Mechanisms Involved in the Neurotoxicity and Abuse Liability of Nitrous Oxide: A Narrative Review.

The recreational use of nitrous oxide (N2O) has increased over the years. At the same time, more N2O intoxications are presented to hospitals. The incidental use of N2O is relatively harmless, but heavy, frequent and chronic use comes with considerable health risks. Most importantly, N2O can inactivate the co-factor cobalamin, which, in turn, leads to paresthesia's, partial paralysis and generalized demyelinating polyneuropathy. In some patients, these disorders are irreversible. Several metabolic cascades have been identified by which N2O can cause harmful effects. Because these effects mostly occur after prolonged use, it raises the question of whether N2O has addictive properties, explaining its prolonged and frequent use at high dose. Several lines of evidence for N2O's dependence liability can be found in the literature, but the underlying mechanism of action remains controversial. N2O interacts with the opioid system, but N2O also acts as an N-methyl-D-aspartate (NMDA) receptor antagonist, by which it can cause dopamine disinhibition. In this narrative review, we provide a detailed description of animal and human evidence for N2O-induced abuse/dependence and for N2O-induced neurotoxicity.

Integrated cognitive behavioral therapy for ADHD in adult substance use disorder patients: Results of a randomized clinical trial.

BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) frequently co-occurs with Substance Use Disorders (SUDs). Standard ADHD pharmacotherapies are not effective in patients with this comorbidity and cognitive behavioral therapy (CBT) has not been tested in this population. This RCT aimed to compare the efficacy of Integrated CBT (CBT/Integrated) directed at adult ADHD and SUD with CBT directed at SUD only (CBT/SUD) in patients with SUD and ADHD (SUD + ADHD). METHODS: Randomized clinical trial among 119 SUD + ADHD patients in a SUD treatment center. CBT/Integrated consisted of 15 individual sessions of motivational therapy, coping skills training and relapse prevention for SUD, and training of planning skills, problem-solving skills and dealing with emotions for ADHD. CBT/SUD consisted of 10 individual SUD treatment sessions only. Primary outcome was ADHD symptom severity according to the ADHD rating scale (ARS) at post-treatment. Secondary outcomes included ADHD symptom severity after two-month follow-up, and treatment response (≥30% ADHD symptom reduction), substance use, depressive or anxiety symptoms, and quality of life at post-treatment and follow-up. RESULTS: CBT/Integrated was more effective than CBT/SUD in the reduction of ADHD symptoms post-treatment: ARS = 28.1 (SD 9.0) vs. 31.5 (SD 11.4) (F = 4.739, df = 1, 282, p = .030; d = 0.34). At follow-up, CBT/Integrated still resulted in lower ARS scores than CBT/SUD, but the difference was not significant at the 0.05 level. For other secondary outcomes, including substance use, no significant between-group differences were present. CONCLUSIONS: Compared to regular SUD cognitive behavioral therapy, integrated cognitive behavioral therapy resulted in a significant extra improvement in ADHD symptoms in SUD + ADHD patients.

Comparing the effect of clozapine and risperidone on cue reactivity in male patients with schizophrenia and a cannabis use disorder: A randomized fMRI study.

OBJECTIVE: Cannabis use disorders (CUDs) are highly comorbid in patients with schizophrenia and associated with poor outcome. Clozapine has been put forward as the first choice antipsychotic in this patient group. However, little is known about the mechanisms underlying the assumed superiority of clozapine. METHODS: A total of 38 patients with DSM-IV schizophrenia (30 with and 8 without a DSM-IV CUD) and 20 healthy comparison subjects were included between April 2009 and June 2012. Patients were randomized to antipsychotic treatment with clozapine or risperidone. At baseline and after 4weeks of medication, brain response to cannabis-related, positive and neutral images was measured using functional MRI. Neural correlates of cue reactivity were assessed in the following regions of interest: amygdala, ventral striatum, insula, thalamus, orbitofrontal cortex and anterior cingulate cortex. Subjective craving was assessed using self-report questionnaires (OCDUS and MCQ). RESULTS: At baseline, patients with a comorbid CUD showed higher subjective craving and greater activation in response to cannabis-related images compared to patients without a CUD and healthy controls in most regions of interest. Clozapine treated patients reported a greater reduction in craving (F(1,28)=6.0, p=0.04) and showed a larger decrease in amygdala activation during cannabis-related images compared to risperidone treated patients (T=3.94, pFWE=0.006). In addition, significant correlations were found between subjective craving and thalamus and insula activation during cannabis-related images. CONCLUSION: These findings provide evidence that clozapine is superior to risperidone in decreasing subjective craving and cue reactivity for cannabis-related images probably due to a differential effect on dopaminergic neurotransmission. TRIAL REGISTRATION: 'Nederlands trial register' (http://www.trialregister.nl), nr NTR1761, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1761.

