Medications for ADHD - Overview

All of the medications described here should always be prescribed only by experienced physicians. Our comments are intended solely to serve as a starting point for a personal consultation with your doctor.

Since ADHD symptoms are overwhelmingly attributable to the dopaminergic and noradrenergic systems, a combination of dopaminergic and noradrenergic medications is recommended.¹²³⁴⁵

Unfortunately, medications for ADHD do not have a curative effect. They merely correct neural dysfunction—much like glasses that correct an existing vision problem as long as they are worn.

Between October 2021 and August 2022, 21.5% of parents whose children were between the ages of 7 and 17 and were attending school (average age 12, 75% boys), and who had received an administrative ADHD diagnosis in 2020, participated in an online survey. Approximately 40% reported currently receiving ADHD treatment (not necessarily medication):⁶

• 76% of parents were satisfied with the treatment. Of those,
  • 36.8% found the treatment to be very effective
  • 49.6% found the treatment to be somewhat effective
  • 11.3% found the treatment to be barely effective
  • 2.3% found the treatment to be completely ineffective
• Children with more severe ADHD symptoms were three times more likely to receive treatment.
• Adolescents from immigrant backgrounds were less likely to receive psychological care.

1. Medications That Affect the Stress Response¶

By “influencing the stress response,” we do not mean sedative or other general effects, but rather the effects of medications on the response of stress regulation systems.

1.1. Anxiolytics¶

Anxiolytics (anti-anxiety medications) generally reduce the reactivity of stress systems even with a single dose.⁷

1.2. Antidepressants¶

Single doses of antidepressants have effects on the stress systems that are partly inhibitory and partly stimulatory.⁷

1.3. Stimulants¶

A stimulating effect alone is not sufficient for a drug to be effective in treating ADHD. For example, although pseudoephedrine and ephedrine are stimulants, they are ineffective in treating ADHD. Furthermore, L-methylphenidate is six times as stimulating as D-MPH, yet only D-MPH is effective for ADHD.⁸

1.3.1. Stimulants and Stress Resistance¶

Stimulants increase the responsiveness of the body’s stress systems.⁷
Stimulants are capable of bringing the attention control of people with ADHD in line with that of non-people with ADHD by increasing their level of motivation.⁹ This could (partly) explain why stimulants are just as helpful for ADHD-HI and ADHD-C as they are for ADHD-I. For more information on the altered function of the DMN in ADHD and its normalization through stimulants, along with additional references, see ⇒ DMN (Default Mode Network) In the article “ ” ⇒ Neurophysiological Correlates of Hyperactivity.

1.3.2. Stimulants and Emotions¶

In a lecture, Barkley¹⁰ explained that stimulants can dampen emotions by inhibiting the limbic system. The higher the dosage, the more the limbic system (including the amygdala) is inhibited. This naturally reduces emotional responses.
Taking too high a dose of stimulants therefore leads to a narrowing of emotional range.
He goes on to report that, for this reason, combination therapies are being used more and more frequently to preserve the major benefits of stimulants while limiting their drawbacks.

1.3.3. Long-Term Adherence – Stages of Medication Use¶

It is often observed that people with ADHD stop taking stimulants a few years (approximately 1.5 to 3 years) after they were first prescribed. A few years later (about 4 to 6 years after the initial prescription), there is another increase in usage.¹¹

Our hypothesis is that this return to increased intake could possibly be mediated, among other things, by the following mechanism:

Stimulants have been shown to increase neuroplasticity by raising levels of dopamine and other neurotrophic factors. This enables better learning (i.e. knowledge acquisition) and better adaptation to experiences—specifically, the internalization and automation of functional behaviors as an adaptive process in response to environmental experiences. For more on this, see ⇒ Neurophysiological Correlates of Learning Difficulties in ADHD.
Taking stimulants now makes it possible to adapt functional behaviors to current demands.
If this adaptation has occurred sufficiently after a few years, a short-term discontinuation of stimulants will not lead to immediate behavioral deficits, since the currently stored behavioral patterns are now adapted to the current environment and therefore continue to function at the moment even without medication.
However, if medication is not taken consistently, the behavioral adjustments that are always necessary to meet new environmental demands do not occur. As environmental demands gradually change, the stored behaviors—which were optimized for earlier environmental demands—become increasingly dysfunctional. Once the difficulties have reached a certain level again, the psychological distress serves as a reminder that the medication was very effective in alleviating these difficulties at the outset, leading to a resumption of medication use.

