ß-Arrestin-Biased Allosteric Modulator of NTSR1 Selectively Attenuates Addictive Behaviors.

Small molecule neurotensin receptor 1 (NTSR1) agonists have been pursued for more than 40 years as potential therapeutics for psychiatric disorders, including drug addiction. Clinical development of NTSR1 agonists has, however, been precluded by their severe side effects. NTSR1, a G protein-coupled receptor (GPCR), signals through the canonical activation of G proteins and engages ß-arrestins to mediate distinct cellular signaling events. Here, we characterize the allosteric NTSR1 modulator SBI-553. This small molecule not only acts as a ß-arrestin-biased agonist but also extends profound ß-arrestin bias to the endogenous ligand by selectively antagonizing G protein signaling. SBI-553 shows efficacy in animal models of psychostimulant abuse, including cocaine self-administration, without the side effects characteristic of balanced NTSR1 agonism. These findings indicate that NTSR1 G protein and ß-arrestin activation produce discrete and separable physiological effects, thus providing a strategy to develop safer GPCR-targeting therapeutics with more directed pharmacological action.

A non-hallucinogenic psychedelic analogue with therapeutic potential.

The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals1. Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to various substances, including opiates, alcohol and psychostimulants. The effects of ibogaine-like those of other psychedelic compounds-are long-lasting2, which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling3,4. However, several safety concerns have hindered the clinical development of ibogaine, including its toxicity, hallucinogenic potential and tendency to induce cardiac arrhythmias. Here we apply the principles of function-oriented synthesis to identify the key structural elements of the potential therapeutic pharmacophore of ibogaine, and we use this information to engineer tabernanthalog-a water-soluble, non-hallucinogenic, non-toxic analogue of ibogaine that can be prepared in a single step. In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce antidepressant-like effects. This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.

Addiction specialists' attitudes toward psychedelics: A National Survey.

BACKGROUND AND OBJECTIVES: In recent years, there has been accelerating scientific and public interest in the use of psychedelics to treat mental health disorders. Our study's objective was to assess the attitudes of addiction specialists regarding therapeutic psychedelics. METHODS: Our study utilized an anonymous online survey to assess the opinions of 145 addiction specialists regarding the therapeutic promise, potential risks, and legalization of psychedelics in the treatment of psychiatric illness and substance use disorders. Psychedelics were defined in the survey as inclusive of nonserotonergic hallucinogens such as ketamine or MDMA in addition to "classic" serotonergic psychedelics. RESULTS: Most respondents expressed positive attitudes to the therapeutic use of psychedelics, but a sizeable minority expressed concern for their addictive potential. Familiarity with psychedelic scientific literature was the strongest positive predictor of belief in the therapeutic potential of psychedelics, while concern for addictive potential was the strongest negative predictor. DISCUSSION AND CONCLUSIONS: Participants overall expressed more positive attitudes to the therapeutic use of psychedelics than we had hypothesized. This may be attributable to the accelerating pace of psychedelics research in recent years. Given the strong influence of concern for addiction risk on attitudes, future study is warranted to explore the findings regarding these concerns. These findings may also represent an opportunity for improved education of physicians regarding the addictive potential, and relative risks/benefits of psychedelics. SCIENTIFIC SIGNIFICANCE: Though there have been several prior studies assessing psychiatrist and psychologist attitudes toward psychedelics, we are unaware of any specifically examining the opinions of addiction specialists.

The Role of the Cerebellum in Drug Reward: A Review.

Drug abuse remains a global problem; nonetheless, its mechanism has not yet been fully understood. Recent studies have reported on the non-motor functions of the cerebellum, and evidence from neuroimaging and behavioral studies has suggested the role of cerebellum in drug reward, which has received increasing attention. Furthermore, emerging technological developments have aided in clarifying the various circuits and functions of the cerebellum. Exploring the role of the cerebellum in drug reward can improve our understanding of the mechanism underlying addiction and facilitate the development of new treatment schemes. This review summarizes the anatomy of the cerebellum and its connections to brain regions considered important in addiction. Subsequently, we investigate the neurological reasons elucidating why the cerebellum is a potential target for drug reward. Additionally, we expound the molecular targets of addictive drugs in the cerebellum, mainly glutamate and endocannabinoids. Unlike previous studies, this article focuses on the influence of alcohol, nicotine, morphine, cannabis, and cocaine on the cerebellum from multiple viewpoints, including imaging and behavioral changes, molecular signals, neurotransmitters, and synaptic transmission. We aim to clarify some drug-induced cerebellar changes to supplement the previous research regarding the relationship between addiction and the cerebellum. Finally, we discuss the limitations and prospects of drug reward research on the cerebellum to provide novel insights into studying the cerebellum and its role in addiction. We recommend that future addiction network models should include the cerebellum to provide new therapeutic targets for treating addiction.

