Stimulants in the treatment of adults with ADHD

By | April 8, 2015

Stimulant treatment of adults with attention deficit hyperactivity disorder can be characterized as follows.

  • Stimulants represent the first-line pharamcotherapy for attention deficit hyperactivity disorder in adults.
  • The two main types of stimulants, methylphenidate and amphetamine compounds, have different effects and are metabolized differently.
  • Methylphenidate does not show up on urine drug screens.
  • Stimulants are not effective for comorbidities within ADHD.
  • Stimulants generally have few medication interactions (except with MAOIs)

Stimulant medications remain the mainstay treatment in children, adolescents, and adults with ADHD. In comparison to the more than 200 controlled studies of stimulant efficacy in pediatric attention deficit hyperactivity disorder (), there are only two open and nine controlled stimulant trials in adults with attention deficit hyperactivity disorder (). In contrast to consistent robust responses to stimulants in children and adolescents of approximately 70% (), controlled studies in adults have shown more equivocal responses to stimulants, ranging from 25% () to 78% () of adults responding to treatment. Controlled trials of methylphenidate (MPH) and mixed amphetamine compound (Adderall) (), demonstrate more robust response compared to pemoline (). At this time there are no available studies in adults of extended-release preparations or new delivery systems of methylphenidate or dextroamphetamine.

Variability in the response rate appears to be related to several factors, including the diagnostic criteria utilized to determine ADHD, varying stimulant doses, high rates of comorbidity, and differing methods of assessing overall response. Dosing of the stimulants, for example, appears to effect outcome. Controlled investigations using higher stimulant dosing (> 1.0 mg/kg/day) resulted in more robust outcomes () than those using lower stimulant dosing (<0.7 mg/kg/day) (). In addition, dose-dependent response to stimulants was found in three studies of adults with attention deficit hyperactivity disorder (). Although commonly used, the utility of dextroamphetamine for attention deficit hyperactivity disorder in adults remains unstudied. Although long-term data are generally lacking, preliminary data from one controlled trial of 117 adults suggests that the response to MPH is sustained at six-month follow-up ().

Pharmacokinetic Issues in Stimulant Treatment

Plasma levels of the stimulants have not been shown to correlate with response in attention deficit hyperactivity disorder in adults (). Moreover, comorbidity with attention deficit hyperactivity disorder and gender has not been associated with variable response (); however, sample sizes have not been large enough to adequately address this issue.

Pharmacodynamics of Stimulant Treatment

The effects of the stimulants in the brain are variable. Preclinical studies have shown that the stimulants block the reuptake of dopamine and nor-epinephrine into the presynaptic neuron and that both drugs increase the release of these monoamines into the extraneuronal space (). While not entirely sufficient, alterations in dopaminergic and noradrenergic function appear necessary for clinical efficacy of the anti-ADHD medications, including the stimulants (). There may be differential responses to the chemically distinct available stimulants because each may have a different mode of action. For example, although methylphenidate (MPH) and amphetamines alter dopamine transmission, they appear to have different mechanisms on release of dopamine from neuronal pools (). The different mechanisms of actions of the amphetamines may explain why adults not responding to one stimulant may respond favorably to another. Moreover, given the differing mechanism of action, it is empirically reasonable, although unstudied, to consider combining methylphenidate with amphetamine in refractory patients.

Initiation of Therapy and Dosing Guidelines

Given the limited controlled data on the use of stimulants in adults with ADHD, there are limited data available to guide dosing parameters in this population. FDA guidelines for dosing reflect general cautiousness and should not be the only guide for clinical practice. For instance, absolute dose limits (in mg) do not adequately consider a patient’s height or weight and may result in underdosing. Although adults were not included in the MTA study, many clinicians extrapolate these results in their treatment of adults (). Other clinicians may turn to the Texas Medication Algorithm Project for guidance (). Doses should be individually titrated based on therapeutic efficacy and tolerability. The overall clinical picture, taking into account all the variables of the patient’s current presentation, should guide selection of an initial stimulant.

Many patient’s respond equally well to either methylphenidate or amphetamine compounds (). Treatment should be started with short-acting preparations at the lowest possible dose. Initiation of treatment with once-daily dosing in the morning is advisable until an acceptable response is noted. Treatment generally starts at 5 mg of methylphenidate, dextroamphetamine, or amphetamine compound once daily and is titrated upward every three to five days until an effect is noted or adverse effects emerge. Repeat dosing through the day is dependent on the duration of effectiveness, wear-off, and side effects. Typically, the half-life of the short-acting stimulants necessitates at least twice-daily dosing, with the addition of similar or reduced afternoon doses dependent on breakthrough symptoms.

