Amfetamine medication (AMP) for ADHD

Due to the responder/non-responder profile, which differs from MPH, amfetamine medication is particularly suitable for people with ADHD who do not respond to MPH, regardless of age, and clearly before the use of non-stimulants (e.g. noradrenergic medication or tricyclic antidepressants).¹ A summary of several studies reports a 69% response rate to amfetamine medication and a 59% response rate to methylphenidate. 87 % of people with ADHD responded to one of the two types of medication.²

Amfetamine medication is also suitable - (even) better than MPH - for the co-treatment of comorbid dysphoria or depression. More on this under Stimulant monotherapy as a first step in comorbid depression and ADHD] In the article Choice of medication for ADHD or ADHD with comorbidity.

In December 2025, we replaced the outdated spelling Amphetamine with the modern spelling Amfetamine.

• 1. Active ingredients of amfetamine drugs
  • 1.1. Dextroamfetamine (D-Amfetamine)
    • 1.1.1. Dextroamfetamine without lysine binding
    • 1.1.2. Dextroamfetamine from lisdexamfetamine (with lysine binding)
  • 1.2. Levoamfetamine (L-Amfetamine)
  • 1.3. Mixed amfetamine salts / amfetamine derivatives
  • 1.4. Methamfetamine
  • (1.5. Fenetyllin)
  • 1.6. Amfetamine derivatives
  • 1.7. Historical: Discovery and development of amfetamine
• 2. Authorization and prescription of amfetamine drugs
  • 2.1. Germany
  • 2.2. Austria
  • 2.3. Switzerland
  • 2.4. Great Britain
  • 2.5. USA
• 3. Effect of amfetamine medication
  • 3.1. Dopamine with amfetamine medication
    • 3.1.1. Effect on DAT
      • 3.1.1.1. Dopamine (re)uptake inhibition via DAT and NET
        • 3.1.1.1.1. DAT inhibition via PKC
      • 3.1.1.2. Increased release of dopamine (DAT efflux)
        • 3.1.1.2.1. Via VMAT2 at high doses
        • 3.1.1.2.2. By increasing intracellular Ca2+
        • 3.1.1.2.3. Increased DAT efflux via TAAR1
    • 3.1.2. Vesicular release
    • 3.1.3. D2 autoreceptor activation
    • 3.1.4. Increase in tyrosine hydroxylase
    • 3.1.5. Increased DA firing / activation in dopaminergic brain regions
      • 3.1.5.1. Increased DA firing in caudate nucleus / putamen (striatum)
      • 3.1.5.2. Increased DA firing in VTA and substantia nigra
      • 3.1.5.3. Increased activation in the right orbitofrontal cortex, left middle frontal lobe, superior frontal lobe and precentral gyri
    • 3.1.6. Reduced DA firing in the nucleus accumbens
    • 3.1.7. Extracellular DA in the striatum increased more than by MPH
    • 3.1.8. Synaptic DA binding reduced by AMP in the same way as by MPH
    • 3.1.9. DA influence indirectly via effects on dopamine cells emanating from other brain regions
    • 3.1.10. Downregulation of dopamine receptors?
  • 3.2. Noradrenaline with amfetamine medication
    • 3.2.1. Noradrenaline reuptake inhibition via NET
    • 3.2.2. Noradrenaline release
    • 3.2.3. Reduction of noradrenaline metabolites only in responders
    • 3.2.4. DA firing and DA bursting increased via noradrenaline α1 receptors
  • 3.3. Monoamine
    • 3.3.1. Monoamine degradation inhibition via MAO
    • 3.3.2. Monoamine release
  • 3.4. Serotonin
    • 3.4.1. Serotonin reuptake inhibition
    • 3.4.2. Serotonin release
  • 3.5. Effect on the HPA axis
    • 3.5.1. ACTH increased
    • 3.5.2. Corticosteroids increased
    • 3.5.3. Increased steroid hormones
  • 3.6. Inhibition of OCT2
  • 3.7. Other effects on brain functions
  • 3.8. Overview of AMP and neurotransmitters
    • 3.8.1. Binding affinity of AMP, MPH, ATX to DAT / NET / SERT
    • 3.8.2. Effect of AMP, MPH, ATX on dopamine / noradrenaline per brain region
• 4. Effect of amfetamine medication compared to MPH / atomoxetine
• 5. Effect on ADHD symptoms
  • 5.1. ADHD-I (without hyperactivity)
  • 5.2. Attention control
  • 5.3. Comorbid depression or dysthymia
  • 5.4. Comorbid anxiety disorders / depression
  • 5.5. Comorbid sleep disorders
  • 5.6. Impulsiveness
• 6. Response rate (responding / non-responding)
• 7. No gender-specific differences in effectiveness
• 8. Calming effect at low doses, activating at high doses
• 9. Dosage of amfetamine medication or MPH
• 10. Effect profile (temporal) / duration of action
• 11. Areas of application of amfetamine medication in relation to MPH
• 12. Side effects
  • 12.1. No liver damage with normal medication dosage
  • 12.2. AMP increases histamine
  • 12.3. No increased cardiovascular risks
  • 12.4. Individual cases of trichotillomania
  • 12.5. Erection, libido, reproduction
  • 12.6. Amfetamine medication for the elderly
  • 12.7. Other
  • 12.8. Overdose
• 13. Degradation of amfetamine
  • 13.1. Degradation of LDX to d-AMP
  • 13.2. Degradation of D-AMP and L-AMP
    • 13.2.1. Primary degradation pathway: renal, acid-dependent
    • 13.2.2. Secondary degradation pathway: CYP2D6, CYP1A2 and CYP3A4
      • 13.2.2.1. Degradation of amfetamine by CYP3A4
      • 13.2.2.2. Degradation of amfetamine by CYP2D6
      • 13.2.2.3. Inhibition of CYP2D6 by amfetamine
    • 13.2.3. Flavin monooxygenase degradation pathway
    • 13.2.4. Dopamine beta-hydroxylase degradation pathway
    • 13.2.5. Methylation (dAMP to methamfetamine )
• 14. Contraindications and interactions
  • 14.1. Shortened half-life (reduced effect)
  • 14.2. Prolonged half-life (increased effect)
  • 14.3. Delayed effect
  • 14.4. Amplifying effect on amfetamine
    • 14.4.1. Alcohol increases amfetamine levels
    • 14.4.2. CYP2D6 inhibitors increase amfetamine levels
  • 14.5. Attenuating effect on amfetamine
  • 14.6. Few interactions of AMP with other medications
  • 14.7. AMP during pregnancy
• 15. Long-term effect: No habituation effects of amfetamine medication
• 16. Preparations
• 17. Taking amfetamine medication abroad

1. Active ingredients of amfetamine drugs¶

AMP has a chiral center with two enantiomers:³

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

Around 1976 it became known that a mixture of L-Amp and D-Amp worked better than D-Amp, which had been used on its own until then⁴
The d-isomer is four times more effective at releasing dopamine than the l-isomer, while noradrenaline is released equally by both isomers or even slightly more by l-amfetamine⁴
The amfetamine mixed salt preparations available in the USA, which consist of equal parts racemic d,l-AMP sulfate, d,l-AMP aspartate monohydrate and two enantiomeric 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. Dextroamfetamine (D-Amfetamine)¶

Dextroamfetamine (the right-turning isomer = dextrorotatory) is also called dexamfetamine or S-(+)-amfetamine.
Dextroamfetamine is the dextrorotatory (D-)enantiomer of amfetamine, as opposed to the levorotatory levoamfetamine (see below).
Dextroamfetamine sulphate is the salt form of dextroamfetamine.

D-amfetamine drugs have a 3 to 4 times stronger effect on the central nervous system than racemic amfetamine drugs, while at the same time having less sympathomimetic effect in the periphery, which is why D-amfetamine drugs are preferred for ADHD treatment.⁵
D-Amfetamine is only more potent than L-Amfetamine with regard to the dopamine transporters, while the effect on noradrenaline transporters is roughly the same.⁶

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

D-Amfetamine is more activating than MPH and is therefore preferably recommended for ADHD-I.⁷
It is also often more effective than MPH for parallel dysthymia / dysphoria / depression due to the noticeable serotonergic effect⁸.

