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
• D-amphetamine as lisdexamfetamine in lysine-bound form (Vyvanse)

In Germany, amphetamine drugs 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 medications are, according to the current European consensus, the first-choice ADHD medication in adults (before methylphenidate), and the second-choice medication in children and adolescents (after methylphenidate)³⁴ While the current text of the 2017 S3 guideline 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, under which the active substances methylphenidate and lisdexamfetamine approved for adults fall.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 considerable individual differences.

• 1. Active ingredients of amphetamine drugs
  • 1.1. Dextroamphetamine (D-amphetamine)
    • 1.1.1. D-amphetamine without lysine binding
    • 1.1.2. D-amphetamine from lisdexamfetamine (with lysine binding)
  • 1.2. Levoamphetamine (L-amphetamine)
  • 1.3. Mixed amphetamine salts / amphetamine derivatives
  • (1.4. Fenetylline)
• 2. Amphetamine drugs work differently and in different parts of the brain than methylphenidate
  • 2.1. Dopamine in amphetamine drugs
    • 2.1.1. Dopamine reuptake inhibitor
    • 2.1.2. Dopamine release by amphetamine medications?
    • 2.1.3. D2 receptor activation in the striatum
    • 2.1.4. Increase in tyrosine hydroxylase
  • 2.2. Norepinephrine in amphetamine drugs
    • 2.2.1. Norepinephrine reuptake inhibitor
    • 2.2.2. Noradrenaline release?
    • 2.2.3. Reduction of norepinephrine metabolites in responders only
    • 2.2.4. Activation of central norepinephrine-α1 receptors in the PFC
  • 2.3. MAO Inhibition
  • 2.4. Serotonin release
  • 2.5. Adrenergic effect
  • 2.6. Effect on HPA axis
    • 2.6.1. ACTH increased
    • 2.6.2. Corticosteroids increased
    • 2.6.3. Steroid hormones increased
  • 2.7. Other effects on brain functions
  • 2.8. Overview of AMP and neurotransmitters
    • 2.8.1. Binding affinity of AMP, MPH, ATX to DAT / NET / SERT
    • 2.8.2. Effect of AMP, MPH, ATX on dopamine / norepinephrine per brain region
• 3. Effect of amphetamine drugs compared to MPH / atomoxetine
• 4. Effect on ADHD symptoms
  • 4.1. ADHD-I (without hyperactivity)
  • 4.2. Attentional control
  • 4.3. Comorbid depression or dysthymia
  • 4.4. Comorbid anxiety disorders / depression
  • 4.5. Comorbid sleep disorders
  • 4.6. Impulsivity
• 5. Response rate (responding / non-responding)
• 6. No gender-specific effect differences
• 7. Dosage amphetamine medication or MPH
• 8. Effect profile (temporal) / duration of action
• 9. Areas of use of amphetamine medications in relation to MPH
• 10. Side effects
  • 10.1. No liver damage with usual drug dosage
  • 10.2. AMP increases histamine
  • 10.3. No increased cardiovascular risks
  • 10.4. Other
• 11. Amphetamine degradation
  • 11.1. LDX degradation
  • 11.2. Degradation of D-AMP and L-AMP
  • 11.3. Ultra fast and slow metabolizers from AMP
• 12. Contraindications and interactions
  • 12.1. Shortened half-life (reduced effect)
  • 12.2. Prolonged half-life (increased effect)
  • 12.3. Delayed effect
  • 12.4. Amplifying effect on amphetamines
    • 12.4.1. Alcohol increases amphetamine levels
    • 12.4.2. CYP2D6 inhibitors increase amphetamine levels
  • 12.5. Attenuating effect on amphetamines
  • 12.6. Few interactions of AMP on other drugs
• 13. Long-term effects: no habituation effects of amphetamine drugs
• 14. Taking amphetamine drugs abroad
• 15. Amphetamine medication versus amphetamine as a drug

1. Active ingredients of amphetamine drugs¶

AMP has a chiral center with two enantiomers:¹³

• Levo-AMP (l-AMP)
  • Noradrenaline release as strong as or stronger than d-AMP
• Dextro-AMP (d-AMP)
  • higher dopamine release than l-AMP

As a consequence, the amphetamine mixed-salt preparations available in the United States, which consist of equal parts of racemic d,l-AMP sulfate, d,l-AMP aspartate monohydrate, and two enantiomerically pure d-AMP salts (d-AMP sulfate and d-AMP saccharate), resulting in a ratio of 3:1 between d-AMP and l-AMP isomers and salts, a relatively greater noradrenaline release than pure d-AMP, with still greater dopamine than noradrenaline release in absolute terms.

