Amlodipine for ADHD

Amlodipine was mentioned as a possible ADHD drug in initial hypothetical studies.¹ (Some of the authors are shareholders or employees of a company researching amlodipine as an ADHD drug)
Amlodipine caused:¹ * (Some of the authors are partners or employees of a company researching amlodipine as an ADHD drug)*

• in SHR (who show increased hyperactivity, impulsivity and attention problems)
  • Hyperactivity reduced
• in adgrl3.1-/- zebrafish (which show increased hyperactivity and impulsivity)²
  • Hyperactivity reduced
  • Impulsiveness reduced

Established ADHD medications also reduced hyperactivity and impulsivity in adgrl3.1-/- zebrafish:

• Methylphenidate²
• Atomoxetine³²
• Guanfacine³
• Clonidine³

Clonidine, atomoxetine and guanfacine significantly altered sleep dynamics across multiple parameters in adgrl3.1-/- zebrafish during the night.³

In addition to amlodipine, aceloclofenac, doxazosin and moxonidine also inhibit the hyperactivity of adgrl3.1 mutants and impair sleep parameters in the same way as atomoxetine.³ Unlike amlodipine, neither aceloclofenac, doxazosin nor moxonidine are known to be strong FIASMA or even FIASMA at all⁴

Amlodipine is a dihydropyridine and an L-type calcium channel blocker.⁵
A typical application is the treatment of

• arterial hypertension (arterial high blood pressure)
• chronic stable and vasospastic angina

The L-type calcium channels Cav1.2 and Cav1.3 regulate calcium influx into neurons and are important for normal brain development, function and plasticity³
They are encoded by the CACNA1C and CACNA1D genes. CACNA1C is an ADHD candidate gene. For more information see CACNA1C, Calcium Voltage-Gated Channel Subunit Alpha1 C In the article Genes as genetic candidates in ADHD with a plausible pathway to ADHD.

CACNA1C encodes the L-type calcium channel (LTCC) Cav1.2 LTCCs are required for normal dopaminergic neurotransmission between the VTA and nucleus accumbens. Reduced CACNA1C levels attenuate the function of the mesolimbic dopamine system: in mice with CACNA1C haploinsufficiency, sub-second frequency dopamine release was insensitive to DAT inhibition. Constitutive CACNA1C haploinsufficiency caused reduced hypermotor activity after acute administration of DAT-specific stimulants. Locomotor sensitization of these mice to the DAT antagonist GBR12909 was weaker than in wild-type mice. Sensitization to GBR12909 was selectively attenuated in the VTA but not in the nucleus accumbens in mice with reduced CACNA1C. CACNA1C appears to modify the presynaptic function of the mesolimbic dopamine system. Since the identified single nucleotide polymorphisms are found in an intronic (non-protein coding, “in intron”) region of CACNA1C, the genetic risk influence is likely to occur via altered CACNA1C levels in certain brain regions.⁶ Hypermotor activity induced by high doses of d-amphetamine is attenuated in mice lacking one copy of CACNA1C.⁷
One study found this gene to be one of the 51 most likely gene candidates for ADHD.⁸
So far, we have not found any connection between CACNA1D and ADHD.

Amlodipine

• crosses the blood-brain barrier
• reduces activation of the cerebrum (neocortex, basal ganglia, hippocampus, amygdala, olfactory centers)

Amlodipine reaches its maximum plasma concentration only after 6 to 12 hours after oral administration and has a half-life of 30 to 50 hours.
Degradation occurs in the liver mainly via CYP3A4 to inactive metabolites.

Amlodipine is available on prescription and as a generic.

Amlodipine showed comparable metabolic effects to established ADHD drugs in terms of amino acids and lipids, particularly glycine, serine, threonine, phenylalanine, lysophosphatidylcholine and sphingomyelin⁹
Phenylalanine is a prodrug of dopamine.

