Amphetamine medication (AMP) for ADHD

In the USA, amphetamine drugs are available as:¹

• Mixture of D- and L-amphetamine isomers (racemic mixture)
• Mixed sulfates and saccharinates of D-L-amphetamine isomers (Adderall)
• Pure D-amphetamine sulphate
  • Dexamfetamine hemisulfate (Attentin)
• D-amphetamine as lisdexamfetamine in lysine-bound form (Vyvanse, Vyvanse, Tyvense)
• Racemic methamphetamine sulfate (Desoxyn, USA)

In Germany, amphetamine drugs had to be prepared 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 in 2013 a D-amphetamine prodrug was approved for the treatment of children. Lisdexamfetamine contains D-amp in a lysine-bound form (Vyvanse). Since May 2019, Vyvanse Adult has been approved for the treatment of ADHD in adults (30, 50, 70 mg). In 2023, 20, 40, 60 mg were also approved for adults. Since March 2024, Vyvanse and Vyvanse Adult have been combined to form the drug Vyvanse and are available in 20, 30, 40, 50, 60 and 70 mg in Germany.³ Since March 2024, Vyvanse has also been indicated as a first-line treatment for adults according to the Takeda prescribing information, but is still only indicated for children if MPH has been insufficiently effective.⁴

In Austria, Vyvanse can be prescribed if other medications are ineffective or show side effects. The doctor must justify this to the insurance company.

Amphetamine medication works slightly better in adults than methylphenidate⁵ and has slightly fewer side effects.
According to the current European consensus, amphetamines are the first choice of medication for ADHD in adults (before methylphenidate) and the second choice of medication in children and adolescents (after methylphenidate).⁶⁷ While the current text of the S3 guideline from 2017 still states that lisdexamfetamine can only be used in accordance with approval after prior treatment with MPH⁸, the 2019 S3 guideline is quoted as saying that treatment with psychostimulants is recommended as the first option for adults with ADHD, including the active ingredients methylphenidate and lisdexamfetamine, which are approved for adults.⁹¹⁰

Due to the responder/non-responder profile, which differs from MPH, amphetamine medications are particularly suitable for people with ADHD who do not respond to MPH, clearly before the use of non-stimulants (e.g. noradrenergic medications or tricyclic antidepressants).¹¹ A summary of several studies reports a 69% response rate to amphetamine medication and a 59% response rate to methylphenidate. 87 % of people with ADHD responded to one of the two types of drugs.¹²

Amphetamine medications are also suitable - unlike MPH - for the co-treatment of comorbid dysphoria or depression.¹³¹⁴

According to a Cochrane study, all amphetamine medications work equally well in adults, regardless of the specific form of medication.¹⁵ This distinguishes amphetamine medication 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. Dextroamphetamine without lysine binding
    • 1.1.2. Dextroamphetamine from lisdexamfetamine (with lysine binding)
  • 1.2. Levoamphetamine (L-amphetamine)
  • 1.3. Mixed amphetamine salts / amphetamine derivatives
  • 1.4. Methamphetamine
  • (1.5. Fenetyllin)
• 2. Amphetamine drugs work differently and in different parts of the brain than methylphenidate
  • 2.1. Dopamine with amphetamine medication
    • 2.1.1. Effect on DAT
      • 2.1.1.1. Dopamine (re)uptake inhibition via DAT and NET
        • 2.1.1.1.1. DAT inhibition via PKC
      • 2.1.1.2. Increased release of dopamine (DAT efflux)
        • 2.1.1.2.1. Via VMAT2 at high doses
        • 2.1.1.2.2. By increasing intracellular Ca2+
        • 2.1.1.2.3. Increased DAT efflux via TAAR1
    • 2.1.2. Vesicular release
    • 2.1.3. D2 autoreceptor activation
    • 2.1.4. Increase in tyrosine hydroxylase
    • 2.1.5. Increased DA firing / activation in dopaminergic brain regions
      • 2.1.5.1. Increased DA firing in caudate nucleus / putamen (striatum)
      • 2.1.5.2. Increased DA firing in VTA and substantia nigra
      • 2.1.5.3. Increased activation in the right orbitofrontal cortex, left middle frontal lobe, superior frontal lobe and precentral gyri
    • 2.1.6. Reduced DA firing in the nucleus accumbens
    • 2.1.7. DA influence indirectly via effects on dopamine cells emanating from other brain regions
    • 2.1.8. Downregulation of dopamine receptors?
  • 2.2. Noradrenaline with amphetamine medication
    • 2.2.1. Noradrenaline reuptake inhibition via NET
    • 2.2.2. Noradrenaline release
    • 2.2.3. Reduction of noradrenaline metabolites only in responders
    • 2.2.4. DA firing and DA bursting increased via noradrenaline α1 receptors
  • 2.3. Monoamine degradation inhibition via MAO
  • 2.4. Serotonin release
  • 2.5. Effect on the HPA axis
    • 2.5.1. ACTH increased
    • 2.5.2. Corticosteroids increased
    • 2.5.3. Increased steroid hormones
  • 2.6. Inhibition of OCT2
  • 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 / noradrenaline per brain region
• 3. Effect of amphetamine medication compared to MPH / atomoxetine
• 4. Effect on ADHD symptoms
  • 4.1. ADHD-I (without hyperactivity)
  • 4.2. Attention control
  • 4.3. Comorbid depression or dysthymia
  • 4.4. Comorbid anxiety disorders / depression
  • 4.5. Comorbid sleep disorders
  • 4.6. Impulsiveness
• 5. Response rate (responding / non-responding)
• 6. No gender-specific differences in effect
• 7. Calming effect at low doses, activating at high doses
• 8. Dosage of amphetamine medication or MPH
• 9. Effect profile (temporal) / duration of action
• 10. Areas of application of amphetamine drugs in relation to MPH
• 11. Side effects
  • 11.1. No liver damage with normal medication dosage
  • 11.2 AMP increases histamine
  • 11.3. No increased cardiovascular risks
  • 11.4. Individual cases of trichotillomania
  • 11.5. Erection, libido, reproduction
  • 11.6. Miscellaneous
  • 11.7. Overdose
• 12. Breakdown of amphetamine
  • 12.1. Reduction of LDX
  • 12.2. Degradation of D-AMP and L-AMP
  • 12.3. Duration of action of AMP; influence of CYP2P6 metabolism types
• 13. Contraindications and interactions
  • 13.1. Shortened half-life (reduced effect)
  • 13.2. Prolonged half-life (increased effect)
  • 13.3. Delayed effect
  • 13.4. Amplifying effect on amphetamines
    • 13.4.1. Alcohol increases amphetamine levels
    • 13.4.2. CYP2D6 inhibitors increase amphetamine levels
  • 13.5. Attenuating effect on amphetamines
  • 13.6. Few interactions of AMP with other medications
  • 13.7. AMP during pregnancy
• 14. Long-term effect: No habituation effects of amphetamine medication
• 15. Preparations
• 16. Taking amphetamine medication abroad

1. Active ingredients of amphetamine drugs¶

AMP has a chiral center with two enantiomers:¹⁶

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

Consequences are that the amphetamine mixed salt preparations available in the USA, which consist of equal parts 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 release of noradrenaline than pure d-AMP, but still a greater release of dopamine than noradrenaline in absolute terms.

The following are relevant for the treatment of ADHD:

1.1. Dextroamphetamine (D-amphetamine)¶

Dextroamphetamine is also known as dexamphetamine or dextroamphetamine sulphate.
Dextroamphetamine is the dextrorotatory (D-)enantiomer of amphetamine, as opposed to the levorotatory levoamphetamine (see below).

D-amphetamine drugs have a 3 to 4 times stronger effect on the central nervous system than racemic amphetamine drugs, while at the same time having less sympathomimetic effect in the periphery, which is why D-amphetamine drugs are preferred in ADHD treatment.¹⁷
D-amphetamine is only more potent than L-amphetamine with regard to the dopamine transporters, while the effect on noradrenaline transporters is roughly the same.¹⁸

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

D-amphetamine is more activating than MPH and is therefore preferably recommended for ADHD-I.¹⁹
It is also often more effective than MPH for parallel dysthymia / dysphoria / depression due to the noticeable serotonergic effect²⁰.

