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Amphetamine medication for ADHD

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Amphetamine medication for ADHD

In the U.S., amphetamine medications are available as:1

  • Mixture of D- and L-isomers (racemic mixture)
  • Mixed sulfates and saccharinates of D-L isomers
  • Pure D-amphetamine sulfate
  • Racemic methamphetamine sulfate

In Germany, amphetamine medications had to be manufactured from raw substances by pharmacists for a long time.2 Since 2011, a D-amphetamine has been available in Germany as a finished drug and approved for the treatment of ADHD (Attentin), and since 2013, a D-amphetamine has been approved as lisdexamfetamine in lysine-bound form (Elvanse) for the treatment of children. As of May 2019, Elvanse Adult has been approved for the treatment of ADHD in adults.

In Austria, Elvanse can be prescribed if other drugs are ineffective or show side effects. The physician must justify this to the insurance company.

Amphetamine medications work slightly better than methylphenidate and show slightly fewer side effects.
Amphetamine drugs are according to the current European consensus the ADHD drug of first choice in adults (before methylphenidate), and in children and adolescents the drug of second choice (after methylphenidate)34 While the current text of the S3 guideline of 2017 still states, that lisdexamfetamine can only be used in accordance with the approval after prior treatment with MPH5, in 2019 the S3 guideline is quoted as stating that treatment with psychostimulants is recommended as the first option for adults with ADHD, including methylphenidate and lisdexamfetamine, which are approved for adults.67

Due to the responder/nonresponder profile differing from MPH, amphetamine medications are particularly suitable for ADHD sufferers who do not respond to MPH, clearly before the use of non-stimulants (e.g., noradrenergic medications or tricyclic antidepressants).8 A summary of several studies reported 69% response rate to amphetamine medication, 59% response rate to methylphenidate. 87% of those affected would have responded to either type of drug.9

Amphetamine drugs are also suitable for the co-treatment of comorbid dysphoria or depression, unlike MPH.1011

All amphetamine drugs work equally well in adults, according to a Cochrane study, regardless of the specific drug form.12 This distinguishes amphetamine medications from methylphenidate, where even a switch to another methylphenidate preparation shows significant individual differences.

1. Active ingredients of amphetamine drugs

Relevant to ADHD treatment are:

1.1. Dextroamphetamine (D-amphetamine)

Dextroamphetamine is also called dexamphetamine or dextroamphetamine sulfate.
Dextroamphetamine is the dextrorotatory (D) enantiomer of amphetamine, opposite the levorotatory levoamphetamine (see below).

D-amphetamine drugs act 3 to 4 times more strongly on the central nervous system than racemic amphetamine drugs, with less sympathomimetic effect in the periphery, which is why D-amphetamine drugs are preferred in ADHD treatment.13
D-amphetamine is more potent than L-amphetamine only with respect to dopamine transporters, while the effect on norepinephrine transporters is about the same.14

This opens the possibility of emphasizing dopaminergic (dexamphetamine) or balanced dopaminergic and noradrenergic (levoamphetamine) medication.

D-amphetamine was said to be more activating compared to MPH and therefore preferable for ADHD-I.15
It is also often more effective than MPH in parallel dysthymia/dysphoria/depression due to its noticeable serotonergic effect16.

1.1.1. D-amphetamine without lysine binding

Trade name: Attentin (D since end of 2011), Dexamin (Switzerland: as extemporaneous formulation), Dexedrin

The duration of action is about 6 hours, so that a 2x daily intake is usually necessary.
Increased abuse potential due to lack of lysine binding.

1.1.2. D-amphetamine as lisdexamfetamine (with lysine binding)

Lisdexamfetamine is D-amphetamine that is combined with lysine to form a substance that is ineffective in itself. Lisdexamfetamine is thus a prodrug, i.e. an active ingredient that is only converted into the actual active substance, in this case D-amphetamine, in the intestine. This means that there is a very low risk of abuse.17
The conversion is also very slow (duration of action: 11 to 13 hours).
Since the effect is very uniform throughout the day, the unpleasant rebound effects known from MPH (short-term increased restlessness at the end of the effect) do not occur.
The effect is equivalent to D-amphetamine. A conversion table from dexamphetamine to Elvanse can be found at ADHSpedia.18

Trade names:

  • Elvanse (EU, since late 2013, for children, 20, 30, 40, 50, 60, 70 mg)19
  • Elvanse Adult (EU, since 01.05.19, for adults, 30, 50, 70 mg)19
  • Vyvanse (USA) is available in doses ranging from 10 mg to 70 mg20

Elvanse and Elvanse Adult are the same medication and therefore interchangeable (with health insurance approval).

1.2. Levoamphetamine (L-amphetamine)

Levoamphetamine (L-amphatemin) is the pure levorotatory isomer of amphetamine.

L-amphetamine is less potent than D-amphetamine with respect to dopamine transporters, while the effect on norepinephrine transporters is about the same.14

We are not aware of any L-amphetamine ready-to-use drug approved in Europe. It would have to be manufactured on an individual prescription in pharmacies.

1.3. Mixed amphetamine salts / amphetamine derivatives

  • Aderall (USA): 75% dextroamphetamine and 25% levoamphetamine
  • Evekeo (USA): 50% dextroamphetamine and 50% levoamphetamine

(1.4. Fenetylline)

  • Captagon (in D until 2003; in Belgium until 10); no longer available today

2. Amphetamine drugs work differently and in different parts of the brain than methylphenidate

Amphetamine medications have a more complex mechanism of action than methylphenidate.
The presentation of the effects of amphetamine drugs is contradictory.

