Insular Stimulation Produces Mental Clarity and Bliss.

For the first time, an ecstatic aura has been evoked through the electrical stimulation of the dorsal anterior insula during presurgical invasive intracerebral monitoring in a patient who did not suffer from an ecstatic form of epilepsy. This case provides more evidence that the anterior insula is the major generator of such a mystical-type experience even in individuals with no underlying brain network changes related to a preexisting ecstatic epilepsy. ANN NEUROL 2022;91:289-292.

Emotion Regulation by Psychological Distance and Level of Abstraction: Two Meta-Analyses.

Self-reflection is suggested to attenuate feelings, yet researchers disagree on whether adopting a distant or near perspective, or processing the experience abstractly or concretely, is more effective. Given the relationship between psychological distance and level of abstraction, we suggest the "construal-matching hypothesis": Psychological distance and abstraction differently influence emotion intensity, depending on whether the emotion's appraisal involves low-level or high-level construal. Two meta-analyses tested the effects of psychological distance (k = 230) and level-of-abstraction (k = 98) manipulations on emotional experience. A distant perspective attenuated emotional experience (g = 0.52) but with weaker effects for high-level (g = 0.29; for example, self-conscious emotions) than low-level emotions (g= 0.64; for example, basic emotions). Level of abstraction only attenuated the experience of low-level emotions (g = 0.2) and showed a reverse (nonsignificant) effect for high-level emotions (g = -0.13). These results highlight differences between distancing and level-of-abstraction manipulations and the importance of considering the type of emotion experienced in emotion regulation.

Oxycodone induced euphoria in ED patients with acute musculoskeletal pain. A secondary analysis of data from a randomized trial.

OBJECTIVES: Some opioid-naïve patients with acute musculoskeletal pain who are treated with opioids develop persistent opioid use. The impact of opioid-induced euphoria on this transition to persistent use has not been explored. We determined whether opioid-induced euphoria could be measured as a phenomenon distinct from relief of pain. METHODS: Patients with acute pain were randomized to receive oxycodone/acetaminophen (Oxy) or acetaminophen (APAP). We measured pain using a 0-10 verbal scale. To assess euphoria, participants provided a 0-10 response to each of these: 1) How good did the medication make you feel?; 2) How high did the medication make you feel?; 3) How blissful did the medication make you feel? We analyzed these data using successive multivariable linear regression models, in which each of these items was the dependent variable, and improvement in pain and medication were the independent variables, while controlling for age and sex. RESULTS: 75 were randomized to Oxy, 76 to APAP. Mean "how good" scores were 6.3 (SD 3.3) in the Oxy group and 4.8 (3.3) in the APAP group. Mean "how high" scores were 3.8 (3.7) in the Oxy group and 2.0 (3.0) in the APAP group. Mean "how blissful" scores were 4.9 (3.7) in the Oxy group and 3.1 (3.4) in the APAP group. After controlling for improvement in pain, age, and sex, the between-group difference in "how good" was 1.0 (95%CI: -0.1, 2.0), "how high" 1.5 (95% CI 0.4, 2.6), and "how blissful" 1.5 (95%CI: 0.4, 2.7). DISCUSSION: "How high" and "how blissful" but not "how good" were associated with opioid use after controlling for improvement in pain.

A randomised, double-blind study investigating the relationship between early childhood trauma and the rewarding effects of morphine.

Experiences of childhood trauma (abuse and neglect) are disproportionately higher in those with opioid use disorder (OUD). Childhood trauma may affect the reinforcing and rewarding properties of opioid drugs and responses to pain, potentially via developmental changes to the endogenous opioid system. This has been supported by preclinical research, yet this has not been investigated in non-addicted humans. Physically healthy participants with either a history of severe childhood trauma or no previous history of childhood trauma attended two sessions where they received either an intramuscular active dose of morphine (0.15 mg/kg) or a very low dose control (0.01 mg/kg) in a randomised, double-blind crossover design. Sessions were held 1 week apart. Participants' physical pain threshold and tolerance were measured pre- and post-drug administration using the cold water pressor test, alongside acute subjective and behavioural responses over 2.5 h. The trauma group reported liking the effects of morphine, feeling more euphoric and wanting more of the drug over the session, as well as feeling less nauseous, dizzy, and dislike of the effects of morphine compared to the non-trauma comparison group. Morphine increased pain threshold and tolerance, yet this did not differ between the groups. Childhood trauma may therefore sensitise individuals to the pleasurable and motivational effects of opioids and reduce sensitivity to the negative effects, providing compelling evidence for individual differences in opioid reward sensitivity. This may explain the link between childhood trauma and vulnerability to OUD, with consequent implications on interventions for OUD, the prescribing of opioids, and reducing stigmas surrounding OUD.