The dopamine motive system: implications for drug and food addiction.

Behaviours such as eating, copulating, defending oneself or taking addictive drugs begin with a motivation to initiate the behaviour. Both this motivational drive and the behaviours that follow are influenced by past and present experience with the reinforcing stimuli (such as drugs or energy-rich foods) that increase the likelihood and/or strength of the behavioural response (such as drug taking or overeating). At a cellular and circuit level, motivational drive is dependent on the concentration of extrasynaptic dopamine present in specific brain areas such as the striatum. Cues that predict a reinforcing stimulus also modulate extrasynaptic dopamine concentrations, energizing motivation. Repeated administration of the reinforcer (drugs, energy-rich foods) generates conditioned associations between the reinforcer and the predicting cues, which is accompanied by downregulated dopaminergic response to other incentives and downregulated capacity for top-down self-regulation, facilitating the emergence of impulsive and compulsive responses to food or drug cues. Thus, dopamine contributes to addiction and obesity through its differentiated roles in reinforcement, motivation and self-regulation, referred to here as the 'dopamine motive system', which, if compromised, can result in increased, habitual and inflexible responding. Thus, interventions to rebalance the dopamine motive system might have therapeutic potential for obesity and addiction.

Perspective: Can psychedelic-assisted therapy be a promising aid in compulsive sexual behavior disorder treatment?

Recently, there has been an increase in studies yielding evidence for psychedelics' anxiolytic and anti-depressive qualities. Preliminary evidence for treatment in substance addiction is also available. In our manuscript, we present a perspective on the possible effectiveness and mechanisms of action of psychedelics' introduction in the treatment of Compulsive Sexual Behavior Disorder (CSBD) and other p roblematic sexual behaviors, which are considered representative of the so-called "behavioral addiction" category. Evidence for the efficacy of Mindfulness Based Interventions in CSBD treatment is promising. Psychedelics- and mindfulness-induced states share common characteristics on both a subjective and objective level. One of the proposed mechanisms regards reduction of experiential avoidance through the promotion of exposure and acceptance. On the neurophysiological level, a shift from higher- to lower-level association regions and an impact on 5- HT2A receptors is observed. Elaborated mechanisms explain the possible enhancement of therapeutic processes by psychedelics. Psychedelics' relative safety and low addictive potential support their introduction into traditional forms of therapy for CSBD and other out of control behaviors.

Plants with Anti-Addictive Potential.

Drug addiction is prevalent among individuals of modern society, being a major cause of disability and premature loss of life. Although the drug addiction have profound social, economical and health impact in the world population, its management remains a challenge as available pharmacological treatments remains ineffective for most people. The limited efficacy and adverse effects have led to a search for alternative therapies to treat drug addiction. In this context, natural products are an important source for new chemical substances with a potential therapeutic applicability. Therefore, this chapter will present data obtained after an extensive literature search regarding the use of medicinal plants as a pharmacological alternative for drug addiction treatment.

New Insights in the Involvement of the Endocannabinoid System and Natural Cannabinoids in Nicotine Dependence.

Nicotine, the main psychoactive component in tobacco smoke, plays a major role in tobacco addiction, producing a high morbidity and mortality in the world. A great amount of research has been developed to elucidate the neural pathways and neurotransmitter systems involved in such a complex addictive behavior. The endocannabinoid system, which has been reported to participate in the addictive properties of most of the prototypical drugs of abuse, is also implicated in nicotine dependence. This review summarizes and updates the main behavioral and biochemical data involving the endocannabinoid system in the rewarding properties of nicotine as well as in nicotine withdrawal and relapse to nicotine-seeking behavior. Promising results from preclinical studies suggest that manipulation of the endocannabinoid system could be a potential therapeutic strategy for treating nicotine addiction.