1.1.1. Dextroamfetamine 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

No approval for adults in Germany, therefore off-label. Reimbursement by health insurance companies is very difficult. Approval for adults has been applied for,

The half-life of the D-enantiomer is⁹

• for children aged 6 to 12 years 9 hours
• 11 hours for adolescents aged 13 to 17 years
• for adults 10 hours

1.1.2. Dextroamfetamine from lisdexamfetamine (with lysine binding)¶

Lisdexamfetamine (LDX) is a prodrug of D-amfetamine 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 into the actual active substance, in this case D-amfetamine. This means that there is a very low risk of abuse.¹⁰ The subjective effect of intravenous administration is identical to that of oral administration, and the Cmax of d-amp is also identical.⁴ This massively reduces the risk of abuse. Nevertheless, the effect is linear and dose-dependent up to 250 mg. LDX therefore does not offer protection against overdose.¹¹

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.¹¹ Unlike LDX, the pharmacologically active d-AMP crosses the blood-brain barrier and enters the CNS, where it exerts its effect.³

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-Amfetamine. A conversion table from dexamfetamine to Vyvanse can be found at ADHSpedia.¹⁴ Further conversion tables are available from Kühle¹⁵ and for American preparations from Stutzman et al.¹⁶

Trade names:

• Vyvanse (EU, since the end of 2013, for children, 20, 30, 40, 50, 60, 70 mg)¹⁷
• Vyvanse Adult (EU, since 01.05.19, for adults, 30, 50, 70 mg)¹⁷. 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 from 10 mg to 70 mg¹⁸
• 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 mg¹⁹

Generics:

• Since August 2024, lisdexamfetamine has been available in Germany as a generic (e.g. Lisdexamfetamine Ratiopharm), whereby 100-capsule packs are also available 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 2023.²⁰
Lisdexamfetamine is also approved in the USA for binge eating.²¹

Due to its long-lasting effect, dextroamfetamine is subject to steady-state formation. Steady state appears to be reached on day 5.²² Consequences are that when dosing lisdexamfetamine like dextroamfetamine, dosage titrations should not be made below a weekly rhythm.

1.2. Levoamfetamine (L-Amfetamine)¶

Levoamfetamine (L-amfetamine) is the purely levorotatory isomer of amfetamine. Another name is (-)-amfetamine.

L-amfetamine is less potent than D-amfetamine in terms of dopamine transporters, while the effect on noradrenaline transporters is roughly the same.²³ This makes it slightly more noradrenergic than D-amfetamine, but still predominantly dopaminergic.²⁴
L-amfetamine increases blood pressure and pulse rate more than D-amfetamine²⁵

The half-life of the L-enantiomer is⁹

• for children aged 6 to 12 years 11 hours
• 13 to 14 hours for adolescents aged 13 to 17 years
• for adults 13 hours

We are not aware of any ready-to-use L-amfetamine medication approved in Europe. It would have to be produced on individual prescription in pharmacies.

Equivalents of lisdexamfetamine:

Lisdexamfetamine	Dextroamfetamine	Dextroamfetamine sulphate
10 mg	2.95 mg	4.02 mg
20 mg	5.90 mg	8.04 mg
30 mg	8.84 mg	12.05 mg
40 mg	11.79 mg	16.07 mg
50 mg	14.74 mg	20.09 mg
60 mg	17.69 mg	24.11 mg
70 mg	20.64 mg	28.13 mg

The Lisdexamfetamine to Dextroamfetamine conversion rate is 0.2948.²⁶
The conversion rate of dexamfetamine to dexamfetamine sulphate can be estimated at 1.363.¹¹

1.3. Mixed amfetamine salts / amfetamine derivatives¶

• Aderall (USA): 75 % dextroamfetamine and 25 % levoamfetamine
  * 25 % each of D-amfetamine sulphate, DL-amfetamine sulphate, D-amfetamine accharate and DL-amfetamine aspartate monohydrate
  * The different salts are metabolized at different rates, which leads to a slower rise and fall in the blood plasma concentration curve
  * Immediate release: Tablet with immediate release of the active ingredient
  * Sustained release (Adderall® XR):
  * Amfetamine salts in capsule with two types of pellets:
  * 50 % with immediate release
  * 50% with enteric coating, which first dissolves in the intestine, and thus with a delay, and then releases the amfetamine salt it contains
  * Adderall® XR was first approved in the USA in 2001
  * Crushing an Adderall® XR tablet removes the retarding effect. All of the amfetamine contained is released immediately.
• Evekeo (USA): 50 % dextroamfetamine and 50 % levoamfetamine

Amfetamine mixed salts are a combination of different stimulants:²⁷

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

While D,L-amfetamine sulphate mixtures are the most commonly used ADHD medication in the USA, D,L-amfetemine 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 amfetamine sulphate each was quoted as €200.

1.4. Methamfetamine¶

• Desoxyn, USA

(1.5. Fenetyllin)¶

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

1.6. Amfetamine derivatives¶

There are a large number of derivatives of amfetamine. Many are abused as drugs.
Most, but not all, amfetamine derivatives are central stimulants. Fenfluramine and p-chlorobenzphetamine have been shown to have no stimulant effect on the central nervous system.²⁸

The terms amfetamine and amfetamine medication in this article refer to medications with amfetamine as an active ingredient that are still approved today and are used to treat ADHD.

1.7. Historical: Discovery and development of amfetamine¶

In the 1880s, the chemist Lazăr Edeleanu synthesized amfetamine for the first time. Nagai Nagayoshi extracted ephedrine for the first time from Ephedra spp. used in Chinese traditional medicine and synthesized methamphetamine for the first time in 1893²⁹
Ephedrine was available over the counter in Europe and the USA in the 1920s as a decongestant and, due to its bronchodilator and adrenaline-like effect, as a helpful medication for asthma.
in 1927, Gordon Alles synthesized racemic amfetamine and documented that it increased arousal and caused insomnia in humans and animals.
in 1935, Smith, Kline and French Co. marketed amfetamine under the name Benzedrine® for narcolepsy, postencephalitic parkinsonism and depression. Benzedrine was available over the counter as a decongestant inhaler containing a cotton strip soaked in volatile amfetamine oil, which soon led to abuse as a psychostimulant drug.
A few years later, Smith, Kline and French Co. brought the stronger isomer dextroamfetamine onto the market as Dexedrine®.
in 1937, Charles Bradley reported on the positive effect of Benzedrine on children with behavioral problems.
benzedrine and Dexedrine became prescription-only in 1939.

2. Authorization and prescription of amfetamine drugs¶

2.1. Germany¶

In Germany, amfetamine medication had to be prepared from raw substances by pharmacists for a long time.³⁰ Since 2011, a D-amfetamine (Attentin) has been available in Germany as a finished drug and approved for the treatment of ADHD (Attentin), and in 2013 a D-amfetamine prodrug (Lisdexamfetamine) was approved for the treatment of children. Lisdexamfetamine contains D-Amp in 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 and 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 Germany³¹

In Germany, lisdexamfetamine has been approved as a first-line medication for adults with ADHD since March 2024. It may still only be prescribed for children and adolescents if MPH is not effective enough.^{32333435363738}
The 2017 S3 guideline still pointed out in the long version³⁹ (page 72/198) that lisdexamfetamine could only be used in accordance with approval after prior treatment with MPH, without restricting this statement to children.
Due to the economic efficiency requirement, doctors in Germany are still only allowed to prescribe lisdexamfetamine on prescription if all cheaper medications (methylphenidate, in this case Medikinet before Ritalin adult) were not effective or caused side effects.

Lisdexamfetamine is approved in Germany for adults without age restriction and therefore also for seniors aged 60 and over. Nevertheless, there are no data on the safety and efficacy of lisdexamfetamine in people aged 60 and over. Methylphenidate and all other stimulants must be used off-label from the age of 60.⁴⁰

2.2. Austria¶

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

2.3. Switzerland¶

In Switzerland, lisdexamphetamine has been marketed under the brand name Vyvanse® since 2014. Vyvanse® is approved as part of an overall therapeutic strategy for the treatment of ADHD that has persisted since childhood in children aged 6 and over, adolescents and adults. For children aged 6 years and older and adolescents, Vyvanse® may only be used if the response to previously received treatment with methylphenidate is considered clinically inadequate.

Attentin® is approved in Switzerland for the treatment of ADHD in children from the age of six and adolescents up to the age of 18 as part of an overall therapeutic strategy if the clinical response to previous treatment with methylphenidate was inadequate.

