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.

In an exploratory randomized, double-blind, placebo-controlled, cross-over study, psychoactive doses of intravenous delta-9-tetrahydrocannabinol fail to produce antinociceptive effects in healthy human volunteers.

RATIONALE: Animal studies and anecdotal human reports suggest that cannabinoids have antinociceptive effects. Controlled human studies have produced mixed results. OBJECTIVES: We sought to reduce existing variability by investigating the effects of intravenous delta-9-tetrahydrocannabinol (THC) in several pain paradigms within the same human subjects, addressing some of the limitations to the published literature. METHODS: In this exploratory randomized, double-blind, placebo-controlled, cross-over study, healthy human subjects received 0.01 mg/kg or 0.03 mg/kg intravenous THC or placebo (ethanol vehicle) infused over 10 min on three test days, each separated by at least 72 h. Capsaicin (250 µg) was injected intradermally to induce chemical pain and hyperalgesia. Four other forms of acute pain were induced: mechanical (von Frey filament), hot and cold (thermode), and electrical (pulse generator). Pain ratings were obtained before drug administration, at peak drug effects, and 2 h after drug administration and included both objective and subjective measures. THC drug effects and vital signs were also collected during experimental sessions. Nonparametric analysis with repeated measures was performed. RESULTS: THC induced euphoria, perceptual and cognitive alterations, and tachycardia in a dose-related manner, but failed to have significant effects in experimentally induced acute chemical, mechanical, thermal, or electrical pain and capsaicin-induced hyperalgesia. CONCLUSIONS: In this exploratory controlled study, intravenous THC lacked significant antinociceptive properties in experimental models of acute pain and capsaicin-induced hyperalgesia in healthy human subjects. Continued study of THC and other cannabinoids through high-quality, controlled studies in both healthy volunteers and patients with pain conditions is warranted to inform the growing demand for the clinical application of cannabinoids in pain management.

Opioid-induced Euphoria Among Emergency Department Patients With Acute Severe Pain: An Analysis of Data From a Randomized Trial.

BACKGROUND: Parenteral opioids are commonly used to treat acute severe pain. We measured pleasurable sensations in patients administered intravenous analgesics to determine if these sensations were associated with receipt of an opioid, after controlling for relief of pain. Pleasurable sensations not accounted for by relief of pain were considered opioid-induced euphoria. METHODS: These data were from a randomized study of 1 mg of hydromorphone versus 120 mg of lidocaine for abdominal pain. To assess euphoria, participants were asked to provide a 0 to 10 response to each of these questions: 1) How good did the medication make you feel? 2) How high did the medication make you feel? and 3) How happy did the medication make you feel? Pain at baseline and 30 minutes was also measured on a 0 to 10 scale. To determine the relative importance of pain relief versus medication type, we built three linear regression models in which each euphoria question was the dependent variable and pain relief, medication type, and medication-induced side effects were the independent variables. RESULTS: Seventy-seven patients received lidocaine and 77 hydromorphone. Hydromorphone patients reported greater pain improvement than lidocaine patients (mean difference = 1.5, 95% confidence interval [CI] = 0.6 to 2.3) and higher scores on all three euphoria questions ("feeling good" difference = 1.9, 95% CI = 0.8 to 3.0; "feeling high" difference = 1.5, 95% CI = 0.4 to 2.7; "feeling happy" difference = 1.7, 95% CI = 0.6 to 2.8). In the regression models, hydromorphone administration (ß-coefficient = 0.16, p = 0.03) and pain relief (ß-coefficient = 0.45, p < 0.01) were both associated with "feeling good." "Feeling high" and "feeling happy" were associated with pain improvement (p < 0.01) but not with hydromorphone administration (p = 0.07 for "high" and p = 0.06 for "happy"). Medication-induced side effects were not associated with these measures of euphoria. CONCLUSION: Among emergency department patients with acute pain, hydromorphone-induced euphoria, though measurable, was generally less important for patients than relief of pain.

