Adult ADD

Note: If you are a prescribing clinician, you may want to read the page about professional issues involved in prescribing higher doses of stimulants.
Stimulant Dosing for Adults

Summary: While the maximum daily dose of stimulants set by the FDA for children is 60 mg per day, the FDA has not set a maximum dose for adults, who may need higher doses because they weigh more and because they often need the effects of the medication to last longer each day than do children.

A study of optimal doses was carried out on over 200 patients treated in two private practices.   Optimal doses were defined as those at which each patient obtained the maximal  effect on symptoms with an acceptable level of side effects.   Doses were started low and increased every three to seven days until optimal dosing was achieved or the medication was stopped because treatment with it was not successful.

For about two thirds of patients, optimal dosing was between 10 and 60 mg per day while the remaining third need higher doses.   Only 1% needed doses slightly above 200 mg per day.  Optimal lydexamfetamine (Vyvanse) doses were about one and a half times greater than than optimal doses of the other stimulants.

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There is an ongoing debate about the dosing guidelines to follow when prescribing stimulant medication (amphetamines and methylphenidates) for ADD. While a number of organizations have proposed guidelines, there is relatively little published clinical evidence for those guidelines and virtually no information about dosing used in ordinary clinical practice despite the recent popularity of the concept of evidence-based medicine.

While the upper limit of daily dosing of stimulants approved for children by the FDA is 60 mg per day of amphetamines, 70 mg per day of Vyvanse, 72 mg per day of Concerta, and 40 mg per day for methylphenidate, the FDA has not established specific dosing limits for adults. This is an unintended consequence of the FDA’s drug approval process: pharmaceutical companies apply to the FDA for approval after testing a drug within certain dose ranges for a certain target population. They are more likely to get a new drug approved if they do safety testing on an age limited population and at a low dose. Once a drug is approved for a specified dose and age group, doctors can use their judgment in prescribing the drug for any condition for any population at any dose. Such prescribing is called “off-label” and is perfectly legitimate and often very important but should be done with reasonable caution.

In the case of the stimulants, all studies submitted to the FDA for approval have been done on children at doses appropriate for children. There appears to be a correlation between body weight and optimal daily dose of the stimulants so limits established for a population with an average weight, say, of 100 pounds, may be too restrictive for 200 pound adults. In addition, almost all studies have been done on the stimulants’ effects over an eight hour period. Adults are much more likely to need to experience the benefits of treatment over periods of up to 14 hours, which would require a larger daily dose.

Many clinicians unfamiliar with stimulant treatment, choose to err on the side of caution and apply child dosage limits to adults.  Clinicians with more experience have found these limits inappropriate for many adults. Yet there is very little published information about dosing in adults. Most recommendation and guidelines fail to document the clinical experience on which they were based. (For information for clinicians who are considering prescribing higher doses, click here.)

To provide evidence-based data about dosing of stimulants for ADD, the editors of AdultADD.Info, Marc D. Schwartz MD and Nicholas A. Schwartz MD, carried out a study of the optimal total daily doses of stimulants taken by random adult patients from their practices who were being treated with LIS, AMP, and/or MPH. The optimal dose was defined as the dose at which patients received the most benefit with an acceptably low level of side effects.

Patient Sample
Charts of patients over the age of 17 diagnosed with ADD who achieved an optimal effect from stimulant treatment were selected from the authors’ practices. A careful medical history had been taken of each patient. When indicated, a medical exam was required of patients, particularly of their cardiac status, prior to the initiation of stimulant treatment.

Dosing Strategy Used to Achieve Optimal Doses
Patients included in the study were taking short-acting and beaded-delivery AMP, short-acting, beaded and OROS delivery MPH, or LIS. Focalin doses were doubled for the purpose of the dosage calculations since they contain only the active (dextro) isomer of the two isomers usually present in MPH.