1.1.1. Dextroamphetamine without lysine binding¶

Trade name: Attentin (Germany since the end of 2011), Dexamine (Switzerland: as magistral formulation), Dexedrine

Duration of action approx. 6 hours, so that it is usually necessary to take it twice a day.
Increased potential for abuse as no lysine binding.

Medice (2017): Attentin® - Guide for prescribing physicians

1.1.2. Dextroamphetamine 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 first converted in the body into the actual active substance, in this case D-amphetamine. This means that there is a very low risk of abuse.²¹ Nevertheless, the effect is dose-dependent and linear up to 250 mg. LDX therefore offers no protection against overdose.²²

Due to the necessary and slow conversion step from LDX to d-AMP, the effect occurs approx. 1 hour later than when taking d-AMP sulphate.²² Unlike LDX, the pharmacologically active d-AMP crosses the blood-brain barrier and enters the CNS, where it exerts its effect.¹⁶

Since the effect is quite uniform over the duration of action, the unpleasant rebound effects known from MPH (short-term increased restlessness at the end of the effect) are eliminated or are significantly weaker.
The effect corresponds to D-amphetamine. A conversion table from dexamphetamine to Vyvanse can be found at ADHSpedia.²⁴ Further conversion tables are available from Kühle²⁵and for American preparations from Stutzman et al.²⁶

Trade names:

• Vyvanse (EU, since the end of 2013, for children, 20, 30, 40, 50, 60, 70 mg)²⁷
• Vyvanse Adult (EU, since 01.05.19, for adults, 30, 50, 70 mg)²⁷. Since 2023, 20, 40 and 60 mg have also been approved in Germany.
• Vyvanse and Vyvanse adult were combined in 2023 to form a single medicine with a single approval. It was already an identical product. Since March 2024, Vyvanse has been available in 20, 30, 40, 50, 60 and 70 mg in Germany for children and adults.
• Vyvanse (USA) is available in doses of 10 mg to 70 mg²⁸ Lisdexamfetamine is also approved for binge eating in the USA.²⁹
• Tyvense (USA) is available in doses from 20 mg to 70 mg
• Teva-Lisdexamfetamine (Canada) is available in doses of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg and 70 mg³⁰

Generics:

• Since August 2024, lisdexamfetaim has been available in Germany as a generic (Lisdexamfetamine Ratiopharm), with 100-capsule packs also on the market.

Lisdexamfetamine has only been classified as a BtM in Germany since 2013.
Austria appears to be the only country in which Vyvanse is not classified as a narcotic (Austrian term: addictive drug), even as of 2023.³¹

Due to its long-lasting effect, lisdexamfetamine is subject to steady state formation. Steady state appears to be reached on day 5.³² Consequences of this are that when dosing lisdexamfetamine (Vyvanse), dosage titrations should not be made below a weekly rhythm.

1.2. Levoamphetamine (L-amphetamine)¶

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

L-amphetamine is less potent than D-amphetamine in terms of dopamine transporters, while the effect on noradrenaline transporters is roughly the same.¹⁸ This makes it slightly more noradrenergic than D-amphetamine, but still predominantly dopaminergic.³³
L-amphetamine increases blood pressure and pulse rate more than D-amphetamine³⁴

We are not aware of any ready-to-use L-amphetamine medication approved in Europe. It would have to be produced on 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:³⁵

D-amphetamine saccharate
D-amphetamine sulfate
D,L-amphetamine sulfate
D,L-amphetamine aspartate monohydrate

While D,L-amphetamine sulphate mixtures are the most commonly used ADHD medication in the USA, D,L-amphetemine mixtures are only available in a few pharmacies in Germany, which produce them themselves. The production is associated with a waiting time of several weeks. The cost of 180 capsules of 5 mg amphetamine sulphate each was quoted as €200.

1.4. Methamphetamine¶

• Desoxyn, USA

(1.5. Fenetyllin)¶

• Captagon (in Germany until 2003; in Belgium until 2010); no longer available today

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

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

It is sometimes argued that amphetamine drugs merely inhibit dopamine reuptake and release dopamine and noradrenaline. More well-founded accounts 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 the effect and no release of dopamine, noradrenaline or serotonin.

In the US, 52.9% of adolescents with ADHD receive MPH and 39.3% receive amphetamine medication as their first prescribed medication. Over the course of treatment, MPH is the primary prescribed medication for around 40% and 33% AMP is the primary prescribed medication.³⁶

In principle, amphetamine drugs are said to have an intraneuronal effect, while methylphenidate and atomoxetine have an extraneuronal effect.³⁷ As amphetamine drugs also address at least the dopamine transporter and the D2 autoreceptor, this is unlikely to be tenable.
AMP acts primarily in the striatum and further in the cortex and ventral tegmentum.³⁸

The first computer models now exist that can seriously simulate the effect of ADHD drugs. A computer model for the simulation of type 1 diabetes has already been approved by the FDA as a replacement for preclinical animal studies³⁹
A model comparing MPH and AMP in children and adults with ADHD takes into account the effect on 99 proteins involved in ADHD⁴⁰

2.1. Dopamine with amphetamine medication¶

The dopamine increase caused by D-amphetamine in the PFC is much more pronounced and also much more dose-dependent than with MPH, and is therefore easier to control.³⁷
AMP causes:

• extracellular dopamine levels increased 6-fold⁴¹
• tonic dopamine firing enhanced by AMP depleting vesicular stores and promoting non-exocytotic release through reverse transport⁴²
• phasic dopamine firing: contradictory data
  • amplified by upregulating vesicular dopamine release⁴²
  • Stimulants reduce the phasic release of dopamine⁴¹
    • AMP promoted the release of dopamine from vesicles by reducing the affinity of the vesicles for dopamine uptake (from K(m) 0.8 to K(m) 32). However, the amount of dopamine released per pulse was reduced by 82 % (according to another source by 25 to 50 %). The D2 antagonist sulpiride reduced the inhibition of release, i.e. promoted the release. This was reduced in D2-KO mice. In inhibited D2 autoreceptors, AMP increased the extracellular release of dopamine.⁴³
  • AMP reduces vesicular release⁴⁴⁴⁵ (this can affect both tonic and phasic release)

2.1.1. Effect on DAT¶

2.1.1.1. Dopamine (re)uptake inhibition via DAT and NET¶

Stimulants (MPH such as AMP inhibit dopamine reuptake⁴⁶ and thus lead (in low doses) to a 6-fold increase in extracellular dopamine levels.⁴¹
The increased extracellular dopamine level acts on presynaptic dopamine D2 autoreceptors at the nerve ending. The D2 autoreceptor activation causes a 2- to 3-fold increase in impulse-associated (phasic) dopamine release. This increase is therefore relatively smaller than the increase in extracellular dopamine. The (relatively smaller) increase in phasic dopamine acts on the postsynaptic D2 dopamine receptors and causes reduced locomotor activity. Higher doses of stimulants increase extracellular dopamine more strongly and result in marked behavioral stimulation that cannot be overcome by phasic activation of inhibitory postsynaptic D2 receptors. High D-Amp doses cause supersaturation of extracellular postsynaptic D1 and D2 receptors, so that they exceed the inhibitory presynaptic effect of low D-AMP doses.⁴¹

• Amphetamine drugs block the dopamine and noradrenaline transporters in a different way to 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 noradrenaline transporters and bind to the same site where the monoamines bind to the transporter, thereby also inhibiting NE and DA reuptake.⁴⁷
• D-amphetamine works
  • Primarily as a dopamine reuptake inhibitor.⁴⁸
  • Equally as a dopamine and noradrenaline reuptake inhibitor⁴⁷
• “Amphetamines can also stabilize dopamine and noradrenaline transporters in channel configurations, reverse flow through intracellular vesicular monoamine transporters, and cause internalization of dopamine transporters”⁴⁹
  D-AMP drug doses cause a D-AMP plasma concentration of around 150 nM, which is sufficient to occupy a significant proportion of the dopamine transporters. This effect coincides with that of MPH.⁴¹
• D-amphetamine has approximately three times the affinity for noradrenaline transporters (NET) for reuptake inhibition and two and a half times the affinity for dopamine transporters (DAT) compared to racemic methylphenidate.³⁷

2.1.1.1.1. DAT inhibition via PKC¶

• AMP possibly inhibits DAT via PKC⁵⁰
  • Several protein kinases regulate DAT function⁵¹⁵²
  • AMP increases the activity of striatal particulate PKC via a calcium-dependent signaling pathway⁵³
  • PKC activation leads to phosphorylation in the N-terminal of the rat striatal DAT⁵⁴
  • PKC activation stimulates DAT-mediated dopamine release⁵⁰
  • PKC inhibitors and the downregulation of PKC⁵⁰
    • Inhibit efflux
    • Leave dopamine uptake unchanged

2.1.1.2. Increased release of dopamine (DAT efflux)¶

The increased DAT efflux increases extracellular dopamine.