Medicinal cannabis (Bedrolite) substitution therapy in inpatients with a psychotic disorder and a comorbid cannabis use disorder: A case series.

Cannabis use disorders are frequently comorbid in patients with a psychotic disorder and are associated with worse outcomes. To date there are no proven effective strategies to achieve cannabis abstinence in this population. An alternative for abstinence might be harm reduction, i.e. replacing the use of street cannabis with high tetrahydrocannabinol and low cannabidiol levels by medicinal cannabis variants with relatively low tetrahydrocannabinol and relatively high cannabidiol levels, thereby reducing the psychosis inducing effects of cannabis and enhancing the antipsychotic effects of cannabis. Here we present the data of a case series with seven inpatients diagnosed with a psychotic disorder and a treatment-resistant cannabis use disorder who received substitution therapy with a low tetrahydrocannabinol medicinal cannabis variant (Bedrolite). The results suggest that the low tetrahydrocannabinol medicinal cannabis variant Bedrolite is not effective in the treatment of inpatients with a psychotic disorder and comorbid cannabis use disorder. Bedrolite is thus not very likely to become an effective harm reduction strategy in these patients.

Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control study.

BACKGROUND: Prescription opioid use is highly associated with risk of opioid-related death, with 1 of every 550 chronic opioid users dying within approximately 2.5 years of their first opioid prescription. Although gabapentin is widely perceived as safe, drug-induced respiratory depression has been described when gabapentin is used alone or in combination with other medications. Because gabapentin and opioids are both commonly prescribed for pain, the likelihood of co-prescription is high. However, no published studies have examined whether concomitant gabapentin therapy is associated with an increased risk of accidental opioid-related death in patients receiving opioids. The objective of this study was to investigate whether co-prescription of opioids and gabapentin is associated with an increased risk of accidental opioid-related mortality. METHODS AND FINDINGS: We conducted a population-based nested case-control study among opioid users who were residents of Ontario, Canada, between August 1, 1997, and December 31, 2013, using administrative databases. Cases, defined as opioid users who died of an opioid-related cause, were matched with up to 4 controls who also used opioids on age, sex, year of index date, history of chronic kidney disease, and a disease risk index. After matching, we included 1,256 cases and 4,619 controls. The primary exposure was concomitant gabapentin use in the 120 days preceding the index date. A secondary analysis characterized gabapentin dose as low (<900 mg daily), moderate (900 to 1,799 mg daily), or high (≥1,800 mg daily). A sensitivity analysis examined the effect of concomitant nonsteroidal anti-inflammatory drug (NSAID) use in the preceding 120 days. Overall, 12.3% of cases (155 of 1,256) and 6.8% of controls (313 of 4,619) were prescribed gabapentin in the prior 120 days. After multivariable adjustment, co-prescription of opioids and gabapentin was associated with a significantly increased odds of opioid-related death (odds ratio [OR] 1.99, 95% CI 1.61 to 2.47, p < 0.001; adjusted OR [aOR] 1.49, 95% CI 1.18 to 1.88, p < 0.001) compared to opioid prescription alone. In the dose-response analysis, moderate-dose (OR 2.05, 95% CI 1.46 to 2.87, p < 0.001; aOR 1.56, 95% CI 1.06 to 2.28, p = 0.024) and high-dose (OR 2.20, 95% CI 1.58 to 3.08, p < 0.001; aOR 1.58, 95% CI 1.09 to 2.27, p = 0.015) gabapentin use was associated with a nearly 60% increase in the odds of opioid-related death relative to no concomitant gabapentin use. As expected, we found no significant association between co-prescription of opioids and NSAIDs and opioid-related death (OR 1.11, 95% CI 0.98 to 1.27, p = 0.113; aOR 1.14, 95% CI 0.98 to 1.32, p = 0.083). In an exploratory analysis of patients at risk of combined opioid and gabapentin use, we found that 46.0% (45,173 of 98,288) of gabapentin users in calendar year 2013 received at least 1 concomitant prescription for an opioid. This study was limited to individuals eligible for public drug coverage in Ontario, we were only able to identify prescriptions reimbursed by the government and dispensed from retail pharmacies, and information on indication for gabapentin use was not available. Furthermore, as with all observational studies, confounding due to unmeasured variables is a potential source of bias. CONCLUSIONS: In this study we found that among patients receiving prescription opioids, concomitant treatment with gabapentin was associated with a substantial increase in the risk of opioid-related death. Clinicians should consider carefully whether to continue prescribing this combination of products and, when the combination is deemed necessary, should closely monitor their patients and adjust opioid dose accordingly. Future research should investigate whether a similar interaction exists between pregabalin and opioids.