Gambling Disorder as an Addictive Disorder and Creative Psychopharmacotherapy.

Addiction does not mean "addiction to substances" only. At the core of the definition of substance dependence is the loss of control. Gambling addiction belongs to non-substance / non-chemical addictions or behavioral/behavioral addictions. The concept of behavioral addictions is new and revolutionary in psychiatry. Gambling addiction, formerly pathological or problematic gambling occurs due to loss of control over gambling. There is growing evidence to suggest that behavioral addictions resemble substance addictions in many domains, including phenomenology, tolerance, comorbidity, overlapping genetic contribution, neurobiological mechanisms, and response to treatment. Behavioral addiction has been proposed as a new class in the Diagnostic Statistical Manual Fifth Revision (DSM-5), but the only category included is gambling addiction. The prevalence of gambling disorders in adolescence is very high and for certain disorders (especially related to the use of the Internet) it becomes more pronounced over time. In this paper, we presented a comprehensive overview of gambling disorders from definition, epidemiology, manifestations, comorbidities, assessment, treatment options, and existing forms of treatment. Given the complexity of the approach to the treatment of gamblers, a creative individualized integrative approach is necessary, which is the basis of creative psychopharmacotherapy. Due to the possibility of the emergence of problem gambling and other impulse-control deficits we need to be very careful when commencing a patient on dopamine replacement therapy or therapy with aripiprazole.

The Molecular-Container Calabadion-2 Prevents Methamphetamine-Induced Reinstatement in Rats: A Potential Approach to Relapse Prevention?

BACKGROUND: Reexposure to methamphetamine with a single "priming dose" can trigger intense cravings and precipitate relapse in methamphetamine-dependent individuals. The acyclic cucurbit[n]uril "molecular container" calabadion-2 shows a high affinity to bind and sequester methamphetamine in vitro and attenuates its locomotor-stimulating effect in rats. The present study investigates whether pretreatment with calabadion-2 is sufficient to prevent the reinstatement of drug seeking by a priming dose of methamphetamine in rats. METHODS: Male Long-Evans rats were trained to self-administer i.v. methamphetamine (0.06 mg/kg/infusion). Following 10 days of stable self-administration, rats underwent extinction training and were subsequently tested on a multi-phase reinstatement procedure. Drug-primed reinstatement sessions (0.3 mg/kg methamphetamine, i.v.) were preceded by either saline or calabadion-2 (130 mg/kg). Additional reinstatement tests were conducted after administration of yohimbine (1.0 mg/kg, i.v.) to define the pharmacological specificity of calabadion-2. RESULTS: Pretreatment with calabadion-2 significantly attenuated methamphetamine-induced reinstatement of responding. Cal2 did not affect drug-seeking behavior stimulated by the pharmacological stressor yohimbine, indicating a mechanism of action specific to methamphetamine. CONCLUSIONS: These results demonstrate the effectiveness of calabadion-2 in a preclinical model relapse-like behavior. With further structural optimization, molecular containers may provide a novel and efficacious pharmacokinetic approach to relapse prevention for methamphetamine-dependent individuals.

Effects of naltrexone on alcohol, sucrose, and saccharin binge-like drinking in C57BL/6J mice: a study with a multiple bottle choice procedure.