Treatment with stimulants appears to be moving in the direction of longer-acting delivery systems. For instance, the new OROS system found in Concerta delivers methylphenidate for approximately 8-9 hours and thus has a behavioral life of between 10 and 14 hours. Concerta can be initiated at 18 mg and increased in weekly increments as tolerated to an effective dose. Typical adult dosing of methylphenidate is up to 30 mg three to four times daily, amphetamine 15-20mg three to four times a day, and pemoline 75-225 mg daily. If an adult with attention deficit hyperactivity disorder symptoms is unresponsive or experiences significant side effects to the initial stimulant, consideration of an alternative stimulant or class of agents is recommended.

Monitoring Treatment with Stimulants

Once pharmacotherapy is initiated, monthly contact with the patient is suggested during the initial phase of treatment to carefully monitor response to the intervention and adverse effects. Given that many adults with attention deficit hyperactivity disorder have comorbidites, once a successful regimen of medications is identified, the clinician must monitor for symptoms of comorbidity. For instance, some concerns have been raised about the anxiogenic properties of Adderall, and thus patients with comorbid anxiety disorder should be closely monitored (). If issues of substance use are present, then consider the use of urine screens or hair sampling. Remember that methylphenidate will not be identified on the urine screen as amphetamine since it is metabolized primarily to ritalinic acid ().

Side Effects of Stimulants

The side effects of the stimulants in attention deficit hyperactivity disorder adults have been reported to be mild, with the following side effects most frequently reported: insomnia, edginess, diminished appetite, weight loss, dysphoria, obsessiveness, tics, and headaches (). No cases of stimulant-related psychosis at therapeutic doses have been reported in adults (). Likewise, despite the theoretical abuse potential of the stimulants, there have been no reports of stimulant abuse in controlled or retrospective studies of adults with attention deficit hyperactivity disorder (). Although concerns about adverse cardiovascular effects of stimulants have been raised (), effects appear benign, with minimal elevations of heart rate and blood pressure weakly correlated with dose (). Studies of stimulants in normotensive adults demonstrate elevations of 4 mm Hg of systolic and diastolic blood pressure as well as increases in heart rate of less than 10 beats per minute ().

While these studies are reassuring in normotensive adults, long-term data are lacking, as are data in adults with borderline hypertension. It is recommended that clinicians inquire about familial hypertension, regularly follow patient’s blood pressure, and proceed with caution in patients with borderline hypertension. The addition of low-dose beta-blockers (i.e., propanolol at 10 mg up to three times daily) or busipirone (5-10 mg up to three times daily) may be helpful in reducing the edginess/agitation associated with stimulant administration ().

Although not observed in short term studies of pemoline in attention deficit hyperactivity disorder adults (), elevated liver function tests remain a concern when using this medication, and the FDA recommends liver enzyme tests every two weeks. While the benefit of biweekly liver function tests is debatable, discussion and close observation of hepatitis symptoms, including change in urine/stool characteristic, abdominal pain, persistent flulike symptoms, or jaundice are useful in monitoring for hepatic dysfunction with pemoline. Pemoline may have a role in the treatment of attention deficit hyperactivity disorder and comorbid substance use disorders.

Medication Interactions

The interactions of the stimulants with other prescription and nonprescription medications are generally mild and not a source of concern (). Whereas coadministration of sympathomimetics (i.e., pseudoephedrine) may potentiate both medication effects, the antihistamines may diminish the stimulant’s effectiveness. Excretion of amphetamines can be enhanced by acidification of the urine, and thus in some cases clinicians may need to limit the amount of citrus juices patients drink at the time they take their medications. Extreme caution should be exercised when using stimulants and antidepressants of the monoamine oxidase inhibitor (MAOI) type because of the potential for hypertensive reactions with this combination. The concomitant use of stimulants and TCAs is common practice, with a recent study indicating no significant drug interactions.

New Stimulant Preparations

As already discussed, several new delivery systems for methylphenidate are available. Similarly, clinicians can expect several other stimulant preparations to be available soon. These include S1I381, a once daily formulation of Adderall. This compound utilizes the Micotrol delivery system employed in Carbatrol (a long-acting form of carbamazepine). Recent trials in children and adolescents have been published and are promising ().

Despite the increasing use of stimulants for adults with ADHD, up to 50% do not respond, have untoward side effects, or manifest comorbidity that stimulants may exacerbate or be ineffective in treating (). Reports of nonstimulant treatments for attention deficit hyperactivity disorder adults have included the use of antidepressants, antihypertensives, and amino acids.


Selections from the book: “Clinician’s Guide to Adult ADHD: Assessment and Intervention (Practical Resources for the Mental Health Professional)”. Edited by Sam Goldstein and Anne Teeter Ellison, 2002.