Amphetamine drugs release dopamine into the extracellular space ^{37 4846}
Amphetamines therefore not only act as dopamine reuptake inhibitors, but also reverse the DAT function so that the DAT not only does not reabsorb dopamine, but also releases it from the cell (efflux).⁵⁵
This is newly synthesized dopamine. There is no doubt that this is not a depletion of dopamine reserves, as amphetamine drugs would otherwise have no lasting effect.
It is questionable whether this is dopamine that was previously stored in vesicles. There is no doubt that amphetamine drugs (characteristic of drugs: high dose, rapid application, rapid onset of action) 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 this is the case.

2.1.1.2.1. Via VMAT2 at high doses¶

• (Only) at a very high dosage as a drug, amphetamines also act on the vesicular monoamine transporter 2 (VMAT2) for dopamine and noradrenaline and then trigger an accumulating release of dopamine from the synaptic vesicles. The high amount of dopamine is then 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.¹⁸ In other words: Amphetamines can enter presynaptic monoamine vesicles and cause an efflux of neurotransmitters towards the synapse.⁵⁶
• An administration of 1 mg/kg AMP (injected) already caused a dopamine DAT efflux that was significantly higher at 10 mg/kg.⁵⁷

2.1.1.2.2. By increasing intracellular Ca2+¶

AMP increases intracellular Ca2+, which supports phosphorylation of DAT at the N-terminus of the transporter. Phosphorylation (by CaMKII and possibly also by PKCβ) increases probability of DAT efflux from cytoplasmic DA.⁵⁸

2.1.1.2.3. Increased DAT efflux via TAAR1¶

• AMP acts on DAT via TAAR1
  Amphetamine enables the trace amine-associated receptor 1 (TAAR1) to phosphorylate the DAT transporter. This interrupts the reuptake of dopamine and the DAT is stimulated to release dopamine (efflux).⁵⁶
• AMP also leads to increased intracellular accumulation of DAT⁵⁹

2.1.2. Vesicular release¶

• AMP reduces vesicular release because as a lipophilic weak base and as a substrate for VMAT, AMP promotes the redistribution of dopamine from the synaptic vesicles into the cytosol by collapsing the vesicular pH gradient.⁴⁴ As a result, AMP reduces the number of dopamine molecules released per vesicle.⁴⁵
• Amphetamine initially reduces VMAT2, while prolonged administration increases it.⁶⁰ MPH increases VMAT2 per se.⁶¹⁶²
• AMP can inhibit vesicular release by indirectly activating D2 autoreceptors. The activation of D2 autoreceptors regulates potassium channels, which in turn regulate the probability of exocytic dopamine release.⁴⁵
• A computer model determined⁶³
  • A maximum release of dopamine at 0.5-1.0 mg/kg AMP (lower at lower doses than at higher doses)
  • Most of the dopamine released resulted from AMP-stimulated dopamine neosynthesis
    • The dopamine produced was immediately converted into DOPAC, which is excreted extracellularly
    • The dopamine was not stored in vesicles
• According to Stahl, AMP does not release dopamine, at least at low doses¹⁸
• AMP caused a gradual 10-fold increase in extracellular dopamine in the striatum over approximately 30 minutes in wild-type mice in vitro and in vivo, while simultaneously reducing the dopamine pool available for electrically stimulated release. If vesicular dopamine was previously released into the cytosol by reserpine, extracellular dopamine did not increase; however, AMP caused a rapid increase in dopamine within 5 minutes. In DAT-KO mice, extracellular dopamine did not increase, but at the same time electrically stimulable dopamine release was also reduced. DAT are therefore required for the dopamine-releasing effect of AMP, but not for the vesicle-emptying effect. Dopamine emptying of the vesicles is the rate-limiting step for the AMP effect on dopamine.⁶⁴
• AMP (10 microm) promoted the release of dopamine from vesicles by reducing the affinity of vesicles for dopamine uptake (from K(m) 0.8 to K(m) 32 microm). However, the amount of dopamine released per pulse was reduced by 82 % (according to another source by 25 to 50 %). The D2 antagonist sulpiride reduced the inhibition of release, i.e. promoted the release. This was reduced in D2-KO mice.
  In inhibited D2 autoreceptors, AMP increased the extracellular release of dopamine.⁴³

• Emptying of the vesicular DA stores through a weak alkaline effect on the intravesicular pH gradient. The intravesicular pH gradient is required for the concentration of DA.
• Different effect on release-ready vesicles and reserve pool vesicles:⁴²
  • stimulus-dependent effect in the dorsal striatum
    • stimulates vesicular dopamine release
      • by a firing of short duration
      • via vesicle pool ready for release
    • Release reduced
      • through a firing of long duration
      • which accesses the reserve pool
    • these opposing effects of vesicular dopamine release were associated with simultaneous increases in tonic and phasic dopamine responses
  • in the ventral striatum
    • only increased vesicular release and increased phasic signals

2.1.3. D2 autoreceptor activation¶

Basically, D-amphetamine activates D2 dopamine autoreceptors in the striatum.⁶⁵
However, drug doses of D-AMP do not cause a significant reduction in dopamine release via activation of the D2 autoreceptors.⁶⁶⁶⁷

Since drugs such as levodopa or piribedil show no positive effect in ADHD, although they reduce the firing rate of the dopaminergic neurons of the substantia nigra pars compacta, it is doubtful whether the reduction of hyperactivity in ADHD by stimulants is based on presynaptic inhibition. Presumably, the reduction of hypermotor activity by stimulants in ADHD is rather based on an increase in dopamine release.⁶⁶

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 L-dopa levels, but this does not appear to occur via a change in the phosphorylation of tyrosine hydroxylase.⁶⁸

2.1.5. Increased DA firing / activation in dopaminergic brain regions¶

2.1.5.1. Increased DA firing in caudate nucleus / putamen (striatum)¶

High (well above drug dose) D-amphetamine administration (2.5 to 10 mg/kg in the rat into the abdominal cavity), leads to increased dopaminergic firing in the caudate nucleus and putamen and causes focused-repetitive (stereotypic) behavior.⁶⁹⁷⁰ The D2 antagonist haloperidol (2 mg/kg) terminates the excessive firing in the caudate nucleus and putamen and the reduced firing in the nucleus accumbens⁶⁹

2.1.5.2. Increased DA firing in VTA and substantia nigra¶

D2 antagonists prevent increased firing in the substantia nigra and VTA (in vivo).⁷¹

2.1.5.3. Increased activation in the right orbitofrontal cortex, left middle frontal lobe, superior frontal lobe and precentral gyri¶

Improvement in ADHD symptoms with LDX was associated with significantly increased activation in a number of brain regions previously implicated in reinforcement processing under choice and feedback conditions (e.g., left caudate and putamen, right orbitofrontal cortex, left middle frontal lobe, superior frontal lobe, and precentral gyri).⁷²

2.1.6. Reduced DA firing in the nucleus accumbens¶

In the nucleus accumbens, 7.5 mg/kg D-Amp led to a reduction in dopaminergic firing.⁶⁹ The D2 antagonist haloperidol (2 mg/kg) terminated the excessive firing in the caudate nucleus and putamen and the reduced firing in the nucleus accumbens⁶⁹

2.1.7. DA influence indirectly via effects on dopamine cells emanating from other brain regions¶

Amphetamine appears to influence the activity of dopamine cells indirectly via its effects on dopamine cells originating in other brain regions.⁷³

Amphetamine can excite dopamine neurons by modulating glutamate neurotransmission. Amphetamine strongly inhibits inhibitory postsynaptic potentials in dopamine neurons mediated by the metabotropic glutamate receptor (mGluR), but has no effect on excitatory postsynaptic currents mediated by the ionotropic glutamate receptor. Amphetamine desensitizes mGluR-mediated hyperpolarization by:⁷⁴

• DA release
• Activation of postsynaptic alpha1-adrenergic receptors
• Suppression of InsP3-induced calcium release from internal stores
  By selectively suppressing the inhibitory component of glutamate-mediated transmission, amphetamine can promote burst firing of dopamine neurons and thus increase the phasic release of dopamine.

