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Combination medication for ADHD

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Combination medication for ADHD

Contrary to widespread assumptions, there are many ways to combine medications for ADHD (augmentation).1 The combination of several active substances of identical or different pharmacological classes (polypharmacy) is an increasingly common strategy in the treatment of ADHD2, which has been included in various treatment guidelines, particularly for comorbidities and cases that are resistant to monotherapy. 3456
A medical registry analysis found that a combination of different ADHD medication drug classes was used in 10.3% (for health-insured sufferers) to 24.3% (for Medicaid-“insured” sufferers) of all 1,125,119 or 721,986 months of treatment.7

The following drug classes were most frequently involved in combination medication:7

  • Unretarded stimulants: 70.0 %
  • Α2-adrenergic agonists (guanfacine, clonidine): 63.8 %
  • Stimulants with a half-day delay: 51.8 %

Another study found that around a quarter of children and adolescents with ADHD who received stimulants also received supplementary medication:8

  • Children: approx. 24 %
  • Young people: approx. 26.7 %

The most common additional medications given were

  • SSRI
    • Children: approx. 7.4 %
    • Young people: approx. 13.8 %
  • Atypical antipsychotics
    • Children approx. 4.8 %
    • Young people: approx. 5.8 %
  • Guanfacine
    • Children approx. 6 %
    • Young people: approx. 3 %

Barkley reports that the typical ADHD medications each address around 70 % of the same brain regions, but also respond to around 30 % of other brain regions. He therefore recommends combination medication in order to achieve a broader effect with fewer side effects.9

All the combinations or intake options described below are based on examinations or reports from affected persons, which were carried out in consultation with the attending physician. We expressly warn against unauthorized dosage or intake by those affected!

1. Methylphenidate preparations among themselves

It is possible to combine different methylphenidate preparations, especially retarded and unretarded, without any problems10
Unretarded MPH is particularly important for balancing the duration of action and adapting to particular stress situations. Unretarded MPH can extend the duration of action in the afternoon or early evening or bridge the time in the morning until the appropriate intensity of action of the sustained-release preparation is reached.11
One study found that 40% of adults with ADHD receive such a combination to extend daytime coverage.12 Similarly, Mason reports from his own medical practice that most of his adult ADHD patients take sustained-release stimulants, which typically last 8 to 10 hours, so most of them need additional unretarded medication to supplement to get through the day.13

Occasionally, (experienced) sufferers report that they cope better with 2 different half-day MPH retard preparations in the morning and in the early afternoon than with a repeated intake of the same retard preparation. These sufferers also often use unretarded MPH to extend their daily coverage.
It must be mentioned that the fine-tuning of such combinations is usually largely carried out by the patient themselves and requires that the attending physician recognizes the necessary sense of responsibility to accompany them in the adequate adjustment of medication. In the case of children, this is likely to be difficult, especially if taking the medication evenly throughout the day causes difficulties.

2. Amphetamine drugs among each other

The combination of different amphetamine medications is usually not used to improve symptoms or reduce side effects, but to provide better daily coverage.

Some sufferers report good experiences with a combination of Attentin (unretarded D-amphetamine) and retarded amphetamine (Elvanse). While Elvanse only releases the amphetamine bound to lysine very slowly via the intestine and blood, which can take up to 2 hours until the full effect sets in, Attentin is reported to have a noticeable onset of effect after around 15 minutes, which corresponds to unretarded MPH.

While Elvanse works for 10 to 11 hours after ingestion in most patients (a few patients report metabolization within 6 hours, individual cases even faster), Attentin has an effect time of around 5 hours.

Some sufferers have good experiences with taking a small dose of Attentin in the morning and taking Elvanse at the same time or a few hours later. Others report that taking Attentin in the afternoon or early evening helps them to get through a long day. As a rule, the Elvanse dose is reduced slightly after a previous Attentin dose.
In addition, many sufferers report that they cope best with two smaller doses of Elvanse taken at different times.

While many people affected by Elvanse report improved evening sleepiness and thus improved sleep behavior, if the sleepiness worsens and does not subside even after a few weeks, a change in the intake times should be considered in order to achieve an earlier end to the effective period.

3. Amphetamine medication and methylphenidate

Many sufferers report taking amphetamine medication and (especially unretarded) MPH at different times on the same day in consultation with their doctor. No negative experiences are known.
Here, too, the greatest significance of (unretarded) MPH lies in the delayed supplementation of the duration of action of the retarded amphetamine medication (Elvanse) early in the morning or in the evening.

In the (rather rare) cases in which MPH or AMP alone does not have a sufficient effect up to the usually acceptable daily doses, parallel administration of MPH and AMP is also possible.

There are also a number of medications that can support the effect of other medications for ADHD.

4. Guanfacine/clonidine in addition to stimulants

Guanfacine, which like clonidine is an α₂-adrenoceptor agonist, appears to be approved in some countries for combination medication with stimulants in ADHD,1415 and in children with ADHD who respond poorly to stimulants alone, together with stimulants improve symptoms significantly more than stimulants alone.

A meta-study found 16 studies that consistently reported greater improvement in ADHD symptoms with a combination of alpha-2 agonists with stimulants compared to monotherapy with alpha-2 agonists, but no greater improvement than with monotherapy with stimulants16
A larger randomized double-blind placebo-controlled study over 9 weeks in children with inadequate ADHD symptom improvement with stimulants showed significant improvements with additional guanfacine without additional side effects. Apparently, several publications cover the same study.171819
Several other studies also came to positive results of augmentative administration of guanfacine in patients with ADHD who were not optimally controlled with stimulants alone, in relation to children20 and in relation to children and adolescents.2122
Another double-blind placebo-controlled study on 50 children aged 6 to 12 with ADHD found an improvement in executive functions through individually optimized guanfacine administration in addition to the previous stimulants, without any additional side effects.23 A study on the effects of combined administration of guanfacine and MPH on the EEG in children with ADHD confirms the results.24
A randomized double-blind comparative study between monotherapy with MPH or guanfacine and a combination medication with MPH and guanfacine found a small but consistent benefit of combination therapy in reducing the inattentive subscale scores of ADHD-RS-IV and a greater responding rate than monotherapy. The combination therapy showed no serious cardiovascular events. Sedation, somnolence, lethargy and fatigue were greater with guanfacine monotherapy than with combination therapy. All treatments were well tolerated25

  • Guanfacine alone (symptom reduction of at least 50% in 68% of patients)
  • Methylphenidate alone (symptom reduction of at least 50% in 81% of those affected)
  • Combination medication of MPH and guanfacine (symptom reduction of at least 50% in 91% of patients)

Combined treatment with MPH and guanfacine showed greater improvements in working memory than placebo or guanfacine alone, but was not superior to monotherapy with MPH, even in other cognitive domains26
A combination therapy of MPH and guanfacine showed lower cardiovascular effects than a monotherapy of MPH or guanfacine.27

A randomized double-blind placebo-controlled study of adults with ADHD who had unsatisfactory improvements in their ADHD symptoms with stimulants and who were additionally augmented individually with 1 to 6 mg guanfacine showed a significant improvement in the guanfacine group and, surprisingly, also in the placebo group. There were no increased side effects.28 Two studies in healthy adults also found no complications with the combination medication of guanfacine with lisdexamfetamine (Elvanse) and MPH.2930 In one individual case, it was reported that augmenting clonidine was able to eliminate nocturnal teeth grinding induced by MPH.31
It would be interesting to see whether guanfacine/clonidine might also be able to reduce other tension-reducing actions (nail biting, lip biting) that sometimes occur as side effects with stimulants. An individual case report is not sufficient evidence for this.

One study came to a positive result of augmenting administration of clonidine with stimulants in ADHD.32 Nevertheless, guanfacine should be preferred today due to its lower side effect profile.

5. Atomoxetine in combination with other ADHD medications

5.1. Atomoxetine and stimulants

Although there is no official approval of a combination medication of atomoxetine and other ADHD-indicated drugs, a study7 found the use of such a combination medication in

  • 22.2% of those with health insurance aged 6 to 17
  • 9.8 % of those with health insurance aged 18 and over
  • 36.1% of those with Medicaid ADHD

Reviews and more recent studies report that the combined administration of atomoxetine and stimulants is safe and effective,3334 even during a medication change phase.35 One study reported on 824 patients who received a combination therapy of atomoxetine and methylphenidate.36 A meta-study found mixed results16

Ryffel-Rawak quotes a personal communication from J. Krause, according to which atomoxetine is particularly effective in combination with stimulants.37 Brown reports 4 cases in which only a combination therapy of atomoxetine with stimulants brought about an appropriate improvement in ADHD symptoms.38 Mason13 reports that when atomoxetine came onto the market in 2003, he switched 35 children with ADHD from stimulants to atomoxetine. In order to make the switch as smooth as possible, the previous stimulant dose was initially halved in a first step and supplemented with half the target dose of atomoxetine. After 14 days, the complete switch to the atomoxetine target dose took place in a second step. Surprisingly, around half of those affected asked to continue the combination of reduced stimulants and half the atomoxetine dose. This combination therapy proved to be very successful. Most of the patients significantly reduced their previous stimulant dose. Side effects were lower than in the patients who received stimulants alone. Those affected by the combination therapy reported in particular that family life had improved because the breakdowns, which many families already regarded as normal outside the stimulant treatment period, had decreased. This seems to us to be a plausible consequence of the fact that atomoxetine, as a peak medication, remains effective almost all day, whereas stimulants only have a limited time during the day.
Mason13 reports on a study conducted by Wilens at Harvard in 2006, in which high doses of atomoxetine and sustained-release MPH (Concerta) were combined in order to test the maximum possible reduction in symptoms. The patients who completed the study showed symptom reductions of more than 90 %. Their ADHD symptoms had disappeared and their attention was normal.
However, it was problematic that the high drug dosage used here triggered intolerable side effects in many patients, which was due to the study design, which was aimed solely at maximizing symptom improvement.

A review of 16 studies showed that a combination medication of atomoxetine and stimulants was usually given due to an unsatisfactory response to monomedication. In most cases, these were male children and adolescents with ADHD-C. A combination of atomoxetine with methylphenidate was reported most frequently. The combination medication improved the symptoms of some, but not all, of those affected. No serious adverse events were reported.39
Another study reports an improvement in symptoms through the additional administration of slow-release MPH in children with ADHD who did not show sufficient symptom improvement on atomoxetine.40 The fact that increased side effects occurred within the first 4 weeks of combination therapy (i.e. in the dosing phase of the additionally administered MPH),41 is not particularly surprising. More relevant is the side effect profile after the single-dose phase.
Another study also reported significant symptom improvements with a combination therapy of atomoxetine and methylphenidate compared to monotherapy.36

Mason13 reports from his own medical practice that most of his adult ADHD patients are on sustained-release stimulants, which typically last 8 to 10 hours, so most of them need additional non-released medications to supplement to get through the day.
In contrast, those patients in his practice who take a combination of atomoxetine with stimulants use low to moderate doses of stimulants and report a duration of effect of more than 12 hours.
Mason reports on individual cases:

  • In one case, the previous administration of 72 mg MPH per day (with an unsatisfactory symptom reduction of 25 %) was changed to 27 mg MPH and 60 mg atomoxetine per day. This resulted in an 80% reduction in symptoms, which persisted for many years without adaptation effects.
  • In another individual case, a reduction in amphetamine medication (Adderall) from 50 to 30 mg / day with simultaneous administration of 40 mg atomoxetine / day led to an improvement in symptom reduction to 67 %.
    A further improvement to 74% symptom reduction was achieved by switching from 50 mg Adderall to 50 mg Vyvanse (in the EU: Elvanse), which corresponds to 20 mg Adderall, while continuing the 40 mg atomoxetine.

Mason himself points out that not everyone affected experienced (such) improvements by switching to a combination therapy of atomoxetine and stimulants. Mason also refers to the experiences of other doctors who achieved comparable positive effects by supplementing stimulants with guanfacine, bupropion or antidepressants.13 A neurologist known to us often worked with a combination of stimulants and bupropion (due to the activating effect of bupropion mostly in ADHD-I, not in ADHD-HI or ADHD-C).

One study reports reduced discontinuation of medication when taking a combination of stimulants and atomoxetine compared to taking each alone.42 This may indicate a reduced rate of side effects.

Barkley reports in a lecture on the advantages of a combination of stimulants and atomoxetine to counteract the dampening of the limbic system caused by stimulants and the associated reduced perception of emotions.43

A study (albeit financed by the atomoxetine manufacturer Lilly) found no advantage in symptom improvement with a combination therapy of atomoxetine with other ADHD medications compared to monotherapy (possibly because the prescription was based on the individual needs of those affected by the treating physicians and was not the same for all test subjects in a group), but also no higher side effects than with monotherapy with atomoxetine (the figures do, however, show reduced side effects with combination therapy).44 It should be noted that atomoxetine alone generally has significantly higher side effects than stimulants alone.

Methylphenidate and atomoxetine increase the efficiency of the prefrontal pyramidal neurons, albeit via different mechanisms:45

  • Methylphenidate reduced non-specific signals, i.e. neuronal noise, via D1 receptors
  • Atomoxetine increased the strength of specific signals via the activation of alpha-2 receptors.
    This explains why a combination of these active substances can be useful for patients with ADHD who do not respond optimally to monotherapy.

According to our observations, a combination of atomoxetine and stimulants is a suitable method for the treatment of ADHD. It combines the advantages of atomoxetine (all-day effect, especially on the symptoms of emotional dysregulation) and stimulants (increased drive during the day). When combining ATX and amphetamine medications, it should be noted that both are metabolized via CYP2D6, which requires correspondingly lower doses. However, as the combination is aimed at the same symptoms, hardly any problems are to be expected here due to the mutual influence on metabolization

5.2. Atomoxetine and hopantenic acid

A Russian article describes benefits of augmentative administration of hopantenic acid (Phenibut, Pantogam) in children with ADHD.46 A single case report by the same lead author suggests similar results.47

Hopanteninic acid reduced the D2 receptor in mice slightly more than atomoxetine and also increased the GABAB receptor.48

Hopanteninic acid (N-pantoyl-GABA) is more commonly used in Russia for the treatment of ADHD. It is not approved in the USA and the EU.

The findings on hopantenic acid are too imprecise to recommend treatment with it.

6. Viloxazine next to MPH

A combination of viloxazine with methylphenidate is possible.49

7. Bupropion and stimulants

One neurologist we know often worked with a combination of stimulants and bupropion (due to the activating effect of bupropion mostly in ADHD-I, not in ADHD-HI or ADHD-C).
When combining bupropion with amphetamine medications, it should be noted that both are metabolized via CYP2D6, which requires correspondingly lower doses. However, as the combination is aimed at the same symptoms, hardly any problems are to be expected here due to the mutual influence on metabolization.
Several patients reported a positive effect of co-medication with bupropion in order to slow down a previously too rapid metabolism of amphetamine medication to an appropriate level.

8. MAO inhibitors and stimulants

A review on the co-medication of stimulants and MAO inhibitors in depression found no problems arising from this.50 One study reports successful co-medication of selegiline and lisdexamfetamine (Elvanse) for ADHD and comorbid depression51

With MAO inhibitors, possible metebolization cross-effects must always be taken into account.