The self-reported reasons parents give for stopping medication often include a distrust of medication (concerns about side effects, weight loss, growth delays), whereas people with ADHD cite entirely different motives, namely the desire to develop freely without medication.¹²

2. Dopaminergic medications¶

Dopaminergic medications play a leading role in the treatment of ADHD, as most symptoms are caused by a deficiency of dopamine (or its effects) in the dlPFC and striatum.

In addition to psychotherapeutic interventions, dopaminergic medications offer the added benefit of increasing the brain’s neuroplasticity, thereby enhancing the effectiveness of therapy or establishing the capacity for therapy.¹³
About 5% of dopamine is metabolized into norepinephrine, so dopaminergic medications always have a (albeit minor) noradrenergic effect as well.¹³¹⁴

Dopaminergic medications target the anterior attention center.
⇒ The dopaminergic and noradrenergic attention centers.

3. Noradrenergic medications¶

Norepinephrine is produced in the locus coeruleus and, among other things, regulates the posterior attention center in the parietal cortex.
⇒ The dopaminergic and noradrenergic attention centers.

3.1. Medications that increase norepinephrine levels¶

Norepinephrine reuptake inhibitors inhibit the norepinephrine transporter (NET). Although the NET generally reabsorbs primarily norepinephrine—thereby increasing the amount of norepinephrine available in the synaptic cleft— In the PFC, however, it reabsorbs more dopamine than norepinephrine, so norepinephrine reuptake inhibitors primarily exert dopaminergic effects in the PFC in the context of ADHD.

Pure norepinephrine reuptake inhibitors are the “second-line” treatment alongside stimulants with dopaminergic and noradrenergic effects. However, they may supplement treatment with MPH when appropriate.
MPH, amphetamine-based medications, and atomoxetine each have dopaminergic and noradrenergic effects; however, atomoxetine exerts noradrenergic and dopaminergic effects only in the PFC, whereas MPH also exerts dopaminergic effects in the striatum.
⇒ Atomoxetine works differently than MPH

3.2. Effects of Noradrenergic Medications¶

People with ADHD subjectively describe the effect of noradrenergic medications as widening the “green zone” between being underchallenged (which causes the person with ADHD to mentally tune out) and being overwhelmed (which drives the person with ADHD into a state of stress). A sense of balance increases. Emotional outbursts (outbursts of anger, emotional overreactions) decrease.

Noradrenergic medications improve ADHD symptoms

• Emotional outbursts (outbursts of anger)
• emotional impulse control
• Alertness
• Vigilance

Dopaminergic medications cannot directly affect these symptoms (if at all, it is through norepinephrine, which is produced when dopamine is broken down).
Amphetamine-based medications are also said to be helpful in this regard.¹⁵

An augmentative, optimally adjusted regimen with noradrenergic medications can subjectively double the benefits provided by methylphenidate. (Some) people with ADHD report that an optimally adjusted dosage, in combination with stimulants, completely eliminated their ADHD symptoms. Unfortunately, this effect was temporary, suggesting receptor up- or downregulation (see 2.4.).

3.3. Onset of action of noradrenergic medications¶

Primarily noradrenergic medications generally need to be administered for 2 to 3 weeks before they take effect.
Noradrenergic medications should be tapered off gradually over the same period of time to prevent depression.
Because of the slow response to a new dosage, noradrenergic medications should not be increased, skipped, or discontinued on short notice.
The onset of action is similar to that of medications that inhibit serotonin reuptake

3.4. The Long-Term Effects of Noradrenergic Medications Are Problematic¶

The effects of noradrenergic medications may diminish slightly over time (unlike those of stimulants).

We suspect that most noradrenergic medications have a tonic effect, meaning they cause a long-term increase in NE levels. However, ADHD symptoms improve only with a transient increase in norepinephrine levels. A tonically elevated NE level is actually counterproductive.¹⁶
Many people with ADHD have reported a short-term positive effect from noradrenergic medications (e.g., nortriptyline), which took effect after just the first few tablets but wore off after a few days. Some individuals have also reported this as an individual reaction to atomoxetine.