2.4. Great Britain¶

The British NICE guideline (NICE, 2018), which, like the German guideline, is considered by experts to be based on the highest level of scientific evidence, explicitly recommends the use of LDX as a first-line therapy for the treatment of adults with ADHD.⁴¹

2.5. USA¶

Amfetamine medications are available in the USA as:⁴²

• Mixture of D- and L-amfetamine isomers (racemic mixture)
• Mixed sulphates and saccharinates of D- and L-amfetamine isomers (Adderall®)
• Pure D-amfetamine sulphate
  • Dexamfetamine hemisulfate (Attentin®, Amfexa®)
• D-Amfetamine as lisdexamfetamine in lysine-bound form (Vyvanse®, Vyvanse®, Tyvense®, generics)
• Racemic methamfetamine sulphate (Desoxyn®, USA)

In the USA, 52.9% of adolescents with ADHD received MPH and 39.3% received amfetamine medication as their first prescribed medication in 2018. Over the course of treatment, MPH is the primary prescribed medication for around 40% and AMP is the primary prescribed medication for 33%.⁴³

3. Effect of amfetamine medication¶

Amfetamine medication works slightly better in adults than methylphenidate⁴⁴ and has slightly fewer side effects.
According to the current European consensus, amfetamine medication is the first choice of medication for ADHD in adults (before methylphenidate) and the second choice of medication in children and adolescents (after methylphenidate) ⁴⁵⁴⁶

Amfetamines are closely related in their chemical structure to the catecholamines dopamine and noradrenaline: this explains why they can bind to the receptors and transporters relevant for these. The great similarity between the monoamines also explains why monoamine transporters are relatively less selective, so that the noradrenaline transporter (at least in the PFC) reabsorbs more dopamine than noradrenaline.⁴

Source: Heal DJ, Smith SL, Gosden J, Nutt DJ (2013): Amphetamine, past and present–a pharmacological and clinical perspective. J Psychopharmacol. 2013 Jun;27(6):479-96. doi: 10.1177/0269881113482532. PMID: 23539642; PMCID: PMC3666194⁴, published under Creative Commons Attribution License

Amfetamine medications have a more complex mechanism of action than methylphenidate.
The description of the effect of amfetamine medication is contradictory. It is sometimes argued that amfetamine drugs merely inhibit dopamine reuptake and release dopamine and noradrenaline. More well-founded accounts from the USA (where amfetamine 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 principle, amfetamine drugs are said to have an intraneuronal effect, while methylphenidate and atomoxetine have an extraneuronal effect.⁴⁷ As amfetamine 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.⁴⁸

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 studies⁴⁹
A model comparing MPH and AMP in children and adults with ADHD takes into account the effect on 99 proteins involved in ADHD⁵⁰

3.1. Dopamine with amfetamine medication¶

The dopamine increase caused by D-amfetamine in PFC is much more pronounced and also much more dose-dependent than with MPH, and is therefore easier to control.⁴⁷
AMP causes:

• extracellular dopamine levels increased 6-fold⁵¹
• tonic dopamine firing enhanced by AMP depleting vesicular stores and promoting non-exocytotic release through reverse transport⁵²
• phasic dopamine firing: contradictory data
  • amplified by upregulating vesicular dopamine release⁵²
  • Stimulants reduce the phasic release of dopamine⁵¹
    • AMP 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). 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.⁵³
  • AMP reduces vesicular release⁵⁴⁵⁵ (this can affect both tonic and phasic release)

3.1.1. Effect on DAT¶

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

Stimulants (MPH such as AMP inhibit dopamine reuptake⁵⁶ and thus lead (in low doses) to a 6-fold increase in extracellular dopamine levels.⁵¹
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 (drugs) cause supersaturation of extracellular postsynaptic D1 and D2 receptors, so that they exceed the inhibitory presynaptic effect of low D-AMP doses.⁵¹

• Amfetamine 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, amfetamine 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.⁵⁷
• Amfetamine is absorbed into the nerve cell through the DAT, whereas MPH is not.⁵⁸
• D-Amfetamine works
  • Primarily as a dopamine reuptake inhibitor.⁵⁹
  • Equally as a dopamine and noradrenaline reuptake inhibitor⁵⁷
• Dextroamfetamine inhibits dopamine transporters with moderate efficacy (Ki 34-225 nM).⁶⁰
• Amfetamine can also stabilize dopamine and norepinephrine transporters in channel configurations, reverse efflux through intracellular vesicular monoamine transporters, and cause internalization of dopamine transporters⁶¹
  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.⁵¹
• D-amfetamine 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.⁴⁷ Since there is barely any DAT but plenty of NET in PFC, dopamine reuptake in PFC occurs primarily through the NET in noradrenergic cells.⁴

3.1.1.1.1. DAT inhibition via PKC¶

• AMP possibly inhibits DAT via PKC⁶²
  • Several protein kinases regulate DAT function⁶³⁶⁴
  • AMP increases the activity of striatal particulate PKC via a calcium-dependent signaling pathway⁶⁵
  • PKC activation leads to phosphorylation in the N-terminal of the rat striatal DAT⁶⁶
  • PKC activation stimulates DAT-mediated dopamine release⁶²
  • PKC inhibitors and the downregulation of PKC⁶²
    • Inhibit efflux
    • Leave dopamine uptake unchanged

3.1.1.2. Increased release of dopamine (DAT efflux)¶

The increased DAT efflux increases extracellular dopamine.

Amfetamine drugs release dopamine into the extracellular space ^{47 5956}
Amfetamine therefore not only acts as a dopamine reuptake inhibitor, but also reverses the DAT function so that the DAT not only does not reabsorb dopamine, but also releases it from the cell (efflux).⁶⁷⁴⁶⁸
It is certain that amfetamine drugs (drug characteristic: high dose, fast application, fast end of effect) release dopamine from the cell. However, it has not been positively proven that amfetamine drugs (characteristic: drug = low dose, slow release, long-lasting effect) also release dopamine from the cell, and if so, to what extent this occurs.
Empirically, there is no doubt that amfetamine drugs do not deplete dopamine stores, as they would otherwise have no lasting effect.

3.1.1.2.1. Via VMAT2 at high doses¶

(Only) at a very high dosage as a drug do amfetamines 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.⁶ In other words: Amfetamine can enter presynaptic monoamine vesicles and cause an efflux of neurotransmitters towards the synapse.⁶⁹
An administration of 1 mg/kg AMP (injected) already caused a dopamine DAT efflux that was significantly higher at 10 mg/kg.⁷⁰

3.1.1.2.2. 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.⁷¹

3.1.1.2.3. Increased DAT efflux via TAAR1¶

• AMP acts on DAT via TAAR1
  Amfetamine 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).⁶⁹
• AMP also leads to increased intracellular accumulation of DAT⁷²

3.1.2. 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.⁵⁴ As a result, AMP reduces the number of dopamine molecules released per vesicle.⁵⁵
• Amfetamine initially reduces VMAT2, while prolonged administration increases it.⁷³ MPH increases VMAT2 per se.⁷⁴⁷⁵
• 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.⁵⁵
• A computer model determined⁷⁶
  • 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 doses⁶
• 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.⁷⁷
• 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.⁵³

• 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:⁵²
  • 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

3.1.3. D2 autoreceptor activation¶

Basically, D-amphetamine activates D2 dopamine autoreceptors in the striatum.⁷⁸
However, drug doses of D-AMP do not cause a significant reduction in dopamine release via activation of the D2 autoreceptors.⁷⁹⁸⁰

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.⁷⁹

3.1.4. Increase in tyrosine hydroxylase¶

Amfetamine 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.⁸¹

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

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

High (well above drug dose) D-amfetamine 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.⁸²⁸³ The D2 antagonist haloperidol (2 mg/kg) terminates the excessive firing in the caudate nucleus and putamen and the reduced firing in the nucleus accumbens⁸²

3.1.5.2. Increased DA firing in VTA and substantia nigra¶

D2 antagonists prevent increased firing in the substantia nigra and VTA (in vivo).⁸⁴

3.1.5.3. 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).⁸⁵

3.1.6. Reduced DA firing in the nucleus accumbens¶

In the nucleus accumbens, 7.5 mg/kg D-Amp led to a reduction in dopaminergic firing.⁸² The D2 antagonist haloperidol (2 mg/kg) terminated the excessive firing in the caudate nucleus and putamen and the reduced firing in the nucleus accumbens⁸²

3.1.7. Extracellular DA in the striatum increased more than by MPH¶

Amfetamine increased extracellular dopamine in the striatum of rats by + 1,400 %, four times as much as MPH with + 360 %.⁸⁶

3.1.8. Synaptic DA binding reduced by AMP in the same way as by MPH¶

Amfetamine reduced the synaptic binding of dopamine in the striatum in rats and primates to the same extent as MPH (around 25 % reduction).⁸⁶

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

Amfetamine appears to influence the activity of dopamine cells indirectly via its effects on dopamine cells originating in other brain regions.⁸⁷

Amfetamine can excite dopamine neurons by modulating glutamate neurotransmission. Amfetamine 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. Amfetamine desensitizes mGluR-mediated hyperpolarization by:⁸⁸

• 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, amfetamine can promote burst firing of dopamine neurons and thus increase the phasic release of dopamine.

