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Metadoxine for ADHD


Metadoxine for ADHD

Metadoxine (pyridoxine-pyrrolidone carboxylate; pyridoxol L-2-pyrrolidone-5-carboxylate).
Metadoxine is an ion pair salt of pyridoxine (vitamin B6) and 2-pyrrolidone-5-carboxylate (PCA, L-PGA).1

Metadoxine retarded is referred to as METADOXINE EXTENDED RELEASE (MDX) in the United States.

Metadoxine is currently being researched for the treatment of ADHD.2

  • is a selective serotonin 2B receptor antagonist3
    • An impaired balance of serotonin-dopamine neurotransmission is thought to be involved in ADHD symptoms in adults.4
  • shows high affinity to the GABA transporter
    • Metadoxin inhibits the activity of the enzyme GABA transaminase, which breaks down GABA.
    • Metadoxin increases inhibitory GABA-ergic synaptic transmission through a presynaptic effect.
    • Because it does not affect dopamine, norepinephrine, or serotonin levels, metadoxine has a novel mechanism of action as a monoamine-independent GABA modulator[8].
  • inhibits the excitatory transmission of glutamate
    • this possibly improves attention in ADHD sufferers5

Metadoxin does not bind to:1

  • Dopamine receptors or dopamine transporters
  • Norepinephrine receptors or norepinephrine transprter
  • Serotonin receptors
  • Does not alter levels of dopamine, norepinephrine, or serotonin

Several double-blind, placebo-controlled trials in adult ADHD sufferers with metadoxine sustained release (1400 mg/day) found significant clinical improvement over placebo in patients with predominantly inattentive symptoms (ADHD-I) (only).657

The drug did not pass a phase III trial. No significant improvement was found compared to placebo, although this may also have been due to above-average improvements under placebo.8 According to another source, the Phase III trial was terminated prematurely by the FDA due to safety concerns.9

Metadoxine could also be helpful in acute alcohol intoxication and in fragile X syndrome (FXS), which has symptoms that can be confused with ADHD.10

Metadoxin enhanced in an FXS animal model (Fmr1 knockout mouse)

  • Learning behavior
  • Memory
  • social interaction

In addition, metadoxin reversed the overactivation of the biomarkers Akt and extracellular signal-regulated kinase (ERK) in the blood and brain of juvenile and adult mice. Metadoxin restored the aberrant neuronal morphology in FXS and reduced the exaggerated basal protein production that is thought to be responsible for learning and memory impairments in FXS.1112

Metadoxin side effects

Metadoxine did not show severe side effects.
The most common side effects were

  • Nausea
  • Fatigue
  • Headache.

  1. Metadoxine extended release (MDX) for adult ADHD. Alcobra Ltd. 2014.

  2. Buoli, Serati, Cahn (2016): Alternative pharmacological strategies for adult ADHD treatment: a systematic review. Expert Rev Neurother. 2016;16(2):131-44. doi: 10.1586/14737175.2016.1135735. PMID: 26693882. REVIEW

  3. (Brea, Castro-Palomino, Yeste, Cubero, Párraga, Domínguez, Loza (2010): Emerging opportunities and concerns for drug discovery at serotonin 5-HT2B receptors. Curr Top Med Chem. 2010;10(5):493-503. doi: 10.2174/156802610791111524. PMID: 20166944. REVIEW

  4. Oades (2008):. Dopamine-serotonin interactions in attention-deficit hyperactivity disorder (ADHD). Prog Brain Res. 2008;172:543-65. doi: 10.1016/S0079-6123(08)00926-6. PMID: 18772050. REVIEW

  5. Manor, Rubin, Daniely, Adler (2014): Attention benefits after a single dose of metadoxine extended release in adults with predominantly inattentive ADHD. Postgrad Med. 2014 Sep;126(5):7-16. doi: 10.3810/pgm.2014.09.2795. PMID: 25295645.

  6. Manor, Newcorn, Faraone, Adler (2013): Efficacy of metadoxine extended release in patients with predominantly inattentive subtype attention-deficit/hyperactivity disorder. Postgrad Med. 2013 Jul;125(4):181-90. doi: 10.3810/pgm.2013.07.2689. PMID: 23933905.

  7. Manor, Ben-Hayun, Aharon-Peretz, Salomy, Weizman, Daniely, Megiddo (2012): Newcorn JH, Biederman J, Adler LA. A randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy, safety, and tolerability of extended-release metadoxine in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2012 Dec;73(12):1517-23. doi: 10.4088/JCP.12m07767. PMID: 23290324.

  8. Pressemitteilung von Alcobra (2017)

  9. Nazarova VA, Sokolov AV, Chubarev VN, Tarasov VV, Schiöth HB (2022): Treatment of ADHD: Drugs, psychological therapies, devices, complementary and alternative methods as well as the trends in clinical trials. Front Pharmacol. 2022 Nov 17;13:1066988. doi: 10.3389/fphar.2022.1066988. PMID: 36467081; PMCID: PMC9713849.

  10. Di Miceli, Gronier (2018): Pharmacology, Systematic Review and Recent Clinical Trials of Metadoxine. Rev Recent Clin Trials. 2018;13(2):114-125. doi: 10.2174/1574887113666180227100217. PMID: 29485008. REVIEW

  11. Kurosaki, Sakano, Pröschel, Wheeler, Hewko, Maquat (2021): NMD abnormalities during brain development in the Fmr1-knockout mouse model of fragile X syndrome. Genome Biol. 2021 Nov 16;22(1):317. doi: 10.1186/s13059-021-02530-9. PMID: 34784943; PMCID: PMC8597091.

  12. Dölen, Osterweil, Rao, Smith, Auerbach, Chattarji, Bear (2007): Correction of fragile X syndrome in mice. Neuron. 2007 Dec 20;56(6):955-62. doi: 10.1016/j.neuron.2007.12.001. PMID: 18093519; PMCID: PMC2199268.