Epidemiology and Characteristics of People with Injury Due to Volatile Substance Use to Induce Euphoria.

BACKGROUND: Unhealthy substance use is a public health challenge. Much of the focus of interventions is upon narcotics, stimulants, hallucinogens, central nervous system depressants, and alcohol. However, inhalants are also commonly used in an unhealthy manner and are under-recognized. The purpose of this study is to describe incident emergency department visits for volatile substance use to induce euphoria (VSUIE) injuries in the U.S. Methods: Data were obtained from the National Electronic Injury Surveillance System (NEISS) for the years 2015 to 2018. Descriptive frequencies, bivariate analyses using Rao-Scott Chi-Square, and multivariable logistic regression analyses were conducted to describe and examine the association between ED visits and VSUIE. Results: The estimated (weighted) number of VSUIE ED visits during 2015-2018 was 13,130 (95% Confidence Interval, CI: 8,383-17876; Coefficient of variation, CV = 0.18) and accounted for 0.02% of all ED visits. Males were more likely than females (p < .0001), and young adults (ages ≥18 to ≤ 35 years) were more likely than older adults to have a VSUIE ED visit (p <.0001). Conclusion: VSUIE ED visits occur more commonly in young adults than older adults and adolescents. The widespread use of volatile substances to induce euphoria is an under-reported public health issue with life-threatening consequences. Use of volatile substances by adolescents is a particular concern which needs attention and interventions to prevent its initiation.

SGLT2-inhibition and Vascular Euphoria a Reconciliation of Vascular Health and Disease Homeostasis.

The concept of SGLT2-inhibition, once regarded as a non-physiological approach to glycemia control, now finds a foundational relevance in risk-modification for cardiovascular, kidney, and metabolic outcomes, spanning beyond type-2 diabetes. Major studies have proven meaningful improvements in various clinical outcomes, with different SGLT2-i agents. Apart from glycosuria, SGLT2-inhibition is associated with several patho-physiological effects, which may contribute to the clinical benefits seen with these agents. This narrative review is an attempt to appraise the different patho-physiological effects mediated by SGLT2-inhibition, based on contemporary evidence. The review classifies these effects in the acronym of EUPHORIA, and grades the possible relevance of each effect, in improving clinical outcomes.

Association studies of dopamine synthesis and metabolism genes with multiple phenotypes of heroin dependence.

BACKGROUND: Heroin dependence is a complex disease with multiple phenotypes. Classification of heroin users into more homogeneous subgroups on the basis of these phenotypes could help to identify the involved genetic factors and precise treatments. This study aimed to identify the association between genetic polymorphisms of DA synthesis and metabolism genes, including tyrosine hydroxylase (TH), DOPA decarboxylase (DDC), solute carrier family 6 member 3 (SLC6A3) and DA beta-hydroxylase (DBH), with six important phenotypes of heroin dependence. METHODS: A total of 801 heroin dependent patients were recruited and fourteen potential functional single nucleotide polymorphisms (SNPs) were genotyped by SNaPshot. Associations between SNPs with six phenotypes were mainly assessed by binary logistic regression. Generalized multifactor dimensionality reduction was used to analyze the gene-by-gene and gene-by-environment interactions. RESULTS: We found that DBH rs1611114 TT genotype had a protective effect on memory impairment after heroin dependence (P = 0.002, OR = 0.610). We also found that the income-rs12666409-rs129915-rs1611114 interaction yielded the highest testing balance accuracy and cross-validation consistency for memory change after heroin dependence. CONCLUSIONS: Our results suggest that the memory change after heroin dependence was a result of a combination of genetics and environment. This finding could lead to a better understanding of heroin dependence and further improve personalized treatment.