It is sometimes argued that amphetamine drugs only inhibit dopamine reuptake and release dopamine and noradrenaline. More well-founded representations from the USA (where amphetamine drugs are prescribed more frequently than in Europe and where there is therefore a more intensive debate about them) cite a reuptake inhibition of dopamine and noradrenaline transporters and no release of dopamine, noradrenaline or serotonin as the effect.

In the U.S., adolescents with ADHD receive MPH as the primary prescribed medication in 52.9% and amphetamine medications in 39.3%. Over the course of treatment, MPH is the primary prescribed medication in about 40% and AMP is the primary prescribed medication in 33%.21

Basically, amphetamine drugs act intraneuronally, whereas methylphenidate and atomoxetine act extraneuronally.22

AMP acts primarily in the striatum and further in the cortex and ventral tegmentum.23

2.1. Dopamine in amphetamine drugs

2.1.1. Dopamine reuptake inhibitor

  • Amphetamine medications block dopamine and norepinephrine transporters in a different manner than methylphenidate. While the reuptake inhibition of MPH is similar to that of antidepressants, amphetamine drugs act as a competitive inhibitor and pseudosubstrate on dopamine and norepinephrine transporters and bind at the same site where monoamines bind to the transporter, inhibiting NE and DA reuptake as well.24
  • Amphetamine medications, like methylphenidate, act as dopamine reuptake inhibitors.8
  • Lisdexamfetamine acts primarily as a dopamine transporter reuptake inhibitor.25 (different: steel, see above: equally as DA- and NE-WAH)
  • “Amphetamines can also stabilize dopamine and noradrenaline transporters in channel configurations, reverse flow through intracellular vesicular monoamine transporters, and cause internalization of dopamine transporters”26
  • D-amphetamine has approximately three times the affinity on norepinephrine transporters (NET) for reuptake inhibition and two and a half times the affinity on dopamine transporters (DAT) as racemic methylphenidate.22

2.1.2. Dopamine release by amphetamine medications?

  • There is a contrarian debate as to whether amphetamine medications release dopamine. There are voices against it14 and for it22258
    It is undoubted that amphetamine drugs (characteristic: high dose, rapidly applied, rapid end of effect) release dopamine. It is questionable whether this is also the case with amphetamine drugs (characteristic: drug-like = low dose, slow release, long-lasting effect), and if so, to what extent.
  • Only at a very high dosage as a drug do amphetamines also act on the vesicular transporter (VMAT2) for dopamine and norepinephrine and then trigger a cumulative release of dopamine from the synaptic vesicles. Thereafter, the high amount of dopamine is swept out into the synaptic cleft by a reversal of action of the dopamine transporters. This mechanism does not take effect at the usual dosage as an ADHD drug.14
    • Different: amphetamine initially decreases VMAT2, whereas prolonged administration increases it.27. MPH increases VMAT2 per se-2829
  • Undoubtedly, amphetamine drugs do not lead to a chronic depletion of dopamine stores. It is empirically proven that amphetamine drugs do not cause habituation effects in ADHD, even in the long term.
  • Amphetamines not only act as dopamine reuptake inhibitors, but they further reverse DAT function so that the DAT not only does not reuptake dopamine, but excretes it from the cell.30

2.1.3. D2 receptor activation in the striatum

D-amphetamine activates D2 dopamine receptors in the striatum.31
The increase in dopamine caused by D-amphetamine in PFC is much more pronounced and also significantly more dose-dependent than with MPH, and thus more controllable.22

2.1.4. Increase of tyrosine hydroxylase

Amphetamine drugs appear to have an activating effect on tyrosine hydroxylase in the dorsal striatum and nucleus accumbens, leading to increased levels of L-dopa, but this does not appear to occur via a change in the phosphorylation of tyrosine hydroxylase.32

2.2. Norepinephrine in amphetamine drugs

2.2.1. Norepinephrine reuptake inhibitor

  • Amphetamine medications block dopamine and norepinephrine transporters in a different manner than methylphenidate. While the reuptake inhibition of MPH is similar to that of antidepressants, amphetamine drugs act as a competitive inhibitor and pseudosubstrate on dopamine and norepinephrine transporters, binding at the same site where monoamines bind to the transporter, thereby inhibiting NE and DA reuptake as well.2433
  • “Amphetamines can also stabilize dopamine and noradrenaline transporters in channel configurations, reverse flow through intracellular vesicular monoamine transporters, and cause internalization of dopamine transporters”26
  • D-amphetamine has about one-third the reuptake inhibition on the norepinephrine transporters (NET) and dopamine transporters (DAT) as racemic methylphenidate.22
  • Amphetamine (as well as ephedrine) also inhibit on the intracellular norepinephrine transporter, which takes up norepinephrine from the nerve cell into the vesicles (the neurotransmitter stores)33

2.2.2. Noradrenaline release?

  • Whether amphetamine in drug doses has a noradrenaline-releasing effect is a matter of controversial debate, as is the case with dopamine. There are voices against it14 as well as for it.825
  • D-amphetamine secondarily increases norepinephrine release.31 This is always the case with dopaminergic drugs due to the conversion of dopamine (to approx. 5 - 10 %) into norepinephrine.
  • Undoubtedly, amphetamine drugs do not lead to a chronic depletion of norepinephrine stores. It is empirically proven that amphetamine drugs do not cause habituation effects in ADHD, even in the long term.