Addressing the stimulant treatment gap: A call to investigate the therapeutic benefits potential of cannabinoids for crack-cocaine use.

Crack-cocaine use is prevalent in numerous countries, yet concentrated primarily - largely within urban contexts - in the Northern and Southern regions of the Americas. It is associated with a variety of behavioral, physical and mental health and social problems which gravely affect users and their environments. Few evidence-based treatments for crack-cocaine use exist and are available to users in the reality of street drug use. Numerous pharmacological treatments have been investigated but with largely disappointing results. An important therapeutic potential for crack-cocaine use may rest in cannabinoids, which have recently seen a general resurgence for varied possible therapeutic usages for different neurological diseases. Distinct potential therapeutic benefits for crack-cocaine use and common related adverse symptoms may come specifically from cannabidiol (CBD) - one of the numerous cannabinoid components found in cannabis - with its demonstrated anxiolytic, anti-psychotic, anti-convulsant effects and potential benefits for sleep and appetite problems. The possible therapeutic prospects of cannabinoids are corroborated by observational studies from different contexts documenting crack-cocaine users' 'self-medication' efforts towards coping with crack-cocaine-related problems, including withdrawal and craving, impulsivity and paranoia. Cannabinoid therapeutics offer further benefits of being available in multiple formulations, are low in adverse risk potential, and may easily be offered in community-based settings which may add to their feasibility as interventions for - predominantly marginalized - crack-cocaine user populations. Supported by the dearth of current therapeutic options for crack-cocaine use, we are advocating for the implementation of a rigorous research program investigating the potential therapeutic benefits of cannabinoids for crack-cocaine use. Given the high prevalence of this grave substance use problem in the Americas, opportunities for such research should urgently be created and facilitated there.

Integrated cognitive behavioral therapy for patients with substance use disorder and comorbid ADHD: two case presentations.

Two cases of integrated cognitive behavioral therapy (ICBT) for substance use disorder (SUD) and Attention Deficit Hyperactivity Disorder (ADHD) are presented illustrating that ICBT is a promising new treatment option.

Recovery of neurocognitive functions following sustained abstinence after substance dependence and implications for treatment.

BACKGROUND: Substance Use Disorders (SUDs) have been associated with impaired neurocognitive functioning, which may (partly) improve with sustained abstinence. New treatments are emerging, aimed at improving cognitive functions, and being tested. However, no integrated review is available regarding neurocognitive recovery following sustained abstinence. OBJECTIVES: In this review, results from prospective studies on neurocognitive recovery using neuropsychological assessments before and after sustained abstinence from SUDs are summarized and discussed. RESULTS: Thirty-five prospective studies were selected for this review, including twenty-two alcohol, three cannabis, four cocaine, three (meth)amphetamine, and three opioid studies. Results suggest that some cognitive functions (partially) recover after sustained abstinence, and that there are predictors of an unfavorable course such as poly-substance use and number of previous detoxifications. CONCLUSIONS: Prospective studies indicate that sustained abstinence after SUDs generally results in (partial) neurocognitive recovery. However, a final answer regarding full recovery awaits prospective studies with neurocognitive assessments before, during, and after sustained abstinence from SUDs. New interventions that might enhance neurocognitive recovery after abstinence are discussed, including neurocognitive training, medication and neuromodulation.

The effect of clozapine and risperidone on attentional bias in patients with schizophrenia and a cannabis use disorder: An fMRI study.