3.1.10. Downregulation of dopamine receptors?¶

Reports of immediate downregulation of dopamine receptors by administration of amfetamine are based on studies in which rats were given doses of amfetamine. This concerns the dosage level (5, 10, 15 mg/kg for 4 or 20 days twice daily) as well as the form (injection).⁸⁹ Interestingly, a single dose of D-AMP even increased the number of receptors.⁸⁹⁸⁰
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 amfetamine 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.⁸⁰
More on receptor status at High-affinity and low-affinity receptor status In the article Dopamine effect on receptors

However, it is conceivable that amfetamine in drug doses does not cause a desensitization of the postsynaptic or extrasynaptic (the majority of dopamine receptors are located outside synapses) D1 and D2 receptors directly, but via a detour by increasing the extracellular dopamine level. However, this hypothesis has not yet been experimentally proven.⁸⁰ It is possible that this pathway leads to reduced psychomotor activity through amfetamine 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 gradual titration of stimulants.

3.2. Noradrenaline with amfetamine medication¶

While D-Amp and L-Amp increase extracellular dopamine in the PFC and striatum in a dose-dependent manner, they increase extracellular noradrenaline only in the PFC.⁴

A: extracellular noradrenaline in the PFC, dose-dependent change due to D-Amp and L-AMP
B: extracellular dopamine in the striatum, dose-dependent change through D-Amp and L-AMP

Source: Heal DJ, Smith SL, Gosden J, Nutt DJ (2013): Amphetamine, past and present–a pharmacological and clinical perspective. J Psychopharmacol. 2013 Jun;27(6):479-96. doi: 10.1177/0269881113482532. PMID: 23539642; PMCID: PMC3666194⁴, published under Creative Commons Attribution License

3.2.1. Noradrenaline reuptake inhibition via NET¶

• Amfetamine 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, amfetamine 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 noradrenalone and dopamine reuptake.⁵⁷⁹⁰
• Dextroamfetamine inhibits noradrenaline transporters with moderate efficacy (Ki 39-55 nM).⁶⁰
• Amfetamine can also stabilize dopamine and norepinephrine transporters in channel configurations, reverse efflux through intracellular vesicular monoamine transporters, and cause internalization of dopamine transporters.⁶¹
• D-Amfetamine has about a third of the reuptake inhibition on the noradrenaline transporter (NET) and dopamine transporter (DAT) as racemic methylphenidate.⁴⁷
• Amfetamine (as well as ephedrine) also inhibits the intracellular noradrenaline transporter, which takes up noradrenaline from the nerve cell into the vesicles (the neurotransmitter stores)⁹⁰

3.2.2. Noradrenaline release¶

• Whether amfetamine 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 against⁶ as well as in favor.⁵⁶⁵⁹
• D-Amfetamine secondarily increases the release of noradrenaline.⁷⁸ This is always the case with dopaminergic drugs due to the conversion of dopamine (approx. 5 to 10 %) into noradrenaline.
• There is no doubt that amfetamine medication does not lead to a chronic depletion of noradrenaline reserves in the sense of a deficiency state. It is empirically proven that amfetamine medication for ADHD does not lead to long-term habituation effects

2.5 mg/kg AMP in mice:⁹¹

• 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

3.2.3. Reduction of noradrenaline metabolites only in responders¶

• Several independent studies have found that D-amfetamine drugs reduce the urinary metabolite of noradrenaline, MHPG. The decrease in urinary MPHG is thought to be an important indicator of stimulant onset, indicating a lowering of noradrenaline levels by dextroamfetamine drugs.⁹²](https://psycnet.apa.org/psycinfo/1982-21744-001)
• Furthermore, the reduction in noradrenaline metabolites only occurs in people with ADHD who respond positively to dexamfetamine (responders).⁹³
• 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.⁹⁴
  The authors conclude that the level of noradrenaline in ADHD is reduced.
• Furthermore, in several studies with people with ADHD, it was found that behavioral improvements were proportional to the reduced noradrenal metabolite levels (using D-amfetamine medication).⁹⁵

In contrast to the reduction of metabolites in urine by D-amfetamine, the noradrenaline increase in the PFC mediated by D-amfetamine is about as pronounced as that of MPH, but significantly more dose-dependent and therefore more controllable.⁴⁷

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

D-Amp (1 to 2 mg/kg) acts via alpha1-adrenoceptors⁹⁶ (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.⁸⁴⁹⁷

D-amfetamine appears to activate the noradrenaline α1-receptor in the PFC, as the α1-receptor antagonist prazosin completely neutralized the effect of D-amfetamine in the PFC. In contrast, D-amfetamine does not appear to target either the α2 receptor or the β receptor, as the effect of D-amfetamine persisted when the α2 or β receptors were blocked.⁹⁸
D-amfetamine promotes the up-state of cortical neurons by activating⁹⁹

• 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.⁹⁹

3.3. Monoamine¶

3.3.1. Monoamine degradation inhibition via MAO¶

Amfetamine medication acts - albeit rather weakly⁴ - as an MAO inhibitor,¹⁰⁰⁴⁸ unlike low-dose MPH. Whether high-dose MPH acts as an MAO inhibitor is unknown.⁴⁷

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.¹⁰⁰ This effect triggers peripheral hypertension and an increase in heart rate. As this mechanism of action occurs indirectly at the presynapse, ephedrine and amfetamine drugs are also called “indirect sympathomimetics”, while active ingredients that act directly at the postsynaptic receptors are called sympathomimetics.¹⁰⁰

3.3.2. Monoamine release¶

Dextroamfetamine increases monoamine release from presynaptic terminals¹⁰¹, possibly via interaction with vesicular monoamine transporter 2 and reversal of plasma membrane monoamine transporters.⁶⁰

3.4. Serotonin¶

3.4.1. Serotonin reuptake inhibition¶

Dextroamfetamine also inhibits serotonin transporters (Ki 1.4-3.8 μM) to a small extent.¹⁰¹

3.4.2. Serotonin release¶

Amfetamine medication is said to release a small amount of serotonin.¹⁰²⁵ Here too, it is unclear whether this is really the case even when dosed at drug level, or whether this effect is only limited when dosed as a drug. In any case, Stahl does not report a serotonergic effect of amfetamine drugs.⁵⁷

2.5 mg/kg AMP in mice:⁹¹

• 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.¹⁰⁴
• Other sources indicate a serotonin-increasing effect of amfetamine salts due to inhibition of monoamine oxidase.⁸
• Amfetamine 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.¹⁰⁵
• MPH itself has an agonistic effect on the 5-HT1A receptor.⁴⁸

3.5. Effect on the HPA axis¶

3.5.1. ACTH increased¶

Lisdexamfetamine and d-amfetamine significantly increased ACTH plasma levels in healthy subjects.¹⁰⁶

3.5.2. Corticosteroids increased¶

• D-amfetamine drugs such as lisdexamfetamine (Vyvanse) increase cortisol levels, but not testosterone levels.¹⁰⁶
• 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 now 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.

3.5.3. Increased steroid hormones¶

Lisdexamfetamine and d-amfetamine significantly increased the plasma levels of, among others, in healthy subjects:¹⁰⁶

• 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, amfetamine 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.¹⁰⁷ Another study in rhesus monkeys found reduced testosterone levels with MPH administration.¹⁰⁸

A reduction in testosterone levels was observed in rodents after administration of amfetamine.¹⁰⁹¹¹⁰

3.6. 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 PMAT¹¹¹, d-amfetamine 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).¹¹¹¹¹²
d-Amfetamine binds approximately equally strongly to hOCT2 and hOCT3 and to these by an order of magnitude (factor 10) weaker than to DAT¹¹²

Binding of amfetamine to OCT may contribute to cellular and behavioral effects of amfetamine.¹¹²

OCT2 reuptake inhibitors have an antidepressant effect.¹¹³ In addition, even much lower doses of venlafaxine or reboxetine have an antidepressant effect in OCT2-KO mice than in wild-type mice¹¹⁴
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.

3.7. Other effects on brain functions¶

• D-Amfetamine increases metabolism in the right caudate nucleus and decreases it in the right Rolandi region and in the right anterior inferior frontal regions.¹¹⁵
• Neuroprotective effect in case of stroke or traumatic brain injury
  • D-amfetamine (like 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 appropriate training measures are taken at the same time.¹¹⁶ D-amfetamine increases dopamine, which has a neurotrophic effect (promotes neuroplasticity). Dopaminergic drugs such as (D-)amfetamine 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.
  • Low-dose methamfetamine given within 12 hours of a stroke or traumatic brain injury was neuroprotective and improved cognitive abilities and functional behavior.¹¹⁷
  • There are similar reports with regard to MPH, although it also seems to depend on the rapid administration after the craniocerebral trauma¹¹⁸
• Methylphenidate and amfetamine drugs increase the power of alpha (in rats), while atomoxetine and guanfacine do not.¹¹⁹
• Lisdexamfetamine (Vyvanse) has the following effects¹²⁰
  • Increased acetylcholine levels in the cortex
  • Increased histamine levels in the cortex and hippocampus (which escitalopram given in parallel only prevents in the hippocampus)

Amfetamine medication is therefore not just a substitute for methylphenidate, but has its own area of application.