Designer benzodiazepines' pharmacological effects and potencies: How to find the information.

BACKGROUND: Scientific data on the psychopharmacological effects of new psychoactive substances (NPSs) are scarce. Web fora contain a wealth of information posted by users as trip reports (TRs), but the reliability of the reports remains questionable because of the nature of the used molecule and the potential for dose inaccuracies. We focused on the TRs of designer benzodiazepine (DBZD) users since their psychopharmacological effects are similar to prescription benzodiazepines (BZDs). Moreover, the impact of functional groups on the BZD rings with regards to the potency has been fairly/quite studied, allowing structural analysis. METHODS: DBZDs offering more than 15 TRs with at least two accounts on experienced effects were included. Data were analyzed with the empirical phenomenological psychological method. Reported effects were analyzed and the pharmacological potencies of DBZDs were compared by calculating a 'potency score'. RESULTS: In total, 197 TRs for clonazolam, deschloroetizolam, diclazepam, etizolam, flubromazepam, flubromazolam, meclonazepam, metizolam, nifoxipam and pyrazolam were analyzed. Effects similar to prescription BZDs were reported for all the selected DBZDs. Pyrazolam was reported to be the most anxiolytic DBZD, flubromazolam the most hypnotic, etizolam the most euphoric and flubromazolam and clonazolam as the most amnesic DBZDs. Diclazepam and pyrazolam were not reported to induce euphoria. Flubromazepam, flubromazolam, clonazolam and meclonazepam were the most potent and deschloroetizolam, nifoxipam, metizolam and pyrazolam the least potent. The chemical structure of the different DBZDs and the functional groups on the BZD rings confirmed this ranking, except for nifoxipam. CONCLUSIONS: When information on NPSs obtained from Internet fora are abundant, it could be considered as an appreciable data source.

Subjective responses to amphetamine in young adults with previous mood elevation experiences.

RATIONALE: One risk factor for alcohol and substance misuse is hypomanic experiences, or periods of mood elevation. Young people who report hypomanic states are more likely to develop bipolar disorder (BP), and BP and other mood disorders increase the risk of addiction. We recently reported that young adults with a history of mood elevation experience less subjective effects from a low dose of alcohol, which may be predictive of future alcohol use. The finding with alcohol raised the question of whether this dampened response to a drug also applies to other drugs, such as amphetamine. OBJECTIVE: This study assessed responses of d-amphetamine in healthy young adults with varying experiences of mood elevation, as measured by the Mood Disorders Questionnaire (MDQ). METHODS: Healthy 18-19-year-olds (N = 30) with a range of MDQ scores participated in three 4-h laboratory sessions in which they received placebo, 10 mg, or 20 mg d-amphetamine. They completed mood questionnaires and cardiovascular measures. RESULTS: Individuals with higher MDQ scores reported less stimulation and euphoria after 10 mg, but not 20 mg, d-amphetamine, than individuals with lower scores. MDQ scores were not related to cardiovascular responses to the drug. CONCLUSIONS: A history of mood elevation experiences or hypomania states is related to dampened response to a low dose of a psychostimulant drug, extending previous findings with dampened response to alcohol. This phenotype for mood disorders of dampened responses to drugs may contribute to risk for subsequent drug use or misuse.

Chronic High-Dose Buprenorphine Does Not Block Subjective High from Diacetylmorphine in a Patient in Heroin-Assisted Treatment.

We present the case of a 35-year-old woman in heroin-assisted treatment (HAT) expressing the wish for the transition to oral opioid agonist treatment. After failed attempts to change to oral diacetylmorphine and slow-release oral morphine, respectively, she was induced on overlapping buprenorphine (BUP) treatment with the Bernese method. Gradual dose increases to BUP 48 mg per day did not result in attenuation of subjective effects of IV diacetylmorphine (DAM) 190 mg. Instead, the patient showed increased sedation. BUP was then reduced to 32 mg per day. After the gradual reduction of IV DAM, she reinitiated illicit substance use. IV DAM was again raised to an effective dose leading to stabilization and reduction of illicit substance use. BUP was subsequently reduced to 8 mg per day. This combination was continued as the patient felt comfortable and reported less early morning withdrawal than with exclusive DAM treatment. We discuss possible underlying mechanisms and explanations as well as clinical implications.