Provider Perspectives of Battlefield Acupuncture: Advantages, Disadvantages and Its Potential Role in Reducing Opioid Use for Pain.

OBJECTIVES: Nonpharmacological options to treat pain are in demand, in part to address the opioid crisis. One such option is acupuncture. Battlefield acupuncture (BFA) is an auricular needling protocol currently used to treat pain in the Veterans Health Administration. We aimed to identify the advantages and disadvantages of BFA from providers' perspectives. METHODS: We rely on an inductive qualitative approach to explore provider perceptions through thematic analysis of semistructured interviews with 43 BFA providers across the nation. RESULTS: We identified the following themes. Disadvantages included: (1) clinical guidelines are insufficient; (2) patients often request multiple BFA visits from providers; (3) BFA can be uncomfortable; (4) BFA may not be an effective treatment option unless it can be provided "on demand"; and (5) BFA can promote euphoria, which can have deleterious consequences for patient self-care. Perceived advantages included: (1) BFA can simultaneously effectively control pain while reducing opioid use; (2) BFA may alleviate the pain that has been unsuccessfully treated by conventional methods; (3) BFA gives providers a treatment option to offer patients with substance use disorder; (4) BFA helps build a trusting patient-provider relationship; (5) BFA can create the opportunity for hope. CONCLUSIONS: Providers perceive BFA to have many benefits, both clinical and relational, including ways in which it may have utility in addressing the current opioid crisis. BFA is easy to deliver and has potential clinical and relational utility. Efforts to better understand effectiveness are warranted.

Characterisation and outcome of neuropsychiatric symptoms in patients with anti-NMDAR encephalitis.

BACKGROUND: Encephalitis due to anti-N-methyl-D-aspartate receptor antibodies (ANMDARE) is the most frequent immune-mediated encephalitis. It is distinguished by the subacute onset of neuropsychiatric symptoms. OBJECTIVE: To evaluate the characteristic neuropsychiatric symptoms and their outcome in patients diagnosed with ANMDARE. METHODS: This was a prospective, longitudinal study in patients with a diagnostic suspicion of ANMDARE that presented to the National Institute of Neurology from March 2018 to February 2019. A comparative analysis of two groups (positive N-methyl-D-aspartate receptor [NMDAR] vs. negative NMDAR antibodies in cerebrospinal fluid [CSF]) was done on admission and at discharge. Neuropsychiatric systematic assessments included the Neuropsychiatric Inventory Questionnaire, the Bush Francis Catatonia Rating Scale, the Confusion Assessment Method Severity, the Montreal Cognitive Assessment, and the Overt Agitation Severity Scale. RESULTS: 24 individuals were analysed: 14 had positive NMDAR antibodies, and 10 had negative NMDAR antibodies in CSF. On admission, agitation/aggression, euphoria/exaltation, and disinhibition were more common in patients with positive antibodies. Excited catatonia and delirium were diagnosed more frequently in patients with positive antibodies. At discharge, there was an important decrease in neuropsychiatric symptoms, but substantial cognitive impairment remained. The mean hospitalisation length was 41.71 (SD 39.33) days for patients with definitive ANMDARE (p 0.259). CONCLUSIONS: Neuropsychiatric symptoms profile in ANMDARE was associated with the early onset of euphoria/exaltation and disinhibition, accompanied by marked psychomotor agitation. When ANMDARE was suspected, the presence of excited-type catatonia and delirium showed a tendency to predict definitive ANMDARE. At discharged, most patients recovered from catatonia, delirium, and psychosis, but marked cognitive symptoms, anxiety, and depression persisted at discharge.

Opioid-Induced "Likeability" and "Feeling Good" Are Not Associated With Return Visits to an ED Among Migraine Patients Administered IV Hydromorphone.