Studies on the effect of amlodipine on ADHD in humans have not yet been conducted.
There are studies that report a correlation of ADHD with elevated ASM levels. ASM can be reduced by a strong FIASMA such as amlodipine. However, there are quite a few other strong FIASMAs, none of which have been noted as ADHD medications. However, amlodipine also acts as an antihypertensive. In light of the fact that the main model animal for ADHD, SHR, shows greatly increased blood pressure with age, research into amlodipine as an ADHD drug is plausible.

In forums, participants with ADHD who had already taken amlodipine rarely reported an improvement in their ADHD symptoms, which was also weaker than with conventional ADHD medication.¹⁰ Out of 23 reports, we counted 21 negative and two positive reports (end of April 2025). Regardless of the effect on ADHD and blood pressure reduction, a strong sedative effect (less impairing when taken in the evening) and several serious side effects were reported

Against the background of the reported positive effect on several dopaminergic metabolic pathways and the simultaneous antihypertensive effect, a preferred prescription as an antihypertensive in ADHD patients could be considered if an antihypertensive is absolutely necessary anyway.
However, in view of the known side effects, use as an ADHD medication in people with ADHD without one of the existing indications (arterial hypertension, coronary heart disease (CHD), chronic stable angina pectoris, Prinzmetal’s angina)¹¹ is unlikely to be advisable.

Metabolic pathways:
Methylphenidate particularly altered the d-glutamine and d-glutamate metabolism and the phenylalanine metabolism in adgrl3.1 zebrafish⁹

• 1. Lysophosphatidylcholine (LPC)
• 2. S-ASM, sphingomyeline and ceramide
• 2.1. S-ASM, sphingomyelin and ceramide in ADHD
• 2.2. S-ASM, sphingomyelin and ceramide for other disorders

1. Lysophosphatidylcholine (LPC)¶

Lysophosphatidylcholines (LPC, lysoPC, lysolecithins) are phosphoholipids. They are formed by the hydrolysis of phosphatidylcholine by phospholipase A2 using S-adenosylmethionine (SAM).

• strong cytotoxins
• involved in the development of
  • inflammatory diseases
    • pro-inflammatory
    • can induce the migration of lymphocytes and macrophages
    • can increase the production of pro-inflammatory cytokines
    • can cause oxidative stress
  • Arteriosclerosis
  • neuropathic pain
    • can induce demyelinating processes in nerve tracts
      • are used to generate a multiple sclerosis animal model.¹²
• can stimulate the immune system
• can promote the differentiation of monocytes into dendritic cells
• increased with Parkinson’s disease¹³¹⁴
• possibly involved in the negative symptoms of schizophrenia¹⁵¹⁶

Lysophosphatidylcholines have an inhibitory effect on dopamine neurotransmission by

• inhibit the dopamine transporter¹⁴
• impair the binding of the dopamine D1 and D2 receptors¹⁴
• reduce the dopamine turnover rate^{1413 13 14}
• Increase dopamine levels¹³¹⁴

Lysophosphatidylcholines reduced motor activity and dopamine turnover and increased dopamine levels in rats ¹³¹⁴
Against this background, a reduction of lysophosphatidylcholines in ADHD is desirable.

ADHD.medications and related active ingredients reduce LPC:

• Guanfacine: reduced LPC (14:0) and LPC (22:6)⁹
• Atomoxetine: decreased LPC (14:0), LPC (18:1), LPC (18:2), LPC (20:1), LPC (20:4), LPC (22:1), LPC (22:6) in adgrl3.1 zebrafish compared to untreated adgrl3.1 zebrafish and reduced LPC (18:2), LPC (20:1), LPC (22:1) in adgrl3.1 zebrafish compared to wild-type zebrafish⁹
• Methylphenidate: significantly reduced LPC (22:6) in adgrl3.1 zebrafish⁹
• Amlodipine: reduced LPC in adgrl3.1 zebrafish⁹
• Dextroamphetamine reduced LPC¹⁷
• Cocaine reduced LPC in the nucleus accumbens¹⁸

1-oleoyl-lysophosphatidylcholine binds to the GPR-119 receptor.¹⁹

2. S-ASM, sphingomyeline and ceramide¶

The acid sphingomyelinase (ASM, sphingomyelin phosphodiesterase 1, encoded by the ADHD candidate gene SMPD1) Catalyzes sphingomyelin in the cell membrane to ceramide and phosphorylcholine. Ceramide is a second messenger. All other sphingolipids are synthesized from ceramide. Increased S-ASM serum levels therefore correlate with reduced sphingolipid serum levels.

