Brief exposure to enriched environment rapidly shapes the glutamate synapses in the rat brain: A metaplastic fingerprint.

Environmental enrichment (EE) has been shown to produce beneficial effects in addiction disorders; however, due to its configurational complexity, the underlying mechanisms are not yet fully elucidated. Recent evidence suggests that EE, acting as a metaplastic agent, may affect glutamatergic mechanisms underlying appetitive memory and, in turn, modulate reward-seeking behaviours: here, we have investigated such a possibility following a brief EE exposure. Adult male Sprague-Dawley rats were exposed to EE for 22 h and the expression of critical elements of the glutamate synapse was measured 2 h after the end of EE in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc) and hippocampus (Hipp) brain areas, which are critical for reward and memory. We focused our investigation on the expression of NMDA and AMPA receptor subunits, their scaffolding proteins SAP102 and SAP97, vesicular and membrane glutamate transporters vGluT1 and GLT-1, and critical structural components such as proteins involved in morphology and function of glutamatergic synapses, PSD95 and Arc/Arg3.1. Our findings demonstrate that a brief EE exposure induces metaplastic changes in glutamatergic mPFC, NAc and Hipp. Such changes are area-specific and involve postsynaptic NMDA/AMPA receptor subunit composition, as well as changes in the expression of their main scaffolding proteins, thus influencing the retention of such receptors at synaptic sites. Our data indicate that brief EE exposure is sufficient to dynamically modulate the glutamatergic synapses in mPFC-NAc-Hipp circuits, which may modulate rewarding and memory processes.

Remote clinical trials: A timely opportunity for a virtual reality approach and its potential application in neurology.

The COVID-19 pandemic boosted the expansion and development of new remote models of care and clinical research modalities. Health systems are going to implement telemedical innovations in the near future. Virtual clinical trials (VCT), also known as remote or decentralized ones, may profoundly change the way how clinical studies are conducted, for the benefit of patients with chronic and neurological diseases who are often fragile and may have limited access to traditional healthcare facilities. Despite significant progress, several limitations still need to be addressed to implement telemedicine technologies for VCT. The information and communication technology (ICT) devices (e.g., mobile apps and wearables) may be applied to VCTs but show some practical issues that may hamper the compliance with rigorous research criteria and protocols. We herewith discuss the advantages and disadvantages of virtual reality (VR) in combination with other ICT devices and solutions to improve the conduction of VCT in patients with neurological disorders. The so-called "digital divide," that is, the gap between people who can and those who cannot access high-speed and broadband internet connections, and issues related to VR, such as VR sickness, should be addressed to improve larger VCT participation to neurological patients.

Smokers "Context Reactivity" in Virtual Domestic Environments.

INTRODUCTION: Although the effects of proximal smoking cues have been widely studied in smokers, little is known on the features associated with background spatial context effect, that is, "context reactivity." The aim of this study was to investigate context reactivity exhibited by smokers in virtual cue-free domestic scenarios. METHODS: Sixty-nine participants divided in 2 cohorts (33 smokers and 36 non-smokers) were exposed to a virtual reality session with 4 domestic room scenarios presented in a balanced order: bedroom, bathroom, kitchen, and living room. RESULTS: We showed that (i) it is possible to elicit smoking craving in smokers in virtual reality, and (ii) these effects are room dependent and (iii) associated with a lower sense of presence; furthermore, (iv) smokers reported higher craving scores for alcohol and food in a room-dependent fashion compared to non-smokers. CONCLUSION: Our study provides an experimental paradigm for assessing context reactivity in smokers and suggests a potential use for the identification of non-pharmacological interventions as a co-adjuvant of smoking cessation treatment.

Environmental Enrichment Induces Meningeal Niche Remodeling through TrkB-Mediated Signaling.

Neural precursors (NPs) present in the hippocampus can be modulated by several neurogenic stimuli, including environmental enrichment (EE) acting through BDNF-TrkB signaling. We have recently identified NPs in meninges; however, the meningeal niche response to pro-neurogenic stimuli has never been investigated. To this aim, we analyzed the effects of EE exposure on NP distribution in mouse brain meninges. Following neurogenic stimuli, although we did not detect modification of the meningeal cell number and proliferation, we observed an increased number of neural precursors in the meninges. A lineage tracing experiment suggested that EE-induced ß3-Tubulin+ immature neuronal cells present in the meninges originated, at least in part, from GLAST+ radial glia cells. To investigate the molecular mechanism responsible for meningeal reaction to EE exposure, we studied the BDNF-TrkB interaction. Treatment with ANA-12, a TrkB non-competitive inhibitor, abolished the EE-induced meningeal niche changes. Overall, these data showed, for the first time, that EE exposure induced meningeal niche remodeling through TrkB-mediated signaling. Fluoxetine treatment further confirmed the meningeal niche response, suggesting it may also respond to other pharmacological neurogenic stimuli. A better understanding of the neurogenic stimuli modulation for meninges may be useful to improve the effectiveness of neurodegenerative and neuropsychiatric treatments.