Cannabis use disorders (CUDs) are highly comorbid in patients with schizophrenia and are associated with poor outcome. Clozapine has been put forward as the first choice antipsychotic in this comorbid group. However, little is known about the mechanisms underlying the assumed superiority of clozapine. We compared the effects of clozapine and risperidone on attentional bias, subjective craving and associated regional brain activity in patients with schizophrenia and CUD. Overall, 36 patients with schizophrenia and 19 healthy controls were included. Patients were randomised to antipsychotic treatment with clozapine or risperidone. At baseline and after 4 weeks of medication use, regional brain responses were measured during a classical Stroop and a cannabis word Stroop using functional magnetic resonance imaging. Clozapine-treated CUD patients showed a larger reduction in craving and in activation of the insula during the cannabis word Stroop, while risperidone-treated patients showed a larger decrease in activation of the right anterior cingulate cortex during the classical Stroop. A significant association was found between decreases in subjective craving and decreases in insula activation during the cannabis word Stroop. These findings strongly suggest that clozapine may be a better treatment choice in patients with schizophrenia and CUD than risperidone.

Facilitators and barriers in treatment seeking for cannabis dependence.

BACKGROUND: Relatively few cannabis dependent people seek treatment and little is known about determinants of treatment seeking. METHODS: Treatment determinants were compared among 70 DSM-IV cannabis dependent patients and 241 non-treatment seeking DSM-IV cannabis dependent community subjects. In addition, perceived facilitators for treatment seeking were assessed in patients, whereas perceived barriers were assessed in 160/241 cannabis dependent community subjects not prepared to seek treatment (precluders), of whom 63/160 showed an objective treatment need, and 30/241 showed a subjective treatment need. RESULTS: Compared to non-treatment seekers, patients reported more cannabis use (176.9 versus 82.8 joints monthly), more symptoms of dependence (5.6 versus 4.5), higher perceived lack of social support (70.0% versus 41.1%), more pressure to seek treatment (58.6% versus 21.6%), a more positive attitude to treatment, and more previous treatments. In addition, patients reported more mental health problems (internalising disorders 57.1% versus 24.5%; externalising disorders 52.9% versus 35.3%) and more functional impairments (8.4 versus 4.8 monthly days out of role). Cannabis dependent 'precluders' reported desire for self-reliance (50.0%), preference for informal help (22.5%), and absent treatment need (16.9%) as their main reasons not to seek treatment, whereas cannabis dependent community subjects with a subjective treatment need mainly expressed desire for self-reliance (36.7%), treatment ineffectiveness (16.7%), and avoiding stigma (13.3%). CONCLUSIONS: Functional impairment, mental health problems and social pressure are important reasons to seek treatment in people with cannabis dependence. Treatment participation might improve if desire for self-reliance and the preference for informal help are considered, and perceived ineffectiveness of treatment and stigmatisation are publicly addressed.

Effects of non-invasive neurostimulation on craving: a meta-analysis.

This meta-analysis was conducted to evaluate the available evidence regarding the effects of non-invasive neurostimulation of the dorsolateral prefrontal cortex (DLPFC), on craving in substance dependence and craving for high palatable food. Non-invasive neurostimulation techniques were restricted to repetitive Transcranial Magnetic Stimulation (rTMS) and transcranial Direct Current Stimulation (tDCS). A total of 17 eligible studies were identified. Random effects analysis revealed a pooled standardized effect size (Hedge's g) of 0.476 (CI: 0.316-0.636), indicating a medium effect size favouring active non-invasive neurostimulation over sham stimulation in the reduction of craving (z=5.832, p<0.001). No significant differences were found between rTMS and tDCS, between the various substances of abuse and between substances of abuse and food, or between left and right DLPFC stimulation. In conclusion, this meta-analysis provides the first clear evidence that non-invasive neurostimulation of the DLPFC decreases craving levels in substance dependence.

Evidence-based pharmacological treatment of substance use disorders and pathological gambling.

This review summarizes our current knowledge of the pharmacological treatment of substance use disorders and pathological gambling using data mainly from randomized controlled trials and meta-analyses regarding these randomized controlled trials. The review is restricted to the selection of first and second line pharmacological treatments for smoking, alcohol dependence, opioid dependence, cocaine dependence, cannabis dependence and pathological gambling. It is concluded that great progress has been made in the last three decades and that currently evidence-based pharmacological treatments are available for smoking cessation, alcohol and opioid dependence and pathological gambling. At the same time a series of existing and new pharmacological compounds are being tested in cocaine and cannabis dependence. The review concludes with a summary of additional strategies to increase the effect size of already available pharmacological interventions, including polypharmacy, combining pharmacotherapy with psychotherapy and psychosocial support, and improved patient-treatment matching.