2.2.3. Reduction of norepinephrine metabolites in responders only

  • Several independent studies have found that D-amphetamine drugs decrease the metabolite of norepinephrine, MHPG, in urine. The decrease in urinary MPHG is thought to be an important indicator of a stimulant hit, suggesting a lowering of norepinephrine levels by dextroamphetamine drugs.34](https://psycnet.apa.org/psycinfo/1982-21744-001)
  • Moreover, the norepinephrine metabolite reduction occurs only in ADHD sufferers who respond positively to dexamphetamine (responders).35
  • Also, when methylphendiate was administered, only responders showed a significant decrease in urinary MPHG, whereas nonresponders did not show a decrease in urinary MPHG.36
    The authors conclude that there is a reduced level of noradrenaline in ADHD.
  • Furthermore, in several studies with ADHD sufferers, behavioral improvements were found to be proportional to the decreased level of noradrenmetabolitenal (by means of D-amphetamine medication).37

In contrast to the reduction of metabolites in urine by d-amphetamine, the noradrenaline increase mediated by d-amphetamine in PFC is about as pronounced as that of MPH, but much more dose-dependent, and thus more controllable.22

2.2.4. Activation of central norepinephrine-α1 receptors in the PFC

D-amphetamine appears to activate the norepinephrine α1-receptor in the PFC, because the α1-receptor antagonist prazosin completely neutralized the effect of D-amphetamine in the PFC. Experiments with α1-receptor-selective antagonists suggest that D-amphetamine acts via activation of central but not peripheral α1A-receptors.38
In contrast, D-amphetamine does not appear to address either the α2-receptor or the β-receptor, as the effects of D-amphetamine persisted when the α2- or β-receptors were blocked.38

Cirazoline did not reduce the effect of D-amphetamine. Cirazoline probably acts as a38

  • Α1-receptor agonist
  • Α2-receptor antagonist
  • Partial α1B-receptor agonist
  • Partial α1D-receptor agonist

2.3. MAO Inhibition

Amphetamine medications act as MAO inhibitors,3923 differently than low-dose MPH. Whether high-dose MPH acts as an MAO inhibitor is unknown.22

MAO is an enzyme that breaks down dopamine and norepinephrine in the cell. MAO inhibitors thus increase the amount of dopamine and norepinephrine available in the cell. Additionally, as dopamine and norepinephrine continue to be synthesized in the nerve cell, norepinephrine and dopamine levels in the cell continue to increase. This leads to a reversal of the action of the transporters (which actually return DA and NE from the synaptic cleft to the cell), so that they release NE and DA into the synaptic cleft, even without being triggered by a nerve signal to transmit.39 This effect triggered peripherally high blood pressure and heart rate increase. Since this mechanism of action occurs indirectly at the presynapse, ephedrine and amphetamine drugs are also called “indirect sympathomimetics,” while agents that act directly at postsynaptic receptors are called sympathomimetics.39

2.4. Serotonin release

Amphetamine drugs are said to release serotonin to a small extent.13 Again, it is unclear whether this is really the case even when dosed at drug levels, or whether this effect is limited only when dosed as drugs. In any case, Stahl does not report a serotonergic effect of amphetamine drugs.24

Serotonin release by amphetamine drugs

Amphetamine drugs (MDMA, MBDB) simultaneously increase serotonin release. It is assumed that amphetamine-induced serotonin release not only affects psychomotor activation, but also influences subjective well-being (including euphoria when taken as a drug).40 MDBD causes almost no dopamine release.

Hyperactivity induced by 5 mg or 10 mg/kg MDMA (= 10 to 20 times higher dosage than as drug) could be suppressed by prior administration of 2.5 and 10 mg/kg of the selective serotonin reuptake inhibitor fluoxetine. Fluoxetine had the same effect with respect to the interactive effects of MDMA and P-chloroamphetamine.41 This suggests that MDMA causes hyperactivity by increasing serotonin via the serotonin transporter, which was blocked by fluoxetine as a serotonin reuptake inhibitor.

  • There is evidence that increased serotonin release indirectly increases dopamine levels.41
  • Other sources indicate a serotonin enhancing effect of amphetamine salts due to inhibition of monoamine oxidase.16
  • Amphetamine increased c-Fos expression in the mPFC, striatum, and nucleus accumbens. A serotonin 1A receptor agonist decreased c-Fos increase in the mPFC and striatum, but not in the nucleus accumbens.42
  • MPH itself acts agonistically at the 5-HT1A receptor.23

2.5. Adrenergic effect

D-amphetamine promotes the up-state of cortical neurons via activation of43

  • Central α1A-adrenoceptors
  • D1 receptors
  • D2 receptors
  • But not by D1 or D2 receptors alone

In contrast, the dopamine/norepinephrine precursor L-DOPA did not promote the Up state.