The Effects of Nicotine on Cortical Excitability After Exercise: A Double-Blind Randomized, Placebo-controlled, Crossover Study.

PURPOSE: The use of smokeless tobacco/nicotine products is common among athletes, but clear evidence for their positive or negative effect on sports performance is lacking. Nicotine is a psychoactive substance involved in numerous neuronal processes including cortical excitability. The aim of this study was to evaluate its effect on cortical excitability associated with aerobic exercise in nicotine-naive healthy volunteers. METHODS: Ten nicotine-naive healthy volunteers were recruited for this double-blind, randomized, crossover study to compare the effect of snus (8 mg nicotine), an oral, smokeless tobacco product, to placebo on cortical excitability before and after aerobic exercise. Transcranial magnetic stimulation (TMS) was used to measure changes in corticomotor excitability (motor-evoked potentials, MEPs) and electromyography of leg muscles during maximal voluntary contractions (MVC) to assess changes in muscle contractions. Before and after aerobic exercise and with or without nicotine treatment, MEPs and MVCs were measured. RESULTS: Analysis of TMS data showed lower motor cortex activation (lower MEP amplitude) after snus administration compared with placebo, whereas electromyography data showed no difference in muscle contraction between snus and placebo treatment. CONCLUSIONS: These findings suggest a general reduction in cortical excitability, without no relevant effect on physical performance.

Cytokine-, Neurotrophin-, and Motor Rehabilitation-Induced Plasticity in Parkinson's Disease.

Neuroinflammation and cytokine-dependent neurotoxicity appear to be major contributors to the neuropathology in Parkinson's disease (PD). While pharmacological advancements have been a mainstay in the treatment of PD for decades, it is becoming increasingly clear that nonpharmacological approaches including traditional and nontraditional forms of exercise and physical rehabilitation can be critical adjunctive or even primary treatment avenues. Here, we provide an overview of preclinical and clinical research detailing the biological role of proinflammatory molecules in PD and how motor rehabilitation can be used to therapeutically modulate neuroinflammation, restore neural plasticity, and improve motor function in PD.

Exercise performance increase in smokeless tobacco-user athletes after overnight nicotine abstinence.

The use of nicotine administered through smokeless tobacco (snus) has increased among athletes. The purpose of this study was to investigate the ergogenic effects of snus on aerobic performance during exercise until exhaustion in athletes after abstinence or satiety nicotine conditions. The study utilized a randomized, controlled, within-subject design experiment. Sixteen male snus-user athletes completed an exercise until exhaustion at a constant load of their 80% of V ˙ O 2 max (calculated by a maximal incremental test) in two separate sessions, corresponding to nicotine conditions: 12-hour overnight abstinence and satiety. A portion of 1 g of snus (~8 mg/g of nicotine) was administered 25 minutes before each experimental test. In each session, time to exhaustion (TTE), global rating of perceived exertion, cardiovascular and metabolic responses, and muscle and cerebral oxygenation were measured. Nicotine and cotinine analysis confirmed session conditions (abstinence or satiety). Snus induced a significant increase (+13.1%) of TTE following abstinence (24.1 ± 10.7 minutes) compared to satiety condition (20.9 ± 8.0 minutes; P = 0.0131). The baseline values revealed that abstinence of snus induced significant increase in the oxygenation of the muscular tissues (+4%), in metabolic values and in cardiovascular parameters, when compared to satiety condition. Our results indicate an increase of exercise performance (+13.1% TTE) due to snus administration in an abstinence condition. Considering that twelve hours of abstinence from snus-contained nicotine affected metabolic, cardiovascular and muscular tissue oxygenation, we suggest that snus administration at test time might relieve these withdrawal changes and yield an increase in time to exhaustion.

The metaplastic effects of NMDA receptors blockade on reactivation of instrumental memories in rats.