2.1.8. Downregulation of dopamine receptors?¶

Reports of immediate downregulation of dopamine receptors by administration of amphetamine are based on studies in which rats were given doses of amphetamine. This concerns the dosage level (5, 10, 15 mg/kg for 4 or 20 days twice daily) as well as the form (injection).⁷⁵ Interestingly, a single dose of D-AMP even increased the number of receptors.⁷⁵⁶⁷
So far, we are not aware of any reports of downregulation when administered in the dose and form of medication.

Similarly, only studies with drug doses of amphetamines appear to change the dopamine receptor affinity or receptor status from high-affinity to low-affinity. Drug doses could alter the balance between receptor status towards low-affinity.⁶⁷
More on receptor status at High-affinity and low-affinity receptor status In the article Dopamine effect on receptors

However, it is conceivable that amphetamine in drug doses does not cause a desensitization of the postsynaptic or extrasynaptic (the majority of dopamine receptors are located outside of synapses) D1 and D2 receptors directly, but via the detour of increasing the extracellular dopamine level. However, this hypothesis has not yet been experimentally proven.⁶⁷ It is possible that this pathway leads to reduced psychomotor activity through amphetamine medication. In our view, however, this is contradicted by the fact that this effect already occurs with the first dose. On the other hand, this pathway could explain why many people with ADHD benefit from a slow and small-step titration of stimulants,

2.2. Noradrenaline with amphetamine medication¶

2.2.1. Noradrenaline reuptake inhibition via NET¶

• Amphetamine drugs block the dopamine and noradrenaline transporters in a different way to 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 noradrenaline transporters and bind to the same site where the monoamines bind to the transporter, thereby also inhibiting NE and DA reuptake.⁴⁷⁷⁶
• “Amphetamines can also stabilize dopamine and noradrenaline transporters in channel configurations, reverse flow through intracellular vesicular monoamine transporters, and cause internalization of dopamine transporters”⁴⁹
• D-amphetamine has about a third of the reuptake inhibition on the noradrenaline transporter (NET) and dopamine transporter (DAT) as racemic methylphenidate.³⁷
• Amphetamine (as well as ephedrine) also inhibit the intracellular noradrenaline transporter, which takes up noradrenaline from the nerve cell into the vesicles (the neurotransmitter stores)⁷⁶

2.2.2. Noradrenaline release¶

• Whether amphetamine has a noradrenaline-releasing effect when administered as a drug is the subject of controversial debate, as is the case with dopamine. There are voices against¹⁸ as well as in favor.⁴⁶⁴⁸
• D-amphetamine secondarily increases the release of noradrenaline.⁶⁵ This is always the case with dopaminergic drugs due to the conversion of dopamine (approx. 5 - 10 %) into noradrenaline.
• There is no doubt that amphetamine drugs do not lead to a chronic depletion of noradrenaline reserves in the sense of a deficiency state. It is empirically proven that amphetamine medication for ADHD does not lead to long-term habituation effects

2.5 mg/kg AMP in mice:⁷⁷

• stereotypical behavior (a sign of strongly increased extracellular dopamine); as strong as 20 mg/kg MPH
• extracellular dopamine increased
• extracellular noradrenaline increased
• extracellular serotonin increased

2.2.3. Reduction of noradrenaline metabolites only in responders¶

• In several independent studies, D-amphetamine drugs were found to decrease the urinary metabolite of norepinephrine, MHPG. The decrease of MPHG in urine is thought to be an important indicator of stimulant onset, indicating a lowering of norepinephrine levels by dextroamphetamine drugs.⁷⁸](https://psycnet.apa.org/psycinfo/1982-21744-001)
• Furthermore, the reduction in noradrenaline metabolites only occurs in people with ADHD who respond positively to dexamphetamine (responders).⁷⁹
• Even with the administration of methylphenidate, only the responders showed a significant decrease in MPHG in the urine, while MPHG in the urine of the non-responders did not decrease.⁸⁰
  The authors conclude from this that noradrenaline levels are reduced in ADHD.
• Furthermore, several studies with people with ADHD found that behavioral improvements were proportional to the reduced noradrenal metabolite levels (using D-amphetamine medication).⁸¹

In contrast to the reduction of metabolites in urine by D-amphetamine, the noradrenaline increase in PFC mediated by D-amphetamine is approximately as pronounced as that of MPH, but is significantly more dose-dependent and therefore more controllable.³⁷

2.2.4. DA firing and DA bursting increased via noradrenaline α1 receptors¶

D-Amp (1 to 2 mg/kg) acts via alpha1-adrenoceptors⁸² (but not via alpha2- or beta-adrenoceptors) to increase dopaminergic firing and bursting in substantia nigra and VTA (in vivo). This adrenergic pathway is usually masked by the reduction in dopaminergic firing mediated by D2 autoreceptors and is visualized by D2 antagonists or by simultaneous administration of D1/D5 and D2/D3/D4 blockers. The selective norepinephrine uptake blocker nisoxetine did not increase the DA firing rate, but did increase DA bursts.⁷¹⁸³

D-amphetamine appears to activate the noradrenaline α1-receptor in the PFC, as the α1-receptor antagonist prazosin completely neutralized the effect of D-amphetamine in the PFC. In contrast, D-amphetamine does not appear to target either the α2 receptor or the β receptor, as the effect of D-amphetamine persisted when the α2 or β receptors were blocked.⁸⁴
D-amphetamine promotes the up-state of cortical neurons by activating⁸⁵

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

In contrast, the dopamine/noradrenaline precursor L-DOPA did not promote the up state.

Arousal is associated with an increased up state, while slow-wave sleep, general anaesthesia and calm 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, while the transition to a sustained up state is required for arousal and attention.⁸⁵

2.3. Monoamine degradation inhibition via MAO¶

Amphetamine drugs act as MAO inhibitors,⁸⁶³⁸ differently than low-dose MPH. Whether high-dose MPH acts as an MAO inhibitor is unknown.³⁷

MAO is an enzyme that breaks down dopamine and noradrenaline in the cell. MAO inhibitors thus increase the amount of dopamine and noradrenaline available in the cell. As dopamine and noradrenaline continue to be synthesized in the nerve cell, the noradrenaline and dopamine levels in the cell continue to rise. This leads to a reversal of the effect of the transporters (which actually return DA and NE from the synaptic cleft into the cell), so that they release NE and DA into the synaptic cleft, even without this being triggered by a nerve signal to be transmitted.⁸⁶ This effect triggers peripheral hypertension and an increase in heart rate. As this mechanism of action occurs indirectly at the presynapse, ephedrine and amphetamine drugs are also called “indirect sympathomimetics”, while active ingredients that act directly at the postsynaptic receptors are called sympathomimetics.⁸⁶

2.4. Serotonin release¶

Amphetamine drugs are said to release a small amount of serotonin.⁸⁷¹⁷ Here, too, it is unclear whether this is really also the case when dosed at drug level, or whether this effect is only limited when dosed as drugs. In any case, Stahl does not report a serotonergic effect of amphetamine drugs.⁴⁷

2.5 mg/kg AMP in mice:⁷⁷

• stereotypical behavior (a sign of strongly increased extracellular dopamine); as strong as 20 mg/kg MPH
• extracellular dopamine increased
• extracellular noradrenaline increased
• extracellular serotonin increased

• There is evidence that an increased release of serotonin indirectly increases dopamine levels.⁸⁹
• Other sources point to a serotonin-increasing effect of amphetamine salts due to inhibition of monoamine oxidase.²⁰
• Amphetamine increases c-Fos expression in the mPFC, striatum and nucleus accumbens. A serotonin 1A receptor agonist reduced the c-Fos increase in the mPFC and striatum, but not in the nucleus accumbens.⁹⁰
• MPH itself has an agonistic effect on the 5-HT1A receptor.³⁸