BACKGROUND: Parenteral opioids are used in more than 50% of emergency department (ED) visits for migraine. Use of opioids for migraine has been associated with subsequent ED visits, perhaps because of opioid-induced euphoria. In this study, we quantify the extent to which nontherapeutic effects of opioids influence migraine outcomes. We hypothesized that "feeling good" and medication likeability would in fact be associated with receipt of opioids (rather than relief of migraine pain) and that receipt of opioids (rather than relief of migraine pain) would be associated with return visits to the ED. METHODS: During an ED-based clinical trial, migraine patients were randomized to receive hydromorphone 1 mg or prochlorperazine 10 mg + diphenhydramine 25 mg IV. Thirty minutes after medication administration, we asked, (1) How much did you like the medication you received? and (2) How good did the medication make you feel? Participants were asked to provide answers on a 0-10 scale. We also determined 0-10 pain scores at baseline and 1 hour and number of return visits for headache during the subsequent month. RESULTS: Sixty-three patients received prochlorperazine and 64 hydromorphone. Prochlorperazine pain scores improved by 6.8 (SD: 2.6), hydromorphone by 4.7 (SD: 3.3) (95%CI for difference of 2.1: 1.0, 3.2). On the 0-10 likeability scale, prochlorperazine patients reported a mean of 7.2 (SD: 2.8), hydromorphone 6.9 (SD: 2.9) (95% CI for difference of 0.3: -0.7, 1.3). On the 0-10 feeling good scale, prochlorperazine patients reported a mean of 7.5 (SD: 2.3), hydromorphone 6.8 (SD: 2.8) (95%CI: for difference of 0.7: -0.2, 1.6). In the hydromorphone group, 8/57 (14%, 95%CI: 7, 26%) returned to the ED vs 5/63 (8%, 95%CI: 3,18%) in the prochlorperazine group. In regression modeling, feeling good was independently associated with pain relief (P < .01) but not with medication received (P = .67) or return visits (P = .12). Similarly, medication likeability was independently associated with pain relief (P < .01) but not medication received (P = .12) or return visits (P = .16). CONCLUSION: We did not detect an association between hydromorphone and medication likeability, feeling good, or return visits to the ED. Headache relief was associated with medication likeability and feeling good.

Development of the perceived stigma scale and the concealment of epilepsy scale for the Turkish population.

The aim of this study was to develop two culture-specific scales to measure the level of felt stigma, and level of concealment of Turkish adult people with epilepsy (PWE). For this purpose, a 10-item felt-stigma scale and a 17-item disclosure of epilepsy scale were developed and then applied to 200 adult PWE. After item and factor analyses of the stigma scale, the 10 items with a one-factor solution explained 45.6% of the variance with a 0.86 internal consistency value. Higher scores represent higher felt stigma. The concealment of epilepsy scale has 17 items loaded on one factor, which explained 45.1% of the variance. Cronbach's alpha coefficient was found to be 0.92. The higher the score, the higher the concealment of illness by the participant. For convergent validity, the relationship between stigma and disclosure scales was examined, and a positive significant relation (r=0.64, p<0.000) was found.

Human abuse potential of brivaracetam in healthy recreational central nervous system depressant users.