Studies in ADHD animal models found markers of cholesterol metabolism that correlated with hyperactivity and changes in the lipid composition of the brain, such as altered phospholipids and sphingolipids, which are important for myelin sheath formation and neuronal signaling.²⁰ SHR showed aberrant levels of 3-hydroxymethylglutaric acid, 3-phosphoglyceric acid, adenosine monophosphate, cholesterol, lanosterol and o-phosphoethanolamine compared to Wistar Kyoto rats. MPH caused 3-hydroxymethylglutaric acid and cholesterol to be similar to Wistar Kyoto levels.
In SHR, the activity of 3-hydroxy-3-methyl-glutaryl-CoA reductase and the expression of sterol regulatory element-binding protein-2 and ATP-binding cassette transporter A1 were decreased in the PFC. MPH upregulated sterol regulatory element-binding protein-2 and ATP-binding cassette transporter A1.

S-ASM reduces extracellular dopamine.
Increased ASM and resulting increased ceramide correlated with decreased basal extracellular dopamine in the nucleus accumbens and dorsal hippocampus. Serotonin and noradrenaline levels remained little changed. At the same time, overexpression of ASM enhanced the dopamine response to alcohol and reduced norepinephrine responses.²⁴

2.1. S-ASM, sphingomyelin and ceramide in ADHD¶

One study found highly significantly elevated levels of S-ASM in the serum of adults with ADHD. The elevation correlated significantly with ADHD symptom severity in both untreated and MPH- or atomoxetine-treated people with ADHD, as well as with the severity of sleep disturbances. in males (only), MPH reduced serum S-ASM levels, but not to the level of unaffected individuals.²²

Children with ADHD were found to have 20-30% lower serum sphingolipid levels²⁶

• Sphingomyelins C16:0, C18:0, C18:1, C24:1
  • reduced sphingomyelin levels in serum identified people with ADHD with 79 % sensitivity and 78 % specificity.
• Ceramide C24:0
• Deoxyceramide C24:1

Gross motor problems in ADHD (gait, balance, motor persistence, coordination) correlated with elevated sphingomyelin and ceramide plasma levels.²⁷

Several lines of evidence suggest that ADHD medications and their related active ingredients reduce S-ASM (S-ASM converts sphingomyelin to ceramide):

• (Only) in males with ADHD, MPH decreased serum S-ASM levels, but not to the level of non-affected individuals.²²
• Methylphenidate increased sphingomyelin in adgrl3.1 zebrafish⁹
• Guanfacine increased sphingomyelin in adgrl3.1 zebrafish⁹
• Cocaine reduced the sphingolipid ceramide in the nucleus accumbens¹⁸

Amlodipine is a FIASMA (functional inhibitor of S-ASM)¹¹, therefore indirectly increases sphingomyelin. Against the background of reduced sphingomyelin levels in ADHD, a positive effect of amlodipine would be conclusive in this respect. However, there are many drugs that act as FIASMA, none of which is known to be a particularly effective ADHD drug. Unlike amlodipine, neither aceloclofenac nor doxazosin, moxonidine or atomoxetine, all of which also reduce increased hyperactivity in adgrl3.1-/- zebrafish, are FIASMA⁴
However, if FIASMA help to increase extracellular dopamine levels, they could be considered as a supportive medication, although this is unlikely to be the central pathway of action for remedying ADHD symptoms.