This is followed by Scheidtmann’s observation that noradrenergic medications (e.g., antidepressants) do not help with motor rehabilitation when used as long-term medication, since tricyclic antidepressants permanently stimulate the noradrenergic receptors, causing the receptors to lose their sensitivity (particularly with regard to learning processes).¹⁷
This is consistent with the experience regarding the use of noradrenergic tricyclic antidepressants for ADHD. It is often reported that patients respond very well initially, but that this response diminishes with continued medication.

While dopaminergic medications can be discontinued on an hourly or daily basis as needed, or their dosage increased temporarily, without any problems, this is not recommended for noradrenergic medications. Noradrenergic medications carry a risk of depression if taken in excessive doses or if the dosage fluctuates erratically.

A clearly structured daily routine, with a sensible balance between activity and breaks, is intended to train the noradrenergic system and help restore normal norepinephrine production.¹⁸

3.5. Contraindications¶

Benzodiazepines reduce activity in the locus coeruleus, thereby decreasing the production and transport of norepinephrine to other parts of the brain. For this reason, they should generally be contraindicated for ADHD. Surprisingly, however, they are helpful in the short term; nevertheless, due to their massive potential for dependence—which sets in after just 14 days at standard dosages—they should not be prescribed. MPH and amphetamine-based medications, on the other hand, do not carry a risk of dependence.

In addition, there are other secondary effects and interactions.

4. Serotonergic medications¶

To date, there are no serotonergic medications that are effective for ADHD with acceptable side effects.¹⁹

4.1. General Information About SSRIs¶

4.1.1. Onset of action of serotonergic medications¶

Although serotonergic medications alter serotonin levels very rapidly, they generally need to be taken for 2 to 3 weeks before they take effect. It can therefore be assumed that serotonin levels themselves do not mediate the actual effect.

Serotonergic medications should be tapered off gradually over at least the same period of time to avoid side effects. According to other reports, the process of tapering off serotonergic medications can take more than half a year. We have now received numerous reports from people with ADHD who derived little benefit from antidepressant medication but who suffered severe side effects—particularly when discontinuing antidepressants—that were many times more severe than the side effects of ADHD medications.

Because of the slow response to changes in dosage, serotonergic medications should not be increased, skipped, or discontinued on short notice.

4.1.2. SSRIs and σ-receptors¶

SSRIs sorted in descending order by binding affinity to the σ1 receptor:

• Fluvoxamine²²
  • less affinity, but highly selective for the serotonin transporter
  • Sigma-1 agonist
    • addresses cognitive impairments typical of depression²²
    • improves psychotic symptoms²²
    • enhances nerve growth factor-induced neurite growth in PC12 cells²²
• Sertraline²²
  • Sigma-1 antagonist
    • addresses cognitive impairments typical of depression²²
    • worsens psychotic symptoms²²
    • reduces nerve growth factor-induced neurite growth in PC12 cells²²
• Fluoxetine²²
• Citalopram²²
  • Escitalopram is the active S-enantiomer of racemic citalopram.²³
• Paroxetine (virtually no binding)²²
  • Paroxetine also has anticholinergic effects
    This can lead to difficulty concentrating and forgetfulness²²

4.1.3. Single doses of SSRIs increase anxiety and the risk of panic attacks¶

Single doses of escitalopram increase the risk of panic attacks.²⁴ Anxiety and tension were also increased by a single dose of chlorimipramine/chlomipramine/clomipramine, a tricyclic antidepressant that acts primarily as a serotonin reuptake inhibitor²⁵, but also acts as an antagonist of the histamine H1 receptor, the muscarinic acetylcholine receptor, and the A1 adrenoceptor.²⁶

4.1.4. SSRIs Increase Oxytocin Levels¶

SSRIs increase blood levels of oxytocin. This may account for some of the antidepressant effects of SSRIs.²⁷

4.1.5. SSRIs require histamine¶

An intact histamine system is necessary for the antidepressant effect of SSRIs.²⁸

4.1.6. Antidepressants work via PPARα¶

Fluoxetine (SSRI) ²⁹, venlafaxine (SNRI)³⁰, and reboxetine (NRI) ³¹ rely (in part) on PPARα for their antidepressant effects.