2.5. Effect on the HPA axis¶

2.5.1. ACTH increased¶

Lisdexamfetamine and d-amphetamine significantly increased plasma levels in healthy subjects of, among others:⁹¹

• ACTH

2.5.2. Corticosteroids increased¶

• D-amphetamine drugs such as lisdexamphetamine drugs (Vyvanse) increase cortisol levels but not testosterone levels.⁹¹
• The following were increased
  • Glucocorticoids (as with methylphenidate; the increase was even greater with the drugs MDMA or LSD)
    • Cortisol
    • Cortisone
    • Corticosterone
    • 11-Dehydrocorticosterone,
    • 11-Deoxycortisol
• The following remained unchanged
  • Mineralocorticoids
    • Aldosterone
    • 11-Deoxycorticosterone

The increase in the cortisol level causes a stronger addressing of the glucocorticoid receptor (GR) by cortisol. Cortisol causes the HPA axis to be switched off again via GR 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 switch off the HPA axis again after a stress reaction. In addition, in ADHD-HI (unlike ADHD-I) there is often deficient GR function, which makes HPA axis deactivation even more difficult.
Find out more at Medication for ADHD at ⇒ Dexamethasone for ADHD. If the release of cortisol is increased by AMP, this could improve the resilencing of the HPA axis in ADHD-HI. However, as AMP also works in ADHD-I, the primary mechanism of action is likely to be different.

2.5.3. Increased steroid hormones¶

Lisdexamfetamine and d-amphetamine significantly increased plasma levels in healthy subjects of, among others:⁹¹

• Androgens
  • Dehydroepiandrosterone
  • Dehydroepiandrosterone sulfate
  • Androstenedione (Δ4-androstene-3,17-dione)
  • Progesterone (only for men)

The androgen remained unchanged

• Testosterone

Since aggression correlates with an increased testosterone to cortisol ratio, amphetamine drugs have an anti-aggressive effect due to the relative increase in cortisol levels.
More on this at ⇒ Neurophysiological correlates of aggression

A study in adolescent rhesus monkeys found that both active ingredients increased testosterone levels, MPH even more than AMP, as a consequence of 12 months of AMP or MPH administration in drug doses.⁹² Another study in rhesus monkeys found reduced testosterone levels with MPH administration.⁹³

A reduction in testosterone levels was observed in rodents following amphetamine administration.⁹⁴⁹⁵

2.6. Inhibition of OCT2¶

Basic information on uptake-2 transporters can be found at Dopamine degradation by organic cation transporters (OCT) In the article Dopamine reuptake, dopamine degradation

Organic cation transporter 2 (OCT2) is involved in the degradation of dopamine. OCTs take up dopamine and noradrenaline as well as serotonin and, to a somewhat greater extent, histamine in glial cells, where they are broken down by COMT. OCT2 and OCT3 are also located on (also dopaminergic) neurons.
While methylphenidate only binds to OCT1 (IC50: 0.36) and neither to OCT2, OCT3 nor PMAT⁹⁶, d-amphetamine acts as a highly effective hOCT2 reuptake inhibitor (Ki: 10.5 mM) and moderately effective hOCT1 reuptake inhibitor (Ki: 202 mM), while it only interacted with hOCT3 from 100 μM (Ki: 460 mM) (hOCT: human OCT) ⁹⁶⁹⁷
d-Amphetamine binds approximately equally strongly to hOCT2 and hOCT3 and to these by an order of magnitude (factor 10) weaker than to DAT⁹⁷

Binding of amphetamine to OCT may contribute to cellular and behavioral effects of amphetamine.⁹⁷

OCT2 reuptake inhibitors have an antidepressant effect.⁹⁸ In addition, even much lower doses of venlaflaxine or reboxetine have an antidepressant effect in OCT2-KO mice than in wild-type mice⁹⁹
We think it is worth considering whether this approach could also support the effect of dopamine reuptake inhibitors in ADHD.
These correlations could also explain why AMP, which also acts as an OCT2 inhibitor, has a better antidepressant effect than MPH, which only binds to OCT1.

2.7. Other effects on brain functions¶

• D-amphetamine increases metabolism in the right caudate nucleus and decreases it in the right Rolandic region and in the right anterior inferior frontal regions.¹⁰⁰
• D-amphetamine (as well as L-dopa, which has no effect on ADHD, although it has a dopaminergic effect) is also suitable for restoring brain function after strokes, but only if suitable training measures are taken at the same time.¹⁰¹ D-amphetamine increases dopamine, which has a neurotrophic effect (promotes neuroplasticity). Dopaminergic drugs such as (D-)amphetamine drugs or MPH can therefore 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), while atomoxetine and guanfacine do not.¹⁰²
• Lisdexamfetamine (Vyvanse) has the following effects¹⁰³
  • Increased acetylcholine levels in the cortex
  • Increased histamine levels in the cortex and hippocampus (which escitalopram given in parallel only prevents in the hippocampus)

Amphetamine medication is therefore not just a substitute for methylphenidate, but has its own area 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 an inhibition of the activity of the respective transporters.¹⁰⁴
The values given in the following table by Easton et al. refer to values in the synaptosome as well as to the DAT in the striatum and the NET in the PFC.

Binding affinity: stronger with smaller number (KD = Ki)	DAT	NET	SERT
MPH	34 - 200104 , 34133	23833, 339104	> 10,000104
d-AMP (Vyvanse, Attentin)	34 - 41104 , 206 (sulphate) 33	** 23.3 - 38.9**104 , 54.8 (sulphate)33	3,830 - 11,000104
l-AMP	138104 , 1435 (sulphate) 33	** 30.1**104 , 259 (sulphate)33	57,000104
ATX	1451 - 1600104 235533	** 2.6 - 5**104 , 20.633	** 48 - 77**104
GBR-12909	40.233
Desipramine		4.933

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

The active ingredients methylphenidate (MPH), amphetamine (AMP) and atomoxetine (ATX) alter extracellular dopamine (DA) and noradrenaline (NE) to different degrees in different regions of the brain. Table based on Madras,¹⁰⁴ 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 medication compared to MPH / atomoxetine¶

In MPH nonresponders, lisdexamfetamine (EU: Vyvanse) and atomoxetine were compared in a randomized double-blind study with n = 200 subjects. Lisdexamfetamine was significantly more effective than atomoxetine in 2 of 6 categories and in the overall assessment.¹⁰⁵
Lisdexamfetamine (EU: Vyvanse) also had a good effect on comorbid depression symptoms in a double-blind study.¹⁰⁶ MPH is not known to have any positive effects on depression symptoms.
A 2-year study in children and adolescents (n = 314) showed a responder rate of between 70 and 77 % with good efficacy and manageable side effects.¹⁰⁷

4. Effect on ADHD symptoms¶

In people with ADHD who respond positively to D-amphetamine medication as well as MPH, the effect of D-amphetamine medication is at least equal to MPH¹⁰⁸, and 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.

According to the current European consensus, amphetamine medication is the first choice of medication for ADHD in adults (before methylphenidate) and the second choice of medication in children (after methylphenidate).⁶⁷

Amphetamine medication should also always be tried if MPH does not work (non-responder).

4.1. ADHD-I (without hyperactivity)¶

MPH has a stronger activating and drive-enhancing effect on most people with ADHD than AMP medication. Contrary reports¹⁰⁹ are not consistent with our experience.
Statements in the specialist literature that amphetamine medication is more suitable for people with ADHD-I than MPH, partly because people with ADHD-I are above-average AMP nonresponders,¹¹⁰ cannot be confirmed from our experience either
We know several persons with ADHD-HI who are significantly better helped by amphetamine medication than MPH and people with ADHD-I who cope better with MPH. We are not aware of any 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. Attention control¶

People with ADHD have reduced extrinsic and intrinsic motivation. For example, they need higher rewards to be just as motivated for something as non-affected people. However, once motivation is awakened in persons with ADHD, their attention and controllability can no longer be reliably distinguished from that of non-affected people. ⇒ Motivational shift towards own needs explains regulation problems
Attention correlates with a deactivation of the default mode network (DMN), among other things. Stimulants are able to align the attentional control of people with ADHD (or the motivational capacity, from which attention follows) with that of non-affected people, which is then also reflected in a normalization of DMN deactivability.¹¹¹

More on the deviant function of the DMN in ADHD and its normalization by stimulants, including further sources at ⇒ DMN (Default Mode Network) In the article ⇒ Neurophysiological correlates of hyperactivity.
The cited references refer to the effect of methylphenidate. However, it can be assumed that the effect is achieved by stimulants in general.