Chronic alcohol (ethyl alcohol, EtOH) binging has been associated with long-term neural adaptations that lead to the development of addiction. Many of the neurobiological features of EtOH abuse are shared with other forms of binging, like pathological feeding. The drinking-in-the-dark (DID) paradigm has been used extensively to study the neurobiology of EtOH binge-like drinking due to its ability to promote high intakes relevant to human behavior. DID can also generate high consumption of other tastants, but this procedure has not been fully adapted to study forms of binging behavior that are not alcohol-driven. In the present study, we used a modified version of DID that uses multiple bottle availability to promote even higher levels of EtOH drinking in male C57BL/6J mice and allows a thorough investigation of tastant preferences. We assessed whether administration of systemic naltrexone could reduce binging on EtOH, sucrose, and saccharin separately as well as in combination. Our multiple bottle DID procedure resulted in heightened levels of consumption compared with previously reported data using this task. We found that administration of the opioid receptor antagonist naltrexone reduced intakes of preferred, highly concentrated EtOH, sucrose, and saccharin. We also report that naltrexone was able to reduce overall intakes when animals were allowed to self-administer EtOH, sucrose, or saccharin in combination. Our modified DID procedure provides a novel approach to study binging behavior that extends beyond EtOH to other tastants (i.e. sucrose and artificial sweeteners), and has implications for the study of the neuropharmacology of binge drinking.

Effects of Intranasal Oxytocin on Stress-Induced Cigarette Craving in Daily Smokers.

BACKGROUND: Cigarette smoking is a well-known public health concern, and there is an urgent need to develop new treatments to reduce smoking or facilitate abstinence. One factor that is known to contribute to relapse is stress, making the stress response an important target for treatment. The neuropeptide oxytocin (OT) is believed to have stress-reducing effects, and in addition there is evidence that it reduces drug craving. The purpose of the present study was to examine the effects of intranasal OT on stress-induced cigarette craving in regular smokers after 12 h of abstinence. METHOD: Daily smokers (n = 48) completed a stress induction task and a nonstressful control task at two different sessions, receiving intranasal OT (40 IU) or placebo (PBO) before or after the task. Subjects were randomly assigned to one of three groups: Group PP (n = 16) received PBO before and after the stress/control tasks, Group OP (n = 16) received OT before the tasks and PBO after, and Group PO (n = 16) received PBO before the tasks and OT shortly after completing the tasks. Cigarette craving as well as subjective and physiological responses to stress was assessed. RESULTS: OT did not alter responses to stress, whether it was administered before or after the stressful task, on measures of cigarette craving, anxiety, heart rate, blood pressure, and cortisol levels. CONCLUSIONS: The current study findings do not support several previous reports that OT reduced either stress or drug craving. IMPLICATIONS: This study finds a null result of the neuropeptide oxytocin on stress-induced cigarette craving. Reporting null findings is part of the process of identifying potential treatments for addictive disorders.

Pharmacotherapy of Sexual Addiction.

PURPOSE OF REVIEW: We reviewed recent data on sexual addiction and its treatment. We examined the different definitions of this disorder, related to the pathophysiological mechanisms. We addressed the pharmacological treatment of sexual addiction. RECENT FINDINGS: Hypersexual behavior can be considered an addictive disorder. Sexual addiction is accompanied by significant psychiatric and addictive comorbidities and is responsible for life impairment. A comprehensive and efficient treatment must be proposed. Selective serotonin reuptake inhibitors seem the first-line pharmacological treatment for sexual addiction. Naltrexone could be another therapeutic option. Psychotherapy and preferentially cognitive-behavioral therapy should be used in association with pharmacotherapy and treatments of comorbidities.

How does ayahuasca work from a psychiatric perspective? Pros and cons of the entheogenic therapy.

OBJECTIVE: Ayahuasca is a hallucinogenic plant preparation, traditionally consumed in sacred ceremonies by indigenous North-Westerner Amazonian countries like Colombia, Peru, Brazil, and Ecuador. It is fundamental to carefully balance benefits/risks related to the ayahuasca intake, both during ceremonies and experimental settings. The aim is at evaluating and comparing the potential therapeutic benefits versus health risks related to ayahuasca intake (both acutely and chronically), focusing on its application in psychedelic psychiatry. DESIGN: A comprehensive mini overview focusing on psychiatric outcomes following ayahuasca intake both in healthy volunteers and in clinical samples. RESULTS: Preclinical, observational, and experimental studies in healthy volunteers as well as in clinical samples suggest that ayahuasca may be beneficial as an antidepressant, emotional regulator, anxiolytic, and antiaddictive drug, by exerting fast-acting and enduring clinical effects. Ayahuasca appears to be safe and well tolerated, nausea and emesis being the most reported and transient side effects. Some findings suggest not to use ayahuasca in bipolar or psychotic patients because of an increased risk of manic switch and/or psychotic onset. CONCLUSIONS: Further research should be carried out in randomized, double-blind, placebo-controlled trials, by implementing neuroimaging studies, in order to better evaluate therapeutic potential of ayahuasca in mental disorders.