Metaplasticity, defined as the plasticity of synaptic plasticity, could affect learning and memory at different neural levels. It was hypothesized that metaplasticity changes on glutamate receptors may affect memory destabilization, promoting or preventing reconsolidation. We investigated the metaplastic effect of NMDA channel blocker MK-801 on sucrose instrumental memory reconsolidation in a behavioural rat model associated to the assessment of molecular markers of metaplasticity, memory retrieval, destabilization and reconsolidation. Following instrumental conditioning and forced abstinence, rats were intraperitoneally treated with MK-801 or vehicle 24 h before the exposure to memory retrieval or not-retrieval. Separate groups were tested for in-vivo extinction of responding (24 h and 7 d after reactivation) or ex-vivo assessment of transcription factor Zif268 and ribosomal protein rpS6 phosphorylation in nucleus accumbens (NAc) and amygdala (Amy). MK-801 significantly inhibited instrumental responding at extinction test, suggesting reconsolidation blockade of instrumental memory. The decrease of Zif268 and phosphorylated-rpS6 levels in NAc and Amy in MK-801/Retrieval vs. Vehicle/Retrieval group supported the behavioural findings. An increase of GluN2B, GluA1 and mGluR5 in NAc, and GluN2B in Amy, 24 h after MK-801 indicated the trigger of associated metaplastic changes. Our findings show that metaplastic changes induced by NMDA receptors blockade affected sucrose instrumental memory retrieval as shown by both behavioural and molecular changes. We hypothesize that these findings however suggested a switch to extinction rather than a reconsolidation.

The motor way: Clinical implications of understanding and shaping actions with the motor system in autism and drug addiction.

To understand others' minds is crucial for survival; however, it is quite puzzling how access to others' minds can be--to some extent--direct and not necessarily mediated by conceptual reasoning. Recent advances in neuroscience have led to hypothesize a role for motor circuits not only in controlling the elementary physical features of movement (e.g., force, direction, and amplitude), but also in understanding and shaping human behavior. The concept of "motor cognition" refers to these aspects, and neurophysiological, neuroimaging, and behavioral studies in human and nonhuman primates support this view. From a clinical perspective, motor cognition represents a challenge in several domains. A thorough investigation of the neural mechanisms mediating motor action/intention understanding and automatized/compulsive behaviors seems to be a promising way to tackle a range of neurodevelopmental and drug-related disorders. On the one hand, anomalies in motor cognition may have cascade effects on social functioning in individuals with autism spectrum disorder (ASD); on the other, motor cognition may help explain the pathophysiology of drug-seeking and drug-taking behaviors in the most severe phase of drug addiction (i.e., see drug dependence, motor low-order cue reactivity). This may represent a promising approach that could improve the efficacy of rehabilitative interventions. The only way to shed light on multifactorial disorders such as ASD and drug addiction is through the investigation of their multiple factors. This motor way can promote new theoretical and experimental perspectives that would help bridge the gap between the basic neuroscience approach and clinical practice.

Evidence for caspase-dependent programmed cell death along with repair processes in affected skeletal muscle fibres in patients with mitochondrial disorders.

Mitochondrial disorders are heterogeneous multisystemic disorders due to impaired oxidative phosphorylation causing defective mitochondrial energy production. Common histological hallmarks of mitochondrial disorders are RRFs (ragged red fibres), muscle fibres with abnormal focal accumulations of mitochondria. In contrast with the growing understanding of the genetic basis of mitochondrial disorders, the fate of phenotypically affected muscle fibres remains largely unknown. We investigated PCD (programmed cell death) in muscle of 17 patients with mitochondrial respiratory chain dysfunction. We documented that in affected muscle fibres, nuclear chromatin is condensed in lumpy irregular masses and cytochrome c is released into the cytosol to activate, along with Apaf-1 (apoptotic protease-activating factor 1), caspase 9 that, in turn, activates effector caspase 3, caspase 6, and caspase 7, suggesting the execution of the intrinsic apoptotic pathway. Whereas active caspase 3 underwent nuclear translocation, AIF (apoptosis-inducing factor) mainly stayed within mitochondria, into which an up-regulated Bax is relocated. The significant increase in caspase 2, caspase 3 and caspase 6 activity strongly suggest that the cell death programme is caspase-dependent and the activation of caspase 2 together with PUMA (p53 up-regulated modulator of apoptosis) up-regulation point to a role for oxidative stress in triggering the intrinsic pathway. Concurrently, in muscle of patients, the number of satellite cells was significantly increased and myonuclei were detected at different stages of myogenic differentiation, indicating that a reparative programme is ongoing in muscle of patients with mitochondrial disorders. Together, these data suggest that, in patients with mitochondrial disorders, affected muscle fibres are trapped in a mitochondria-regulated caspase-dependent PCD while repairing events take place.