9. MPH and tipepidine

Tipepidine (3-[di-2-thienylmethylene]-1-methylpiperidine) is a synthetic, non-opioid cough blocker (antitussive). Tipepidine increases dopamine levels in the nucleus accumbens by inhibiting GIRK channels, but without increasing motor activity or producing methamphetamine-like behavioural sensitization.
It has been used in Japan since 1959 and could be an interesting alternative to MPH and AMP due to its lack of stimulant properties.52

Tipepidine alone shows significant improvements in ADHD symptoms.53
A placebo-based double-blind study found a positive effect of tipepidine given in addition to MPH.54

10. Desipramine and stimulants

One study found no negative interactions of combination therapy with desipramine and stimulants.55

Desipramine is the active metabolite of imipramine. Desipramine medications are largely no longer available. Imipramine and MPH are known to interact with each other.

11. Antipsychotics alongside stimulants

A meta-study found evidence for a benefit of augmentative administration of risperidone or divalproex in comorbid aggression16

Contrary to basic research, studies have shown that co-medication with stimulants and antipsychotics can be more effective in the treatment of ADHD than taking stimulants alone. Nevertheless, this co-medication is uncommon in clinical practice.56 However, the improvement with a combination of thioridazine and MPH compared to MPH alone only lasted a few weeks and then remained at the level of MPH alone. While MPH was often associated with a lack of appetite, thioridazine showed an increase in appetite as a side effect.57 Atypical antipsychotics are said to have an even stronger effect in terms of weight gain and metabolic syndrome.58 An improvement in ADHD symptoms was already seen with low-dose neuroleptic augmentation of MPH.59
According to a registry study, 3.9% of children and adolescents with ADHD who received stimulants were augmented with atypical antipsychotics.60

The idea that stimulants significantly reduce the metabolic effect of antipsychotics has been refuted. However, there is no evidence to date of a consistent improvement through combination treatment with antipsychotics and stimulants compared to stimulant monotherapy. Comedication can be particularly helpful in cases of comorbid aggression when monotherapy with stimulants and a combination of stimulants with behavioral interventions have not been sufficient to treat aggression.61 One study reports that comedication of MPH and risperidone is particularly promising for comorbid conduct disorder (CD).62

While stimulants increase the dopamine level / the dopamine effect, i.e. have an agonistic effect, antipsychotics act as dopamine antagonists. This initially makes comedication seem contradictory and illogical. However, they act on different receptor subtypes and brain regions. The main effect of antipsychotics is a blockade of the mesolimbic D2 receptors, while stimulants increase synaptic DA in the mesocortical system. Presumably, the synergistic interaction between antipsychotics and stimulants is even more complicated, as both drugs also exert effects outside the brain regions mentioned.58

12. Combination medication with other substances

The active ingredients listed below are not prescription drugs. Like the additional administration of vitamins, minerals or polyunsaturated fatty acids, they can support the treatment of ADHD,

In the following, studies are presented that were explicitly prepared for combination therapy with stimulants. However, the administration of vitamins, minerals or polyunsaturated fatty acids in addition to stimulants is not subject to any particular concerns, but should only be carried out after prior testing of blood values, as an overdose of vitamins or minerals can have considerable harmful effects.

Vitamins, minerals, dietary supplements for ADHD

12.1. Resveratrol next to MPH

Resveratrol is an antioxidant.
A double-blind placebo-controlled study found positive effects of 500 mg resveratrol in addition to the MPH already given to children with ADHD in the parent evaluation, but not in the teacher evaluation.63

12.2. L-carnosine next to MPH

L-carnosine is a bioactive dipeptide consisting of the amino acids ß-alanine and histidine.
A double-blind placebo-controlled study found positive effects of 800 mg L-carnosine in addition to the MPH already given to children with ADHD in the parent evaluation, but not in the teacher evaluation.64

12.3. Zinc sulphate next to MPH

A double-blind placebo-controlled study on children with ADHD found positive effects of zinc sulphate, which was administered in addition to the MPH already given.65

12.4. L-methylfolate next to MPH

A study of augmentation of optimally adjusted MPH with 15 mg L-methylfolate in 44 adults with ADHD showed no improvement, but rather increased the need for MPH.66

13. Combination therapy with ADHD medication for comorbid disorders

To avoid duplicate presentation, see Choice of medication for ADHD or ADHD with comorbidity


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