4.2. Notes on Selective Serotonin Reuptake Inhibitors (SSRIs) for ADHD¶

SSRIs (selective serotonin reuptake inhibitors) should be used with caution in cases of ADHD.
Clinical evidence does not support the effectiveness of selective serotonin reuptake inhibitors (SSRIs) in treating the core symptoms of ADHD. ³²

4.2.1. The Difference Between Dysphoria as a Common Symptom of ADHD and Depression That Requires Treatment¶

Many clinicians do not recognize dysphoria associated with inactivity as a primary symptom of ADHD; instead, they confuse it with dysthymia or depression and therefore treat people with ADHD inappropriately, as if they had true depression.
However, dysphoria associated with inactivity is a functional stress symptom (the drop in mood during inactivity is intended to encourage the person with ADHD to remain active until the stressor is overcome) and is typical of ADHD. It is not a symptom of dysthymia or depression.
Differential Diagnosis of Depression and Dysphoria Associated with Inactivity ⇒ Depression and Dysphoria in ADHD.

In practice, it has been shown that treatment with a significantly reduced dose of escitalopram (compared to its use as an antidepressant) can improve dysphoric mood. In this context, doses of 2 to 5 mg per day may already be sufficient (instead of 10 to 20 mg as an antidepressant).
However, simply switching ADHD treatment from methylphenidate to amphetamine-based medications (Vyvanse) often provides a fully adequate improvement, and this approach is therefore strongly preferred.
Unlike in ADHD-HI, treatment of dysphoria with SSRIs should be avoided in ADHD-I. In ADHD-I, SSRIs should only be considered in cases of severe depression.

4.2.2. SSRIs Do Not Improve Attention¶

Unlike stimulants, selective serotonin reuptake inhibitors do not improve cognitive abilities. In a cohort study of n = 766,244 participants, a significant improvement in test scores was observed among people with ADHD who were taking stimulant medication. Selective serotonin reuptake inhibitors, on the other hand, had no effect on test scores.³³³⁴

4.2.3. SSRIs increase DAT activity¶

Citalopram and escitalopram (15% to 17% increase in DAT activity)³⁵³⁶ (+20% DAT binding with escitalopram)³⁷ appear to enhance DAT activity^{3839 40} , which would be detrimental in ADHD.
The same is known to be true of paroxetine (10% increase in DAT).³⁸⁴¹
Venlafaxine increased DAT binding.⁴²

Sertraline, on the other hand, appears to inhibit the DAT, which should be helpful for ADHD.
No increase in DAT activity has been observed with bupropion³⁸, and fluoxetine.

If there are also sleep problems (as is often the case with ADHD), medications that increase serotonin levels are also said to be harmful.⁴³

4.2.4. SSRIs increase the cortisol stress response: beneficial in ADHD-HI, detrimental in ADHD-I¶

Escitalopram at a higher dose (20 mg)—but not at 10 mg—increases the cortisol response to acute stress.²⁴⁴⁴ Similar findings have been reported for other SSRIs ⁴⁵ as well as for the administration of tryptophan, a serotonin precursor.⁴⁶

At both 10 and 20 mg, escitalopram did not increase anxiety either before or during a stress test, but it did prolong it afterward.²⁴

When treating comorbid depression in ADHD, it is essential to be aware that an increase in the cortisol response to stress may be beneficial for people with ADHD-HI (who often have a blunted cortisol response, which prevents the HPA axis from shutting down), but may be detrimental from this perspective in people with ADHD-I (who very often have an excessive cortisol response).

Nevertheless, it is unclear whether the long-term effects of SSRIs (escitalopram)—which normalize HPA axis activity in approximately 50% of people with depression—are also effective for the ADHD-I subtype.

• The Depression League recommends SSRIs, particularly for atypical depression⁴⁸, which, like the ADHD-HI subtype, represents an externalizing form of stress expression and correlates with a blunted cortisol stress response.
• The Handbook of Psychopharmacotherapy ⁴⁹ notes that in cases of severe (here: melancholic) depression (which, like the ADHD-I subtype, exhibits an internalizing stress phenotype with an excessive cortisol response to an acute stressor), treatment with tricyclic antidepressants (primarily amitriptyline and clomipramine) or SNRIs (in this case, duloxetine and venlafaxine) is superior to treatment with SSRIs.⁵⁰⁵¹
• The suboptimal efficacy of SSRIs is further discussed in the section on the SSRI sertraline, which is said to be more effective than other SSRIs in treating severe melancholic depression.⁵²
• Ritzmann also expresses criticism of SSRIs for treating melancholic depression in Schweizerische pharma-Kritik.⁵³

4.2.5. SSRIs for Impulsivity Problems in ADHD-HI¶

In one specific case, we observed a positive effect on impulsivity issues, such as those typically seen in ADHD-HI. Neurophysiologically, impulsivity correlates with low serotonin levels. Even a very low dose of escitalopram (2 to 5 mg—compared to 10 to 20 mg/day when used as an antidepressant ⁵⁴) can help reduce impulsivity, which may allow for a reduction in the dosage of concomitantly administered stimulants.

