Adderall

Authors:

Dustin Martin, Jacqueline K. Le

Findings:

Amphetamine has pharmacological effects on attention, cognition, emotions, and appetite.

All Effects:

Authors:

Xavier Castells

Findings:

Based on low to very low-quality evidence from short-term RCTs, amphetamines (lisdexamfetamine, dexamphetamine, mixed amphetamine salts (MAS)) reduced clinician- and patient-rated ADHD symptom severity compared to placebo. However, amphetamines did not improve overall treatment retention and were associated with a higher rate of withdrawal due to adverse events. Lisdexamfetamine and MAS showed efficacy on clinician ratings, while evidence for dexamphetamine was very low quality and non-significant; all types showed some effect on patient ratings. No clear dose-response effect or differences between immediate- and sustained-release formulations were found.

Participants:

Systematic review included 19 studies with N=2521 adults (over 18 years) with ADHD diagnosed by standardised criteria (e.g., DSM-IV, DSM-IV-TR, DSM-5). Mean age was 35.3 years (range 20.2-41.2). Participants were mostly male (57.2%) and Caucasian (84.5%). Most had combined type ADHD (78.8%). Sample sizes in individual studies ranged from 17 to 420.

Dosage:

Studies investigated dexamphetamine (range: 10.2 mg/d to 21.8 mg/d), lisdexamfetamine (range: 30 mg/d to 70 mg/d), and mixed amphetamine salts (MAS; range: 12.5 mg/d to 80 mg/d). Subgroup analyses did not find evidence that higher doses within these ranges were associated with greater efficacy.

Study Quality Assessment:

Systematic review of 19 randomised controlled trials (RCTs). All studies were placebo-controlled; 3 also included an active comparator (guanfacine, modafinil, or paroxetine). 6 studies used a cross-over design, others parallel-group. Mean study length was short (5.3 weeks). No included study was rated as having an overall low risk of bias due to issues including unclear sequence generation/allocation concealment, potential unblinding due to subjective drug effects (performance/detection bias), attrition bias (some studies rated high risk), and potential carry-over effects in cross-over studies without adequate washout. 16/19 studies were funded by the pharmaceutical industry; 1 publicly funded; 2 unreported. Overall quality of evidence was rated as low or very low using the GRADE approach. Limitations acknowledged: short duration of studies, restrictive inclusion criteria limiting external validity.

All Effects:

Authors:

Stephen V Faraone

Findings:

This review summarizes the pharmacology of amphetamine and methylphenidate, both first-line ADHD treatments. Their primary effect is increasing central dopamine and norepinephrine activity, impacting executive and attentional function, though through distinct mechanisms involving transporters (DAT, NET), VMAT-2, MAO (amphetamine), and serotonin receptors (methylphenidate). Clinical implications for ADHD with comorbidities are discussed.

Participants:

Individuals with attention-deficit/hyperactivity disorder (ADHD) who may have comorbid psychiatric conditions (depression, anxiety, substance use disorder, sleep disturbances) - discussed in the context of a literature review.

Study Quality Assessment:

Systematic literature review of PubMed conducted in April 2017. Mentions a PRISMA Flow Diagram.

All Effects:

Authors:

A Sinha, O Lewis

Findings:

Reports a case of acute myocardial infarction (AMI) and atrial fibrillation in a 31-year-old adult taking mixed amphetamine salts (Adderall), temporally associated with taking a higher than usual dose (30mg vs 20mg daily) and consuming alcohol. Reviews literature indicating CNS stimulants are associated with increased heart rate and blood pressure in adults. Large observational studies show mixed results regarding serious cardiovascular events (MI, stroke, sudden death) with short-term stimulant use in adults, while some studies suggest increased arrhythmia risk in younger populations, especially those with congenital heart disease. Concludes definite conclusions on long-term cardiovascular safety cannot currently be made.

Participants:

Presents a case report of a 31-year-old Caucasian man diagnosed with ADHD at 15. Reviews literature involving adults, children, and young adults with ADHD treated with stimulant medications, citing studies with large sample sizes (e.g., meta-analysis N=2665; observational studies N=43,999 users, N=150,359 users).

Dosage:

Case report subject: Prescribed mixed amphetamine salts (Adderall). Initial dose 7.5 mg (taken for 5 years). Restarted 6 months prior to presentation at 20 mg twice daily. Self-reduced dose to 20 mg once daily 3 months prior. Event occurred after taking 20 mg in the morning and 10 mg in the afternoon (total 30 mg) on the day of presentation.

Study Quality Assessment:

The primary text is a case report ('Case Rep Cardiol'). It reviews findings from other studies including a meta-analysis (Mick et al.), large observational cohort studies (Holick et al., Schelleman et al., Habel et al.), a retrospective cohort study (Cooper et al.), and a self-controlled case series study (Ju-Young S. et al.). Limitations of reviewed studies are mentioned (e.g., Habel et al.: short median exposure, considered only severe events, potential 'healthy user effect' bias; Schelleman et al.: limited adjustment in primary analyses). Patient consent was obtained for the case report. Authors declared no conflict of interests. Article is open access under Creative Commons Attribution License.

All Effects:

Authors:

Samuele Cortese, MD

Findings:

This network meta-analysis compared ADHD medications in children, adolescents, and adults. At ~12 weeks, based on clinician ratings, all included drugs (amphetamines, atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, modafinil) except modafinil in adults were more efficacious than placebo for ADHD core symptoms. Amphetamines showed the highest efficacy but were less tolerated than placebo in both age groups; methylphenidate showed better acceptability than placebo in children/adolescents, while amphetamines did in adults. Based on efficacy and tolerability, methylphenidate is supported as first-choice for children/adolescents, and amphetamines for adults, for short-term treatment.

Participants:

Children (aged ≥5 years and <12 years), adolescents (aged ≥12 years and <18 years), and adults (≥18 years) with a primary diagnosis of ADHD according to DSM or ICD criteria. Total included: 14,346 children and adolescents, 10,296 adults.

Dosage:

Primary analysis restricted to studies using medications within the therapeutic range (as per FDA recommendations, where applicable). Sensitivity analyses investigated effects at different dose regimens, including FDA-licensed doses and doses recommended in guidelines but differing from FDA recommendations. Post-hoc analysis separated lisdexamfetamine from other amphetamines.

Study Quality Assessment:

Systematic review and network meta-analysis of 133 double-blind randomised controlled trials (parallel group, crossover, or cluster). Included published and unpublished data. Assessed risk of bias using the Cochrane risk of bias tool (rated overall low in 23.5% of child/adolescent studies and 27.5% of adult studies; unclear/high in the rest). Assessed confidence of estimates with GRADE approach for network meta-analyses (confidence varied from high/moderate to low/very low, especially for indirect comparisons). Excluded enrichment design trials. Acknowledged limitations: paucity of data beyond 12 weeks, significant statistical heterogeneity, small number of head-to-head trials, inability to perform some planned sensitivity analyses due to data scarcity. Funding sources mentioned: Stichting Eunethydis and UK National Institute for Health Research Oxford Health Biomedical Research Centre.

All Effects: