We examined whether cannabis use contributes to the increased risk of psychotic disorder for non-western minorities in Europe.

We used data from the EU-GEI study (collected at sites in Spain, Italy, France, the United Kingdom, and the Netherlands) on 825 first-episode patients and 1026 controls. We estimated the odds ratio (OR) of psychotic disorder for several groups of migrants compared with the local reference population, without and with adjustment for measures of cannabis use.

The OR of psychotic disorder for non-western minorities, adjusted for age, sex, and recruitment area, was 1.80 (95% CI 1.39–2.33). Further adjustment of this OR for frequency of cannabis use had a minimal effect: OR = 1.81 (95% CI 1.38–2.37). The same applied to adjustment for frequency of use of high-potency cannabis. Likewise, adjustments of ORs for most sub-groups of non-western countries had a minimal effect. There were two exceptions. For the Black Caribbean group in London, after adjustment for frequency of use of high-potency cannabis the OR decreased from 2.45 (95% CI 1.25–4.79) to 1.61 (95% CI 0.74–3.51). Similarly, the OR for Surinamese and Dutch Antillean individuals in Amsterdam decreased after adjustment for daily use: from 2.57 (95% CI 1.07–6.15) to 1.67 (95% CI 0.62–4.53).

The contribution of cannabis use to the excess risk of psychotic disorder for non-western minorities was small. However, some evidence of an effect was found for people of Black Caribbean heritage in London and for those of Surinamese and Dutch Antillean heritage in Amsterdam.

Auditory frequency modulation learning (‘auditory learning’) is a key component of targeted cognitive training (TCT) for schizophrenia. TCT can be effective in enhancing neurocognition and function in schizophrenia, but such gains require significant time and effort and elude many patients.

As a strategy to increase and/or accelerate TCT-induced clinical gains, we tested the dose- and time-course effects of the pro-attentional drug, amphetamine (AMPH; placebo, 2.5, 5 or 10 mg po; within-subject double-blind, order balanced) on auditory learning in schizophrenia patients [n = 32; M:F = 19:13; age 42.0 years (24–55)]. To understand predictors and/or mechanisms of AMPH-enhanced TCT, we also measured auditory fidelity (words-in-noise (WIN), quick speech-in-noise (QuickSIN)) and neurocognition (MATRICS comprehensive cognitive battery (MCCB)). Some measures were also acquired from age-matched healthy subjects (drug free; n = 10; M:F = 5:5).

Patients exhibited expected deficits in neurocognition. WIN and QuickSIN performance at low signal intensities was impaired in patients with low v. high MCCB attention/vigilance (A/V) scores; these deficits were corrected by AMPH, maximally at 2.5–5 mg (d's = 0.79–1.29). AMPH also enhanced auditory learning, with maximal effects at 5 mg (d = 0.93), and comparable effects 60 and 210 min post pill. ‘Pro-learning’ effects of AMPH and AMPH-induced gains in auditory fidelity were most evident in patients with low MCCB A/V scores.

These findings advance our understanding of the impact of pro-attentional interventions on auditory information processing and suggest dose- and time-course parameters for studies that assess the ability of AMPH to enhance the clinical benefits of TCT in schizophrenia patients.

To evaluate the relative bioavailability of a single dose of amphetamine extended-release oral suspension (AMPH EROS) compared with a single dose of extended-release mixed amphetamine salts (ER MAS) in healthy, fasted adult subjects.

The study population consisted of healthy adult volunteers. The study drug used in this study was 7.5 mL of 2.5 mg/mL AMPH EROS equivalent to 18.8 mg of amphetamine base administered after an overnight fast of at least 10 hours. AMPH EROS comprises a 3.2:1 enantiomeric ratio of d-amphetamine to l-amphetamine. The reference product was one 30 mg ER MAS capsule (equivalent to 18.8 mg of amphetamine base). Relative bioavailability between the products was determined by a statistical comparison of the area under the curve and maximum concentration (Cmax) for d-amphetamine and l-amphetamine. PK (PK) blood samples were collected prior to dosing (0-hour) and at 1, 2, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 12, 14, 16, 24, 36, 48, and 60 hours after drug administration, totaling 20 samples in each period.