Impulse purchases, as they occur primarily in ADHD-I, could, in our view, be attributable instead to a craving for immediate reward and be attributed more to spontaneous gratification of needs (as is also the case with addiction) than to externalizing impulsivity induced by low serotonin levels.

4.2.6. SSRIs Do Not Improve ADHD Symptoms¶

SSRIs showed no effect on ADHD.⁸⁵⁵
In a large-scale double-blind study of the serotonergic antidepressant vortioxetine, no improvement in ADHD symptoms was observed after 6 weeks compared with placebo.⁵⁶

The updated European consensus on the diagnosis and treatment of ADHD in adults logically concludes that SSRIs are not effective in treating ADHD.⁵⁷

We are aware of reports from numerous people with ADHD who have taken SSRIs. None of them experienced a positive effect on their ADHD. Overall negative effects were frequently reported.
Particularly problematic is the fact that it takes several weeks for any (antidepressant) effects to become apparent, and even more so the sometimes significant side effects associated with tapering off the medication, which in some cases require a very gradual tapering process (especially with venlaflaxin).

One hypothesis is that the use of SSRIs for ADHD could be enhanced by combining them with 5-HT1A antagonists. The authors explain that the inhibitory somatodendritic 5-HT1A autoreceptors, which reduce the firing rate of 5-HT neurons, are desensitized only after long-term SSRI treatment. The authors speculate that previous studies did not observe medication use over a sufficiently long period and point to pharmacological studies in animal models in which the effect of SSRIs was successfully enhanced by antagonizing the inhibitory 5-HT1A autoreceptors prior to the administration of the SSRI fluoxetine.⁵⁸
However, this hypothesis is contradicted by the fact that even cohort studies examining long-term medication use have found no improvement in attention with SSRIs.

4.2.6. SSRIs and Stimulants: Risk of Serotonin Syndrome¶

A combination of SSRIs and stimulants should be used with caution due to the risk of serotonin syndrome.⁵⁹
However, at normal dosages, the serotonergic effect of stimulants is limited.

Serotonergic mechanisms:⁶⁰

• Increases serotonin synthesis
  L-tryptophan
• Increases serotonin release
  • Amphetamines
    • only slightly effective for medication dosing
  • Cocaine
  • Methadone
  • Mirtazapine
• Serotonin reuptake inhibition
  • SSRI
  • SNRI
  • TZA
    • particularly clomipramine
  • St. John’s wort
  • Methadone
  • Pethidine
  • Tramadol
  • Fentanyl
  • Dextromethorphan
  • Buprenorphine
  • Tilidine
• Inhibition of serotonin breakdown
  • MAO inhibitors
  • Linezolid
  • Methylene blue
  • Procarbazine
• Direct serotonin agonists
  • Buspirone
  • Triptans
  • Ergotamines
  • LSD
• Increased serotonin receptor sensitivity
  • Lithium

Serotonin syndrome can result from an overdose of serotonergic medications, from a combination of multiple serotonergic medications, from cross-metabolism interactions, or from interactions with opioids. It usually becomes apparent within 24 hours and typically subsides 24 hours after discontinuing the triggering medication.
The severity of symptoms can vary greatly.
Possible symptoms:⁶¹⁶²⁶⁰

• Central nervous system symptoms
  • Agitation, restlessness, nervousness
  • Confusion
  • Hypomania
  • Impaired consciousness
  • Coma
  • Anxiety
  • Startle response
  • Delirium with confusion
  • Somnolence
• Autonomic-vegetative symptoms
  • rapid heartbeat
  • High blood pressure
  • high body temperature, fever
  • Sweating
  • Chills
  • Nausea, vomiting
  • Diarrhea
  • Abdominal pain
  • Pupil dilation
• Neuromuscular symptoms
  • Improved reflexes
  • Tremor
  • Ataxia
  • Tremors
  • Myoclonus (muscle twitching)
  • Muscle spasms
  • Muscle stiffness / Seizures
  • Clonus (a series of reflex muscle contractions following a stretch stimulus)