Doses were started at a low level (one lowest dose pill per day, e.g. one 30 mg Vyvanse pill per day) and gradually increased every three to seven days until the maximum benefit had been achieved with an acceptable level of side effects. Occasionally, patients exceeded their ultimately optimal dose during this process and, because of side effects or lack of additional benefit, reduced it to what was determined to be their optimal level.

The term “optimal dose” refers to the total daily dose of medication taken. This study does not examine the range of optimal individual doses taken in the course of day.

Twenty three patients had achieved an optimal effect on two different stimulants taken consecutively. Some of these had changed medications because of cost considerations. Most had been switched after achieving an optimal benefit on the first medication to see if another stimulant medication might have a even more beneficial effect or have even fewer side effects than the one they started on. Information about their dosing with both medications they took are included in this study.

A number of patients had started taking stimulants but had stopped because they were unable to achieve optimal results, that is, the doses of medication(s) they took were either ineffective or caused unacceptable side or adverse effects. The great majority of these treatment failures occurred at doses within the FDA approved dose limits. Data about these patients are not included in this study. It is important to bear this in mind lest one conclude that the optimal dose ranges found in this study patients are applicable to all patients. It is the authors estimate that about 15% of patients did not achieve an optimal dose usually because they experienced unacceptable side effects, sometimes at a ineffective dose, sometimes at an effective dose and about 5% were unable to achieve an optimal effect at any dose level the patient and treating clinician were comfortable with. In a future study, we will more carefully examine the frequency and reasons optimal dosing was not achieved in those patients.

Of 268 charts that met the initial selection criteria, data from 8 were not included. Seven had taken two types of stimulants concurrently. Five of these had taken LIS at the beginning of the day and AMP later in the day when the LIS was wearing off. Two had taken AMP and MPH concurrently because they experienced each as having a somewhat different beneficial effect. Calculating a daily dose of one medication was not possible in these instances.

It should be noted that a small percentage of patients included in the study were referred to one of the authors because the dose of medication they had been taking, most often at or below the FDA approved level, was ineffective, but their treating clinician was unwilling to prescribe a higher dose. For most of these patients, higher doses were found to be effective and not to have adverse effects. For that reason, the distribution of doses found in this study is probably slightly higher than that in ADD practices that do not include such referrals.

Findings
We first examined the average, minimum, and maximum daily doses required to achieve an optimal result with AMP, MPH and LIS.

Average, Minimum and Maximum Dosing

Distribution of Optimal Dosing
The distribution of optimal daily doses for 132 patients taking AMP are noted in the chart below.

The optimal dose for 72% of patients (96/132)  ranged up to 60 mg per day.  28% required a higher dose including almost 5% who required a dose over 140 mg per day.  All of the latter weighed more than 200 pounds.   The highest optimal dose was 210 mg per day.

The distribution of optimal daily doses for 33 patients taking methylphendate are noted in the chart below.

The optimal dose for 66% of patients (22/33)  taking MPH ranged up to 60 mg per day.  33% required a higher dose including almost 6% who required a dose over 140 mg per day.  All of the latter weighed more than 200 pounds.   The highest optimal dose was 210 mg per day.

Dosing of Vyvanse
The distribution of optimal daily doses for 39 patients taking lisdextroamfetamine are noted in the chart below.

The optimal dose for only 33% of patients (13/39)  ranged up to 60 mg per day.  67% required a higher dose including almost 41% who required a dose over 140 mg per day.

There has been a considerable amount of interest in how optimal doses of LIS compare to those of AMP and MPH. As noted in the table above, the average optimal doses of AMP and MPH were fairly similar to each other (about 56 mg per day) as were the minimum and maximum doses required to achieve optimal benefit. In contrast, the average dose of LIS was about one and a half times larger than either, 90 mg per day.

Twenty three patients had taken both AMP or MPH and LIS. Among these, the average optimal daily dose of AMP or MPH was 67 mg per day while the optimal dose of LIS was 121 mg per day, a little less than twice as large.