Neurotoxic effects of ecstasy on the thalamus.

BACKGROUND: Neurotoxic effects of ecstasy have been reported, although it remains unclear whether effects can be attributed to ecstasy, other recreational drugs or a combination of these. AIMS: To assess specific/independent neurotoxic effects of heavy ecstasy use and contributions of amphetamine, cocaine and cannabis as part of The Netherlands XTC Toxicity (NeXT) study. METHOD: Effects of ecstasy and other substances were assessed with (1)H-magnetic resonance spectroscopy, diffusion tensor imaging, perfusion weighted imaging and [(123)I]2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane ([(123)I]beta-CIT) single photon emission computed tomography (serotonin transporters) in a sample (n=71) with broad variation in drug use, using multiple regression analyses. RESULTS: Ecstasy showed specific effects in the thalamus with decreased [(123)I]beta-CIT binding, suggesting serotonergic axonal damage; decreased fractional anisotropy, suggesting axonal loss; and increased cerebral blood volume probably caused by serotonin depletion. Ecstasy had no effect on brain metabolites and apparent diffusion coefficients. CONCLUSIONS: Converging evidence was found for a specific toxic effect of ecstasy on serotonergic axons in the thalamus.

Effect of olanzapine and risperidone on subjective well-being and craving for cannabis in patients with schizophrenia or related disorders: a double-blind randomized controlled trial.

OBJECTIVE: To examine whether subjective well-being and craving for cannabis were different in patients with schizophrenia or related disorders treated with either olanzapine or risperidone. METHOD: A 6-week, double-blind, randomized trial of olanzapine and risperidone was carried out in 128 young adults with recent onset schizophrenia or related disorders. Primary efficacy measures were the mean baseline-to-endpoint change in total scores on the Subjective Well-Being under Neuroleptics scale, the Obsessive-Compulsive Drug Use Scale, the Drug Desire Questionnaire, and the cannabis use self-report. An analysis of covariance was used to test between-group differences. RESULTS: Estimated D(2) receptor occupancy did not differ between olanzapine (n = 63) and risperidone (n = 65). Similar improvements in subjective well-being were found in both groups. In the comorbid cannabis-using group (n = 41, 32%), a similar decrease in craving for cannabis was found in both treatment conditions. CONCLUSIONS: Both olanzapine and risperidone were associated with improved subjective well-being. No evidence was found for a differential effect of olanzapine or risperidone on subjective experience or on craving for cannabis in dosages leading to comparable dopamine D(2) occupancy. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN46365995.

Psychophysiological determinants and concomitants of deficient decision making in pathological gamblers.

Psychophysiological responses are considered to be a mediating factor in the development of pathological gambling (PG) and PG has been associated with differential arousal levels during gambling. Yet little is known about the specific psychophysiological responses to wins and losses in PG. This study investigated heart rate (HR) and skin conductance responses (SCRs) during the Iowa Gambling Task (IGT) in an adult PG group (n=46) and a normal control (NC) group (n=47). Anticipatory psychophysiological reactions to disadvantageous and advantageous choices during the IGT and psychophysiological responses to wins and losses were measured. The PG group performed worse than the NC group on the IGT and exhibited lower anticipatory SCRs and HR decreases when pondering choices of disadvantageous card decks during the IGT. The PG group showed a decrease in HR after losses and wins, whereas the NC group showed a decrease in HR after losses, but an increase in HR after wins. Reward and punishment sensitivity as measured by the self-report BIS/BAS scale influenced IGT performance and psychophysiological responses, but in general these effects were similar for the PG group and the NC group. Lower anticipatory psychophysiological responses to disadvantageous choices in PG suggest impaired risk assessment in this group. Absence of a HR increase after wins possibly implies that reward sensitivity is decreased in PG. Because levels of reward and punishment sensitivity were associated with differential anticipatory HR responses to advantageous and disadvantageous decks, it would be advisable to include this taxonomy in studies on psychophysiological responses to rewards and losses.