5. The Effect of Antidepressants on Depression¶

For general information on this topic, see the article Depression and Dysphoria in ADHD and, more specifically, under

• Effect of SNRIs on Depression via Corticosteroid Receptors *
• (Some) antidepressants work by inhibiting S-ASM (FIASMA)

6. Notes on Tricyclic Antidepressants for ADHD¶

Tricyclic antidepressants are considered the fifth-line choice of medication for ADHD. Tricyclic antidepressants have a very broad spectrum of action. They typically also

• noradrenergic
  • as a norepinephrine reuptake inhibitor (fairly potent)⁶³
• dopaminergic
  • as a dopamine reuptake inhibitor⁶⁴

In numerous double-blind, placebo-controlled studies involving children and adults, tricyclic antidepressants have demonstrated results equivalent to those of stimulants in treating hyperactive-impulsive behavior.^{653 66 67} Combination therapy with stimulants and tricyclic antidepressants may be more effective than monotherapy, particularly for hyperactivity, inattention, and oppositional symptoms; however, regular cardiac examinations must be ensured.⁶⁸

TZA should be administered in cases of non-response from

• both types of stimulants (methylphenidate and amphetamine-based medications)
• Guanfacine
• Atomoxetine

be a last choice of medication.

Tricyclic antidepressants are traditionally effective for comorbid anxiety, depression, and dysphoria. Imipramine is recommended for comorbid bedwetting (enuresis).⁶⁹

Another brief summary of studies on tricyclic antidepressants and other non-stimulant medications for ADHD-HI can be found in Budur et al. 2005.⁷⁰

During treatment with tricyclic antidepressants, regular monitoring of the ECG, blood pressure, and heart rate is required.³

Certain tricyclic antidepressants (trimipramine) and similar antidepressants (trazodone) have proven to be highly effective for treating sleep problems associated with ADHD. Unlike conventional sleep aids, they do not carry a risk of dependence.

7. General Information on Antipsychotics for ADHD¶

7.1. Dopaminergic Effects of Antipsychotics¶

Neuroleptics/antipsychotics act as D2 receptor antagonists, meaning they block the D2 receptor. However, they are not able to normalize the presynaptic increase in dopamine release associated with psychosis or schizophrenia; rather, they block the postsynaptic D2 receptor. This blockade is reversible—that is, it has a certain half-life—so the medication must be taken at regular intervals. Second-generation atypical antipsychotics appear to exert a blocking effect in the temporal cortex, while typical antipsychotics do so in both the temporal cortex and the striatum (Stone et al. 2009).⁷¹
Secondarily, however, antipsychotics also appear to act on D2 autoreceptors, thereby stimulating dopamine release⁷²⁷³
This is considered an adverse side effect in the treatment of psychosis with antipsychotics, so it can likely be assumed to be a secondary effect.

In addition to blocking D2 receptors in the limbic system, atypical antipsychotics are also thought to stimulate D1 receptors in the prefrontal cortex (PFC), which is why they can be effective as ADHD medications in exceptional cases.⁷⁴

At first glance, antipsychotics/neuroleptics are likely to be of little help in treating ADHD—from a dopaminergic perspective—since they primarily aim to reduce dopamine activity, whereas ADHD is characterized precisely by a dopamine deficiency. The benefit for ADHD would likely stem from a side effect that occurs as an adverse reaction during the treatment of psychoses.
A study found that antipsychotics are prescribed off-label for ADHD primarily in relation to comorbid behavioral disorders, but barely in relation to ADHD itself.⁷⁵
The mechanisms of action of stimulants and antipsychotics are potentially contradictory. A closer examination of dopamine pathways and dopamine receptors confirms concerns about interactions. A study examines the efficacy of concurrent use for several indications, particularly with regard to comorbid ADHD and aggression. A model of complex dopamine mechanisms could explain this dilemma and suggest approaches for the concurrent use of stimulants and antipsychotics.⁷⁶

7.2. α-Adrenergic effects of antipsychotics¶

Antipsychotics (D2 antagonists) are nevertheless believed to have a positive effect on ADHD at low doses, even though they reduce dopamine uptake. The most common off-label use of antipsychotics (25%) is for ADHD.⁷⁷ However, the effect (at low doses) on ADHD is not attributed to dopaminergic action, but rather to the blockade of the α-adrenergic receptor (antagonism), which positively stimulates the release of dopamine in the nucleus accumbens as well as dopamine uptake.⁷⁸⁷⁹⁸⁰