Zolpidem stimulant effect: Induced mania case report and systematic review of cases.

INTRODUCTION: Zolpidem is the most widely prescribed hypnotic agent worldwide. This easy-access drug seems to have a high addictive potential among specific populations and is now listed by the World Health Organization (WHO) as being as dangerous as benzodiazepines for dependence and abuse. Many side effects have been reported, but drug-induced mania is still extremely rare. We conducted a systematic review to study the zolpidem-induced stimulation, euphoric or manic effects. METHODS: MEDLINE, PsycINFO, Science Direct, and Google Scholar were searched for articles in English, French, German, Italian and Spanish published up to the 15th October 2018. RESULTS: Eighteen relevant cases were identified, highlighting the need for more reports; therefore, one case that occurred in our department was included. The mean usual dose was 363.31 mg (± 292.2), the minimum dose was 10 mg, the maximum dose was 2000 mg, and the mean intake duration was 35.20 months (±48.0). We found that 89.4% of cases were euphoric and 15.7% had drug-induced mania with delusions. A total of 15.7% of cases took zolpidem for relaxant and stimulant effects, 47% of cases suffered various depression or anxiety disorders, of which 62.5% used zolpidem to cope with depression or an anxiety disorder. A total of 26.3% of cases had concomitant drug dependence or abuse. Seventy-five percent of cases suffering from depression consumed zolpidem for more than 1 year, with significantly more increased daily doses than in non-depressed cases (p < .5). CONCLUSIONS: The latest FDA recommendations for lowering zolpidem doses should be adopted by all countries. Zolpidem prescriptions should be contraindicated for populations with identified risk factors.

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.

The Mixed Opioid Receptor Antagonist Naltrexone Mitigates Stimulant-Induced Euphoria: A Double-Blind, Placebo-Controlled Trial of Naltrexone.

OBJECTIVE: Supratherapeutic doses of methylphenidate activate µ-opioid receptors, which are linked to euphoria. This study assessed whether naltrexone, a mixed µ-opioid antagonist, may attenuate the euphoric effects of stimulants, thereby minimizing their abuse potential in subjects with attention-deficit/hyperactivity disorder (ADHD). METHODS: We conducted a 6-week, double-blind, placebo-controlled, randomized clinical trial of naltrexone in adults with DSM-IV ADHD receiving open treatment with a long-acting formulation of methylphenidate (January 2013 to June 2015). Spheroidal Oral Drug Absorption System methylphenidate (SODAS-MPH) was administered twice daily, was titrated to ~1 mg/kg/d over 3 weeks, and was continued for 3 additional weeks depending on response and adverse effects. Subjects were adults with ADHD preselected for having experienced euphoria with an oral test dose of 60 mg of immediate-release methylphenidate (IR-MPH). The primary outcome measure was Question 2 (Liking a Drug Effect) on the Drug Rating Questionnaire, Subject version, which was assessed after oral test doses of 60 mg of IR-MPH were administered after the third and sixth weeks of treatment with SODAS-MPH. RESULTS: Thirty-seven subjects who experienced stimulant-induced (mild) euphoria at a baseline visit were started in the open trial of SODAS-MPH and randomized to naltrexone 50 mg/d or placebo. Thirty-one subjects completed through week 3, and 25 completed through week 6. Naltrexone significantly diminished the euphoric effect of IR-MPH during the heightened-risk titration phase (primary outcome; first 3 weeks) (χ² = 5.07, P = .02) but not the maintenance phase (weeks 4-6) (χ² = 0.22, P = .64) of SODAS-MPH treatment. CONCLUSIONS: Preclinical findings are extended to humans showing that naltrexone may mitigate stimulant-associated euphoria. Our findings provide support for further studies combining opioid receptor antagonists with stimulants to reduce abuse potential. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01673594.