Side and Adverse Effects
Two patients included in the study developed symptoms of suspiciousness bordering on paranoia. One was taking LIS 210 mg per day. On a reduction to 90 mg per day of AMP, the symptoms disappeared within a week. The other sought treatment elsewhere when she was told her dose of stimulants would have to be reduced.
Two patients had a mild increase in Reynaud’s symptoms (coldness of fingers and toes).

Two patients had an increase in blood pressure. Both chose to start anti-hypertensive medication rather than stop their stimulant medication.

Two patients developed a rapid heart beat due to atrial fibrillation. One reduced the dose and the symptoms disappeared. The other was referred to a cardiologist, who prescribed a calcium channel blocker. The fibrillation disappeared and, with the cardiologist’s agreement, the patient resumed stimulant treatment without a recurrence of the fibrillation. Both were on relatively low doses of stimulants.

While many patients obtained optimal benefit from relatively small doses of stimulants, the optimal doses for most patients were equal to or greater than the FDA limitations.

Discussion and Conclusion
The optimal adult daily dose of AMP and MPH in the two practices studied averaged about 56 mg per day and ranged from approximately 5 mg to 210 mg per day. Optimal daily LIS doses averaged 83 mg per day and ranged from 20 mg to 210 mg. In general, the dose of LIS required to get effects equivalent to that of AMP or MPH were 1.5 times higher, that is, 40 mg of AMP or MPH seemed equivalent to 60 mg of LIS. The optimal doses of about a third of the adult patients in this study were equal to or higher than the maximal doses specified in the FDA guidelines.

It is important to bear in mind that a number of patients were not included in this study because they had stopped taking stimulants because these medications were ineffective or caused unacceptable side effects or adverse effects. For this reason, dosing guidelines for all patients cannot be constructed on the basis of these findings. The dose ranges found are nonetheless useful for considering the dosing for those who do not have negative effects.

The literature is very sparse on the dangers of doses higher than those approved by the FDA. The highest daily dose of which I am personally aware was taken by a patient who had been prescribed a reasonable dose of Adderall for ADD but took larger doses on his own to deal with his night-shift sleepiness.  Over a 36 day period, he took a few months supply of his own medication plus a few months supply of the medication of his mother, who was also  being treated for ADD.  His mother carefully documented his dose each day but did not notify his clinician until they ran out of medication. During that time, he took an average of 510 mg per day with a highest daily dose on one day of 960 mg with no apparent problems.  I believe such doses are very dangerous and it is difficult for me to imagine that any responsible clinician would prescribe them.

While no dose is risk free, higher doses are more likely than lower doses to cause increases in blood pressure, paranoia, and psychosis than lower doses. It would be useful to know what is the incidence rate of adverse reactions of various doses of stimulants prescribed and overseen by clinicians.  Is there a certain dose at which risk rapidly rises? There are numerous reports of people taking more than a gram of stimulants per day with no adverse effect. Is there a dose that is toxic? Are stimulants more or less risky than MAOI’s, than tricyclics, than anti-epileptic medications. There is a risk of sudden cardiac death among patients with a pre-existing heart condition taking any dose of stimulants. Once again, it would seem likely the risk is greater among those taking a higher dose, but there is little or no published data upon which to base clinical decision making.

The risks of high doses are clearly significant for some patients, but doses for adults higher than FDA approved doses for children should not be excluded in clinical practice as this would mean a significant portion of people treated for ADD would be excluded from taking a dose that would be optimal for them. Clinical judgment and open discussion with patients are needed to identify and balance the benefits of higher doses for some patients and the risks involved.

The findings of this study may be of particular interest to clinicians who will not prescribe stimulants for adults at any doses higher than those specified by the FDA for children. From the data presented here, one can conclude that the FDA limitation may not meet the needs of as many as a third of ADD patients, who benefit only from a higher daily dose.

It would be very useful to have more information about other adult populations who have taken doses above those set by the FDA as there may be significant adverse or side effects that did not appear on our relatively small patient population. We hope that such evidence-based information from practicing ADD specialists will prove helpful to clinicians and their adult patients who are being treated for ADD with stimulants.