BACKGROUND: Brivaracetam is a new antiepileptic drug indicated for adjunctive treatment of focal seizures in adults at a dose of 50-200mg/day taken in two equal doses. The objective of this study was to evaluate the abuse potential of brivaracetam compared with alprazolam (positive control), placebo, and levetiracetam. METHODS: This was a randomized, double-blind, triple-dummy, crossover study in healthy male and female recreational central nervous system (CNS) depressant users aged 18-55years, who could distinguish between the subjective effects of alprazolam 2mg and placebo. All participants received single doses of brivaracetam (50 [therapeutic dose], 200, 1000mg [supratherapeutic doses]), alprazolam (1.5, 3mg), placebo, and levetiracetam (4000mg) in random order each separated by 7-10days. Subjective Visual Analogue Scales (VAS) and Addiction Research Center Inventory (ARCI) scales were completed at intervals up to 24h postdose. Primary endpoints were Drug Liking (at this moment) VAS, Overall Drug Liking VAS, Feeling High VAS, and ARCI Pentobarbital Chlorpromazine Alcohol Group (PCAG, sedation) maximum effect (Emax). Maximum effect values on each scale were analyzed using a mixed-effect model (per protocol population, N=44). RESULTS: The maximum effect for both alprazolam doses was significantly greater versus placebo for six designated endpoints, confirming study validity. Drug Liking (at this moment) VAS Emax was significantly lower for brivaracetam 50mg than alprazolam (both doses); there were no significant differences between brivaracetam 200mg and alprazolam (both doses), and brivaracetam 1000mg and alprazolam 1.5mg. Brivaracetam 1000mg (supratherapeutic single dose) had significantly higher Drug Liking (at this moment) VAS Emax than alprazolam 3mg. Overall, Drug Liking VAS Emax for brivaracetam 50 and 200mg was not significantly different from alprazolam (both doses). Brivaracetam 1000mg had significantly higher Overall Drug Liking VAS Emax than alprazolam 1.5mg, but was not significantly different from alprazolam 3mg. Feeling High VAS Emax was lower versus alprazolam with brivaracetam 50 and 200mg, while brivaracetam 1000mg was comparable with alprazolam (both doses). Addiction Research Center Inventory PCAG Emax for brivaracetam (all doses) was significantly lower than alprazolam (both doses). On the secondary/supportive endpoints, compared with alprazolam, brivaracetam had fewer positive effects (ARCI Morphine Benzedrine Group [euphoria]; Good Drug Effects VAS [50mg]) and fewer negative effects (Bad Drug Effects VAS; ARCI Lysergic Acid Diethylamide [dysphoria]). Brivaracetam was not significantly different from alprazolam for Take Drug Again VAS (50, 200mg). For most endpoints, brivaracetam (50-200mg) was not significantly different from levetiracetam (4000mg). CONCLUSION: This study in healthy recreational CNS depressant users showed that single doses of brivaracetam 50mg (therapeutic single dose) had lower sedative, positive, and negative drug effects than alprazolam, while brivaracetam 200 and 1000mg (supratherapeutic single doses) were more similar to alprazolam. The subjective profile of brivaracetam appeared to be similar to that of levetiracetam, but further evaluation using a range of levetiracetam doses would be needed to confirm similar abuse potential.

Prohedonic properties of gamma-hydroxybutyrate are associated with changes in limbic resting-state functional connectivity.

OBJECTIVE: Gamma-hydroxybutyrate (GHB) is an endogenous GHB-/GABA-B receptor agonist and a narcolepsy treatment. However, GHB is also abused for its prohedonic effects. On a neuronal level, it was shown that GHB increases regional cerebral blood flow in limbic areas such as the right anterior insula (rAI) and the anterior cingulate cortex (ACC). We aimed to further explore the association between the subjective and neuronal signatures of GHB. METHOD: We assessed subjective effects and resting-state functional connectivity (rsFC) of an rAI- and an ACC-seed in 19 healthy male subjects after GHB (35 mg/kg p.o.) using a placebo-controlled, double-blind, randomized, cross-over functional magnet resonance imaging design. RESULTS: GHB increased subjective ratings for euphoria (p < 0.001) and sexual arousal (p < 0.01). Moreover, GHB increased rAI-rsFC to the right thalamus and the superior frontal gyrus and decreased ACC-rsFC to the bilateral paracentral lobule (all p < 0.05, cluster corrected). Moreover, GHB-induced euphoria was associated with rAI-rsFC to the superior frontal gyrus (p < 0.05, uncorrected). CONCLUSIONS: GHB induces prohedonic effects such as euphoria and sexual arousal and in parallel modulates limbic rsFC with areas linked to regulation of mood, cognitive control, and sexual experience. These results further elucidate the drug's effects in neuropsychiatric disorders and as drug of abuse.

Affective and emotional dysregulation as pre-dementia risk markers: exploring the mild behavioral impairment symptoms of depression, anxiety, irritability, and euphoria.