3.8. Overview of AMP and neurotransmitters¶

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

The active ingredients methylphenidate (MPH), d-amfetamine (d-AMP), l-amfetamine (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.¹²¹
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 - 200121 , 34124	23824, 339121	> 10,000121
d-AMP (Vyvanse, Attentin)	34 - 41121 , 206 (sulphate) 24	** 23.3 - 38.9**121 , 54.8 (sulphate)24	3,830 - 11,000121
l-AMP	138121 , 1435 (sulphate) 24	** 30.1**121 , 259 (sulphate)24	57,000121
ATX	1451 - 1600121 235524	** 2.6 - 5**121 , 20.624	** 48 - 77**121
GBR-12909	40.224
Desipramine		4.924

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

The active ingredients methylphenidate (MPH), amfetamine (AMP) and atomoxetine (ATX) alter extracellular dopamine (DA) and noradrenaline (NE) to different degrees in different regions of the brain. Table based on Madras,¹²¹ 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

4. Effect of amfetamine 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.¹²²
Lisdexamfetamine (EU: Vyvanse) also had a good effect on comorbid depression symptoms in a double-blind study.¹²³ 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.¹²⁴

5. Effect on ADHD symptoms¶

In people with ADHD who respond positively to D-amfetamine medication as well as MPH, the effect of D-amfetamine medication is at least on a par with MPH¹²⁵, in our experience even significantly better in adults.

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, amfetamine medication is the first choice ADHD medication for adults (before methylphenidate), and the second choice for children (after methylphenidate).⁴⁵⁴⁶

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

5.1. ADHD-I (without hyperactivity)¶

MPH has a stronger activating and drive-enhancing effect on most people with ADHD than AMP medication. Contrary reports¹²⁶ are not consistent with our experience.
Statements in the specialist literature that amfetamine medication is more suitable for people with ADHD-I than MPH, partly because people with ADHD-I are above-average AMP nonresponders,¹²⁷ cannot be confirmed from our experience either
We know several persons with ADHD-HI who are significantly better helped by amfetamine medication than MPH and people with ADHD-I who cope better with MPH. We are not aware of any subtype-specific effect of amfetamine medication or methylphenidate. In our experience, amfetamine medication works just as well for ADHD-HI as for ADHD-I.

5.2. Attention control¶

People with ADHD have a reduced extrinsic and intrinsic motivational capacity. For example, they need higher rewards to be 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 shown by a normalization of DMN deactivability.¹²⁸

More on the deviant function of the DMN in ADHD and its normalization by stimulants, including further references 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 amfetamine medication (Vyvanse) tends to create a more relaxed general alertness and has a slightly more pleasant effect overall.

5.3. Comorbid depression or dysthymia¶

Amfetamine 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 of amfetamine medication, which they are not familiar with from MPH.¹²⁹ This is consistent with the experiences of users known to us.

As amfetamines 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. Amfetamine medication should therefore be used with caution in cases of (even hidden) 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.

5.4. 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.⁵⁷

5.5. Comorbid sleep disorders¶

Amfetamine medication has 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. On the other hand, some people with ADHD report feeling pleasantly tired in the evening and that they no longer have problems falling asleep.

Studies show that amfetamine medication improves overall sleep quality in ADHD.¹³⁰¹³¹

5.6. Impulsiveness¶

People with ADHD reported in forums that MPH worked better against impulsivity than Vyvanse (lisdexamfetamine).¹³²

6. 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 greatly or very greatly improved CGI-I scores)¹³³
A summary of several studies reports a 69% response rate to amfetamine medication and a 59% response rate to methylphenidate. 87% of people with ADHD responded to one of the two types of medication.²
A 2-year study of L-amfetamine medication in children and adolescents (n = 314) showed a responder rate of between 70 and 77% with good efficacy and manageable side effects.¹²⁴
For MPH non-responders, it is therefore highly recommended to test a medication with amfetamine drugs (see 1.2.), and vice versa.

According to a Cochrane study, all amfetamine drugs work equally well in adults.¹³⁴ As the studies evaluated in this study did not examine the effect of LDX and dAMP on the same people, the Cochrane meta-analysis can only make statements about the statistical response rate of the various active ingredients per se, and nothing about whether different AMP active ingredients work differently for individual people with ADHD.

There are reports that dextroamfetamine sulphate can be helpful for individual persons with ADHD for whom LDX did not work (well) or for too long. This is also indicated in a leaflet that describes the parameters to be considered when switching from LDX to dAMP.¹³⁵

In addition, there are increasing reports in practice that different lisdexamfetamine preparations can (but by no means have to) show considerable intraindividual differences. This also applies to people with ADHD who had not previously thought that there could be differences, or who were convinced that the products were completely interchangeable. Some people with ADHD reported that they were able to reliably reproduce differences in effect by switching between different preparations on a daily basis. There is no pharmacological explanation for this.

In carriers of the COMT Val-158 Met gene polymorphism, amfetamine 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, amfetamine 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 amfetamine.¹³⁶

7. No gender-specific differences in effectiveness¶

Amfetamine medications do not appear to show any gender-specific differences in effect.¹³⁷

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

D-Amfetamine 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.⁵¹

9. Dosage of amfetamine medication or MPH¶

About 66% of all persons with ADHD respond equally well to MPH as to amfetamine medication.
22% respond better to amfetamine medication than to MPH.
11% respond better to MPH than to amfetamine medication.¹³⁸
Around 15% of people with ADHD respond best to the active ingredient D-Amfetamine.¹³⁹

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

Highly gifted people with ADHD (here: IQ > 120) are said to respond better to amfetamine medication than less gifted people with ADHD.¹⁴⁰

An interesting study discusses the effectiveness of lisdexamfetamine.¹⁴¹

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.¹⁴² 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.

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

In replicated studies on the duration of action of amfetamine drugs, children had a shorter half-life of around 7 hours, while adults had a longer half-life of around 10 to 12 hours¹⁴³

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:

11. Areas of application of amfetamine medication in relation to MPH¶

According to the current European consensus on the diagnosis and treatment of ADHD in adults, amfetamine medication is the first choice of medication for ADHD in adults (before methylphenidate), and the second choice of medication for children (after methylphenidate)⁴⁵⁴⁶
In children who are MPH non-responders, i.e. who do not respond to MPH, the efficacy of amfetamine medication should be tested.
Persons with ADHD with pronounced dysphoria during inactivity or with comorbid depression benefit particularly from amfetamine medication.
In addition, people with ADHD who require stronger activation may be able to cope better with amfetamine medication.
Highly gifted people are said to respond better to amfetamine medication than to MPH.¹⁴⁰

12. Side effects¶

An evaluation of the reports to the WHO VigiAccess database revealed the following relative frequency of adverse reaction reports for dextroamfetamine (the % figures do not indicate the frequency of occurrence during use):¹⁴⁵

Reporting rate %	Side effect
4.3 %	Unexpected therapeutic response
3.08 %	Headache
1.96 %	Depressive mood
1.86 %	Fatigue
1.74 %	Insomnia
1.68 %	Nausea
1.67 %	Palpitations
1.64 %	Attention deficit disorders
1.43 %	Anxiety
1.35 %	Dizziness
1.16 %	Drowsiness
1.15 %	Decreased appetite
1.13 %	Irritability
1.03 %	Discomfort
0.94 %	Unrest
0.9 %	Dry mouth
0.83 %	Aggressiveness
0.8 %	Excitation

4.84% of the reports concerned an ineffectiveness of the drug, 1.75% a problem with product substitution.
The evaluation does not distinguish between sustained release and immediate release AMP or AMP in prodrug form (lisdexamfetamine). Sustained release / prodrug medications have a lower side effect profile.

12.1. No liver damage with normal medication dosage¶

High doses of amfetamines may be associated with liver damage and certain forms of clinically apparent liver damage. This is most commonly reported with methylenedioxymetamfetamine (MDMA: “ecstasy”).¹⁴⁶

Amfetamine drugs, on the other hand, are dosed so low that this does not occur: the dose makes the poison. See also under ⇒ Stimulants as medication versus stimulants as drugs.

12.2. AMP increases histamine¶

AMP increases histamine,¹⁴⁷¹⁴⁸ as do all other known ADHD medications:

• Atomoxetine
• Methylphenidate
• Modafinil
• Nicotine
• Caffeine

This is why people with histamine intolerance often have problems when 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.

12.3. No increased cardiovascular risks¶

Several large studies found no increased risk of serious cardiovascular events such as stroke, heart attack or cardiac arrhythmia for amfetamine drugs.¹⁴⁹¹⁵⁰
A study over 14 years found a 4% increase in the risk of cardiovascular problems per year of taking stimulants (methylphenidate, amfetamine medication) and, to a lesser extent, the non-stimulant atomoxetine.¹⁵¹

According to a meta-analysis, daily use of amfetamine medication had the following effects¹⁵²

• systolic blood pressure increased by 1.93 mmHg (k = 56 RCT, n = 10,583)
• diastolic blood pressure increased by 1.84 mmHg (k = 56 RCT, n = 10,583)
• Heart rate increased by 3.71 beats per minute (k = 47 RCT, n = 10,075)

12.4. Individual cases of trichotillomania¶

Individual cases of trichotillomania (pulling out hair) have been reported.¹⁵³ Trichotillomania is a specific form of impulse control disorder.