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 for ADHD treatment.¹⁴
D-amphetamine is more potent than L-amphetamine only with respect to dopamine transporters, while the effect on norepinephrine transporters is about the same.¹⁵

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.¹⁶
It is also often more effective than MPH in parallel dysthymia/dysphoria/depression due to its noticeable serotonergic effect¹⁷.

1.1.1. D-amphetamine without lysine binding¶

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

Duration of action approx. 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 from lisdexamfetamine (with lysine binding)¶

Lisdexamfetamine (LDX) is a prodrug of D-amphetamine that is bound to L-lysine to form a substance that is ineffective in itself. Lisdexamfetamine is therefore an active ingredient that is only converted in the body to the actual active substance, in this case D-amphetamine. This means that there is a very low risk of abuse.¹⁸

Lisdexamfetamine (LDX) bound to lysine is rapidly absorbed from the small intestine into the bloodstream. Des occurs by active transport, presumably by peptide transporter 1 [PEPT1]. Due to the required and slow conversion step from LDX to d-AMP, the effect occurs about 1 hour later than when d-AMP sulfate is ingested. Unlike LDX, the pharmacologically active d-AMP crosses the blood-brain barrier and enters the CNS, where it exerts its effect. ¹³

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 Vyvanse can be found at ADHSpedia.¹⁹

Trade names:

• Elvanse (EU, since late 2013, for children, 20, 30, 40, 50, 60, 70 mg)²⁰
• Elvanse Adult (EU, since 01.05.19, for adults, 30, 50, 70 mg)²⁰
• Vyvanse (USA) is available in doses ranging from 10 mg to 70 mg²¹
• Tyvense

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

1.2. Levoamphetamine (L-amphetamine)¶

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

L-amphetamine is less potent than D-amphetamine with respect to dopamine transporters, while its effect on noradrenaline transporters is about the same.¹⁵ As a result, it has a slightly more noradrenergic effect than D-amphetamine, but is still predominantly dopaminergic.

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

Mixed amphetamine salts are a combination of different stimulants:²²

• Amphetamine Aspartate Monohydrate
• Amphetamine sulfate
• Dextroamphetamine Saccharate
• Dextroamphetamine sulfate.

(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 as an effect and no release of dopamine, noradrenaline or serotonin.

In the U.S., adolescents with ADHD receive MPH as the primary prescribed medication in 52.9% and amphetamine medication 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%.²³

Basically, amphetamine drugs act intraneuronally, whereas methylphenidate and atomoxetine act extraneuronally.²⁴

AMP acts primarily in the striatum and further in the cortex and ventral tegmentum.²⁵

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.²⁶
• Amphetamine medications, like methylphenidate, act as dopamine reuptake inhibitors.⁸
• Lisdexamfetamine acts primarily as a dopamine reuptake inhibitor.²⁷ (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”²⁸
• 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.²⁴
• AMP acts via TAAR1 on DAT
  Amphetamine enables trace amine-associated receptor 1 (TAAR1) to phosphorylate the DAT transporter. This interrupts the reuptake of dopamine or stimulates DAT to release dopamine.²⁹

2.1.2. Dopamine release by amphetamine medications?¶

• There is conflicting debate as to whether amphetamine medications release dopamine.
  • There are voices against
    • At least at low doses¹⁵
    • Unquestionably, amphetamine medications do not lead to chronic depletion of dopamine stores. It is empirically proven that amphetamine drugs do not cause habituation effects in ADHD, even in the long term.
  • And votes for²⁴²⁷⁸
    • 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.
    • Amphetamines not only act as dopamine reuptake inhibitors, but they further reverse DAT function so that the DAT not only do not reuptake dopamine, but excrete it from the cell.³⁰
  • 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 medication.¹⁵ Put another way: Amphetamines can enter presynaptic monoamine vesicles and cause efflux of neurotransmitters toward the synapse.²⁹
  • Other view: amphetamine initially decreases VMAT2, whereas prolonged administration increases it.³¹. MPH increases VMAT2 per se-³²³³