Arousal is associated with an increased Up state, whereas slow-wave sleep, general anesthesia, and quiet wakefulness are characterized by an oscillating change between Up and Down states. During arousal, the down states end and the up/down oscillation changes to a sustained up state.
The up/down oscillations appear to be relevant for memory consolidation, whereas the transition to a sustained up state is required for arousal and attention.43

2.6. Effect on HPA axis

2.6.1. ACTH increased

Lisdexamfetamine and d-amphetamine significantly increased plasma levels of, among others, in healthy subjects:44

  • ACTH

2.6.2. Corticosteroids increased

  • D-amphetamine medications such as lisdexamphetamine medications (Elvanse) increase cortisol levels but not testosterone levels.44

  • Increased were

    • Glucocorticoids (as by methylphenidate; even greater increase was by the drugs MDMA or LSD)

      • Cortisol
      • Cortisone
      • Corticosterone
      • 11-dehydrocorticosterone,
      • 11-Deoxycortisol
  • Unchanged

    • Mineralocorticoids

      • Aldosterone
      • 11-Deoxycorticosterone

Increasing cortisol levels causes cortisol to more strongly address the glucocorticoid receptor (GR). Cortisol, via GR, causes the HPA axis to shut down again at the end of the stress response.
In ADHD-HI and ADHD-C (both with hyperactivity), due to the flattened endocrine stress response of the adrenal gland, it can be assumed that the GR are not sufficiently addressed to shut down the HPA axis after a stress response. In addition, in ADHD-HI (unlike ADHD-I), there is often deficient GR function, which further complicates HPA axis shutdown.
See more at Medications for ADHD at Dexamethasone for ADHD. Now, if cortisol release is increased by AMP, this could enhance HPA axis resilencing in ADHD-HI. However, because AMP also acts in ADHD-I, the primary mechanism of action is likely to be different.

2.6.3. Steroid hormones increased

Lisdexamfetamine and d-amphetamine significantly increased plasma levels of, among others, in healthy subjects:44

  • Androgens

    • Dehydroepiandrosterone
    • Dehydroepiandrosterone sulfate
    • Androstenedione (Δ4-Androstene-3,17-dione)
    • Progesterone (only in men)

Unchanged remained the androgen

  • Testosterone

Since aggression correlates with an elevated testosterone to cortisol ratio, amphetamine medications have an inhibitory effect on aggression due to the relative increase in cortisol levels.
See here Neurophysiological correlates of aggression

A study in juvenile rhesus monkeys found as a result of 12 months of AMP or MPH administration in drug doses that both agents increased testosterone levels, MPH even more markedly than AMP.45 Another study in rhesus monkeys found decreased testosterone levels with MPH administration.46

A reduction in testosterone levels by amphetamine administration was observed in rodents.4748

2.7. Other effects on brain functions

  • D-amphetamine increases metabolism in the right caudate nucleus and decreases it in the right Rolandi region and in right anterior inferior frontal regions.49

  • D-amphetamine (as well as L-dopa, which, however, has no effects in ADHD, although it has a dopaminergic effect) is also suitable for restoring brain functions after strokes, but only if appropriate training measures are taken at the same time.50 D-amphetamine increases dopamine, which has neurotrophic effects (promotes neuroplasticity). Dopaminergic drugs such as (D-)amphetamine drugs or also MPH can thereby also support appropriate training measures (e.g. neurofeedback, cognitive behavioral therapy) in ADHD by reducing the restrictions on learning ability.

  • Methylphenidate and amphetamine drugs increase the power of alpha (in rats), whereas atomoxetine and guanfacine do not.51

  • Lisdexamfetamine (Elvanse, Vyvanse) causes52

    • Increased acetylcholine levels in the cortex
    • Increased histamine levels in the cortex and hippocampus (which parallel escitalopram given only prevents in the hippocampus)

Amphetamine drugs are thus not only a substitute for methylphenidate, but have their own field of application.

2.8. Overview of AMP and neurotransmitters

2.8.1. Binding affinity of AMP, MPH, ATX to DAT / NET / SERT

The active ingredients methylphenidate (MPH), d-amphetamine (d-AMP), l-amphetamine (l-AMP) and atomoxetine (ATX) bind with different affinities to dopamine transporters (DAT), noradrenaline transporters (NET) and serotonin transporters (SERT). The binding causes inhibition of the activity of the respective transporters.53

Binding affinity: stronger with smaller number (KD = Ki) DAT NET SERT
MPH 34 - 200 339 > 10,000
d-AMP (Elvanse, Attentin) 34 - 41 23.3 - 38.9 3,830 - 11,000
l-AMP 138 30.1 57,000
ATX 1451 - 1600 2.6 - 5 48 - 77

2.8.2. Effect of AMP, MPH, ATX on dopamine / norepinephrine per brain region

The drugs methylphenidate (MPH), amphetamine (AMP), and atomoxetine (ATX) alter extracellular dopamine (DA) and norepinephrine (NE) differently in different brain regions. Table based on Madras,53 modified.

PFC striatum nucleus accumbens
MPH DA +
NE (+)
DA +
NE +/- 0
DA + NE
+/-


0


AMP DA +
** NE +**
DA +
NE +/- 0
DA + NE
+/-


0


ATX DA +
** NE +**
DA +/- 0
NE +/- 0


DA +/- 0


NE








+/- 0

3. Effect of amphetamine drugs compared to MPH / atomoxetine

In MPH nonresponders, lisdexamfetamine (EU: Elvanse) and atomoxetine were compared in a randomized double-blind trial with n = 200 subjects. Lisdexamfetamine was significantly more effective than atomoxetine in 2 of 6 categories and in the overall assessment.54
Lisdexamfetamine (EU: Elvanse) also had a good effect on comorbid depression symptoms in a double-blind study.55 MPH is not known to have any positive effects on depression symptoms.
A 2-year study in children and adolescents (n = 314) showed responder rates between 70% and 77% with good efficacy and manageable side effects.56

4. Effect on ADHD symptoms

In ADHD sufferers who respond positively to D-amphetamine medication as to MPH, the effect of D-amphetamine medication to MPH is at least equal57, in our experience in adults even significantly better.

For a comparison of the effectiveness of individual medications and forms of treatment, see Effect size of different forms of treatment for ADHD.