 

8. Monoamine oxidase inhibitors (MAO inhibitors)¶

Monoamines are

• Catecholamines
  • Dopamine
  • Norepinephrine
  • Adrenaline
• Serotonin
• Melatonin
• Histamine
• Thyronamin
• Trace amines
  • β-phenylethylamines
  • Tyramine
  • Tryptamine

Monoamine oxidase (MAO) catalyzes the breakdown of monoamines through deamination.
Monoamine oxidase inhibitors reduce the breakdown of monoamines, thereby increasing their availability.

MAO-A breaks down norepinephrine and serotonin in the brain and intestines. MAO-B breaks down dopamine in the brain and liver. MAO-A catalyzes the breakdown of dietary tyrosine peripherally, primarily in the intestines, while MAO-B catalyzes the breakdown of tyrosine in the liver. Together, they prevent dietary tyrosine from being converted into monoamines in the body.⁸⁵
Tyrosine is a precursor for the biosynthesis of DOPA, dopamine, catecholamines, melanin, thyroxine, and tyramine.
Because MAO has a peripheral tyrosine-degrading effect, a low-tyrosine diet (e.g., no cheese, no red wine) must be followed when taking irreversible MAO inhibitors. Otherwise, too much tyrosine would be broken down in the body, leading to elevated levels of the resulting breakdown products. Risk: heart problems, among other things.

MAO inhibitors:

• Selegiline
  • irreversible MOA-B inhibitor.
    “Irreversible” means that MAO must first be resynthesized before it can take effect again.
• Moclobemide
  • reversible selective MAO-A inhibitor.
    “Reversible” means that the effect is not permanent.
• Tranylcypromine
  • irreversible inhibitor of MAO-A and MAO-B
• Greek mountain tea (Sideritis scardica) appears to act as an MAO inhibitor with regard to dopamine, norepinephrine, and serotonin.⁸⁶

9. Drug Tolerance and High Sensitivity in ADHD¶

Based on our observations and the data from the ADxS symptom test, ADHD always involves high sensitivity, which can sometimes be very pronounced.
Highly sensitive people (even those without ADHD) are more likely to have adverse reactions to medications, and these reactions can sometimes be paradoxical.

Examples:

• Pain relievers can
  • have no effect at all
  • effective even at the lowest dosage
• Sedatives can cause agitation
• Anesthetics can have unexpected effects
  We have heard of cases in which anesthetics are said to be effective at significantly lower doses. There is therefore a risk of overdose. We would appreciate it if anesthesiologists could share their relevant experiences with us.
• Caffeine may have a more intense effect (especially when taken with methylphenidate)
• Nicotine can make you feel tired instead of energizing you
  A person with ADHD reported that his bedtime ritual consists of two cigarettes or a cigarillo. Afterward, he has 20 to 30 minutes during which the nicotine makes him feel sleepy and he can fall asleep easily.
• A low dose of stimulants (1/3 to 1/2 of a single daily dose) helps many people with ADHD fall asleep by counteracting racing thoughts

10. Drug Interactions Involving ADHD Medications¶

With ADHD medications (especially tricyclic antidepressants, MAO inhibitors, and medications that target the alpha-2 adrenoceptor), drug interactions are unfortunately common and must be taken into account.

One cross-reaction of stimulants that receives far too little attention involves caffeine. About half of all people with ADHD experience cross-effects from caffeine when titrating stimulants; these can feel like a stimulant overdose or significant stimulant side effects, even if caffeine alone was previously tolerated without any issues. Therefore, caffeine should be strictly avoided during the titration process. Once titration is complete, caffeine is less dangerous even if the same cross-reactions occur, because the cross-reactions can then be easily attributed to the caffeine. People with ADHD who report that they “cannot tolerate” stimulants and who did not consistently avoid caffeine during the titration process should consider a new—slow—titration process without caffeine.

A fairly comprehensive discussion of drug interactions involving ADHD medications, as well as precautions to take when prescribing and taking these medications, can be found in Steinhausen et al.⁸⁷

Norepinephrine Reuptake Inhibitor Treatments. In: Barkley RA (Herausgeber): Attention-deficit hyperactivity disorder: A handbook for diagnosis and treatment. 3rd edition. THE GUILFORD PRESS