12.5. 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 amfetamine medication.

Reports from the ADxS-ADHD forum sometimes report erection problems with amfetamine medication, 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 documented a reduction in testosterone and other sex hormones and a reduction in sperm count with an amfetamine drug, which was reversed by switching back to MPH.¹⁵⁴

Amfetamine 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.¹⁵⁵ Blockade is the opposite of binding. Dopamine agonists such as L-dopa or bromocriptine cause an increase in sexual desire and sexual activity.
Amfetamine (usually associated with drug use) can alter spermatogenesis and lead to oxidative stress and subsequent apoptosis in testicular tissue¹⁵⁶

A pilot study in men with sexual problems reported improvements in the subjective sexual experience (reduced time to orgasm or increased frequency of orgasm) with 5 to 20 mg of amfetamine salts (Adderall) 1 to 4 hours before sexual activity (up to 10 doses/month)¹⁶⁸
In 5 individual cases, the resolution of SSRI-induced sexual dysfunction by low doses of dextroamfetamine or methylphenidate was reported.¹⁶⁹ Further case studies report multiple erections (15-year-old), hypersexual behavior (8-year-old) due to OROS-MPH (Concerta)¹⁷⁰ and priapism (14-year-old).¹⁷¹

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%).¹⁷²

12.6. Amfetamine medication for the elderly¶

There are only a few studies on the effect and safety of amfetamine medication in older people.
One study found no increased risks for lisdexamfetamine in people between 55 and 84 years of age. There were no age-related trends in pulse or blood pressure changes and the safety profile of LDX was identical to that observed in younger adult study participants. The clearance of LDX decreased with age, so that a low dosage is reasonable or a prolonged effect can be expected.¹⁷³
This is consistent with our known experience with stimulants in older people with ADHD. Nevertheless, particularly careful observation of the development of blood pressure is recommended.

12.7. Other¶

Common side effects of amfetamine mixed salts are:²⁷

• Loss of appetite
• Mood swings

Rare serious side effects of amfetamine mixed salts are:²⁷

• psychotic symptoms
• Seizures
• Risk of abuse

The drug MDMA (unlike amfetamine drugs) can damage nerve cells and attack the blood-brain barrier.¹⁷⁴

12.8. Overdose¶

Symptoms of a (severe) overdose of amfetamine (in the sense of poisoning) include

• Agitation¹⁷⁵
• Hyperactivity¹⁷⁶
• Movement disorders¹⁷⁵
• Tremor¹⁷⁵
• Hyperthermia¹⁷⁶
• Tachycardia (rapid heartbeat)¹⁷⁶
• Tachypnea (increased respiratory rate)¹⁷⁶
• Mydriasis (pupil enlargement)¹⁷⁶¹⁷⁵
• Trembling¹⁷⁶
• Seizures¹⁷⁶, in extreme cases up to epileptic forms¹⁷⁵
• Hyperreflexia (excessive reflex response)¹⁷⁵
• combative behavior¹⁷⁵
• Confusion¹⁷⁵
• Hallucinations¹⁷⁵
• Delirium¹⁷⁵
• Fear¹⁷⁵
• Paranoia¹⁷⁵

It is hardly surprising that doses of 11.3 mg / kg LDX trigger toxic effects in rats, as this is significantly higher than drug doses.¹⁷⁷

13. Degradation of amfetamine¶

13.1. Degradation of LDX to d-AMP¶

Lisdexamfetamine (Vyvanse) is converted to d-AMP in the blood cytosol of erythrocytes by an unknown amino acid (probably an aminopeptidase)¹⁷⁸¹⁷⁹ by cleaving the covalent bond between d-amfetamine and L-lysine. Only d-AMP is pharmacologically active. d-AMP is predominantly degraded renally, the rest presumably via CYP2D6.

96% of LDX is excreted in the urine, of which¹⁸

• 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.

13.2. Degradation of D-AMP and L-AMP¶

Dextroamfetamine is said to have a half-life of

• about 7 hours¹⁸⁰
• 9-11 hours

Taking it together with a high-fat meal can extend the half-life of d-AMP by one hour.
A half-life of 11-14 hours is reported for l-Amp.

Two online surveys of around 550 people with ADHD who take lisdexamfetamine showed that around 40% have a single-dose 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

Amfetamine is partially excreted unchanged in the urine. This depends on the pH value of the body, with which the (easily measurable) urine pH value correlates. If the urine pH is acidic, a lot of amfetamine is excreted unchanged (up to more than 50 %); if the urine pH is alkaline, up to less than 5 %.
The remaining amfetamine is metabolized via different pathways.

Phase 1 metabolism of amfetamine

• Catalysis by cytochrome P450 and flavin monooxygenase
  • Flavin monooxygenase oxidizes secondary and tertiary amine analogues of amfetamine¹⁸¹
    Amfetamine is hydroxylated at the a-carbon group, the b-carbon group, the terminal amine and the aromatic ring. These metabolites are subsequently oxidized or conjugated as far as possible.¹⁸¹
    Amfetamine is oxidized to⁹¹⁷⁹
• 4-Hydroxyamfetamine (active metabolite through aromatic hydroxylation)
  • Degradation to 4-hydroxy-norephedrine
• Alpha-hydroxyamfetamine
  • Dismantling via 2YP2D6
  • possibly deamination to phenylacetone (P2P) via a suspected carbinolamine intermediate¹⁸¹
    • Metabolization to benzoic acid
      • direct glucuronidation to benzoic acid
      • or first oxidation to a hydroxyketo analog, which is then converted to benzoic acid¹⁸¹
      • subsequent oxidation of benzoic acid at the benzyl position to p-hydroxynorephedrine (according to some sources by dopamine beta-hydroxylase)
    • Degradation to hippuric acid (glycine conjugate)
• Norephedrine (phenylpropanolamine) (active metabolite)
  • Degradation to 4-hydroxy-norephedrine

Alternative:

• direct oxidation of amfetamine by dopamine beta-hydroxylase to norephedrine¹⁸¹

Alternative:

• N-hydroxylation of amfetamine and related derivatives¹⁸¹
  • the N-hydroxy derivatives can be further oxidized to nitroso, nitro and oximino compounds.
  • the oximino derivative could be hydrolyzed to phenylacetone (so far only described theoretically)
  • further metabolites are possible

Phase 2 reactions¹⁸¹

• Conjugation of ring-hydroxylated metabolites to their corresponding glucuronides
  • Sulfation of the enol form of phenylacetone

13.2.1. Primary degradation pathway: renal, acid-dependent¶

AMP is partially excreted unchanged via the kidneys before it can have a central pharmacological effect. Peripherally, it is already effective before this.
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:¹⁸

• normal urine pH values¹⁸
  • 30 to 40 % of the AMP dose is largely excreted as unchanged parent compound
  • 50% of the dose is excreted as alpha-hydroxyamfetamine or its downstream inactive metabolite, hippuric acid
• acidic urine
  • pH < 6.0: accelerated AMP excretion, up to 50 % of d-AMP is excreted unchanged renally. Weaker / shorter efficacy.¹⁸
  • pH 4.5 to 5.6: 57 % renally excreted within 48 hours (10 mg in 3 healthy individuals)¹⁸²
• alkaline urine
  • pH > 7.5: delayed AMP excretion, only 3 % of d-AMP is excreted unchanged. Stronger / longer effectiveness.¹⁸
  • pH 7.1 to 8.0: only 7 % renally excreted within 48 hours (10 mg in 3 healthy persons)¹⁸²

The half-life of AMP should increase by 7 hours per unit of pH increase. However, this is likely to depend on the initial pH value. Acidifying or alkalizing agents can therefore significantly alter the effect of AMP.

More on this under Acid balance and amfetamine medication In the article Strength and duration of action of ADHD medications.