2.1.3. D2 receptor activation in the striatum¶

D-amphetamine activates D2 dopamine receptors in the striatum.³⁴
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.²⁴

2.1.4. Increase in 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.³⁵

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.²⁶³⁶
• “Amphetamines can also stabilize dopamine and noradrenaline transporters in channel configurations, reverse flow through intracellular vesicular monoamine transporters, and cause internalization of dopamine transporters”²⁸
• D-amphetamine has about one-third the reuptake inhibition on the norepinephrine transporters (NET) and dopamine transporters (DAT) as racemic methylphenidate.²⁴
• 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)³⁶

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 it¹⁵ as well as for it.⁸²⁷
• D-amphetamine secondarily increases norepinephrine release.³⁴ This is always the case with dopaminergic drugs due to the conversion of dopamine (to approx. 5 - 10 %) into norepinephrine.
• Unquestionably, amphetamine medications do not lead to 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.³⁷](https://psycnet.apa.org/psycinfo/1982-21744-001)
• Moreover, the norepinephrine metabolite reduction occurs only in ADHD sufferers who respond positively to dexamphetamine (responders).³⁸
• Also, when methylphendiate was administered, only responders showed a significant decrease in urinary MPHG, whereas nonresponders did not show a decrease in urinary MPHG.³⁹
  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 (by means of D-amphetamine medication) noradrenmetabolitenaline level.⁴⁰

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.²⁴

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.⁴¹
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.⁴¹

Cirazoline did not reduce the effect of D-amphetamine. Cirazoline probably acts as a⁴¹

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

2.3. MAO Inhibition¶

Amphetamine medications act as MAO inhibitors,⁴²²⁵ differently than low-dose MPH. Whether high-dose MPH acts as an MAO inhibitor is unknown.²⁴

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.⁴² 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.⁴²

2.4. Serotonin release¶

Amphetamine drugs are said to release serotonin to a small extent.¹⁴ 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.²⁶

• There is evidence that increased serotonin release indirectly increases dopamine levels.⁴⁴
• Other sources indicate a serotonin enhancing effect of amphetamine salts due to inhibition of monoamine oxidase.¹⁷
• 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.⁴⁵
• MPH itself acts agonistically at the 5-HT1A receptor.²⁵

2.5. Adrenergic effect¶

D-amphetamine promotes the up-state of cortical neurons via activation of⁴⁶

• 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.⁴⁶

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:⁴⁷

• ACTH

2.6.2. Corticosteroids increased¶

• D-amphetamine medications such as lisdexamphetamine medications (Elvanse) increase cortisol levels but not testosterone levels.⁴⁷

• 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 secretion 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:⁴⁷

• 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.⁴⁸ Another study in rhesus monkeys found decreased testosterone levels with MPH administration.⁴⁹

A reduction in testosterone levels by amphetamine administration was observed in rodents.⁵⁰⁵¹

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.⁵²

• 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.⁵³ 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.⁵⁴

• Lisdexamfetamine (Vyvanse) causes⁵⁵

  • 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.⁵⁶

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,⁵⁶ 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.⁵⁷
Lisdexamfetamine (EU: Elvanse) also had a good effect on comorbid depression symptoms in a double-blind study.⁵⁸ 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.⁵⁹

4. Effect on ADHD symptoms¶

In ADHD sufferers who respond positively to D-amphetamine medications as to MPH, the effect of D-amphetamine medications to MPH is at least equal⁶⁰, in our experience in adults even significantly better.

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

Amphetamine medications are the first-choice ADHD medication in adults (before methylphenidate), and the second-choice medication 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 medications in most ADHD sufferers. Contrary reports⁶¹ 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,⁶²
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 reduced extrinsic and intrinsic motivability. For example, they require 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. ⇒ Motivational shift toward own needs explains regulation problems
Attention correlates, among other things, with 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….⁶³

For more on the aberrant function of the DMN in ADHD and its normalization by stimulants, together with 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 mild serotonergic effects and thus have a particular application 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.⁶⁴ 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 putative dysthymia (mild chronic depression) in ADHD sufferers must be neatly distinguished from the original ADHD symptom of dysphoria with inactivity.
See more at ⇒ 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.²⁶

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.⁶⁵⁶⁶

4.6. Impulsivity¶

Sufferers reported in forums that MPH worked better against impulsivity than Elvanse (lisdexamfetamine).⁶⁷