BACKGROUND: Affective and emotional symptoms such as depression, anxiety, euphoria, and irritability are common neuropsychiatric symptoms (NPS) in pre-dementia and cognitively normal older adults. They comprise a domain of Mild Behavioral Impairment (MBI), which describes their emergence in later life as an at-risk state for cognitive decline and dementia, and as a potential manifestation of prodromal dementia. This selective scoping review explores the epidemiology and neurobiological links between affective and emotional symptoms, and incident cognitive decline, focusing on recent literature in this expanding field of research. METHODS: Existing literature in prodromal and dementia states was reviewed, focusing on epidemiology, and neurobiology. Search terms included: "mild cognitive impairment," "dementia," "prodromal dementia," "preclinical dementia," "Alzheimer's," "depression," "dysphoria," "mania," "euphoria," "bipolar disorder," and "irritability." RESULTS: Affective and emotional dysregulation are common in preclinical and prodromal dementia syndromes, often being harbingers of neurodegenerative change and progressive cognitive decline. Nosological constraints in distinguishing between pre-existing psychiatric symptomatology and later life acquired NPS limit historical data utility, but emerging research emphasizes the importance of addressing time frames between symptom onset and cognitive decline, and age of symptom onset. CONCLUSION: Affective symptoms are of prognostic utility, but interventions to prevent dementia syndromes are limited. Trials need to assess interventions targeting known dementia pathology, toward novel pathology, as well as using psychiatric medications. Research focusing explicitly on later life onset symptomatology will improve our understanding of the neurobiology of NPS and neurodegeneration, enrich the study sample, and inform observational and clinical trial design for prevention and treatment strategies.

"Euphoria" or "Only Teardrops"? Eurovision Song Contest performance, life satisfaction and suicide.

BACKGROUND: The popularity of the Eurovision Song Contest (ESC) in Europe has been high for decades. We aimed to assess whether a country's performance in the ESC is associated with life satisfaction and suicide mortality in European countries. METHODS: We analysed nationally representative Eurobarometer survey data on life satisfaction from 33 European countries (N = 162,773) and country-level standardised suicide mortality data for years 2009 to 2015. The associations of winning the Contest, performing terribly, and higher final ranking with life satisfaction and suicide rates were all assessed. RESULTS: Winning the ESC was not statistically significantly associated with increased life satisfaction or suicide rates, although every ten-place increase in final ranking was associated with an increase in life satisfaction (adjusted odds ratios [aOR] 1.04; 95% confidence interval [CI]: 1.02 to 1.05) and a decrease in suicide mortality rates (ß = - 0.30; 95% CI: -0.59 to - 0.01). Terrible performance was associated with greater life satisfaction compared to not competing at all (aOR 1.13; 95%CI: 1.07 to 1.20). CONCLUSION: The good news for participating countries is that just competing at the ESC is associated with higher life satisfaction among the population. As improved performance is linked to Ooh Aah Just a Little Bit of improved life satisfaction, further research into how such international competitions may impact public health is needed.

Neuropsychiatric syndromes of multiple sclerosis.

Neuropsychiatric signs and symptoms occur frequently in individuals with multiple sclerosis (MS), either as the initial presenting complaint prior to a definitive neurological diagnosis or more commonly with disease progression. However, the pathogenesis of these comorbid conditions remains unclear and it remains difficult to accurately elucidate if neuropsychiatric symptoms or conditions are indicators of MS illness severity. Furthermore, both the disease process and the treatments of MS can adversely impact an individual's mental health. In this review, we discuss the common neuropsychiatric syndromes that occur in MS and describe the clinical symptoms, aetiology, neuroimaging findings and management strategies for these conditions.

Psychostimulant effect of dopaminergic treatment and addictions in Parkinson's disease.