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.

Opiate Antagonists Do Not Interfere With the Clinical Benefits of Stimulants in ADHD: A Double-Blind, Placebo-Controlled Trial of the Mixed Opioid Receptor Antagonist Naltrexone.

OBJECTIVE: Methylphenidate activates µ-opioid receptors, which are linked to euphoria. µ-Opioid antagonists, such as naltrexone, may attenuate the euphoric effects of stimulants, thereby minimizing their abuse potential. This study assessed whether the combination of naltrexone with methylphenidate is well-tolerated while preserving the clinical benefits of stimulants in subjects with attention-deficit/hyperactivity disorder (ADHD). METHODS: We conducted a 6-week, double-blind, placebo-controlled, randomized clinical trial of naltrexone in adults with DSM-IV ADHD receiving open treatment with a long-acting formulation of methylphenidate from January 2013 to July 2015. Spheroidal Oral Drug Absorption System (SODAS) methylphenidate was administered twice daily, was titrated to approximately 1 mg/kg/d over 3 weeks, and was continued for 3 additional weeks depending on response and adverse effects. Subjects were adults with ADHD preselected for having experienced euphoria with a test dose of immediate-release methylphenidate. The primary outcome measure was the Adult ADHD Investigator Symptom Report Scale (AISRS). RESULTS: Thirty-seven subjects who experienced stimulant-induced (mild) euphoria at a baseline visit were started in the open trial of SODAS methylphenidate and randomly assigned to naltrexone 50 mg or placebo. Thirty-one subjects completed the study through week 3, and 25 completed through week 6. Throughout 6 weeks of blinded naltrexone and open methylphenidate treatment, the coadministration of naltrexone with methylphenidate did not interfere with the clinical effectiveness of methylphenidate for ADHD symptoms. Additionally, the combination of naltrexone and methylphenidate did not produce an increase in adverse events compared with methylphenidate alone. CONCLUSIONS: Our findings provide support for the concept of combining opioid receptor antagonists with stimulants to provide an effective stimulant formulation with less abuse potential. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01673594​.

From mundane medicines to euphorigenic drugs: How pharmaceutical pleasures are initiated, foregrounded, and made durable.

BACKGROUND: Examining how pharmaceuticals are used to induce pleasure presents a unique opportunity for analyzing not only how pleasure is assembled and experienced through distinct consumption practices but also how mundane medicines can become euphorigenic substances. METHODS: Drawing on qualitative research on the non-medical use of prescription drugs by young adults in the United States, this paper utilizes Actor-Network Theory (ANT) to examine how prescription medicines come to produce pleasure. RESULTS: Our research found an indeterminacy of experience as individuals were initiated into prescription drug pleasures. We also found that euphorigenic effects coalesce and are foregrounded through subsequent use, and that pleasure and other forms of gratification are made durable through repeated and deliberate pharmaceutical consumption. CONCLUSION: Understanding how individuals are socialized into pharmaceutical pleasure, and how assemblages act to constitute the euphorigenic potential of pharmaceutical misuse, may allow for more context-appropriate intervention efforts. We suggest that the euphorigenic properties ascribed to prescription drugs are not inherent in their pharmaceutical formulations, but instead emerge through interactions within networks of heterogeneous actants.

Sweet taste liking is associated with subjective response to amphetamine in women but not men.