The modulation of BDNF expression and signalling dissects the antidepressant from the reinforcing properties of ketamine: Effects of single infusion vs. chronic self-administration in rats.

Ketamine is a drug of abuse with a unique profile, which besides its inherent mechanism of action as a non-competitive antagonist of the NMDA glutamate receptor, displays both antidepressant and reinforcing properties. The major aim of our study was to find a molecular signature of ketamine that may help in discriminating between its reinforcing and antidepressant effects. To this end, we focused our attention on BDNF, a neurotrophin that has been shown to play a role in both antidepressant and reinforcing properties of several drugs. Rats were exposed to self-administer intravenous (IV) ketamine (S/A) for 43 days or to receive a single IV ketamine 0.5mg/kg, or vehicle infusion. Although the dose we employed is lower than that reported by the literature, it however yields Cmax values that correspond to those achieved in humans after antidepressant treatment. Our results show that while the single infusion of ketamine increased the neurotrophin expression in the hippocampus while reducing it in the ventral striatum, a feature shared with other antidepressants, the repeated self-administration reduced mBDNF expression and its downstream signalling in both ventral striatum and hippocampus. Further, we here show that phosphorylation of Akt is oppositely regulated by ketamine, pointing to this pathway as central to the different actions of the drug. Taken together, we here point to BDNF and its downstream signalling pathway as a finely tuned mechanism whose modulation might subserve the different features of ketamine.

The ketamine analogue methoxetamine generalizes to ketamine discriminative stimulus in rats.

Methoxetamine (MXE) is a chemical analogue of ketamine. Originally proposed as a ketamine-like fast-acting antidepressant, owing to similar N-methyl-D-aspartate blocker properties, it is now scheduled for reports of hallucinations and psychosis similar to ketamine and lysergic acid. As little is known about the addictive properties of MXE, the aim of this study was to investigate the similarity between discriminative stimuli of MXE and ketamine, as well as to provide data and protocols that could be used in the future for the characterization of novel ketamine-like drugs. The paradigm used was a two-lever operant conditioning paradigm in which rats were trained to discriminate ketamine (7.5 mg/kg/ml, intraperitoneal) from vehicle. Generalization tests were performed with MXE (0.0625, 0.125, 0.25, 0.5, or 1.0). We also tested the N-methyl-D-aspartate channel blocker MK-801 (0.005-0.1), lysergic acid (0.025-0.30), a serotonergic drug that had similar hallucinogenic effects as ketamine and methamphetamine (0.15-0.60) a drug with no generalization with ketamine, injected intraperitoneally presession (mg/kg). MXE and MK-801 fully generalized to ketamine. Lysergic acid and methamphetamine partially substituted for the ketamine stimulus, although the highest lysergic acid dose showed a 77.7% generalization. The present findings suggest that investigation of 'ketamine-like compounds' should explore not only substances with chemical analogy and common molecular mechanisms with ketamine, but also with similar psychopharmacological effects.

Methoxetamine, a novel psychoactive substance with serious adverse pharmacological effects: a review of case reports and preclinical findings.

An increasing number of novel psychoactive substances are currently available and sold as 'legal highs' or 'research chemicals' accompanied by the indication that they are 'not for human consumption'. Among those that have emerged in the last few years, methoxetamine (MXE) owes its wide popularity to its easy access on the Internet and its reputation of being a 'safe' drug. MXE is an arylcyclohexylamine with a chemical structure analogous to ketamine and phencyclidine, and similar noncompetitive glutamate N-methyl D-aspartate receptor antagonist properties. Yet, very recent preclinical data highlighted a stimulatory effect of MXE on dopamine neurotransmission within the mesolimbic pathway. The aim of this review is to provide an updated review of the behavioral and toxicological effects of MXE as well as the latest findings on its pharmacology that might explain sought effects and frequent occurrence of adverse effects. In light of the growing number of intoxications induced by MXE, knowledge of its short-term and long-term effects is urgently needed. However, the hypothetical rapid antidepressant activity of MXE suggested by its chemical analogy with ketamine and supported by recent preclinical findings deserves further investigation.

Extinction, applied after retrieval of auditory fear memory, selectively increases zinc-finger protein 268 and phosphorylated ribosomal protein S6 expression in prefrontal cortex and lateral amygdala.