Amphetamine medication is the ADHD drug of first choice in adults (before methylphenidate), and the drug of second choice in children (after methylphenidate), according to the current European consensus.34

Amphetamine medications should also always be tried when MPH is not working (nonresponders).

4.1. ADHD-I (without hyperactivity)

MPH has a stronger activating and drive-enhancing effect than AMP drugs in most ADHD sufferers. Contrary reports58 do not coincide with our experience.
From our experience, we also cannot confirm representations in the literature that amphetamine medications are more suitable for ADHD-I sufferers than MPH, partly because ADHD-I sufferers are above-average AMP non-responders,59 .
We know quite a few ADHD-HI sufferers who are helped significantly better by amphetamine medication than MPH and ADHD-I sufferers who cope better with MPH. According to our perception, we cannot determine a subtype-specific effect of amphetamine medication or methylphenidate. In our experience, amphetamine medication works just as well for ADHD-HI as for ADHD-I.

4.2. Attentional control

ADHD sufferers have a reduced extrinsic and intrinsic motivability. For example, they need higher rewards to be as motivated for something as non-affected individuals. However, once motivation is aroused in ADHD sufferers, attention and its controllability are no longer reliably distinguishable from that of nonaffected individuals. Motivation shift towards own needs explains regulation problems
Attention correlates with, among other things, deactivation of the default mode network (DMN). Stimulants are able to bring the attentional control of ADHD sufferers (or the motivability, from which attention follows) into line with that of non-affected persons, which is then also shown by a normalization of DMN deactivability….60

For more on the aberrant function of the DMN in ADHD and its normalization by stimulants, including further references, see DMN (Default Mode Network) In the article Neurophysiological correlates of hyperactivity.
The references given refer to the effect of methylphenidate. However, it can be assumed that the effect is achieved by stimulants in general.

Affected individuals report that MPH allows for greater focus, while amphetamine medications (Elvanse) tend to create a more relaxed general alertness and are somewhat more pleasant overall.

4.3. Comorbid depression or dysthymia

Amphetamine medications arguably also have a mild serotonergic effect and thus have a special area of use in comorbid dysthymia or depression, especially since serotonin reuptake inhibitors (SSRIs) can have adverse effects in ADHD (especially ADHD-I) (see there).

In forums, quite a few sufferers report a significant antidepressant effect of amphetamine drugs, which they do not know from MPH.61 This is consistent with the experience of users known to us.

Since amphetamines can have a stronger drive-enhancing effect than MPH, this may release an existing suicidal tendency that was not previously carried out because of the existing depression. Amphetamine drugs should therefore be used with caution in cases of (even masked) severe depression.

Caution: a supposed dysthymia (mild chronic depression) in ADHD sufferers must be neatly distinguished from the original ADHD symptom of dysphoria with inactivity.
For more on this topic, see Depression and dysphoria in ADHD In the section Differential diagnostics in ADHD.

4.4. Comorbid anxiety disorders / depression

Comorbid anxiety disorders or depression may be exacerbated by stimulants, as anxiety and moods are regulated by dopaminergic activity of the ventromedial PFC in conjunction with the limbic system.24

4.5. Comorbid sleep disorders

Amphetamine drugs have quite a long duration of action (up to 13 hours). Taking them too late (less than 14 hours before going to bed) could therefore cause problems falling asleep. Some amphetamine users, on the other hand, report a pleasant tiredness in the evening and that they no longer have problems falling asleep.

Studies show that amphetamine medications improve overall sheep quality in ADHD.6263

4.6. Impulsivity

Sufferers reported in forums that MPH worked better against impulsivity than Elvanse (lisdexamfetamine).64

5. Response rate (responding / non-responding)

Response here means whether there is an effect on the ADHD symptoms. Affected persons who do not (sufficiently) respond to a medication are called non-responders.

A summary of several studies reported 69% response rates to amphetamine medication and 59% response rates to methylphenidate. 87% of those affected would have responded to either type of drug.9
A 2-year study of L-amphetamine medications in children and adolescents (n = 314) found responder rates between 70% and 77% with good efficacy and manageable side effects.56
This proves that it is highly recommended for MPH nonresponders to test medication with amphetamine drugs (see 1.2.), and vice versa.

In carriers of the COMT Val-158-Met gene polymorphism, amphetamine increased PFC efficiency in subjects with presumably low levels of dopamine in the PFC. In contrast, in carriers of the COMT Met-158-Met polymorphism, amphetamine had no effect on cortical efficiency at low to moderate working memory load and caused deterioration at high working memory load. Individuals with the Met-158-Met polymorphism appear to be at increased risk for an adverse response to amphetamine.65

6. No gender-specific effect differences

Amphetamine medications do not appear to show gender differences in effects.66

7. Dosage amphetamine medication or MPH

About 66% of all ADHD sufferers respond equally well to MPH as to amphetamine medications.
22% respond better to amphetamine medications than to MPH.
11% respond better to MPH than to amphetamine medications.67
About 15% of ADHD sufferers respond best to the drug D-amphetamine.68

According to this result, it would make more sense to try therapy with amphetamine medication first and only try MPH as a second option in case of nonresponding, since ADHD sufferers respond somewhat better to amphetamine medication than to MPH.

