Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Effect of histaminergic manipulation on weight in obese adults: a randomized placebo controlled trial

International Journal of Obesity volume 32, pages 1559–1565 (2008)Cite this article

Abstract

Objective:

To determine the magnitude and determinants of weight loss in humans exposed to betahistine, a centrally acting histamine-1 (H-1) agonist and partial histamine-3 (H-3) antagonist.

Design:

A multicenter randomized, placebo-controlled dose-ranging weight loss trial with a 12-week treatment period.

Subjects:

Two hundred and eighty-one obese but otherwise healthy participants.

Measurements:

Weight and obesity-related comorbidities at baseline and at the end of the intervention.

Results:

Betahistine, at the doses tested, did not induce significant weight loss. With the exception of headache, no difference in adverse effect profile was noted between placebo and treatment groups. Subgroup analysis revealed that age below 50 years, ethnicity (non-Hispanics) and gender (women) were the strongest predictors of weight loss in this population. When these three factors were combined together, the betahistine 48 mg group (n=23) lost −4.24±3.87 kg, whereas the placebo group (n=25) lost −1.65±2.96 kg during this time period (P=0.005).

Conclusion:

Betahistine, at the doses tested, induced significant weight loss with minimal adverse events only in women below 50 years.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Bugajski J, Gadek-Michalska A, Bugajski AJ . Nitric oxide and prostaglandin systems in the stimulation of hypothalamic–pituitary–adrenal axis by neurotransmitters and neurohormones. J Physiol Pharmacol 2004; 55: 679–703.

    CAS  PubMed  Google Scholar 

  2. Lecklin A, Etu-Seppälä P, Stark H, Tuomisto L . Effects of intracerebroventricularly infused histamine and selective H1, H2 and H3 agonists on food and water intake and urine flow in Wistar rats. Brain Res 1998; 793: 279–288.

    Article  CAS  Google Scholar 

  3. Passani MB, Lin JS, Hancock A, Crochet S, Blandina P . The histamine H3 receptor as a novel therapeutic target for cognitive and sleep disorders. Trends Pharmacol Sci 2004; 25: 618–625.

    Article  CAS  Google Scholar 

  4. Morimoto T, Yamamoto Y, Yamatodani A . Brain histamine and feeding behavior. Behav Brain Res 2001; 124: 145–150.

    Article  CAS  Google Scholar 

  5. Parsons ME, Ganellin CR . Histamine and its receptors. Br J Pharmacol 2006; 147 (Suppl 1): S127–S135.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Attoub S, Moizo L, Sobhani I, Laigneau JP, Lewin MJ, Bado A . The H3 receptor is involved in cholecystokinin inhibition of food intake in rats. Life Sci 2001; 69: 469–478.

    Article  CAS  Google Scholar 

  7. Masaki T, Chiba S, Yasuda T, Noguchi H, Kakuma T, Watanabe T et al. Involvement of hypothalamic histamine H1 receptor in the regulation of feeding rhythm and obesity. Diabetes 2004; 53: 2250–2260.

    Article  CAS  Google Scholar 

  8. Wijtmans M, Leurs R, de Esch I . Histamine H3 receptor ligands break ground in a remarkable plethora of therapeutic areas. Expert Opin Investig Drugs 2007; 16: 967–985.

    Article  CAS  Google Scholar 

  9. Clineschmidt BV, Lotti VJ . Histamine: intraventricular injection suppresses ingestive behavior of the cat. Arch Int Pharmacodyn Ther 1973; 206: 288–298.

    CAS  PubMed  Google Scholar 

  10. Itowi N, Nagai K, Nakagawa H, Watanabe T, Wada H . Changes in the feeding behavior of rats elicited by histamine infusion. Physiol Behav 1988; 44: 221–226.

    Article  CAS  Google Scholar 

  11. Orthen-Gambill N . Antihistaminic drugs increase feeding, while histidine suppresses feeding in rats. Pharmacol Biochem Behav 1988; 31: 81–86.

    Article  CAS  Google Scholar 

  12. Sheiner JB, Morris P, Anderson GH . Food intake suppression by histidine. Pharmacol Biochem Behav 1985; 23: 721–726.

    Article  CAS  Google Scholar 

  13. Vaziri P, Dang K, Anderson GH . Evidence for histamine involvement in the effect of histidine loads on food and water intake in rats. J Nutr 1997; 127: 1519–1526.

    Article  CAS  Google Scholar 

  14. Lecklin A, Tuomisto L, MacDonald E . Metoprine, an inhibitor of histamine N-methyltransferase but not catechol-O-methyltransferase, suppresses feeding in sated and in food deprived rats. Methods Find Exp Clin Pharmacol 1995; 17: 47–52.

    CAS  PubMed  Google Scholar 

  15. Lecklin A, Tuomisto L . The blockade of H 1 receptors attenuates the suppression of feeding and diuresis induced by inhibition of histamine catabolism. Pharmacol Biochem Behav 1998; 59: 753–758.

    Article  CAS  Google Scholar 

  16. Doi T, Sakata T, Yoshimatsu H, Machidori H, Kurokawa M, Jayasekara LA et al. Hypothalamic neuronal histamine regulates feeding circadian rhythm in rats. Brain Res 1994; 641: 311–318.