People with ADHD report that MPH allows for greater focus, while amphetamine medications (Vyvanse) tend to create a more relaxed general alertness and have a slightly more pleasant effect overall.

4.3. Comorbid depression or dysthymia¶

Amphetamine medications probably also have a mild serotonergic effect and thus have a special area of 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, a number of people with ADHD report a significant antidepressant effect from amphetamine medication, which they are not familiar with from MPH.¹¹² This is consistent with the experiences of users known to us.

As amphetamines can have a stronger drive-increasing effect than MPH, this can release an existing suicidal tendency that was not previously carried out due to the existing depression. Amphetamine medication should therefore be used with caution in cases of (even concealed) severe depression.

Attention: a supposed dysthymia (mild chronic depression) in people with ADHD must be clearly differentiated from the original ADHD symptom of dysphoria during inactivity.
Find out more at ⇒ Depression and dysphoria in ADHD In the section ⇒ Differential diagnosis of ADHD.

4.4. Comorbid anxiety disorders / depression¶

Comorbid anxiety disorders or depression can be exacerbated by stimulants, as anxiety and moods are regulated by the dopaminergic activity of the ventromedial PFC in conjunction with the limbic system.⁴⁷

4.5. Comorbid sleep disorders¶

Amphetamine drugs have a very long duration of action (up to 13 hours). Taking it too late (less than 14 hours before going to bed) could therefore cause problems falling asleep. In contrast, some people with ADHD who take amphetamines report feeling pleasantly tired in the evening and that they no longer have problems falling asleep.

Studies show that amphetamine medications improve overall sleep quality in ADHD.¹¹³¹¹⁴

4.6. Impulsiveness¶

People with ADHD reported in forums that MPH worked better against impulsivity than Vyvanse (lisdexamfetamine).¹¹⁵

5. Response rate (responding / non-responding)¶

Response here means whether there is an effect on the ADHD symptoms. People with ADHD who do not respond sufficiently to a medication are called non-responders.
Non-responding does not mean having no effect, but merely that the effect remains below the level of symptom improvement specified in the respective study.

One study reported a responder rate of 80% (defined as an improvement of more than 30% in ADHD-RS-IV scores and CGI-I scores of greatly improved or very greatly improved)¹¹⁶
A summary of several studies reports a 69% response rate to amphetamine medication and a 59% response rate to methylphenidate. 87 % of the people with ADHD responded to one of the two types of drugs.¹²
A 2-year study of L-amphetamine medication in children and adolescents (n = 314) showed a responder rate of between 70 and 77% with good efficacy and manageable side effects.¹⁰⁷
For MPH non-responders, it is therefore highly recommended to test a medication with amphetamine drugs (see 1.2.), and vice versa.

In carriers of the COMT Val-158-Met gene polymorphism, amphetamine increased the efficiency of the PFC 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 a 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.¹¹⁷

6. No gender-specific differences in effect¶

Amphetamine drugs do not appear to show any gender-specific differences in effect.¹¹⁸

7. Calming effect at low doses, activating at high doses¶

D-amphetamine appears to have a biphasic action profile. Low doses of 0.5 to 1 mg/kg in rats (equivalent to about 0.2 to 0.6 mg/kg in humans) reduce (hyper)activity, while higher doses increase it.⁴¹

8. Dosage of amphetamine medication or MPH¶

About 66% of all persons with ADHD respond equally well to MPH as to amphetamine medication.
22% respond better to amphetamine drugs than to MPH.
11% respond better to MPH than to amphetamine drugs.¹¹⁹
Around 15% of people with ADHD respond best to the active ingredient D-amphetamine.¹²⁰

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

Highly gifted people with ADHD (here: IQ > 120) are said to respond better to amphetamine medication than less gifted people with ADHD.¹²¹

An interesting study discusses the effectiveness of lisdexamfetamine.¹²²

It is advisable to start with a very low dosage, which is then slowly increased. Even if the optimal dosage were known, an immediate optimal dosage would possibly lead to excessive demands.¹²³ 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 an overdose, signal transmission is just as impaired as if the level is too low.
This explains why low doses should be given at the beginning and then, with persistent persistence, higher doses should be given until a worsening of symptoms is observed.

As the number of dopamine transporters in adults is half that of 10-year-olds, it is advisable to start with a much lower dosage than in children.

9. Effect profile (temporal) / duration of action¶

In replicated studies on the duration of action of amphetamine drugs, children had a shorter half-life of around 7 hours, while adults had a longer half-life of around 10 to 12 hours¹²⁴

The time course of the effect (effect profile) depends less on the active ingredients than on the specific composition of the medication.
Vyvanse has a very elongated effect profile without pronounced peaks, so that barely any flooding or rebound effects are noticeable. See: Graphic representation of the Vyvanse effect profile. However, the graph from Shire’s patent application refers to the plasma level in rats at an extremely high dose of 3 mg/kg.

Another graph shows the The progression of the active substance at 30 mg, 50 mg and 70 mg Vyvanseon page 20.

Empirically, adults report quite unanimously of a gentler and prolonged effect of lisdexamfetamine. The majority cite 5 to 7 hours as the duration of action of a single dose. There is also a fairly unanimous report of a very slow onset of action, with 1 to 2 hours being mentioned in most cases.

An internal (and not representative) Survey at adhs-forum.adx.org on the duration of action of Vyvanse (n= 80) and another survey in a sub-reddit on Vyvanse (n = 467) yielded the following result (n = 547):

Duration of action of a single dose of Vyvanse	% of participants
5 hours and less	40.8 %
6 to 7 hours	26.7 %
8 to 9 hours	15.4 %
10 to 11 hours	11 %
12 hours and more	6.2 %

The surveys are not representative (no consideration of age, weight, dose level or gender), but clearly show that a duration of action of 13 or 14 hours, as stated by the manufacturer, is only exceptionally achieved in adults in practice.
A more detailed Survey on the single-dose duration of action of all ADHD medicationswhich also includes the aforementioned secondary factors, has been running since March 2023 and could show initial results in fall 2023.

Many people with ADHD (we know of dozens of cases from the forum) take 2 or 3 single doses of Vyvanse per day to achieve the required all-day coverage, even if this does not comply with the manufacturer’s instructions. The individually shortened duration of action could also be a consequence of a low dosage of often 30 mg or less per single dose, which was chosen when an overdose was perceived at a higher single dose during the phase of high D-AMP blood plasma levels. In almost no person with ADHD does the sum of the single doses exceed 70 mg / day.
The result of taking multiple smaller doses of Vyvanse on D-AMP blood plasma levels could (hypothetically) look like this:

10. Areas of application of amphetamine drugs in relation to MPH¶

According to the current European consensus on the diagnosis and treatment of ADHD in adults, amphetamine medication is the first choice of medication for ADHD in adults (before methylphenidate) and the second choice of medication for children (after methylphenidate)⁶⁷
In children who are MPH non-responders, i.e. who do not respond to MPH, the efficacy of amphetamine medication should be tested.
People with ADHD with pronounced dysphoria during inactivity or with comorbid depression benefit particularly from amphetamine medication.
In addition, people with ADHD who require stronger activation may be able to cope better with amphetamine medication.
Highly gifted people are said to respond better to amphetamine medication than to MPH.¹²¹

11. Side effects¶

11.1. No liver damage with normal medication dosage¶

High doses of amphetamines may be associated with liver damage and certain forms of clinically apparent liver damage. This is most commonly reported with methylenedioxymetamphetamine (MDMA: “ecstasy”).¹²⁶

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

11.2 AMP increases histamine¶

AMP increases histamine,¹²⁷¹²⁸ as do all other known ADHD medications:

• Atomoxetine
• Methylphenidate
• Modafinil
• Nicotine
• Caffeine

Therefore, people with histamine intolerance often have problems due to taking ADHD medication.
A person with ADHD with histamine intolerance reported that she could not tolerate AMP and sustained release MPH at all, but could tolerate immediate release MPH in small doses.