RATIONALE AND OBJECTIVE: Preference for sweet taste rewards has been linked to the propensity for drug use in both animals and humans. Here, we tested the association between sweet taste liking and sensitivity to amphetamine reward in healthy adults. We hypothesized that sweet likers would report greater euphoria and stimulation following D-amphetamine (20 mg) compared to sweet dislikers. METHODS: Men (n = 36) and women (n = 34) completed a sweet taste test in which they rated their liking of various concentrations of sucrose and filtered water (0.05, 0.10, 0.21, 0.42, and 0.83 M). Participants who preferred the highest concentration were classified as "sweet likers." All others were classified as "sweet dislikers." They then completed four sessions in which they received D-amphetamine (20 mg) and placebo in alternating order, providing self-report measures of euphoria and stimulation on the Addiction Research Center Inventory (ARCI) at regular intervals. We conducted linear mixed effects models to examine relationships between sweet liking and drug-induced euphoria and stimulation. RESULTS: Sweet likers reported significantly greater amphetamine-induced euphoria than did sweet dislikers among women. By contrast, sweet liking was not associated with amphetamine response in men. No associations with stimulation were observed. CONCLUSION: The association between sweet preference and amphetamine response in women is consistent with animal studies linking sweet taste preference and drug reward and also fits with observations that individuals who use drugs show a preference for sweet tastes. Whether the sex difference is related to circulating hormones, or other variables, remains to be determined.

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.

The effects of synthetic cannabinoid UR-144 on the human body-A review of 39 cases.

UR-144 [(1-pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone] is a synthetic cannabinoid, which has been detected in many 'legal highs', seized from the global drug market since the beginning of 2012. It has gained popularity as a 'legal' alternative to classic cannabis in countries where it was not controlled. Despite the widespread distribution of this substance, the data on its effects on the human body are scarce. Therefore, this paper describes the results of analysis and observed effects in 39 cases in which UR-144 was determined in blood. Symptoms were noted from the blood sampling forms filled out by the representative doctor. The determined concentrations of UR-144 were in the range of trace amounts (LOD-0.15ng/mL; LOQ-0.5ng/mL) up to 17ng/mL. The most common observed effects included slurred speech, dilated pupils, sluggish and abnormal pupillary reaction, cheerful behaviour, poor coordination, and staggering. Less frequently observed were: verbosity, narrow pupils, loss of consciousness, pale or reddened facial skin, blackout, euphoria, agitation, hallucinations, hindered communication, shaking hands, seizures, convulsions, somnolence, delayed movements, redness of the conjunctiva, and tachycardia. The discussed cases show the effects observed after UR-144 use. This study can assist in the recognition of possible effects caused by this substance.

Associations Between Behavioral and Neural Correlates of Inhibitory Control and Amphetamine Reward Sensitivity.

Poor inhibitory control and sensitivity to drug reward are two significant risk factors for drug abuse. Although the two have been largely viewed as separate and independent risk factors, there is new evidence to suggest that they may be related at both the behavioral and neural level. This study examined associations between behavioral and neural correlates of inhibitory control and sensitivity to the subjective rewarding effects of amphetamine in humans. Healthy volunteers (n=63) first completed the stop signal task, a behavioral measure of inhibitory control. Then they participated in four sessions in which they received amphetamine (20 mg) and placebo in alternating order, providing self-report measures of euphoria and arousal at regular intervals. Finally, a subset of participants (n=38) underwent an fMRI scan to assess neural correlates of inhibitory control. In the first phase of the study, participants with longer stop signal reaction time (SSRT) reported greater amphetamine-induced euphoria and stimulation than those with shorter SSRT. In the second phase, fMRI of response inhibition showed the expected activation in right prefrontal regions. Further, individuals who exhibited less activation in the right middle frontal gyrus during the inhibition task reported more euphoria during the amphetamine sessions. This study is the first to show associations between poor inhibitory control and amphetamine reward sensitivity at both behavioral and neural levels in humans. These findings extend our understanding of risk for drug abuse in individuals with poor inhibitory control and suggest novel targets for prevention efforts.

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.

Test-retest reliability of the underlying latent factor structure of alcohol subjective response.