The mean subject age was 35.0 (standard deviation ±8) years, and the overall study population comprised 19 (63.3%) males and 11 (36.7%) females. The contrasts for geometric mean ratios for all assessed PK parameters (for both l- and d-amphetamine) between the test article AMPH EROS and reference product ER MAS fell within the prescribed 80% to 125% limits.

The overall PK profile of single-dose AMPH EROS 7.5 mL was found to be comparable with a single dose of oral ER MAS 30 mg.

Evaluate the relative bioavailability of single-dose amphetamine extended-release tablet (AMPH ER TAB) 20 mg, swallowed whole or chewed, and amphetamine extended-release oral suspension (AMPH EROS) 2.5 mg/mL; evaluate food effect on AMPH ER TAB.

Healthy volunteers (18–55 years) were randomized to 1 dose of AMPH ER TAB 20 mg swallowed (fasted), chewed (fed/fasted), or 20 mg AMPH EROS (fasted). A crossover study design was used. Plasma samples were collected each period predose and at time points to 60 hours postdose. d- and l-amphetamine were measured and pharmacokinetic (PK) was calculated (90% confidence intervals of the ratios of the plasma levels) for AUC0-t, AUC0-∞, and Cmax. Comparative relative bioavailability between formulations was determined when ratios were within 80% and 125%. Safety was also assessed.

Thirty-two subjects completed the study. AMPH ER TAB swallowed versus AMPH EROS (fasted): for d- and l-amphetamine, the total and peak exposure was similar: d: AUC0-t: 100.68% to 108.08%, AUC0-∞: 101.47% to 109.52%, Cmax: 98.10% to 103.17%; l: AUC0-t: 100.31% to 108.57%, AUC0-∞: 101.27% to 111.09%, Cmax: 98.2% to 103.37%. For d- and l-amphetamine when the tablet is swallowed whole, Tmax was 5.00 hours (with a range of 2.00–9.00 hours). AMPH ER TAB chewed versus AMPH EROS (fasted): for d- and l-amphetamine, the total and peak exposure was similar: d: AUC0-t: 99.23% to 106.62%, AUC0-∞: 99.58% to 107.59%, Cmax: 99.91% to 105.14%; l: AUC0-t: 98.16% to 106.35%, AUC0-∞: 98.44% to 108.11%, Cmax: 99.53% to 104.75%. For d- and l-amphetamine when the tablet has been chewed, Tmax was 5.00 hours (with a range of 3.00-7.00 hours). PK results were similar for patients in the fasted and fed groups, indicative of no presence of food effect. No serious adverse events (AEs) were reported, overall AE profiles between the tablet and oral suspension were comparable without any unanticipated safety concerns.

Single doses of AMPH ER TAB for both d- and l-amphetamine demonstrated comparable bioavailability to a 20 mg dose of AMPH EROS, 2.5 mg/mL under fasted conditions when chewed and swallowed whole, and demonstrated equivalent peak and overall exposure without apparent food effect. AMPH ER TAB was well-tolerated and consistent with adverse events noted in other amphetamine formulations.

Our aim was to summarize the efficacy and safety of atomoxetine, amphetamines, and methylphenidate in schizophrenia.

We undertook a systematic review, searching PubMed/Scopus/Clinicaltrials.gov for double-blind, randomized, placebo-controlled studies of psychostimulants or atomoxetine in schizophrenia published up to 1 January 2017. A meta-analysis of outcomes reported in two or more studies is presented.

We included 22 studies investigating therapeutic effects of stimulants (k=14) or measuring symptomatic worsening/relapse prediction after stimulant challenge (k=6). Six studies of these two groups plus one additional study investigated biological effects of psychostimulants or atomoxetine. No effect resulted from interventional studies on weight loss (k=1), smoking cessation (k=1), and positive symptoms (k=12), and no improvement was reported with atomoxetine (k=3) for negative symptoms, with equivocal findings for negative (k=6) and mood symptoms (k=2) with amphetamines. Attention, processing speed, working memory, problem solving, and executive functions, among others, showed from no to some improvement with atomoxetine (k=3) or amphetamines (k=6). Meta-analysis did not confirm any effect of stimulants in any symptom domain, including negative symptoms, apart from atomoxetine improving problem solving (k=2, standardized mean difference (SMD)=0.73, 95% CI=0.10–1.36, p=0.02, I2=0%), and trending toward significant improvement in executive functions with amphetamines (k=2, SMD=0.80, 95% CI=−1.68 to +0.08, p=0.08, I2=66%). In challenge studies, amphetamines (k=1) did not worsen symptoms, and methylphenidate (k=5) consistently worsened or predicted relapse. Biological effects of atomoxetine (k=1) and amphetamines (k=1) were cortical activation, without change in β-endorphin (k=1), improved response to antipsychotics after amphetamine challenge (k=2), and an increase of growth hormone–mediated psychosis with methylphenidate (k=2). No major side effects were reported (k=6).