    Article  CAS  Google Scholar 

  17. Sakata T, Fukagawa K, Ookuma K, Fujimoto K, Yoshimatsu H, Yamatodani A et al. Hypothalamic neuronal histamine modulates ad libitum feeding by rats. Brain Res 1990; 537: 303–306.

    Article  CAS  Google Scholar 

  18. Orthen-Gambill N, Salomon M . FMH-induced decrease in central histamine levels produces increased feeding and body weight in rats. Physiol Behav 1992; 51: 891–893.

    Article  CAS  Google Scholar 

  19. Ookuma K, Sakata T, Fukagawa K, Yoshimatsu H, Kurokawa M, Machidori H et al. Neuronal histamine in the hypothalamus suppresses food intake in rats. Brain Res 1993; 628: 235–242.

    Article  CAS  Google Scholar 

  20. Canty P, Valentine J, Papworth SJ . Betahistine in peripheral vertigo: a double blind, placebo-controlled, cross-over study of Serc versus placebo. J Laryngol Otol 1981; 95: 687–692.

    Article  CAS  Google Scholar 

  21. Fossati A, Barone D, Benvenuti C . Binding affinity profile of betahistine and its metabolites for central histamine receptors of rodents. Pharmacol Res 2001; 43: 389–392.

    Article  CAS  Google Scholar 

  22. Arrang JM, Garbarg M, Quach TT, Dam Trung Tuong M, Yeramian E, Schwartz JC . Actions of betahistine at histamine receptors in the brain. Eur J Pharmacol 1985; 111: 73–84.

    Article  CAS  Google Scholar 

  23. Jeck-Thole S, Wagner W . Betahistine: a retrospective synopsis of safety data. Drug Safety 2006; 29: 1049–1059.

    Article  CAS  Google Scholar 

  24. Food and Nutrition Board. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients) National Academy Press: Washington DC, 2005.

  25. Mercer LP, Kelley DS, Bufidranj HM, Haq AA, Humphries LL . Gender affects rat's central nervous system histaminergic responses to dietary manipulation. J Nutr 1996; 126: 3128–3135.

    Article  CAS  Google Scholar 

  26. Kasaoka S, Kawahara Y, Inoue S, Tsuji M, Kato H, Tsuchiya T et al. Gender effects in dietary histidine-induced anorexia. Nutrition 2005; 21: 855–858.

    Article  CAS  Google Scholar 

  27. Bajic D, Hoang QV, Nakajima S, Nakajima Y . Dissociated histaminergic neuron cultures from the tuberomammillary nucleus of rats: culture methods and ghrelin effects. J Neurosci Methods 2004; 132: 177–184.

    Article  CAS  Google Scholar 

  28. Sakata T, Yoshimatsu H, Kurokawa M . Hypothalamic neuronal histamine: implications of its homeostatic control of energy metabolism. Nutrition 1997; 13: 403–411.

    Article  CAS  Google Scholar 

  29. Nillni EA, Vaslet C, Harris M, Hollenberg A, Bjørbak C, Flier JS . Leptin regulates prothyrotropin-releasing hormone biosynthesis. Evidence for direct and indirect pathways. J Biol Chem 2000; 275: 36124–36133.

    Article  CAS  Google Scholar 

  30. Gotoh K, Fukagawa K, Fukagawa T, Noguchi H, Kakuma T, Sakata T et al. Hypothalamic neuronal histamine mediates the thyrotropin-releasing hormone-induced suppression of food intake. J Neurochem 2007; 103: 1102–1110.

    Article  CAS  Google Scholar 

  31. Kow LM, Pfaff DW . Mapping of neural and signal transduction pathways for lordosis in the search for estrogen actions on the central nervous system. Behav Brain Res 1998; 92: 169–180.

    Article  CAS  Google Scholar 

  32. Zhou J, Lee AW, Devidze N, Zhang Q, Kow LM, Pfaff DW . Histamine-induced excitatory responses in mouse ventromedial hypothalamic neurons: ionic mechanisms and estrogenic regulation. J Neurophysiol 2007; 98: 3143–3152.

    Article  CAS  Google Scholar 

  33. Yusuf S, Wittes J, Probstfield J, Tyroler HA . Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. JAMA 1991; 266: 93–98.

    Article  CAS  Google Scholar 

  34. Lagakos SW . The challenge of subgroup analyses—reporting without distorting. N Engl J Med 2006; 354: 1667–1669.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Obecure Ltd., Ramat-Gan, Israel

    N Barak

  2. Outpatient Clinic Unit, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA

    F L Greenway

  3. Scripps Clinic Department of Diabetes and Endocrinology, San Diego, CA, USA

    K Fujioka

  4. Weill Medical College of Cornell University, New York, NY, USA

    L J Aronne

  5. Division of General Internal Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    R F Kushner

Authors
  1. N Barak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F L Greenway
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K Fujioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L J Aronne
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R F Kushner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N Barak.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barak, N., Greenway, F., Fujioka, K. et al. Effect of histaminergic manipulation on weight in obese adults: a randomized placebo controlled trial. Int J Obes 32, 1559–1565 (2008). https://doi.org/10.1038/ijo.2008.135

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2008.135

Keywords

This article is cited by

Search

Advanced search

Quick links