Highly gifted individuals with ADHD (here: IQ > 120) are reported to respond better to amphetamine medication than less gifted individuals with ADHD.69

An interesting study discusses the efficacy of lisdexamfetamine.70

It is recommended to start with a very low dosage, which is only slowly increased. Even if the optimal dosage were known, an immediate optimal dosage would possibly cause an overload.71 The symptoms of ADHD are caused by signal transmission problems between the brain nerves because the neurotransmitter level (dopamine, noradrenaline) is too low. An optimal neurotransmitter level corrects the signal transmission problems. If the neurotransmitter level is too high due to overdose, signal transmission is just as disturbed as if the level is too low.
This explains why low doses should be given at the beginning and then, with patience, high doses should be given until symptom worsening is noted.

Since in adults the number of dopamine transporters drops to half compared to 10-year-olds, starting with a much lower dosage than in children is advised.

8. Impact profile (temporal)

The time course of the effect (effect profile) depends less on the active ingredients than on the specific drug composition.

Elvanse has a very temporally stretched efficacy profile with no pronounced peaks, so that hardly any tarnish or rebound effects are noticeable. See Graphical representation of the Elvanse efficacy profile. However, the graph taken from Shire’s patent application refers to plasma levels in rats at an extremely high dose of 3 mg / kg.

It is open to what extent, in the case of lisdexamfetamine, the binding of D-amphetamine to lysine really leads to a flattened and prolonged concentration of amphetamine in blood plasma. A single dose of (above medically reasonable doses) 40 mg of D-amphetamine or 100 mg of lisdexamfetamine in healthy individuals showed no relevant differences in amphetamine blood plasma concentration.((Dolder, Strajhar, Vizeli, Hammann, Odermatt, Liechti (2017): Pharmacokinetics and Pharmacodynamics of Lisdexamfetamine Compared with D-Amphetamine in Healthy Subjects. Front Pharmacol. 2017 Sep 7;8:617. doi: 10.3389/fphar.2017.00617. PMID: 28936175; PMCID: PMC5594082. n = 24) However, the study does not name the weight of the subjects, so no statement about the dosage / kg body weight is possible. Furthermore, the study data probably indicate a subjective impression of a gentler and longer effect of lisdexamfetamine on the part of the subjects, but the authors do not reflect this. Another limitation of the study is that the subjects were treated with a single dose and there was no dosing in to the dosage tested. The authors themselves cite studies that amphetamine medications require acclimation periods or show (initial) habituation effects.
The results of the study are therefore primarily of pharmacological interest, but of only limited use in practice.

Empirically, sufferers report quite unanimously a gentler and prolonged effect of lisdexamfetamine. A duration of action of between 6 and 12 hours is reported, with 10 hours being the most frequently cited. Also quite unanimously, a very slow onset of action is reported, with 1.5 to 2 hours being mentioned most frequently.

9. Areas of use of amphetamine medications in relation to MPH

Amphetamine medication is the first-choice ADHD medication in adults (before methylphenidate), and the second-choice medication in children (after methylphenidate), according to the current European consensus on the diagnosis and treatment of ADHD in adults34
For children who are MPH nonresponders, that is, who do not respond to MPH, test the efficacy of amphetamine medications.
Affected individuals with marked dysphoria with inactivity or with comorbid depression particularly benefit from amphetamine medications.
Along with this, sufferers who need more activation may do better with amphetamine medications.
Highly gifted individuals are reported to respond better to amphetamine medications than to MPH.69

10. Side effects

10.1. No liver damage with usual drug dosage

High doses of amphetamines may be associated with liver damage and certain forms of clinically apparent liver injury. This is most commonly reported with methylenedioxymetamphetamine (MDMA: “ecstasy”).72

Amphetamine medications, on the other hand, are dosed so low that this does not occur: the dose makes the poison. See also at Amphetamine drugs versus amphetamine as a drug.

10.2. AMP increases histamine

APH increases histamine,7374 as do all other known ADHD medications

  • Atomoxetine
  • Methylphenidate
  • Modafinil
  • Nicotine
  • Caffeine

Therefore, people with histamine intolerance often have problems by taking ADHD medications.
One ADHD sufferer with histamine intolerance reported that she could not tolerate AMP and sustained-release MPH at all, but could tolerate sustained-release MPH in small doses

10.3. No increased cardiovascular risks

One large study found no increased risks of serious cardiovascular events such as stroke, heart attack, or arrhythmia for amphetamine medications among 2,566,995 children.75

10.4. Other

Isolated cases of trichotillomania (pulling out hair) have been reported.76 Trichotillomania is a specific form of impulse control disorder.

The drug MDMA (not amphetamine drugs) can damage nerve cells and attack the blood-brain barrier.77

Two male sufferers reported to us a loss of sensitivity in the genital area after consuming red wine outside the effective time of regularly taken Elvanse

11. Amphetamine degradation

11.1. LDX degradation

Lisdexamfetamine (Elvanse, Vyvanse) is converted to d-AMP in the blood cytosol of erythrocytes by an unknown amino acid. Only d-AMP is pharmacologically active.

LDX is excreted 96% in urine, of which20

  • 42% of the dose as AMP
  • 25 % as hippuric acid
  • 2% than intact LDX

LDX, unlike AMP, is not very sensitive to urine pH.
The half-life of LDX is typically less than 1 hour

11.2. Degradation of D-AMP and L-AMP

D-AMP is metabolized more rapidly than l-AMP, so exposure of d-AMP lasts 9-11 hours and of l-Amp 11-14 hours
Taking it with a high-fat meal may prolong the half-life of d-AMP by one hour.