Retrieval of consolidated memories induces a labile phase during which memory can be disrupted or updated through a reconsolidation process. A central component of behavioral updating during reconsolidation using a retrieval-extinction manipulation (Ret+Ext) is the synaptic removal of a calcium-permeable-α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (CP-AMPARs) in the lateral amygdala-a metabotropic GluR1 receptor (mGluR1) dependent mechanism. In the present study, we investigate the effect of Ret+Ext on the expression of molecular markers that could play a role in the reconsolidation process. Specifically, we tested the effects of Ret+Ext on the global expression of zinc-finger 268 protein (Zif268), a marker previously found to be implicated in memory reconsolidation, to confirm its occurrence after retrieval (Ret) and Ret+Ext. We also evaluated the global expression of phosphorylated ribosomal protein S6 (rpS6P), here proposed as a marker of the mGluR1-mediated memory process induced by Ret+Ext. The expression of both markers (zif268, rpS6P) was assessed by immunolocalization in prelimbic cortex (PRL), infralimbic cortex (IL), ventral subdivision of the lateral amygdala (LA) and hippocampus CA1 (CA1) in fear-conditioned rats. Our results showed that retrieval and Ret+Ext, but not extinction alone, increased Zif268 expression in prefrontal cortex and lateral amygdala. Ret+Ext, but not retrieval, retrieval followed by context exposure or extinction alone, increased the expression of rpS6P in prefrontal cortex and LA. In summary, (i) Zif268 increased after retrieval confirming that reconsolidation is engaged in our conditions, (ii) Zif268 increased after Ret+Ext confirming that it does not simply reflect an extinction or reconsolidation disruption (Zif268 level of expression should be lower in both cases) and (iii) rpS6P increased after Ret+Ext, but not after extinction, suggesting, as expected, a potential mGluR1 mediated molecular mechanism specific for Ret+Ext. Together with the Zif268 increase, our results suggest that the Ret+Ext induced memory process is more similar to reconsolidation updating than extinction facilitation.

Nicotine-seeking reinstatement is reduced by inhibition of instrumental memory reconsolidation.

The reinforcing properties of nicotine play a major role in instrumental conditioning to nicotine taking in smokers. Retrieval of nicotine-related memories may promote relapse to nicotine seeking after prolonged abstinence. Once consolidated, memories are stable, but they return to a labile phase, called reconsolidation, after their retrieval. The aim of our study was to investigate whether it was possible to interfere with the reconsolidation of instrumental nicotine-related memories by acting at glutamatergic receptors [N-methyl-D-aspartate receptors (NMDARs)] to prevent relapse to nicotine-seeking behaviour in the rat. We assessed whether the NMDAR antagonist MK-801, administered before or after nicotine-related instrumental memory retrieval, can reduce reinstatement of nicotine-seeking behaviour in rats previously trained to nicotine self-administration. Following a period of forced abstinence, MK-801 (0.1 mg/kg intraperitoneally) was administered 30 min before or 1 h after the re-exposure to 20 lever presses without any contingency in the training context to retrieve instrumental memory. MK-801 administered after, but not before, retrieval inhibited reinstatement compared with vehicle controls and groups without retrieval of instrumental memory. Interestingly, a retrieval factor effect was observed as an increase of reinstatement in vehicle-treated groups, suggesting a behavioural outcome of the occurrence of instrumental memory reconsolidation. Our findings suggest that, by acting on NMDARs, it is possible to reduce the reinstatement of nicotine-seeking behaviour through inhibition of instrumental nicotine-related memory reconsolidation.

The effect of postretrieval extinction of nicotine pavlovian memories in rats trained to self-administer nicotine.

INTRODUCTION: Retrieval (reactivation) of smoking-related memories is a potent trigger of relapse among ex-smokers, and manipulation of smoking-related memories is considered to be a promising target for therapeutic intervention. Recent studies have shown that postreactivation extinction attenuates drug-related memories and relapse to drug-seeking both in rodents and in humans. We investigated the effect of postreactivation extinction in a rat model of relapse to nicotine-seeking. METHODS: Rats were trained to self-administer nicotine in context A (CxA). Pressing the active lever resulted in the nicotine infusion paired with a cue-light (CS). Nicotine-related Pavlovian memories were then reactivated via presentation of 3 non-contingent CS. We then extinguished nicotine-related memories in a distinct context (CxB) followed 24hr later by the assessment of renewal of responding in CxA. RESULTS: Postreactivation extinction, applied 1 but not 6hr after reactivation, induced a significant reduction of the rate of responding on renewal compared to responding during nicotine self-administration, whereas no such effect of CS-Extinction was observed in No-Reactivation group. However, between-group comparisons of responding during renewal did not show any significant difference. CONCLUSIONS: Current results show that the reactivation of nicotine-related Pavlovian memories may reduce the effect of renewal to exert nicotine-seeking. However, it appears that this effect is small in size and is not significantly different from CS-Extinction alone.