11.3. No increased cardiovascular risks¶

Several large studies found no increased risk of serious cardiovascular events such as stroke, heart attack or cardiac arrhythmia for amphetamine drugs.¹²⁹¹³⁰
A study over 14 years found a 4% increase in the risk of cardiovascular problems per year of taking stimulants (methylphenidate, amphetamines) and, to a lesser extent, the non-stimulant atomoxetine.¹³¹

11.4. Individual cases of trichotillomania¶

Individual cases of trichotillomania (pulling out hair) have been reported.¹³² Trichotillomania is a specific form of impulse control disorder.

11.5. Erection, libido, reproduction¶

The package insert for Vyvanse mentions erectile dysfunction in 1 to 10 out of 100 men. However, the specialist literature or studies do not report any sexual impairments caused by amphetamine medication.

Reports from the ADxS-ADHD forum sometimes report erection problems with amphetamine medications, but barely with MPH.
Two male persons with ADHD reported a loss of sensitivity in the genital area after consuming red wine outside the active period of the regularly taken Vyvanse. In one of the persons with ADHD, low nicotine consumption outside the active period is another suspicious factor.

A single case report documents a reduction in testosterone and other sex hormones and a reduction in sperm count from an amphetamine medication, which was reversed by switching back to MPH.¹³³

Amphetamine drugs also bind to alpha1-adrenoceptors (see above).
A blockade of alpha1-adrenoceptors leads to a delayed detumescence of the erectile tissue and thus to a reduced ability to ejaculate and orgasm, both in women and in men.¹³⁴ Blockade is the opposite of binding. Dopamine agonists such as L-dopa or bromocriptine cause an increase in sexual desire and sexual activity.
Amphetamines (usually in drug use) can alter spermatogenesis and lead to oxidative stress and subsequent apoptosis in testicular tissue¹³⁵

A pilot study in men with sexual problems reported improvements in subjective sexual experience (reduced time to orgasm or increased frequency of orgasm) with 5 to 20 mg amphetamine salts (Adderall) 1 to 4 hours before sexual activity (up to 10 doses/month)¹⁴⁷
In 5 individual cases, the resolution of SSRI-induced sexual dysfunction by small doses of dextroamphetamine or methylphenidate was reported.¹⁴⁸ Further case studies report multiple erections (15-year-old), hypersexual behavior (8-year-old) due to OROS-MPH (Concerta)¹⁴⁹ and priapism (14-year-old).¹⁵⁰

One study reported a doubled rate of testosterone deficiency in adult persons with ADHD after 5 years of stimulant use (1.2%) compared to persons with ADHD without stimulant use (0.67%) or non-stimulant use (0.68%).¹⁵¹

11.6. Miscellaneous¶

Common side effects of amphetamine mixed salts are:³⁵

• Loss of appetite
• Mood swings

Rare serious side effects of amphetamine mixed salts are:³⁵

• psychotic symptoms
• Seizures
• Risk of abuse

The drug MDMA (unlike amphetamine drugs) can damage nerve cells and attack the blood-brain barrier.¹⁵²

11.7. Overdose¶

Symptoms of a (severe) overdose of amphetamines (in the sense of intoxication) include

• Agitation¹⁵³
• Hyperactivity¹⁵⁴
• Movement disorders¹⁵³
• Tremor¹⁵³
• Hyperthermia¹⁵⁴
• Tachycardia (rapid heartbeat)¹⁵⁴
• Tachypnea (increased respiratory rate)¹⁵⁴
• Mydriasis (pupil enlargement)¹⁵⁴¹⁵³
• Trembling¹⁵⁴
• Seizures¹⁵⁴, in extreme cases up to epileptic forms¹⁵³
• Hyperreflexia (excessive reflex response)¹⁵³
• combative behavior¹⁵³
• Confusion¹⁵³
• Hallucinations¹⁵³
• Delirium¹⁵³
• Fear¹⁵³
• Paranoia¹⁵³

12. Breakdown of amphetamine¶

12.1. Reduction of LDX¶

Lisdexamfetamine (Vyvanse) is converted to d-AMP in the blood cytosol of erythrocytes by an unknown amino acid (presumably an aminopeptidase)¹⁵⁵¹⁵⁶ by cleaving the covalent bond between d-amphetamine and L-lysine. Only d-AMP is pharmacologically active.

96% of LDX is excreted in the urine, of which²⁸

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

In contrast to AMP, LDX is less sensitive to changes in urine pH.
The half-life of LDX is typically less than 1 hour.

12.2. Degradation of D-AMP and L-AMP¶

D-AMP is metabolized faster than l-AMP, so that the exposure of d-AMP lasts 9-11 hours and of l-AMP 11-14 hours.
Taking it together with a high-fat meal can extend the half-life of d-AMP by one hour.

AMP is broken down in two ways²⁸

• Hydroxylation by CYP2D6:¹⁵⁷¹⁵⁶
  • 4-Hydroxyamphetamine
  • Noradrenaline (alpha-hydroxyamphetamine, norepinephrine)
  • both are subject to a further metabolism
• oxidative deamination

A study came to other conclusions, according to which CYP2D6 may barely be involved in the degradation of AMP.¹⁵⁸ Other studies also tend to indicate that amphetamine itself is metabolized much less by CYP2D6 than some amphetamine analogues.¹⁵⁹¹⁶⁰
Nevertheless, amphetamine is a strong CYP2D6 inhibitor.¹⁶⁰

AMP is primarily excreted via the kidneys.
Since AMP is slightly basic (pKA = 9.9), AMP excretion is highly dependent on urine pH and flow rate, with recovery of AMP in urine ranging from 1% to 75% and the remainder being metabolized hepatically:²⁸

• 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.
• acidic urine (pH <6.0)
  • accelerated AMP excretion
• alkaline urine (pH >7.5)
  • delayed AMP excretion

The half-life of AMP should increase by 7 hours per unit of pH increase. Acidifying or alkalizing agents can therefore significantly alter the effect of AMP.

12.3. Duration of action of AMP; influence of CYP2P6 metabolism types¶

The CYP2D6 gene is highly polymorphic. In Central Europe, the following alleles are particularly relevant¹⁶¹

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

Poor metabolizers are likely to require lower AMP doses and ultra-rapid metabolizers are likely to require higher AMP doses. However, the effects of CYP2D6 polymorphisms on AMP metabolism are still unclear.²⁸

Based on the experience with the influence of CYP2D6 on the effect 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 metabolization¹⁶¹

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

More on this under –&gt CYP2D6 metabolizing enzyme

Two online surveys of a total of around 550 people with ADHD who take Vyvanse showed that around 40% have a duration of action of 5 hours or less and two thirds have a single-dose duration of action of 7 hours or less. More on this under Effect and duration of action of ADHD medication

13. Contraindications and interactions¶

As with every drug described here, there are also contraindications for amphetamine drugs.
It should not be taken without prior medical consultation.