2.2. S-ASM, sphingomyelin and ceramide for other disorders¶

However, if ADHD could be treated by reducing S-ASM alone, a number of drugs that act as FIASMA (ASM inhibitors), such as maprotiline, fluoxetine, nortriptyline, imipramine, trimipramine, tamoxifen or amitriptyline, would have to be shown to be effective. However, this is unfortunately only the case to a limited extent (reported for nortriptyline and imipramine). We therefore suspect that the increase in ASM in ADHD and the increase in sphingomyelin by the drugs highly effective in ADHD (MPH, amphetamines, guanfacine, atomoxetine) is rather a consequence of a different effect.

This is further contradicted by the fact that ASM activity has been demonstrated in numerous other disorders²², which - with the exception of alcohol addiction and depression - are not characterized by increased comorbidity with ADHD:

• Atherosclerosis
• chronic heart failure
• Diabetes mellitus
• Wilson’s disease
• Cystic fibrosis
• Urinary bladder carcinoma
• non-small cell lung cancer
• Infectious diseases
• Sepsis
• Multiple sclerosis
• Alzheimer’s disease
• Parkinson’s disease
  • The membrane lipid sphingomyelin is reduced in Parkinson’s disease.²⁸ A study on idiopathic Parkinson’s disease found a significant correlation of lower initial sphingomyelin levels with a faster decline in DAT binding levels in caudate and putamen²⁹
• Alcohol dependence
• Depression
  • S-ASM hyperfunction has been found in depression. Some antidepressants may have an antidepressant effect primarily due to the inhibition of S-ASM (FIASMA).
  • More on this at (Some) antidepressants work via S-ASM inhibition (FIASMA) In the article Depression and dysphoria in ADHD.

Another possibility is that the strength of the ASM inhibition (the FIASMA strength) is decisive.
FIASMA was named as the most effective:⁴

Active ingredient, ASM reduction, incubation time in hours
Emetine: 99.6 %, 24 (alkaloid, triggers nausea)
Tamoxifen: 95.9 %, 6 (cancer drug)
Trifluoperazine: 91.7 %, 6 (antipsychotic)
Perhexiline: 91.5 %, 0.5 (drug for the treatment of refractory angina pectoris. Not authorized in the EU)³⁰
Cepharanthine: 90.8 %, 6 (alkaloid)
Thioridazine: 89.6 %, 6 (antipsychotic)
Amitriptyline: 88.3 %, 0.5 (antidepressant)
Amlodipine: 88 %, 0.5 (antihypertensive)
Sertindol: 88 %, 6 (atypical neuroleptic)
Sertraline: 87.7 %, 0.5 (antidepressant)
Clemastine: 87.4 %, 24 (antihistamine)
Benztropine: 87.3 %, 0.5 (anticholinergic)
Protriptyline: 87.3 %, 0.5 (antidepressant)
Clomiphene: 87 %, 0.5 (ovulation stimulator)
Fluoxetine: 87 %, 0.5 (antidepressant)
Nortriptyline: 86.7 %, 0.5 (antidepressant)
Maprotiline: 86.5 %, 0.5 (antidepressant)
Trimipramine: 86.2 %, 0.5 (antidepressant)
Astemizole: 85.7 %, 6 (antihistamine)
Amiodarone: 85.5 %, 24 (antiarrhythmic drug)
Desipramine: 84.4 %, 0.5 (antidepressant)
Tomatidine: 84.2 %, 24 (alkaloid)
Pimethixene: 83.5 %, 24 (antihistamine, anticholinergic)
Fluphenazine: 83.5 %, 0.5 (antipsychotic)
Flupenthixol: 81.8 %, 0.5 (neuroleptic)
Dicyclomine: 81.4 %, 24 (anticholinergic)
Lofepramine: 80.8 %, 24 (antidepressant)

In contrast, the antidepressant venlafaxine has only a minimal FIASMA effect (4.9 %, 0.5 h).