Virtual Reality Environmental Enrichment Effects on Craving for Cigarette in Smokers.

Background: Preclinical studies suggested the exposure to environmental enrichment (EE) as an intervention able to prevent or reduce nicotine-taking and nicotine-seeking behaviors. Virtual reality (VR) may help to test the effects of EE in smokers in a reproducible and feasible manner. Materials and Methods: In the present study, 31 smokers (14 women) were divided into two groups: (1) exposure to a virtual EE (VR-EE) and (2) exposure to a virtual neutral environment (VR-NoEE). Cigarette craving was assessed as basal and evoked, at different timepoints during the session. Behavior activity during VR exposure, mood, and subjective measures were also collected. Results: EE exposure in VR significantly reduced craving scores from basal timepoint. This was not observed in the VR-NoEE group, which significantly increased craving compared with values at neutral scenario. When both groups were exposed to smoking-related VR scenario, the VR-EE group showed an increased craving compared with previous timepoint up to score values not different from those in the VR-NoEE group. A significant positive correlation between basal craving scores and interactive behavior with virtual smoking cues was observed in the VR-NoEE but not in the VR-EE group. Conclusion: These findings suggest that virtual EE might have an inhibitory effect in smokers on basal, but not on evoked cigarette craving. Noteworthily, the interactive activity correlation to craving scores in the VR-NoEE participants was not observed in the VR-EE group, adding further evidence that the enrichment simulation was nonetheless able to modify behavior in the smoking-related scenario.

Ecocebo: How the interaction between environment and drug effects may improve pharmacotherapy outcomes.

This narrative review describes the research on the effects of the association between environmental context and medications, suggesting the benefit of specific design interventions in adjunction to pharmacotherapy. The literature on Evidence-Based Design (EBD) studies and Neuro-Architecture show how contact with light, nature, and specific physical features of urban and interior architecture may enhance the effects of analgesic, anxiolytics, and antidepressant drugs. This interaction mirrors those already known between psychedelics, drugs of abuse, and setting. Considering that the physical feature of space is a component of the complex placebo configuration, the aim is to highlight those elements of built or natural space that may help to improve drug response in terms of efficacy, tolerability, safety, and compliance. Ecocebo, the integration of design approaches such as EBD and Neuro-Architecture may thus contribute to a more efficient, cost-sensitive, and sustainable pharmacotherapy.

Nature-based experience in Venetian lagoon: Effects on craving and wellbeing in addict residential inpatients.

Introduction: It is known that exposure to the natural environment may positively modulate mental processes and behaviors; in particular, it can reduce stress, anxiety, and depressive symptoms. This suggests a potential integration of "nature experience" into the treatment for substance use disorder (SUD) since various types of addiction are associated with anxiety and depression. Considering that only one study has been reported to date in patients with alcohol use disorder, the effect of nature experience in SUD patients' needs to be further investigated. This study aimed to test the effects of exposure to a natural lagoon environment on craving and measures of wellbeing in SUD patients in comparison to exposure to an urban environment. Methods: Twenty-four SUD patients were divided into three groups of eight participants and exposed to two walking sessions (interspersed with a 1-week wash-out period) in a natural environment typical of the Venetian lagoon, an Urban walk, or staying at the residential center based on a Latin-square design. Before and after each session, drug craving, mood, wellbeing, agency, openness to the future, and restorativeness were assessed. Results: The Nature walk significantly decreased craving in participants compared to their pre-walk values, and compared to craving after the Urban walk, with the latter significantly increased vs. pre-walk values. The Nature walk significantly decreased negative mood and increased wellbeing and agency. Openness to the future and restorativeness measures showed significant improvement after the Nature walk compared to the Urban walk. On the other hand, craving scores after the Urban Walk positively correlated with negative mood and a Sense of Negative Agency values and negatively correlated with wellbeing scores. Discussion: Our results confirm that "nature experience" may improve mood, wellbeing, attention, stress relief, openness, and sense of being active in SUD patients. Moreover, we also showed a specific effect on drug craving-a key symptom of SUD.