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.⁵⁹
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.⁶⁸

6. No gender-specific effect differences¶

Amphetamine medications do not appear to show gender differences in effects.⁶⁹

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.⁷⁰
About 15% of ADHD sufferers respond best to the drug D-amphetamine.⁷¹

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 the 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 medications than less gifted individuals with ADHD.⁷²

An interesting study discusses the efficacy of lisdexamfetamine.⁷³

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.⁷⁴ The symptoms of ADHD result from signal transmission problems between the brain nerves because the neurotransmitter level (dopamine, norepinephrine) is too low. An optimal neurotransmitter level fixes 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. Effect profile (temporal) / duration of action¶

In replicated studies of amphetamine drug duration of action, children had a shorter half-life of about 7 hours, whereas adults had a longer half-life of about 10 to 12 hours.⁷⁵ Since unretarded AMP does not act for 10 - 12 hours, we suspect that these are studies of lisdexamfetamine (Elvanse),

The time course of the effect (effect profile) depends less on the active ingredients than on the specific drug composition.
Vyvanse has a very temporally stretched action profile without 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.

Another graph shows the Drug courses at 30 mg, 50 mg, and 70 mg of Vyvanse, there page 20.

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.

An internal (and not representative) Survey on adhs-forum.adx.org on the duration of action of Elvanse yielded the following result (as of October 23, 2022, n = 46):

Duration of effect of a single dose of Elvanse (in hours)	% of participants
5 and less	24 %
6	20 %
10	13 %
14 and more	11 %
7	11 %
9	9 %
8	6 %
11	4 %
12	2 %
13	-

In summary:

• 11% have a fairly long duration of action of 14 hours or more
• 19 % have a duration of action of 10 to 12 hours
• 26% have a duration of action of 7 to 9 hours
• 44% have a very short duration of action of 6 hours or less

A limitation of the survey is that it was addressed multiple times in the context of questions from Elvanse rapid metabolizers. Consequently, it is not a representative sample. However, it shows that a duration of action of 10 to 12 hours, as stated by the manufacturer, is not universally valid.

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.⁷²

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”).⁷⁷

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

10.2. AMP increases histamine¶

APH increases histamine,⁷⁸⁷⁹ 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¶

Several large studies found no increased risks of serious cardiovascular events such as stroke, myocardial infarction, or cardiac arrhythmias for amphetamine medications.⁸⁰⁸¹

10.4. Other¶

Isolated cases of trichotillomania (pulling out hair) have been reported.⁸² 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.⁸³

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.

Common side effects of mixed amphetamine salts include:²²

• Loss of appetite
• Mood swings

More serious side effects of mixed amphetamine salts include:²²

• psychotic symptoms
• Seizures
• Risk of abuse.

11. Amphetamine degradation¶

11.1. LDX degradation¶

Lisdexamfetamine (Vyvanse) is converted to d-AMP in the blood cytosol of erythrocytes by an unknown amino acid (probably an aminopeptidase)⁸⁴. Only d-AMP is pharmacologically active.

LDX is excreted 96% in urine, of which²¹

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

LDX, unlike AMP, is not very sensitive to urine pH changes.
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 ways²¹

• Hydroxylation by CYP2D6:⁸⁵
  • 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:²¹

• 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 results of one study suggest that CYP2D6 may have little involvement in the degradation of AMP⁸⁶

The CYP2D6 gene is highly polymorphic. In Central Europe, particularly relevant are the alleles⁸⁷

• 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.²¹

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 lead to different types of metabolization⁸⁷

• 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

More about this under –&amp;gt CYP2D6 metabolizing enzyme

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:⁸⁸

• Pregnancy / Lactation
  • One study found no decreased weight of newborns of mothers with ADHD who took amphetamine medications during pregnancy.⁸⁹ This is consistent with results from a large cohort study of MPH use during pregnancy.⁹⁰
    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) during pregnancy, but these were so small that the authors did not recommend discontinuing stimulant use during pregnancy.⁹¹ Atomoxetine did not show these slight increases in risk.
    Another Danish cohort study found a doubled risk of miscarriage with stimulant use during pregnancy.⁹²
    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.⁹³
• 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
  • When SSRIs and amphetamine drugs are administered concurrently, the risk of serotonin syndrome should be considered.¹⁷

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 medications (0.21%).⁹⁴ While ADHD sufferers treated with stimulants have 2.4 psychosis cases per 1000 person-years, the figure is 0.214% over the entire population.⁹⁵ The studies do not allow us to determine whether the increased prevalence of psychosis is due to ADHD or stimulants.