No efficacy for stimulants or atomoxetine on negative symptoms is proven. Atomoxetine or amphetamines may improve cognitive symptoms, while methylphenidate should be avoided in patients with schizophrenia. Insufficient evidence is available to draw firm conclusions.

Many studies have concluded that cannabis use disorder (CUD) negatively influences outcomes in first-episode psychosis (FEP). However, few have taken into account the impact of concurrent misuse of other substances.

This 2-year, prospective, longitudinal study of FEP patients, aged between 18 and 30 years, admitted to early intervention programs in Montreal, Quebec, Canada, examined the specific influence of different substance use disorders (SUD) (alcohol, cannabis, cocaine, amphetamines) on service utilization, symptomatic and functional outcomes in FEP.

Drugs and alcohol were associated with lower functioning, but drugs had a greater negative impact on most measures at 2-year follow-up. Half of CUD patients and more than 65% of cocaine or amphetamine abusers presented polysubstance use disorder (poly-SUD). The only group that deteriorated from years 1 to 2 (symptoms and functioning) were patients with persistent CUD alone. Outcome was worse in CUD than in the no-SUD group at 2 years. Cocaine, amphetamines and poly-SUD were associated with worse symptomatic and functional outcomes from the 1st year of treatment, persisting over time with higher service utilization (hospitalization).

The negative impact attributed to CUD in previous studies could be partly attributed to methodological flaws, like including polysubstance abusers among cannabis misusers. However, our investigation confirmed the negative effect of CUD on outcome. Attention should be paid to persistent cannabis misusers, since their condition seems to worsen over time, and to cocaine and amphetamine misusers, in view of their poorer outcome early during follow-up and high service utilization.

Dopamine receptor-mediated 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent intracellular signalling is important for reward-related learning. cAMP activates cAMP-dependent protein kinase (PKA) and exchange protein directly activated by cAMP (Epac). We tested the hypothesis that reward-related learning may be mediated by Epac.

We evaluated conditioned place preference (CPP) on the basis of nucleus accumbens (NAc) injections of amphetamine (20 μg/0.5 μl/side) plus Sp-adenosine 3′,5′-cyclic monophosphorothioate triethylamanine (Sp-cAMPS) (0.1, 1.0, 10, 15, 20 μg/0.5 μl/side), an activator of both PKA and Epac, or amphetamine (20 μg) plus 8-(4-chlorophenylthio)-2′-O-methyladenosine-3′,5′-cyclic monophosphate (8-pCPT) (0.73, 1.27, 1.45, 2.89, 5.78, 11.56 μg/0.5 μl/side), an activator of Epac.

In agreement with previous results, Sp-cAMPS dose-dependently impaired CPP. 8-pCPT impaired CPP at one dose (1.45 μg/0.5 μl/side) and we replicated this effect three times.

The results implicate Epac in the acquisition of reward-related learning.

To measure blood levels of morphine and additional drugs in patients suspected of intravenous (IV) heroin abuse and to evaluate the effects of antidote treatment.

Prehospital blood sampling in 52 patients.

Forty-five patients were blood-positive for heroin, eight of whom were hospitalized. Forty-one patients also had abused additional drugs: minor tranquilizers, ethanol, amphetamine, cocaine, and/or carbamazepine. Seven patients had taken either only methadone or ketobemidione: one was admitted. Treatment with increasing doses of naloxone indicated a necessity for hospitalization. Six of 14 patients treated with naloxone (1.8 mg were hospitalized. Seven patients had an extremely high blood level of morphine (0.2 mg/kg), that could be reverted with naloxone in moderate doses.

This study indicates that under prehospital conditions, it is difficult to identify a patient intoxicated only with intravenous heroin. Nearly all patients treated were cases of multiple drug/alcohol overdoses. Even the symptoms associated with extremely high blood levels of morphine could be reversed with naloxone in moderate doses.