Differential Effects of Saikosaponins A, B2, B4, C and D on Alcohol and Chocolate Self-Administration in Rats.

AIMS: Treatment with saikosaponin A (SSA)-an ingredient of the medicinal herb, Bupleurum falcatum-has been reported to suppress several addictive-like behaviors, including morphine, cocaine, alcohol and chocolate self-administration in male rats. The aim of this investigation was to investigate whether saikosaponins of B. falcatum other than SSA affect alcohol and chocolate self-administration in rats. METHODS: Ovariectomized female Sardinian alcohol-preferring (sP) and Wistar rats were trained to self-administer alcohol (15%, v/v) and a chocolate solution [5% (w/v) Nesquik® in water], respectively, under fixed ratio schedules of reinforcement. The following saikosaponins were compared to SSA: saikosaponin D (SSD; epimer of SSA), saikosaponin C (SSC), saikosaponin B2 (SSB2) and saikosaponin B4 (SSB4). All saikosaponins were tested acutely at the doses of 0, 0.25, 0.5 and 1 mg/kg (i.p.). RESULTS: Treatment with SSA and SSD resulted in highly similar, marked reductions in alcohol self-administration; SSC failed to alter lever-responding for alcohol, while SSB2 and SSB4 produced intermediate reductions. Only SSA and SSD reduced chocolate self-administration, with SSC, SSB2 and SSB4 being ineffective. CONCLUSIONS: The wide spectrum of efficacy of saikosaponins in reducing alcohol and chocolate self-administration suggests that even relatively small structural differences are sufficient to produce remarkable changes in their in vivo pharmacological profile. Together, these results confirm that roots of B. falcatum may be an interesting source of compounds with anti-addictive potential.

Gender differences in unidirectional and bidirectional intimate partner violence in addictions.

Background: Few studies have analyzed the specific characteristics related to uni/bidirectional intimate partner violence (IPV) in patients with addiction problems. Knowing the specific profiles of these patients would allow the development of effective tailored interventions.Objective: This study assessed gender differences in unidirectional and bidirectional IPV among patients undergoing drug addiction treatment.Method: We sampled 122 patients (91 male and 31 female) who sought treatment in an addiction treatment center, and collected cross-sectional self-reported data on violent behaviors (physical, sexual and psychological violence), sociodemographic factors, distorted thoughts about women and violence, impulsiveness, and anger.Results: Ninety-one percent of participants reported experience of IPV (any type and any direction). Sixty-three percent of participants reported bidirectional violence, which was more common among women (83.9%) than men (56.1%). Unidirectional (perpetration only) IPV was reported in 28.7% of participants, and it was more common among men (34.1%) than women (12.9%). No one reported unidirectional (victimization-only) IPV. When only physical and/or sexual violence was considered, bidirectional violence affected 32.0% of the sample; 23.8% were only victims, and 3.3% were only perpetrators (all of them men). Participants who reported bidirectional violence had higher scores for impulsiveness, anger, and distorted thoughts.Conclusions: Bidirectional IPV is commonly reported among patients seeking treatment for addiction, particularly among women, and should be considered in future research and clinical practice.

[Psychotherapy assisted by psychedelics, intense and unusual exposures therapy]. / Psychothérapie assistée par des psychédéliques, un traitement par expositions intenses et inhabituelles.

There is a renewed interest in the use of psychedelics in the treatment of addictions. The mode of action of psychedelics could be explained by the addictolytic effect of the substance or by an amplifying effect a unique experience. If studies are lacking on the intrinsic addictolytic effects of psychedelics in humans, animals and in vitro experiences show an increase in neurogenesis. In humans, the effectiveness could be explained by the intensity of the lived experience. If the purely experiential aspect is the key to the effectiveness of treatment, it strengthens the idea that psychedelics act as reinforcers of the psychotherapeutic experience by exposure to intense and unusual internal stimuli.