13.2.2. Secondary degradation pathway: CYP2D6, CYP1A2 and CYP3A4¶

According to recent publications, the non-renally degraded portion of amfetamine is degraded by aromatic hydroxylation via CYP2D6, CYP1A2 and CYP3A4.⁹³
The extent to which this degradation of amfetamine by CYP450 is medically relevant in humans is controversial. Most studies were carried out in vitro or in vivo in rats.
According to other sources, d-amfetamine is metabolized without CYP involvement¹⁸³

13.2.2.1. Degradation of amfetamine by CYP3A4¶

CYP3A4 is described as a further and secondary metabolization pathway for dextroamfetamine.¹⁸⁴

13.2.2.2. Degradation of amfetamine by CYP2D6¶

There are very few studies on the degradation of amfetamine drugs via CYP2D6 in humans.
One study found that CYP2D6 low metabolizers were 3.67 times more likely to show symptom improvement than intermediate CYP2D6 metabolizers (after correction for phenotype conversion and adjustment for gender, age, dose, duration and treatment adherence). Self-reported side effects were not influenced by CYP2D6 metabolizer phenotype¹⁸⁵
A study of n = 15,000 subjects found a clinically relevant influence of the CYP2D6 gene on amfetamine metabolism in 5% (Supplement Table 2) to 6% (Text).¹⁸⁶
Another study found no statistically significant effect of CYP2D6 metabolization type on dextroamfetamine or lisdexamfetamine, which may have been due to the small number of subjects.¹⁸⁷ The smaller the number of subjects, the clearer the effect must be to be statistically significant.
These results indicate that CYP2D6 plays a medically relevant role in the degradation of amfetamine drugs in humans. However, further studies are required to obtain reliable findings.
For comparison: CYP2D6 slow metabolizers showed up to ten times higher atomoxetine levels than normal metabolizers at a comparable dosage. ATX is primarily metabolized via CYP2D6¹⁸⁸

The medical literature assumes that amfetamine is degraded by CYP2D6, without elaborating on this or naming other degradation pathways.
^189190191
FDA warns CYP2D6 slow metabolizers of problems with amfetamine drugs.¹⁹² Stahl’s Essential Prescriber’s Guide¹⁹³ names amfetamine as a substrate of CYP2D6. In the Child medication fact book for psychiatric practice, Feder et al. (2023) name CYP2D6 as the main degradation pathway for dextroamfetamine¹⁹⁴
The EUR Research Information Portal “only” refers to a known mutual influence between amfetamine and clonidine, which is degraded via CYP2D6¹⁹⁵
The product information for Adderall mentions possible metabolization by CYP2D6 and warns of changes in effect due to CYP2D6 inhibitors.¹⁹⁶
Until there are studies that provide specific dosing recommendations, physicians should at least consider as a realistic possibility that CYP2D6 inhibitors may increase amphetamine levels, which is equivalent to increasing the dose.¹⁹⁷

The literature on ADHD only draws conclusions from in vitro laboratory studies on human cells or in vivo laboratory studies on rodents:
According to most sources, dextroamfetamine is metabolized by CYP2D6¹⁷⁹¹⁹⁸ , at least weakly¹⁹⁹
A number of sources quite naturally assume that amfetamine is broken down by CYP2D6 without further problematizing this ²⁰⁰²⁰¹
Others conclude that poor CYP2D6 metabolizers require lower AMP doses and ultra-rapid metabolizers may require higher AMP doses. However, they further note that the effects of CYP2D6 polymorphisms on AMP metabolism are still unclear^{14318 202} so the extent to which the CYP2D6 genotype influences the efficacy of amfetamine drugs in ADHD is still unclear²⁰³
Although CYP2D6 is involved in the degradation of d-AMP, it is not the dominant degradation pathway²⁰⁴

The further the specialist literature moves away from practical use as a drug in humans, the lower the proportion of CYP2D6 in the metabolization of amfetamine is assumed to be. It should be noted that these studies were not only predominantly conducted on rodents and less on humans, but also often focused more on the degradation of amfetamine in drug doses than on the degradation of the comparatively low drug doses:
Amfetamine itself appears to be significantly less metabolized by CYP2D6 than some amfetamine analogues.²⁰⁵²⁰⁶ In vivo, CYP2D6 appears to be less involved in the degradation of amfetamine than in vitro²⁰⁷
Neither amfetamine (AM, beta-phenylisopropylamine) nor the amfetamine derivatives N-ethylamfetamine (NEA), N-butylamfetamine (NBA), 4-methoxyamfetamine (M-AM), 4-methoxy-N-ethylamfetamine (M-NEA) or 4-methoxy-N-butylamfetamine (M-NBA) were N-dealkylated to a significant extent in microsomal human cell preparations expressing CYP2D6. The only metabolites formed from AM, NEA and NBA were the corresponding 4-hydroxylated compounds, whose formation rates were low. All 4-methoxylated substrates were efficiently O-demethylated by CYP2D6 to their corresponding phenols. The size of the N-alkyl group influenced the formation rates of these phenolamines. In contrast to the reported results with 2- and 3-methoxyamfetamines, none of the 4-methoxyamfetamines were ring-oxidized to 2- or 3-hydroxy-4-methoxyamfetamines or to dihydroxyamfetamines in the CYP2D6 enzyme system.²⁰⁵
The N,N-dialkylated amfetamine, N-methyl-N-propargylamfetamine (deprenyl; DEP) was N-demethylated and N-depropargylated by CYP2D6. In contrast, N-benzyl-N-methylamfetamine (benzphetamine; BPA) did not form metabolites by CYP2D6. N-allyl-N-methylamfetamine (AMA), N,N-diallylamphthamine (DAA) and N-methyl-N-propylamfetamine (MPA) showed CYP2D6-catalyzed N-dealkylation. The rates of CYP2D6-catalyzed reactions on N,N-dialkylated amfetamines depended on the type and degree of unsaturation of the N-substituents.²⁰⁸
In rats and rabbits, amfetamine and six amfetamine derivatives showed that amfetamine itself had the highest affinity (lowest K(m)) for CYP2C3 and that increasing the size of the substituent on the nitrogen atom reduced the affinity. The rate increased with the size of the substituent. The rates of N-demethylation of BZP and deprenyl by rat CYP2C11 and 2C13 were much higher than those of reactions at other N-alpha positions. This suggests that rat CYP2C enzymes have a more stringent regioselectivity than rabbit CYP2C3 for the deamination/dealkylation of phenylisopropylamines.²⁰⁹
In rats, a CYP2D1 inhibitor led to an increased or prolonged AMP effect and a doubled AUC of AMP.²¹⁰ CYP2D1 in rats corresponds to CYP2D6 in humans.

13.2.2.3. Inhibition of CYP2D6 by amfetamine¶

Amfetamine is a strong CYP2D6 inhibitor.²⁰⁶ A CYP2D6 inhibitor inhibits the activity of CYP2D6 and causes other drugs that are metabolized by CYP2D6 to be broken down more slowly, so that overdoses can occur quickly.

The CYP2D6 gene is highly polymorphic. In Central Europe, the following alleles are particularly relevant²²⁰

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

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 metabolization²²⁰

• 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

Anecdotal reports:

• In the ADxS forum, several people with ADHD reported a significant prolongation of the duration of action of a single dose of amfetamine medication by berberine, which is metabolized by CYP2D6 and CYP3A4 and is therefore a competitor for these enzymes. Bupropion also prolongs the effect of amfetamine drugs. Bupropion is a strong CYP2D6 inhibitor and is not affected by CYP3A4.
• Furthermore, a case of serotonin syndrome and severe side effects was reported to us when paroxetine was administered in addition to lisdexamfetamine. Paroxetine is degraded via CYP2D6 and is itself a strong inhibitor of CYP2D6. In the reported case, both drugs had to be discontinued immediately within 2 days as an emergency measure.

Until a more reliable study situation is available, a metabolization by or interaction with CYP2D6 should at least be considered according to the precautionary principle for amfetamine drugs.

13.2.3. Flavin monooxygenase degradation pathway¶

Flavin monooxygenase (FMO3) is a monooxidase system comparable to CYP.