RATIONALE: Alcohol subjective experiences are multi-dimensional and demonstrate wide inter-individual variability. Recent efforts have sought to establish a clearer understanding of subjective alcohol responses by identifying core constructs derived from multiple measurement instruments. OBJECTIVE: The aim of this study was to evaluate the temporal stability of this approach to conceptualizing alcohol subjective experiences across successive alcohol administrations in the same individuals. METHODS: Healthy moderate alcohol drinkers (n = 104) completed six experimental sessions each, three with alcohol (0.8 g/kg), and three with a non-alcoholic control beverage. Participants reported subjective mood and drug effects using standardized questionnaires before and at repeated times after beverage consumption. We explored the underlying latent structure of subjective responses for all alcohol administrations using exploratory factor analysis and then tested measurement invariance over the three successive administrations using multi-group confirmatory factor analyses. RESULTS: Exploratory factor analyses on responses to alcohol across all administrations yielded four factors representing "Positive mood," "Sedation," "Stimulation/Euphoria," and "Drug effects and Urges." A confirmatory factor analysis on the separate administrations indicated acceptable configural and metric invariance and moderate scalar invariance. CONCLUSIONS: In this study, we demonstrate temporal stability of the underlying constructs of subjective alcohol responses derived from factor analysis. These findings strengthen the utility of this approach to conceptualizing subjective alcohol responses especially for use in prospective and longitudinal alcohol challenge studies relating subjective response to alcohol use disorder risk.

The Pharmacology and Toxicology of the 'Holy Trinity'.

Combining opioids with benzodiazepines and skeletal muscle relaxants ('The Holy Trinity') has been reported to potentiate the 'high'. Through unique interactions with colocalized µ-opioid and GABAA receptors, the combined use of these agents induces a synergistic increase in dopamine in the nucleus accumbens (NAc) and depression of respiration. The inhibition of GABA release mediated by µ1 -opioid receptor activation results in a subsequent increase in dopamine in the NAc. Benzodiazepines activate the GABAA R to suppress respiration in the medullary respiratory centres. The skeletal muscle relaxant, carisoprodol, appears to bind to a unique binding domain within the GABAA R to further enhance the respiratory depressant effects of the benzodiazepines. Therefore, the opioids, the benzodiazepines and carisoprodol alone or in combination are capable of inducing respiratory depression. Current guidelines for opioid prescribing recommend against the concomitant use of benzodiazepines but do not recognize the potential risk associated with the addition of skeletal muscle relaxants.

Intravenous Use of Prescription Psychostimulants; A Comparison of the Pattern and Subjective Experience between Different Methylphenidate Preparations, Amphetamine and Cocaine.

BACKGROUND/AIMS: Methylphenidate (MPH) has been the most commonly used intravenous (i.v.) substance in Iceland in recent years. In Iceland, MPH is available in 3 forms: immediate-release (IR) tablets (MPH IR, short-acting), sustainable-release (SR) capsules (MPH SR, long-acting) and osmotic-release (OROS) tablets (MPH OROS, long-acting). The aims of the study were to compare the pattern and subjective effects of i.v. MPH use to other i.v. psychostimulants and examine whether the pattern of use differs among MPH preparations. METHODS: This is a nationwide descriptive study. Information was collected from 95 i.v. substance users undergoing inpatient detoxification and reporting i.v. MPH use in the last 30 days using a semi-structured interview. RESULTS: MPH SR was both the most commonly used (96%) and preferred i.v. psychostimulant (57%). The intensity and duration of 'euphoria' did not differ between cocaine and MPH SR. No participant reported MPH OROS as their preferred substance even though a third had used it in the past month. CONCLUSIONS: The pattern of i.v. MPH use is similar to other psychostimulants among treatment seeking patients. MPH OROS was the least preferred i.v. psychostimulant, despite having the largest market share in Iceland. The results indicate that MPH OROS has less abuse potential than other MPH preparations.