AMP is degraded in two ways:20

  • Hydroxylation by CYP2D6:78
    • 4-Hydroxyamphetamine
    • Norepinephrine (alphahydroxyamphetamine, norepephrine)
    • both are subject to further metabolism
  • oxidative deamination

AMP is excreted primarily through the kidneys.
Since AMP is slightly basic (pKA = 9.9), AMP excretion is highly dependent on urine pH and flow rate, with urinary AMP recovery ranging from 1% to 75% and the remainder being hepatically metabolized:20

  • normal urine pH values
    • 30 to 40% of the AMP dose is largely excreted as unchanged parent compound
    • 50% of the dose is excreted as alpha-hydroxyamphetamine or its downstream inactive metabolite, hippuric acid [20,36]
  • acidic urine (pH <6.0)
    • accelerated AMP excretion
  • alkaline urine (pH >7.5)
    • delayed AMP excretion

The half-life of AMP is reported to increase by 7 hours per unit of pH increase. Acidifying or alkalizing agents may therefore significantly alter the AMP effect.

11.3. Ultra fast and slow metabolizers from AMP

The CYP2D6 gene is highly polymorphic. In Central Europe, particularly relevant are the alleles79

  • CYP2D6*3
  • CYP2D6*4
  • CYP2D6*5
  • CYP2D6*6
  • CYP2D6*9
  • CYP2D6*41

Poor metabolizers are likely to require lower AMP doses and ultrafast metabolizers are likely to require higher AMP doses. However, the effects of CYP2D6 polymorphisms on AMP metabolism are still unclear.20

Based on experience with the influence of CYP2D6 on the effects of other drugs (CYP2D6 is responsible for the metabolization of 20-30% of all drugs), the different CYP2D6 gene variants result in different types of metabolization:79

  • Slow metabolizers - approx. 7 %
    • especially slow dosing important
    • special low dosage helpful
  • moderately fast metabolizers - approx. 40%
  • Fast metabolizer - ca 46 %
  • Ultrasonic fast metabolizer - approx. 7
    • CYP2D6*XN allele
    • increased enzyme activity
    • is associated with therapy resistance (non-responders)
    • increased dose may be helpful

12. Contraindications and interactions

As with any drug described here, there are contraindications to amphetamine medications.
It should be warned against taking it without prior medical consultation.

For lisdexamfetamine:80

  • Pregnancy / Lactation
    • One study found no reduction in neonatal weight of mothers with ADHD who took amphetamine medications during pregnancy.81 This is consistent with results from a large cohort study of MPH use during pregnancy.82
      Another study comprehensive study found a slight reduction in birth weight and slight increases in the risks of preeclampsia, placental abruption, or preterm birth with stimulant use (AMP or MPH) in pregnancy, but these were so small that the authors did not recommend discontinuing stimulant use in pregnancy.83 Atomoxetine did not show these slight increases in risk.
      Another Danish cohort study found a doubled risk of miscarriage with stimulant use during pregnancy.84
      Another Danish cohort study found an increase in malformations in children born to mothers who had taken MPH in the first trimester of pregnancy, but the authors said this was not relevant.85
  • Hypersensitivity to the active substance
  • Monoamine oxidase inhibitors (MAO inhibitors) at the same time or 14 days before taking them
    • Risk: hypertensive crisis
  • Hyperthyroidism / Thyrotoxicosis
  • Arousal states
  • Symptomatic cardiovascular disease
  • Advanced arteriosclerosis
  • Moderate to severe hypertension
  • Glaucoma
  • Serotonin reuptake inhibitor
    • With concomitant administration of SSRIs and amphetamine drugs, the risk of serotonin syndrome should be considered.16

According to a very large study, the risk of developing psychosis is lower for ADHD sufferers taking MPH (0.10%) than for those treated with amphetamine drugs (0.21%).86 While ADHD sufferers treated with stimulants have 2.4 psychosis cases per 1000 person-years, the figure is 0.214% over the total population.87 The studies do not allow us to say whether the increased prevalence of psychosis is due to ADHD or stimulants.

12.1. Shortened half-life (reduced effect)

  • With acidification of the urine80
    e.g. through
    • Ascorbic acid
    • Thiazide diuretics
    • Protein-rich nutrition
    • Diabetes mellitus

12.2. Prolonged half-life (increased effect)

  • For alkalized urine80
    e.g. through
    • Sodium hydrogen carbonate (baking powder, soda)
    • Diet high in fruits / vegetables
    • Urinary tract infections
    • Vomiting

12.3. Delayed effect

Lisdexamfetamine (Elvanse) has a maximum blood level delayed by one hour (4.7 hours instead of 3.8 hours after ingestion) with high-fat meals.88 However, other parameters, such as duration of action, do not change.

12.4. Amplifying effect on amphetamines

12.4.1. Alcohol increases amphetamine levels

Alcohol can increase amphetamine levels.89

12.4.2. CYP2D6 inhibitors increase amphetamine levels

Because amphetamine is degraded by CYP2D6, CYP2D6 inhibitors may increase amphetamine levels, necessitating dose reduction. After discontinuation of CYP2D6 inhibitors, a dose increase of amphetamine medication may be required.89

Substrates metabolized by CYP2D6 include:7879

  • Class I antiarrhythmics
    • Propafenone
  • Beta blocker
    • Alprenolol
    • Carvedilol
    • Metoprolol
    • Timolol
  • Neuroleptics
    • Aripiprazole
    • Flupentixol
    • Fluphenazine
    • Haloperidol
    • Perphenazine
    • Promethazine
    • Risperidone
    • Thioridazine
    • Zuclopenthixol
  • HT3 receptor antagonists
  • Cancer Drugs
    • Tamoxifen (antiestrogen)
  • Amphetamine and derivatives
    • Dexamphetamine (Elvanse, Attengtin)
  • Opioids
    • Tramadol
  • Some tricyclic antipedressants
    • Amitriptyline
    • Imipramine
    • Trimipramine
    • Nortryptyline
  • some SNRI
    • Venlafaxine

Subsequently, substrates of CYP2D6 should be used with caution when amphetamine medications are given concomitantly, as they may slow the breakdown of amphetamine medications.