FMO oxidizes secondary and tertiary amine analogues of amfetamine¹⁸¹
(+/-)-Amfetamine hydroxylamine is converted to phenylpropanone oxime by human FMO3 with a stereoselectivity ratio of trans/cis of 5:1. Methamfetamine is oxidized by human FMO3 at the N-position to methamfetamine hydroxylamine.²²¹

13.2.4. Dopamine beta-hydroxylase degradation pathway¶

Dextroamfetamine, but not levoamfetamine, is degraded by dopamine-β-hydroxylase (DBH). DBH catalyzes the removal of the pro-R hydrogen atom and the formation of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, from d-amfetamine.²²³
Amfetamine also appears to be degraded by dopamine beta-hydroxylase.²²⁴²²⁵
This is contradicted by the fact that pretreatment with a dopamine β-hydroxylase inhibitor prior to amfetamine administration led to a reduction in amfetamine metabolites, but did not change the amfetamine level in the brain.²²⁶

13.2.5. Methylation (dAMP to methamfetamine )¶

A laboratory study found evidence of degradation of medical dextroamfetamine to methamfetamine by N-methylation in humans in vivo. 31% of the urine samples contained dextromethamfetamine, albeit less than 1%. Degradation via this pathway therefore occurs in such small quantities that it is probably of no medical relevance, but it is important for the detection of amfetamine in cases of suspected drug use. No methamfetamine (neither dMeth nor lMeth) was found during the degradation of lisdexamfetamine or dextroamfetamine in vitro. Among methamfetamine drugs, no racemate of levo- and dextromethamhetamine was usually found, but predominantly pure lMeth or dMeth ²²⁷²²⁸

The propylamines MDA (methylenedioxyamfetamine), MDMA and MDE (methylenedioxyethylamfetamine) are additionally metabolized to glycine conjugates of the corresponding 3,4-disubstituted benzoic acids, the so-called hippuric acid derivatives, which could occur by COMT-catalyzed methylation and/or glucuronidation/sulfation²¹⁹

For AMP drugs vs. AMP medications in the lab, see also Drug testing and ADHD medications

14. Contraindications and interactions¶

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

• Pregnancy / breastfeeding
  • No disadvantages for the child if the mother continued to take D-Amp during pregnancy. In contrast, there was an increased risk of abortion if D-Amp intake was discontinued during pregnancy. There were advantages if no D-Amp was taken before and during pregnancy. Early discontinuation could therefore be helpful when trying to conceive.²²⁹
  • A cohort study found no increased risk of ADHD or other neuronal developmental disorders from MPH or AMP use during pregnancy.²³⁰
  • Risk of neuronal developmental disorders for the offspring unchanged when taking ATX during pregnancy (Swedish cohort study, n = 861,650 children of n = 572,731 mothers from 2008-2017)²³¹
  • CYP development in the fetus, newborns and infants²³²
    • Liver microsomes of the fetus show only 1 % of the CYP2D6 activity of an adult.
    • Within a month after birth, this value increases to around 20% of the activity of an adult.
      • The immaturity of the CYP2D6 system at birth could explain the syndrome of irritability, tachypnea, tremor and increased muscle tone in newborns whose mothers took SSRIs, unless it is alternatively a withdrawal reaction to the SSRIs.
        • If this is relevant, we believe that amfetamine medication should not be taken during pregnancy until it has been clarified whether amfetamine medication is broken down by CYP2D6.
      • At 3 years of age, the CYP metabolization ability is well developed
      • Children have proportionally more liver parenchyma than adults, so that the weight-adjusted metabolic capacity is greater in childhood
  • Weight of newborns
    • Unchanged, of mothers with ADHD who took amfetamine medication during pregnancy.²³³ This is consistent with results from a large cohort study of MPH use during pregnancy.²³⁴
    • 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.²³⁵ Atomoxetine did not show these slight increases in risk.
  • Miscarriages
    • Doubled risk of miscarriage when taking stimulants during pregnancy.²³⁶
  • Malformations
    • A 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.²³⁷
    • No increased risk (small study)²³⁸

For lisdexamfetamine:²³⁹

• 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 amfetamine medication at the same time.⁸

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 amfetamine medication (0.21%).²⁴⁰ 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%.²⁴¹ The studies do not allow any conclusion to be drawn as to whether the increased prevalence of psychosis is attributable to ADHD or stimulants.
The studies do not allow any conclusion to be drawn as to whether the increase in the prevalence of psychosis is due to the existence of ADHD or to the administration of stimulants.
Another study found an 8-fold risk for people with ADHD when taking ADHD medication (0.34% vs. 0.048%).²⁴² As this does not compare people with ADHD with and without medication, but people with ADHD with medication against the population as a whole, it is not possible to draw any reliable conclusions about the contribution of ADHD medication. The absolute risk of first-time psychosis or mania when starting medication was drug-dependent:

• Atomoxetine: 0.60 % (highest)
• Amfetamine medication: 0.33 %
• Methylphenidate: 0.19 %

14.1. Shortened half-life (reduced effect)¶

Attenuation of the effect of dexamfetamine:²⁴³

• 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 dexamfetamine
• Substances that acidify urine (ammonium chloride, sodium dihydrogen phosphate, etc.)
  • increase ionized excretion products of dexamfetamine in the urine, resulting in increased renal excretion

• Acidification of the urine (reduced pH value)²³⁹
  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 alkaline residues remain in the rest of the body, which increase the pH value.
The effect of food after digestion on the acid load of minerals and protein on the kidneys 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.²⁴⁴ A vegetarian diet thus correlates with a prolonged amfetamine drug effect.
Foods with a high oxalate content can increase acid formation.²⁴⁵
One study gives the following calculation method:²⁴⁶ 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 amfetamine medication. Foods with a high PRAL value cause acidic urine and thus promote a shortened effect of amfetamine medication. According to this model, hard cheese is suitable for shortening the effect of amfetamine drugs, while raisins could prolong it.

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

14.2. Prolonged half-life (increased effect)¶

• With alkalized urine (increased pH value):²³⁹
  e.g. through
  • Sodium hydrogen carbonate (baking powder, soda)
  • Diet with a high fruit / vegetable content
  • Urinary tract infections
  • Vomiting
  • Clonidine²⁴³

Enhanced effect of dexamfetamine due to:²⁴³

• Disulfiram
• Substances that increase the pH value in the 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 reduced expression of the CACNA1C gene can lead to a prolonged effect of dopamine reuptake inhibitors.²⁴⁷ Conversely, increased CACNA1C expression may lead to a shortened effect.

14.3. 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).²⁴⁸ However, other parameters, such as the duration of action, do not change.

14.4. Amplifying effect on amfetamine¶

14.4.1. Alcohol increases amfetamine levels¶

Alcohol can increase amfetamine levels.¹⁹⁷

14.4.2. CYP2D6 inhibitors increase amfetamine levels¶

Since amfetamine is broken down by CYP2D6, drugs that are also broken down by CYP2D6 can slow down the breakdown of amfetamine as well as their own breakdown, as competition for the CYP2D6 enzyme arises.
CYP2D6 inhibitors may increase amfetamine levels, necessitating a dose reduction. After discontinuation of CYP2D6 inhibitors, an increase in the dose of amfetamine medication may be necessary.¹⁹⁷
CYP2D6 inducers can accelerate degradation and thus reduce the effect.

One study found no effect of lisdexamfetamine on CYP2D6, CYP1A2 or CYP3A.²⁴⁹

See under CYP2D6 metabolizing enzyme

14.5. Attenuating effect on amfetamine¶

Have a weakening effect on amfetamine:²⁵⁰

• 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.

14.6. Few interactions of AMP with other medications¶

In contrast to the above-mentioned interactions of amfetamine drugs with other drugs, barely any interactions of amfetamine drugs with other drugs are known.¹⁹⁷

Amfetamines can increase the release of serotonin and inhibit the reuptake of serotonin. Therefore, concomitant use of amfetamines and SSRIs carries the risk of dangerously high extracellular serotonin levels (serotonin syndrome).²⁰³²⁵¹
We are aware of such cases, e.g. parallel use of lisdexamfetamine and the SSRI paroxetine.

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

• CYP2D6
• CYP1A2
• CYP3A4.

The clinical relevance is classified as low.²⁵⁰

Attenuating effect on²⁵⁰

• Antihypertensives such as guanethidine

Reinforcing on²⁵⁰

• Analgesic effect of opioids

14.7. AMP during pregnancy¶

A small prospective study of n = 13 children whose mothers received amfetamine medication while breastfeeding found no disadvantages for the children.²⁵²

15. Long-term effect: No habituation effects of amfetamine medication¶

A meta-analysis of 87 randomized placebo-controlled double-blind studies found no evidence of a decrease in the effect of methylphenidate, amfetamine drugs, atomoxetine or α2 antagonists with prolonged use.²⁵³

16. Preparations¶

Amfetamine medications are available as various preparations.

Amfetamine medications are available in the USA as:⁴²

• Mixture of D- and L-amfetamine isomers (racemic mixture)
• Mixed sulfates and saccharinates of D-L-amfetamine isomers (Adderall)
• Pure D-amfetamine sulphate
  • Dexamfetamine hemisulfate
    • United Kingdom: Amfexa®
    • Germany, Denmark, Finland, Iceland, Luxembourg, Norway, Sweden: Attentin®
    • Approved for children and young people aged 6 to 17 years
    • Doses: 5 mg tablets, 10 mg break-in tablets
    • Dosage: 5-10 mg/day orally, with an increase of 5 mg per week, up to a maximum dose of 20 mg/day (up to 40 mg for older children in exceptional cases)²⁵⁴
• D-Amfetamine as lisdexamfetamine in lysine-bound form (Vyvanse, Tyvense)
• Racemic methamfetamine sulphate (Desoxyn)

Vyvanse, Tyvense

Vyvanse / Tyvense contains lisdexamfetamine. Lisdexamfetamine is dextroamfetamine bound to lysine. The lysine binding causes a very slow and even release of dextroamfetamine 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

17. Taking amfetamine medication abroad¶

See under Taking stimulants abroad