomial logistic regression, adjusted for income, schooling, anxiety, and insomnia. RESULTS: We observed associations between facets of the FFMQ and specific aspects of hypnotic dependence. The facet "observing" was inversely associated with the "concern about lack of availability of the hypnotic" [aOR = 0.87 95% CI (0.79-0.97)], and the facet "non-reacting to inner experience" with "noncompliance with the prescription recommendations" [aOR = 0.86 95% CI (0.75-0.99)]. The total score of the FFMQ was inversely associated to those two dependence subscales [aOR = 0.94 95% CI (0.89-0.99)]. "Observing" and "non-reactivity to inner experience" were also inversely associated with the "impairments related to the withdrawal symptoms" [aOR = 0.84 95% CI (0.73-0.97)] and [aOR = 0.78 95% CI (0.63-0.96)], respectively. The FFMQ was not associated with "awareness of problematic hypnotic use". CONCLUSION: Dispositional mindfulness, specifically the facets "observing" and "non-reactivity to inner experience, were inversely associated with the components of hypnotic dependence related to the anticipation of having the substance, its expected effect, and the impairments caused by the abstinence. We discuss the implications of those results for the clinical practice and future investigations.

The thalamo-cortical resting state functional connectivity and abstinence-induced craving in young smokers.

Craving is a significant predicator of smoking relapse. Thus, revealing the neural correlates of craving to smoke in young smokers is important to improve the success of quit attempts. The abstinence-induced craving to smoke has not been explored extensively, although previous studies had investigated the neural substrates of cue-induced craving. Especially, the critical roles of thalamus had been revealed in cigarettes smoking. However, the implication of thalamus resting state functional connectivity (RSFC) in abstinence-induced craving remains unclear. In the current study, by employing a within-subject design in 25 young smokers, both the left and right thalamus RSFC patterns differences were investigated between smoking abstinence condition and smoking satiety condition in young smokers. Moreover, a correlation analysis was employed to assess the relationship between these RSFC changes and abstinence-induced changes in subjective craving. We found young smokers in abstinence state showed reduced RSFC between the left thalamus and right dorsal lateral prefrontal cortex (dlPFC) as well as the right anterior cingulate cortex (ACC) compared with smoking satiety state. There were no significant different RSFC of right thalamus detected across the two sessions. Additionally, the left thalamus-right dlPFC RSFC changes were correlated with the changes in craving induced by 12-h abstinence (i.e., abstinence minus satiety). The present findings provides new evidence that abstinence-induced cravings to smoke are associated with abnormal thalamus RSFC and may shed new insights into the neural mechanism of abstinence-induced craving in young smokers.

Reversible cerebral vasoconstriction syndrome secondary to caffeine withdrawal.

We describe a 39-year-old man who developed thunderclap headaches during a hospital admission for accidental superficial burns. His magnetic resonance brain imaging was normal expect for diffuse segmental vasoconstriction. Prior to admission, he was consuming excessive amounts of caffeine which was restarted and slowly tapered and stopped over weeks. Repeat magnetic resonance angiogram showed resolution of segmental vasoconstriction. The implications of prescribed and non-prescribed drugs on cerebral vasculature have been discussed.

Peripheral immune system suppression in early abstinent alcohol-dependent individuals: Links to stress and cue-related craving.

BACKGROUND: Peripheral immune system cytokines may play an integral role in the underlying sensitized stress response and alcohol craving during early alcohol withdrawal. To date, the nature of these immune changes during early abstinence have not been examined. METHODS: A total of 39 early abstinent, treatment-seeking, alcohol-dependent individuals and 46 socially drinking controls were exposed to three guided imageries: stress, alcohol cue and neutral. These were presented randomly across consecutive days. Plasma measures of tumor necrosis factor alpha (TNFα), tumor necrosis factor receptor 1 (TNFR1), interleukin-6 (IL-6), and interleukin-10 (IL-10), were collected at baseline, immediately after imagery and at various recovery time-points. Ratings of alcohol craving, negative mood and anxiety were also obtained at the same time-points. RESULTS: The alcohol group demonstrated decreased basal IL-10 compared with controls particularly following exposure to alcohol cue. They also showed a dampened TNFα and TNFR1 response to stress and cue, respectively, and a generalized suppression of IL-6. In the alcohol group, these immune system adaptations occurred alongside significant elevations in anxiety, negative mood and alcohol craving. CONCLUSIONS: Findings demonstrate that broad immunosuppression is still observed in alcohol-dependent individuals after 3 weeks of abstinence and may be linked to motivation for alcohol.

Compromised neuroplasticity in cigarette smokers under nicotine withdrawal is restituted by the nicotinic α4ß2-receptor partial agonist varenicline.