12.1. Shortened half-life (reduced effect)¶

• In case of acidification of the urine (reduced ph value)⁸⁸
  e.g. through
  • Ascorbic acid
  • Thiazide diuretics
  • Protein-rich nutrition
  • Diabetes mellitus

Attenuation of the effect of dexamfetamine by:⁹⁶

• Adrenoreceptor blockers (beta blockers)
  • e.g.:
    • Propranolol
• Lithium
• Phenothiazine
• Haloperidol
• Substances that lower pH in the gastrointestinal tract
  • e.g:
    • Guanethidine
    • Reserpine
    • Glutamic acid
    • Hydrochloric acid
    • Ascorbic acid
    • Fruit juice
  • cause decreased uptake of dexamfetamine
• Substances that acidify urine (ammonium chloride, sodium dihydrogen phosphate, etc)
  • increase ionized excretion products of dexamfetamine in urine, whereupon renal excretion increases

12.2. Prolonged half-life (increased effect)¶

• With alkalinized urine (increased ph value)⁸⁸
  e.g. through
  • Sodium hydrogen carbonate (baking powder, soda)
  • Diet high in fruits / vegetables
  • Urinary tract infections
  • Vomiting
  • Clonidine⁹⁶

Enhanced effect of dexamfetamine due to:⁹⁶

• Disulfiram
• Substances that increase pH in gastrointestinal tract increase dexamfetamine uptake
  • e.g:
    • Sodium bicarbonate (baking powder)
• Substances that increase urine pH increase non-ionized excretion products in urine, which decreases renal excretion and thus increases blood levels of dexamfetamine
  • e.g:
    • Acetazolamide
    • some thiazides

There is evidence that decreased expression of the CACNA1C gene may lead to a prolonged effect of dopamine reuptake inhibitors.⁹⁷ Conversely, increased expression is likely to result in a shortened effect.

12.3. Delayed effect¶

Lisdexamfetamine (Elvanse) has a one-hour delay in maximum blood level (4.7 hours instead of 3.8 hours after ingestion) with high-fat meals.⁹⁸ 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.⁹⁹

12.4.2. CYP2D6 inhibitors increase amphetamine levels¶

Because amphetamine is degraded by CYP2D6, drugs that are also degraded by CYP2D6 may slow the degradation of amphetamine as well as their own degradation because of competition for the CYP2D6 enzyme.
CYP2D6 inhibitors may increase amphetamine levels, requiring dose reduction. After discontinuation of CYP2D6 inhibitors, a dose increase of amphetamine medication may be required.⁹⁹
CYP2D6 inducers may accelerate degradation and thus reduce efficacy.

See here under CYP2D6 Metabolizing enzyme

12.5. Attenuating effect on amphetamines¶

Have an attenuating effect on aphetamine:¹⁰⁰

• Chlorpromazine
• Haloperidol
• Lithium carbonate

A single affected person reported to us a loss of efficacy 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.⁹⁹

Amphetamine is reported to have a slight inhibitory effect on cytochromes

• CYP2D6
• CYP1A2
• CYP3A4.

The clinical relevance is considered to be low.¹⁰⁰

Attenuating effect on¹⁰⁰

• Antihypertensives such as guanethidine

Reinforcing on¹⁰⁰

• 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.¹⁰¹

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.⁷⁴
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 perception¹⁰²
  • 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)¹⁰²

  • 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)¹⁰²

Amphetamine drugs, on the other hand, are low-dosed, have a long-term uniform 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 medications 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 produces 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.¹⁰³

ADHD sufferers with comorbid cocaine addiction showed a significant reduction in addictive behavior when treated with stimulants, corresponding to a decrease in ADHD symptoms.¹⁰⁴
Another study reports that factors such as onset and interruptions of medication use in ADHD may influence the likelihood of subsequent addiction.²³ 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).¹⁰⁵ According to this analysis, the risk of later addiction, whether to alcohol or other substances, is 1.9-fold lower (i.e., almost halved).¹⁰⁶