BACKGROUND: Dopamine replacement therapy in PD has been associated with both behavioral addictions and dopamine addiction. OBJECTIVES: To investigate potential association between l-dopa induced neuropsychiatric fluctuations and addictions in PD. METHODS: A cohort of 102 patients with PD suffering from motor complications of l-dopa treatment was prospectively analyzed. We evaluated dopamine addiction, behavioral addictions, and neuropsychiatric fluctuations using the Ardouin scale of behavior in PD. RESULTS: Patients with (n = 51) or without (n = 51) neuropsychiatric fluctuations did not differ in age, disease duration, medication, or UPDRS III motor score during on and off drug condition. Patients with neuropsychiatric fluctuations had a higher H & Y stage in off-drug condition. A multivariate model showed that dopamine addiction (odds ratio: 8.9; P = 0.02) and behavioral addictions (odds ratio: 3.76; P = 0.033) were more frequent in the presence of neuropsychiatric fluctuations. Behavioral addictions and dopamine addiction were more frequent in the presence than in the absence of on-drug euphoria (46% vs. 13.9%; P < 0.001 and 27% vs 6.2 %; P = 0.003), while conversely, no association emerged between dopamine or behavioral addictions and presence of off-drug dysphoria. Patients with neuropsychiatric fluctuations had a poorer quality of life and a more frequent history of anxiety disorder. CONCLUSIONS: The psychostimulant effects of dopamine treatment during on-drug euphoria, rather than avoidance of off-drug dysphoria, appear to drive both behavioral addictions and abuse of medication. © 2017 International Parkinson and Movement Disorder Society.

Early signal of diverted use of tropicamide eye drops in France.

AIMS: Tropicamide is a mydriatic drug used as eye-drops for diagnostic or therapeutic purposes. From 2013, a diverted use by intravenous route has been suspected in Eastern Europe in opioids users. To date, no signal of misuse has been identified in France. The aims of this study were to investigate any early signals of a diverted use of tropicamide eye drops and to collect information regarding motives for the misuse and tropicamide-induced effects. METHODS: Information was obtained at three levels: (1) at regional level (Midi-Pyrénées area), from reimbursement data and pharmacists' reports on suspicious requests; (2) at national level: from reimbursement data and prescriptions suggesting possible abuse from the OSIAP (Ordonnances Suspectes, Indicateur d'Abus Possible) survey; and (3) at international level: from VigiBase® reports and Web sources. Beta-blocker eye-drops were used as comparators. RESULTS: In France, in 2014-2015, 17 (0.91%, 95% CI [0.53-1.46%]) falsified prescriptions involving tropicamide were identified in the OSIAP survey (compared with 0%, 95% CI [0-0.19%] for beta-blockers). Moreover, 37 other suspicious prescriptions were presented in 2015 (notified in 2016). In Midi-Pyrénées, seven patients aged 35-49 were reimbursed for 19-45 vials of 10 ml, in a year. Since September 2014, the regional Addictovigilance Centre has received 91 notifications of suspicious requests to obtain tropicamide. In VigiBase® , two cases were identified but none in France. An increased interest in tropicamide-related Internet searches was observed from Russia and Ukraine. CONCLUSIONS: These results represent the first early warnings of a tropicamide diverted use in France. Tropicamide abusers would seek euphoria or hallucinations. The high doses involved in intravenous administration could lead to serious complications.

Genetic variation associated with euphorigenic effects of d-amphetamine is associated with diminished risk for schizophrenia and attention deficit hyperactivity disorder.

Here, we extended our findings from a genome-wide association study of the euphoric response to d-amphetamine in healthy human volunteers by identifying enrichment between SNPs associated with response to d-amphetamine and SNPs associated with psychiatric disorders. We found that SNPs nominally associated (P ≤ 0.05 and P ≤ 0.01) with schizophrenia and attention deficit hyperactivity disorder were also nominally associated with d-amphetamine response. Furthermore, we found that the source of this enrichment was an excess of alleles that increased sensitivity to the euphoric effects of d-amphetamine and decreased susceptibility to schizophrenia and attention deficit hyperactivity disorder. In contrast, three negative control phenotypes (height, inflammatory bowel disease, and Parkinson disease) did not show this enrichment. Taken together, our results suggest that alleles identified using an acute challenge with a dopaminergic drug in healthy individuals can be used to identify alleles that confer risk for psychiatric disorders commonly treated with dopaminergic agonists and antagonists. More importantly, our results show the use of the enrichment approach as an alternative to stringent standards for genome-wide significance and suggest a relatively novel approach to the analysis of small cohorts in which intermediate phenotypes have been measured.