Nicotine modulates neuroplasticity and improves cognitive functions in animals and humans. In the brain of smoking individuals, calcium-dependent plasticity induced by non-invasive brain stimulation methods such as transcranial direct current stimulation (tDCS) and paired associative stimulation (PAS) is impaired by nicotine withdrawal, but partially re-established after nicotine re-administration. In order to investigate the underlying mechanism further, we tested the impact of the α4ß2-nicotinic receptor partial agonist varenicline on focal and non-focal plasticity in smokers during nicotine withdrawal, induced by PAS and tDCS, respectively. We administered low (0.3 mg) and high (1.0 mg) single doses of varenicline or placebo medication before stimulation over the left motor cortex of 20 healthy smokers under nicotine withdrawal. Motor cortex excitability was monitored by single-pulse transcranial magnetic stimulation-induced motor evoked potential amplitudes for 36 hours after plasticity induction. Stimulation-induced plasticity was absent under placebo medication, whereas it was present in all conditions under high dose. Low dose restituted only tDCS-induced non-focal plasticity, producing no significant impact on focal plasticity. High dose varenicline also prolonged inhibitory plasticity. These results are comparable to the impact of nicotine on withdrawal-related impaired plasticity in smokers and suggest that α4ß2 nicotinic receptors are relevantly involved in plasticity deficits and restitution in smokers.

Focus on cannabinoids and synthetic cannabinoids.

The recent emergence of a multitude of synthetic cannabinoids (SCs) has generated a wealth of new information, suggesting the usefulness of state-of-the-art on lato sensu cannabinoids. By modulating a plurality of neurotransmission pathways, the endocannabinoid system is involved in many physiological processes that are increasingly explored. SCs desired and adverse effects are considered to be more intense than those observed with cannabis smoking, which is partly explained by the full agonist activity and higher affinity for cannabinoid receptors. Neurological and cardiovascular side effects observed after cannabinoid poisoning generally respond to conventional supportive care, but severe outcomes may occur in a minority of cases, mainly observed with SCs. The likelihood of severe abuse and addiction produced by SCs are of concern for the scientific community also interested in the potential therapeutic value of cannabinoids.

Oxytocin for the treatment of drug and alcohol use disorders.

There is growing interest in the use of oxytocin (OT) as a potential treatment for alcohol and other substance-use disorders. OT is a neuropeptide that modulates adaptive processes associated with addiction including reward, tolerance, associative learning, memory, and stress responses. OT exerts its effects through interactions with the hypothalamic-pituitary-adrenal axis and multiple neurotransmitter systems including the dopamine mesolimbic reward and corticotrophin-releasing factor stress systems. The effects of OT on stress systems are of high interest, given the strong link between stress, drug use and relapse, and known dysregulation of hypothalamic-pituitary-adrenal-axis activity associated with substance-use disorders. At the same time, the OT system is itself altered by acute or chronic drug exposure. This review summarizes the preclinical and clinical literature on the OT system and its relevance to drug and alcohol addiction. In addition, findings from recent clinical trials conducted in participants with cocaine, cannabis, or alcohol use disorder are included and evidence that OT may help to normalize blunted stress responses, and attenuate withdrawal-associated hypercortisolism, negative mood, and withdrawal symptoms is summarized.

Caffeine discontinuation improves acute migraine treatment: a prospective clinic-based study.

BACKGROUND: Caffeine has both excitatory and vasoconstrictive effects on central nervous system. Caffeine use might be associated with development and chronification of migraine. We aimed to evaluate the effect of caffeine cessation on the acute treatment of migraine. METHODS: We prospectively recruited migraine patients who consumed caffeine drinks daily and instructed them to discontinue their caffeine intake. Triptans were prescribed for acute treatment. Patients were followed up after at least two weeks after screening and evaluated the efficacy of acute treatment with the migraine assessment of current therapy (Migraine-ACT) questionnaire. Excellent efficacy was defined as Migraine-ACT score of 4. Chronic migraine, body mass index, allodynia, depression, anxiety, antiemetic use, and use of prophylactic medication were included in the multivariate analysis if the univariate p < 0.2. FINDINGS: Among 108 patients included, 36 completely discontinued their caffeine intake (abstinence group). The efficacy of acute treatment was assessed at median 34.5 days (interquartile range, 28-89) after the screening. Twenty-six patients (72.2 %) in the abstinence group and 29 (40.3 %) in the non-abstinence group reported an excellent efficacy (p = 0.002). The abstinence group also showed a trend toward greater reduction of headache impact test-6 (HIT-6) scores (p = 0.085). Caffeine abstinence was independently associated with an excellent efficacy of acute treatment (multivariate odds ratio, 3.2; 95 % confidence interval, 1.2-8.4; p = 0.018) after controlling for covariates. CONCLUSIONS: Caffeine abstinence is associated with better efficacy of acute migraine treatment. Our uncontrolled study results encourage a further confirmatory study on this issue.