For lisdexamfetamine:¹⁶²

• Pregnancy / breastfeeding
  • A cohort study found no increased risk of ADHD or other neuronal developmental disorders from MPH or AMP use during pregnancy.¹⁶³
  • One study found no reduction in the weight of newborns of mothers with ADHD who took amphetamine medication during pregnancy.¹⁶⁴ This is consistent with results from a large cohort study of MPH use during pregnancy.¹⁶⁵
    Another comprehensive study found a slight reduction in birth weight and a slight increase in the risks of pre-eclampsia, placental abruption or premature birth when taking stimulants (AMP or MPH) during pregnancy, although this was so small that the authors did not recommend discontinuing stimulant use during pregnancy.¹⁶⁶ Atomoxetine did not show these slight increases in risk.
    Another Danish cohort study found a doubled risk of miscarriage when taking stimulants during pregnancy.¹⁶⁷
    Another Danish cohort study found an increase in malformations in children of mothers who had taken MPH in the first trimester of pregnancy, but the authors did not consider this to be relevant.¹⁶⁸ A smaller study found no increased risk.¹⁶⁹
    One study found no disadvantages for the child if the mother continued to take D-Amp during pregnancy. However, if D-Amp intake was discontinued during pregnancy, there was an increased risk of abortion. There were advantages if no D-Amp was taken before and during pregnancy. Early discontinuation could therefore be helpful if you wish to have children.¹⁷⁰
• Hypersensitivity to the active ingredient
• Monoamine oxidase inhibitors (MAO inhibitors) at the same time or 14 days before use
  • Risk: hypertensive crisis
• Hyperthyroidism / thyrotoxicosis
• Excitation states
• Symptomatic cardiovascular disease
• Advanced arteriosclerosis
• Moderate to severe hypertension
• Glaucoma
• Serotonin reuptake inhibitors
  • The risk of serotonin syndrome should be taken into account when administering SSRIs and amphetamine medication at the same time.²⁰

According to a very large study, the risk of developing psychosis is lower for people with ADHD taking MPH (0.10%) than for those treated with amphetamine medication (0.21%).¹⁷¹ While people with ADHD treated with stimulants have 2.4 cases of psychosis per 1000 person-years, the figure for the population as a whole is 0.214%.¹⁷² The studies do not allow any conclusion to be drawn as to whether the increased prevalence of psychosis is attributable to ADHD or stimulants.

13.1. Shortened half-life (reduced effect)¶

Attenuation of the effects of dexamphetamine:¹⁷³

• Adrenoreceptor blockers (beta blockers)
  • e.g.:
    • Propranolol
• Lithium
• Phenothiazines
• Haloperidol
• Substances that lower the pH value in the gastrointestinal tract
  • e.g:
    • Guanethidine
    • Reserpine
    • Glutamic acid
    • Hydrochloric acid
    • Ascorbic acid
    • Fruit juice
  • cause reduced absorption of dexamphetamine
• Substances that acidify urine (ammonium chloride, sodium dihydrogen phosphate, etc.)
  • increase ionized excretion products of dexamphetamine in urine, resulting in increased renal excretion

• Acidification of the urine (reduced pH value)¹⁶²
  e.g. through
  • Ascorbic acid
  • Thiazide diuretics
  • High protein diet
  • Diabetes mellitus

Caution: Foods that taste acidic often have an alkalizing effect in the body beyond the digestive tract.
Example: Lemon juice has a pH value of 2.4 and therefore has an acidic effect on the mouth and stomach. After digestion, however, only an alkaline residue remains in the rest of the body, which increases the pH value.
The effect of food after digestion on the acid load of the kidneys due to minerals and protein is indicated by the PRAL value (potential renal acid load). This value is not suitable for assessing the acid load of the mouth and stomach (as is relevant for heartburn).
The higher the PRAL value, the more acidic the effect on the kidneys and the rest of the body after the digestive organs.

Urine pH has been shown to be a good PRAL marker. An alkaline urine pH value correlates with a diet with a negative PRAL value, while urine pH values below 6.0 correlate with an acidifying diet.
A distinction must be made between plant and animal proteins. After 7 days of a vegetarian diet, the pH urine value increases and the PRAL value decreases, as does 2 or 3 days of a vegetarian diet per week.¹⁷⁴ A vegetarian diet thus correlates with a prolonged amphetamine drug effect.
Foods with a high oxalate content can increase acid formation.¹⁷⁵
One study gives the following calculation method:¹⁷⁶ PRAL (mEq/d) = 0.49 x protein (g/d) + 0.037 x phosphorus (mg/d) - 0.021 x potassium (mg/d) - 0.026 x magnesium (mg/d) - 0.013 x calcium (mg/d).

In other words, foods with a strongly negative PRAL value cause alkaline (less acidic) urine and thus promote a prolonged effect of amphetamine drugs. Foods with a high PRAL value cause acidic urine and thus promote a shortened effect of amphetamine drugs. According to this model, hard cheese is suitable for shortening the effects of amphetamine drugs, while raisins could prolong them.

More on this under Acid balance and amphetamine medication In the article Effect and duration of action of ADHD medication

13.2. Prolonged half-life (increased effect)¶

• With alkalized urine (increased pH value)¹⁶²
  e.g. through
  • Sodium hydrogen carbonate (baking powder, soda)
  • Diet with a high fruit / vegetable content
  • Urinary tract infections
  • Vomiting
  • Clonidine¹⁷³

Enhanced effect of dexamphetamine due to:¹⁷³

• Disulfiram
• Substances that increase the pH value in the gastrointestinal tract increase dexamphetamine 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 dexamphetamine
  • e.g:
    • Acetazolamide
    • some thiazides

There is evidence that reduced expression of the CACNA1C gene can lead to a prolonged effect of dopamine reuptake inhibitors.¹⁷⁷ Conversely, increased CACNA1C expression may lead to a shortened effect.

13.3. Delayed effect¶

Lisdexamfetamine (Vyvanse) has a maximum blood level that is delayed by one hour with high-fat meals (4.7 hours instead of 3.8 hours after ingestion).¹⁷⁸ However, other parameters, such as the duration of action, do not change.

13.4. Amplifying effect on amphetamines¶

13.4.1. Alcohol increases amphetamine levels¶

Alcohol can increase amphetamine levels.¹⁷⁹

13.4.2. CYP2D6 inhibitors increase amphetamine levels¶

As amphetamine is broken down by CYP2D6, drugs that are also broken down by CYP2D6 can slow down the breakdown of amphetamine as well as their own breakdown, as competition for the CYP2D6 enzyme arises.
CYP2D6 inhibitors can increase amphetamine levels, making a dose reduction necessary. After discontinuation of CYP2D6 inhibitors, an increase in the dose of amphetamine medication may be necessary.¹⁷⁹
CYP2D6 inducers can accelerate degradation and thus reduce the effect.

See under CYP2D6 metabolizing enzyme

13.5. Attenuating effect on amphetamines¶

Have an attenuating effect on amphetamine:¹⁸⁰

• Chlorpromazine
• Haloperidol
• Lithium carbonate

A single person with ADHD reported a loss of efficacy of Vyvanse due to Dienogest 2 mg (Zafrilla) in endometriosis, while the effect of Attentin remained unchanged.

13.6. Few interactions of AMP with other medications¶

In contrast to the above-mentioned interactions of amphetamine drugs with other drugs, barely any interactions of amphetamine drugs with other drugs are known.¹⁷⁹

Amphetamine is said to have a slight inhibitory effect on the cytochromes

• CYP2D6
• CYP1A2
• CYP3A4.

The clinical relevance is classified as low.¹⁸⁰

Attenuating effect on¹⁸⁰

• Antihypertensives such as guanethidine

Reinforcing on¹⁸⁰

• Analgesic effect of opioids

13.7. AMP during pregnancy¶

A small prospective study of n = 13 children whose mothers received amphetamine medication while breastfeeding found no disadvantages for the children.¹⁸¹

14. Long-term effect: No habituation effects of amphetamine medication¶

A meta-analysis of 87 randomized placebo-controlled double-blind studies found no evidence of a decrease in the effect of methylphenidate, amphetamine drugs, atomoxetine or α2 antagonists with prolonged use.¹⁸²

15. Preparations¶

Amphetamine medications are available as various preparations.

In the USA, amphetamine drugs are available as:¹

• Mixture of D- and L-amphetamine isomers (racemic mixture)
• Mixed sulfates and saccharinates of D-L-amphetamine isomers (Adderall)
• Pure D-amphetamine sulphate
  • Dexamfetamine hemisulfate (Attentin)
• D-amphetamine as lisdexamfetamine in lysine-bound form (Vyvanse, Tyvense)
• Racemic methamphetamine sulphate (Desoxyn)

Vyvanse, Tyvense

Vyvanse / Tyvense contains lisdexamfetamine. Lisdexamfetamine is dextroamphetamine bound to lysine. The lysine binding causes a very slow and even release of dextroamphetamine in the blood and thus a prolonged effect.
Available in the USA:
Capsules: 10, 20, 30, 40, 50, 60, 70 mg
Chewable tablets: 10, 20, 30, 40, 50, 60 mg

16. Taking amphetamine medication abroad¶

See under Taking stimulants abroad