Un regain d'intérêt est constaté pour l'usage des psychédéliques dans le traitement des addictions. Le mode d'action des psychédéliques pourrait être expliqué par l'effet addictolytique de la substance ou par un effet amplificateur d'un vécu d'une expérience unique. Si des études manquent sur les effets addictolytiques intrinsèques des psychédéliques, la recherche fondamentale met en évidence une augmentation de la neurogenèse dans le cortex préfrontal. Chez l'homme, l'efficacité pourrait être expliquée par l'intensité de l'expérience vécue. Si l'aspect purement expérientiel est la clé de l'efficacité du traitement, cela renforce l'idée que les psychédéliques agissent comme renforçateurs de l'expérience psychothérapeutique par une exposition à des stimuli internes intenses et inhabituels.

Apomorphine-induced sensitization in rats exposed to restraint stress: Relationship with adaptation to stress.

Drug abuse and impaired adaptation to stress are inter-related. Drug abuse is more potentiated upon exposure to stress and an impairment to cope with stress may lead to depression. On the other hand, use of addictive compounds increase the vulnerability to depression by inhibiting the adaptation to stress. Present study investigates relationship between behavioral tolerance to repeated restraint stress and apomorphine-induced sensitization. Apomorphine was injected either before or after the restraint stress episode, to monitor drug-induced behavioral sensitization and place preference. Apomorphine-induced sensitization and place preference were enhanced if the drug is experiencing during restraint stress. Conversely, apomorphine-induced sensitization and place preference were attenuated if the drug is experiencing after restraint stress. It shows that apomorphine, if experienced during restraint stress, produces greater sensitization Conversely, sensitization effects of apomorphine are blocked in animals receiving apomorphine after the termination of restraint stress. The results tend to show that drug of abuse may be effective for the treatment but not prevention of stress-induced depression.

Existing and Future Drugs for the Treatment of the Dark Side of Addiction.

The identification of a heuristic framework for the stages of the addiction cycle that are linked to neurocircuitry changes in pathophysiology includes the binge/intoxication stage, the withdrawal/negative affect stage, and the preoccupation/anticipation (craving) stage, which represent neuroadaptations in three neurocircuits (basal ganglia, extended amygdala, and frontal cortex, respectively). The identification of excellent and validated animal models, the development of human laboratory models, and an enormous surge in our understanding of neurocircuitry and neuropharmacological mechanisms have provided a revisionist view of addiction that emphasizes the loss of brain reward function and gain of stress function that drive negative reinforcement (the dark side of addiction) as a key to compulsive drug seeking. Reversing the dark side of addiction not only explains much of the existing successful pharmacotherapies for addiction but also points to vast new opportunities for future medications to alleviate this major source of human suffering.

Demand elasticity predicts addiction endophenotypes and the therapeutic efficacy of an orexin/hypocretin-1 receptor antagonist in rats.

Behavioral economics is a powerful, translational approach for measuring drug demand in both humans and animals. Here, we asked if demand for cocaine in rats with limited drug experience could be used to identify individuals most at risk of expressing an addiction phenotype following either long- or intermittent access self-administration schedules, both of which model the transition to uncontrolled drug-seeking. Because the orexin-1 receptor antagonist SB-334867 (SB) is particularly effective at reducing drug-seeking in highly motivated individuals, we also asked whether demand measured after prolonged drug experience could predict SB efficacy. Demand elasticity (α) measured immediately following acquisition of cocaine self-administration ('baseline α') was positively correlated with α assessed after 2w of long- or intermittent access. Baseline α also predicted the magnitude of compulsive responding for cocaine, drug-seeking in initial abstinence and cued reinstatement following long-, intermittent- or standard short access. When demand was measured after these differential access conditions, α predicted the same addiction endophenotypes predicted by baseline α, as well as primed reinstatement and the emergence of negative emotional mood behavior following abstinence. α also predicted the efficacy of SB, such that high demand rats showed greater reductions in motivation for cocaine following SB compared to low demand rats. Together, these findings indicate that α might serve as a behavioral biomarker to predict individuals most likely to progress from controlled to uncontrolled drug use, and to identify individuals most likely to benefit from orexin-based therapies for the treatment of addiction.