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Histamine H3 receptor antagonists / inverse agonists for ADHD and ASA


Histamine H3 receptor antagonists / inverse agonists for ADHD and ASA

The H3 receptor is mainly localized in the central nervous system. The H3 receptor acts as:1

  • presynaptic autoreceptor
    • modulates the release of histamine
  • presynaptic heteroreceptor
    • regulates the release of other neurotransmitters such as monoamines and amino acids

Histamine H3 receptor antagonists / inverse agonists enhance the activity of histaminergic neurons in the brain, thereby promoting arousal and cognition.2 H3 antagonists / inverse agonists have great potential for the treatment of a variety of CNS disorders, including3

  • ADHD
  • Alzheimer’s disease
  • mild cognitive impairment
  • Schizophrenia

Histamine H3 receptor antagonists showed positive cognitive effects4 as a consequence of dopamine release in PFC and ACC.5
The H3 histamine receptor is thought to be involved in arousal, control of pituitary hormone secretion, cognitive functions, motivation, goal-directed behavior, memory and sleep-wake cycles.6

A number of H3 antagonists / inverse agonists have been investigated in animal studies. Among other things, they were found to increase dopamine levels by reducing dopamine reuptake in the areas of the brain relevant to ADHD and to improve the social deficits typical of ASD.
This may be a key to the frequent comorbidity of ADHD and ASD.
The H3R inverse antagonist samelisant (SUVN-G3031) caused:7

  • dose-dependent increase in the histamine level
  • dose-dependent significant increase in dopamine and noradrenaline levels in the cortex
    • Dopamine more elevated than noradrenaline
  • only slight increase in the dopamine level in the striatum
  • no influence on the dopamine level in the striatum or nucleus accumbens
  • significant increase in wakefulness with a simultaneous decrease in NREM sleep in orexin KO mice
  • significant reduction in episodes with direct REM sleep onset

A larger double-blind RCT study of 335 adults with ADHD found only slight improvements of an H3 antagonist (Bavisant) compared with 80 mg atomoxetine and 54 mg OROS-MPH. The mean change in ADHD-RS-IV total score after 42 days of use was:8

  • -8.8 in the placebo group, 2.7 % TEA
  • -9.3 Bavisant 1 mg, 61.8 % TEA
  • -11.2 Bavisant 3 mg, 82.4 % TEA
  • -12.2 Bavisant 10 mg, 89 % TEA
  • -15.3 Atomoxetine 80 mg, 83.8 TEA
  • -15.7 OROS methylphenidate 54 mg, 82.4 % TEA
    TEA indicates the frequency of side effects.

MK-0249 is a histamine H3 receptor antagonist.9
A randomized, double-blind, placebo-controlled crossover study found no short-term efficacy of MK-0249 on ADHD symptoms in adults. As a side effect, 32% reported increased insomnia, compared to 11% for placebo. The remaining adverse event rate was identical to placebo.10

Although the first HR3 antagonists are available as drugs (e.g. pitolisant (as Ozawade® for daytime sleepiness in obstructive sleep apnea or as Wakix® for narcolepsy)), no drug has yet been approved for the treatment of ADHD or ASD.
To date, no therapeutic benefit of H3 antagonists (which reduce histamine levels and increase dopamine levels) on ADHD has been found.11 Clinical trials of H3 receptor drugs for ADHD (MK-0249, Bavisant, PF-03654746) in phase 2 trials were unsuccessful or were discontinued in phase 2 (betahistine).6

More on H3 agonists at H3 histamine receptor in the article Histamine.

  1. Ito (2009): Histamine H3-receptor inverse agonists as novel antipsychotics. Cent Nerv Syst Agents Med Chem. 2009 Jun;9(2):132-6. doi: 10.2174/187152409788452036. PMID: 20021346.

  2. Hino N, Marumo T, Kotani M, Shimazaki T, Kaku-Fukumoto A, Hikichi H, Karasawa JI, Tomishima Y, Komiyama H, Tatsuda E, Nozawa D, Nakamura T, Chaki S (2020): A Novel Potent and Selective Histamine H3 Receptor Antagonist Enerisant: In Vitro Profiles, In Vivo Receptor Occupancy, and Wake-Promoting and Procognitive Effects in Rodents. J Pharmacol Exp Ther. 2020 Nov;375(2):276-285. doi: 10.1124/jpet.120.000185. PMID: 32862143.

  3. Esbenshade TA, Fox GB, Cowart MD (2006): Histamine H3 receptor antagonists: preclinical promise for treating obesity and cognitive disorders. Mol Interv. 2006 Apr;6(2):77-88, 59. doi: 10.1124/mi.6.2.5. PMID: 16565470. REVIEW

  4. Stocking, Letavic (2008): Histamine H3 antagonists as wake-promoting and pro-cognitive agents. Curr Top Med Chem. 2008;8(11):988-1002. doi: 10.2174/156802608784936728. PMID: 18673168., REVIEW

  5. Vohora, Bhowmik (2012): Histamine H3 receptor antagonists/inverse agonists on cognitive and motor processes: relevance to Alzheimer’s disease, ADHD, schizophrenia, and drug abuse. Front Syst Neurosci. 2012 Oct 23;6:72. doi: 10.3389/fnsys.2012.00072. PMID: 23109919; PMCID: PMC3478588.

  6. 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.

  7. Nirogi R, Benade V, Daripelli S, Subramanian R, Kamuju V, Bhyrapuneni G, Muddana NR, Mekala VR, Petlu S, Jayarajan P, Badange R, Shinde A, Jasti V (2021): Samelisant (SUVN-G3031), a potent, selective and orally active histamine H3 receptor inverse agonist for the potential treatment of narcolepsy: pharmacological and neurochemical characterisation. Psychopharmacology (Berl). 2021 Jun;238(6):1495-1511. doi: 10.1007/s00213-021-05779-x. PMID: 33550481.

  8. Weisler RH, Pandina GJ, Daly EJ, Cooper K, Gassmann-Mayer C (2012): 31001074-ATT2001 Study Investigators. Randomized clinical study of a histamine H3 receptor antagonist for the treatment of adults with attention-deficit hyperactivity disorder. CNS Drugs. 2012 May 1;26(5):421-34. doi: 10.2165/11631990-000000000-00000. PMID: 22519922. RCT

  9. 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

  10. Herring, Wilens, Adler, Baranak, Liu K, Snavely, Lines, Michelson (2012): Randomized controlled study of the histamine H3 inverse agonist MK-0249 in adult attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2012 Jul;73(7):e891-8. doi: 10.4088/JCP.11m07178. PMID: 22901359.

  11. Higuchi, Yanai, Okamura, Meguro, Arai, Itoh, Iwata, Ido, Watanabe, Sasaki (2000): Histamine H1 receptors in patients with Alzheimer’s disease assessed by positron emission tomography, Neuroscience, Volume 99, Issue 4, 2000, Pages 721-729, ISSN 0306-4522,

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