Methylphenidate and amphetamine are the two most widely used stimulants in managing Attention Deficit Hyperactivity Disorder (ADHD)1. Reynaud’s phenomenon (RP) is a reversible distal vasoconstriction presenting with various dermatological symptoms. RP can secondarily develop after certain medications as well2.

The review was undertaken to synthesize the incidence of RP within ADHD population treated with stimulants, and any causal relation of RP and stimulant-use.

PubMed, Psych-Info and Google Scholar were searched using these keywords: skin change, Raynaud, stimulants and methylphenidate. All relevant study types were included. Results were synthesized narratively.

Initial search yielded 240 articles with 5 articles fulfilling our inclusion criteria. One was retrospective case-controlled study while remaining 4 were case reports. Six cases were identified with an age of 12-19 years, who presented with RP after being treated with methylphenidate-or-dextroamphetamine. In one case, multiple clinical signs of RP were seen with cold distal fingers, transient color changes and even frank ulceration3–6. In two cases, it was seen that RP was dose-dependent with stimulant use and got resolved after decreasing the dosage respectively. In case-control study, 32 cases with RP and 32 controls were enrolled. The results showed a statistically significant association (χ2 =5, p=0.01) between RP and past-or-current stimulant usage.7

The literature review suggests weak evidence of the association between RP and stimulant use but no evidence of any causal link. Further studies are needed to identify characters that can predict this adverse effect in vulnerable ADHD individuals.

No significant relationships.

Stimulants are considered the mainstay of treatment for attention-deficit/hyperactivity disorder (ADHD), and most patients are put on a long-term regimen with these psychostimulants. However some children treated with psychostimulants have reported psychosis as an adverse effect.

Understand the capacity of psychostimulant medications to induce psychotic symptoms and determine the frequency of such reactions in adolescents and young adults.

Non-systematic review of the literature in English, through research in PubMed. Additionally, a clinical case is exposed, which was treated at the psychiatric inpatient unit of the Tamega e Sousa hospital center.

Some patients, including some with no identifiable risk factors, can develop drugrelated signs or symptoms of psychosis or mania, such as hallucinations, at usual doses of frequently used ADHD drugs. Age of onset of psychosis can be significantly earlier in individuals with a history of stimulant use. In our clinical case, a young man of 18 years, previously diagnosed with ADHD, was medicated with atomoxetine two months prior being admitted to our psychiatric unit. There was no reported history of a similar psychiatric condition, and no risk factors were identified. At admission, he had bizarre behavior, with allucinatory activity and delusions of persecution. Atomoxetine was suspended and started oral antipsychotic, with improvement of symptoms and stabilization of the clinical condition.

In adolescents and young adults with ADHD undergoing stimulant therapy, any psychotic symptoms or mood changes need to be carefully assessed at regular intervals by the physicians and the caregivers, in order to observe change in the symptoms.

No significant relationships.

The prevalence of attention deficit/hyperactivity disorder in the general population is common and is now diagnosed in 4%–12% of children. Children with CHD have been shown to be at increased risk for attention deficit/hyperactivity disorder. Case reports have led to concern regarding the use of attention deficit/hyperactivity disorder medications in children with underlying CHD. We hypothesised that medical therapy for patients with CHD and attention deficit/hyperactivity disorder is safe.

A single-centre, retrospective chart review was performed evaluating for adverse events in patients aged 4–21 years with CHD who received attention deficit/hyperactivity disorder therapy over a 5-year span. Inclusion criteria were a diagnosis of CHD and concomitant medical therapy with amphetamines, methylphenidate, or atomoxetine. Patients with trivial or spontaneously resolved CHD were excluded from analysis.

In 831 patients with CHD who received stimulants with a mean age of 12.9 years, there was only one adverse cardiovascular event identified. Using sensitivity analysis, our median follow-up time was 686 days and a prevalence rate of 0.21% of adverse events. This episode consisted of increased frequency of supraventricular tachycardia in a patient who had this condition prior to initiation of medical therapy; the condition improved with discontinuation of attention deficit/hyperactivity disorder therapy.

The incidence of significant adverse cardiovascular events in our population was similar to the prevalence of supraventricular tachycardia in the general population. Our single-centre experience demonstrated no increased risk in adverse events related to medical therapy for children with attention deficit/hyperactivity disorder and underlying CHD. Further population-based studies are indicated to validate these findings.

Drug classes are grouped based on their chemical and pharmacological properties, but prescription and illicit drugs differ in other important ways. Potential differences in genetic and environmental influences on the (mis)use of prescription and illicit drugs that are subsumed under the same class should be examined. Opioid and stimulant classes contain prescription and illicit forms differentially associated with salient risk factors (common route of administration, legality), making them useful comparators for addressing this etiological issue.