  • some SSRIs are CYP2D6 inhibitors
    • Fluoxetine (strong)8978
    • Paroxetine (strong)8978
    • Bupropion (moderate)89
    • Duloxetine (moderate)89
    • Sertraline78; dubious90

Subsequently, SSRIs should be used with caution when amphetamine medications are given concurrently, as they may potentiate the effects of amphetamine medications.

12.5. Attenuating effect on amphetamines

Have an attenuating effect on aphetamine:91

  • Chlorpromazine
  • Haloperidol
  • Lithium carbonate

A single affected person reported to us a loss of effect of Elvanse by dienogest 2 mg (Zafrilla) in endometriosis, while the effect of attentin remained unchanged.

12.6. Few interactions of AMP on other drugs

In contrast to the aforementioned interactions on amphetamine medications by other medications, there are few known interactions of amphetamine medications on other medications.89

Amphetamine is reported to have a slight inhibitory effect on cytochromes

  • CYP2D6
  • CYP1A2
  • CYP3A4.

The clinical relevance is considered to be low.91

Attenuating effect on91

  • Antihypertensives such as guanethidine

Reinforcing on91

  • Analgesic effect of opioids

13. Long-term effects: no habituation effects of amphetamine drugs

A meta-analysis of 87 randomized placebo-controlled double-blind trials found no evidence of diminishing effects of methylphenidate, amphetamine medications, atomoxetine, or α2-antagonists with prolonged use.92

14. Taking amphetamine drugs abroad

Taking amphetamine drugs abroad is possible under certain conditions.

Schengen countries:
A medical certificate is required here, which must be countersigned by the head of the health department.

Other states and USA:
Special provisions apply here.

Muslim countries in particular have draconian penalties for drug possession.71
Taking stimulants to Arab countries is not without danger without careful preparation, although they are medicines. Here you should inform yourself exactly.

15. Amphetamine medication versus amphetamine as a drug

Amphetamines are also traded and consumed illegally as drugs (e.g., as ecstasy, chystal meth).
As with any drug, the amount and method of use determines whether it is helpful or harmful. With amphetamines, the intoxicating effect comes from

  • Massively higher dosage than as a drug

    • Only a high dosage occupies enough DAT with more than 50% of the dopamine receptors to cause drug perception93
    • Only the high dosage leads to dopamine release via the VMAT2 receptors.
      AMP drugs, which have a purely reuptake-inhibiting effect, do not use this route of action
  • Rapid absorption of active substance (e.g. through the nose)93

    • Even a high dosage, taken slowly, does not act like a drug
  • Short duration of action (high speed of upward and downward change in dopamine levels is crucial)93

Amphetamine drugs, on the other hand, are low-dosed, have a long-term consistent effect (especially as lisdexamfetamine) and are also administered orally, which results in such a slow distribution of active ingredients that no intoxicating effect can occur. When taken according to a doctor’s prescription, no addictive effects are known, which unfortunately cannot be said of many other medically prescribed drugs. On the contrary, stimulants as ADHD drugs significantly and sustainably reduce the risk of addiction.
Amphetamine drugs are available today as pro-drug (lisdexamfetamine). This means that they are available in a form in which they are simply ineffective when abused (abusive ingestion in massive overdose through the nose or intravenously), because they are present in a compound of active ingredients, are metabolized to the drug active ingredient only during digestion over many hours, very slowly, and therefore cannot trigger a drug high, but can only accomplish the salutary effect of a constant and functional dopamine level.

Unretarded MPH, taken sequentially, like retarded MPH, sets multiple dopamine maxima (all of which are so low that they do not develop a drug effect). Lisdexamfetamine, on the other hand, sets only one maximum and thus causes more consistent dopamine (and norepinephrine) reuptake inhibition.
To achieve the most uniform DA and NE level increase possible with unretarded MPH, it should be administered at shortened intervals (2 to 2.5 hours) below the actually optimal single dose. Thus, instead of administering 7.5 mg every 3.5 hours (for example), administering 5 mg every 2.5 hours would produce more even DA and NE levels and thus better symptom reduction. Stahl illustrates the difference between short-term high/rapidly decreasing stimulant levels (= phasic DA) and low long-term steady stimulant levels (= tonic DA) as the crucial difference between drug effects and salutary drug effects.94

ADHD sufferers with comorbid cocaine addiction showed a significant reduction in addictive behavior when treated with stimulants, corresponding to a decrease in ADHD symptoms.95
Another study reports that factors such as onset and interruptions of medication use in ADHD may influence the likelihood of subsequent addiction.21 It should be noted, however, that addiction is epidemic in the U.S. (one in 13 Americans has a diagnosis of addiction), due in particular to inappropriate prescribing of pain medications (opioids), which does not occur in Europe. To what extent the study could be transferable to conditions outside the USA and especially in Europe is unclear.

A meta-analysis of 6 studies with n = 1,014 subjects showed a significantly reduced risk of later addiction for participants medicated with stimulants (here: MPH).96 According to this analysis, the risk of later addiction, whether to alcohol or other substances, is 1.9-fold lower (i.e., almost halved).97


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