A total of 2410 individual Australian twins [Mage = 31.77 (s.d. = 2.48); 67% women] were interviewed about prescription misuse and illicit use of opioids and stimulants. Univariate and bivariate biometric models partitioned variances and covariances into additive genetic, shared environmental, and unique environmental influences across drug types.

Variation in the propensity to misuse prescription opioids was attributable to genes (41%) and unique environment (59%). Illicit opioid use was attributable to shared (71%) and unique (29%) environment. Prescription stimulant misuse was attributable to genes (79%) and unique environment (21%). Illicit stimulant use was attributable to genes (48%), shared environment (29%), and unique environment (23%). There was evidence for genetic influence common to both stimulant types, but limited evidence for genetic influence common to both opioid types. Bivariate correlations suggested that prescription opioid use may be more genetically similar to prescription stimulant use than to illicit opioid use.

Prescription opioid misuse may share little genetic influence with illicit opioid use. Future research may consider avoiding unitary drug classifications, particularly when examining genetic influences.

Substance use and psychiatric illness, particularly psychotic disorders, contribute to violence in emergency healthcare settings. However, there is limited research regarding the relationship between specific substances, psychotic symptoms and violent behaviour in such settings. We investigated the interaction between recent cannabinoid and stimulant use, and acute psychotic symptoms, in relation to violent behaviour in a British emergency healthcare setting.

We used electronic medical records from detentions of 1089 individuals under Section 136 of the UK Mental Health Act (1983 amended 2007), an emergency police power used to detain people for 24–36 h for psychiatric assessment. The relationship between recent cannabinoids and/or stimulant use, psychotic symptoms, and violent behaviour, was estimated using logistic regression.

There was evidence of recent alcohol or drug use in 64.5% of detentions. Violent incidents occurred in 12.6% of detentions. Psychotic symptoms increased the odds of violence by 4.0 [95% confidence intervals (CI) 2.2–7.4; p < 0.0001]. Cannabinoid use combined with psychotic symptoms increased the odds of violence further [odds ratios (OR) 7.1, 95% CI 3.7–13.6; p < 0.0001]. Recent use of cannabinoids with stimulants but without psychotic symptoms was also associated with increased odds of violence (OR 3.3, 95% CI 1.4–7.9; p < 0.0001).

In the emergency setting, patients who have recently used cannabinoids and exhibit psychotic symptoms are at higher risk of violent behaviour. Those who have used both stimulants and cannabinoids without psychotic symptoms may also be at increased risk. De-escalation protocols in emergency healthcare settings should account explicitly for substance use.

Emotional lability (EL) is an associated feature of attention-deficit/hyperactivity disorder (ADHD) in adults, contributing to functional impairment. Yet the effect of pharmacological treatments for ADHD on EL symptoms is unknown. We conducted a systematic review and meta-analysis to examine the effects of stimulants and atomoxetine on symptoms of EL and compare these with the effects on core ADHD symptoms.

A systematic search was conducted on the databases Embase, PsychInfo, and Ovid Medline® and the clinicaltrials.gov website. We included randomised, double-blind, placebo-controlled trials of stimulants and atomoxetine in adults aged 18–60 years, with any mental health diagnosis characterised by emotional or mood instability, with at least one outcome measure of EL. All identified trials were on adults with ADHD. A random-effects meta-analysis with standardised mean difference and 95% confidence intervals was used to investigate the effect size on EL and compare this to the effect on core ADHD symptoms.

Of the 3,864 publications identified, nine trials met the inclusion criteria for the meta-analysis. Stimulants and atomoxetine led to large mean weighted effect-sizes for on ADHD symptoms (n = 9, SMD = −0.8, 95% CI:−1.07 to −0.53). EL outcomes showed more moderate but definite effects (n = 9, SMD = −0.41, 95% CI:−0.57 to −0.25).

In this meta-analysis, stimulants and atomoxetine were moderately effective for EL symptoms, while effect size on core ADHD symptoms was twice as large. Methodological issues may partially explain the difference in effect size. Reduced average effect size could also reflect heterogeneity of EL with ADHD pharmacotherapy responsive and non-responsive sub-types. Our findings indicate that EL may be less responsive than ADHD symptoms overall, perhaps indicating the need for adjunctive psychotherapy in some cases. To clarify these questions, our findings need replication in studies selecting subjects for high EL and targeting EL as the primary outcome.

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.