Advertisement

Psychopharmacology

, Volume 228, Issue 1, pp 109–118 | Cite as

Psychopharmacology of theobromine in healthy volunteers

  • Matthew J. Baggott
  • Emma Childs
  • Amy B. Hart
  • Eveline de Bruin
  • Abraham A. Palmer
  • Joy E. Wilkinson
  • Harriet de Wit
Original Investigation

Abstract

Background

Theobromine, a methylxanthine related to caffeine and present in high levels in cocoa, may contribute to the appeal of chocolate. However, current evidence for this is limited.

Objectives

We conducted a within-subjects placebo-controlled study of a wide range of oral theobromine doses (250, 500, and 1,000 mg) using an active control dose of caffeine (200 mg) in 80 healthy participants.

Results

Caffeine had the expected effects on mood including feelings of alertness and cardiovascular parameters. Theobromine responses differed according to dose; it showed limited subjective effects at 250 mg and negative mood effects at higher doses. It also dose-dependently increased heart rate. In secondary analyses, we also examined individual differences in the drug’s effects in relation to genes related to their target receptors, but few associations were detected.

Conclusions

This study represents the highest dose of theobromine studied in humans. We conclude that theobromine at normal intake ranges may contribute to the positive effects of chocolate, but at higher intakes, effects become negative.

Keywords

Theobromine Caffeine Genetics Subjective Cognitive Healthy volunteers 

Notes

Acknowledgments

This research was supported by Unilever R and D. Additional support from T32 MH020065 (MJB), DA02812 (HdW), T32 DA007255 (ABH), and DA021336 (AAP).

Supplementary material

213_2013_3021_MOESM1_ESM.docx (39 kb)
ESM 1 (DOCX 38 kb)

References

  1. Alsene K, Deckert J, Sand P, de Wit H (2003) Association between A2a receptor gene polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology 28:1694–1702PubMedCrossRefGoogle Scholar
  2. Brandt J (1991) The Hopkins Verbal Memory Test: development of a new memory test with six equivalent forms. Clin Neuropsychol pp 125–142Google Scholar
  3. Brice CF, Smith AP (2002) Effects of caffeine on mood and performance: a study of realistic consumption. Psychopharmacology 164:188–192PubMedCrossRefGoogle Scholar
  4. Bruinsma K, Taren DL (1999) Chocolate: food or drug? J Am Diet Assoc 1249–56Google Scholar
  5. Brunk SF, Ferguson RK, Toubes DB, Leaverton PE, Nordschow CD, Wilson WR (1973) A teaching format in clinical pharmacology. Comparison of two xanthines and a placebo. J Clin Pharmacol 13:121–126Google Scholar
  6. Brunyé TT, Mahoney CR, Lieberman HR, Giles GE, Taylor HA (2010a) Acute caffeine consumption enhances the executive control of visual attention in habitual consumers. Brain Cogn 186–192Google Scholar
  7. Brunyé TT, Mahoney CR, Lieberman HR, Taylor HA (2010b) Caffeine modulates attention network function. Brain Cogn 72:181–188PubMedCrossRefGoogle Scholar
  8. Carney JM (1982) Effects of caffeine, theophylline and theobromine on scheduled controlled responding in rats. Br J Pharmacol 451–454Google Scholar
  9. Carney JM, Holloway FA, Modrow HE (1985) Discriminative stimulus properties of methylxanthines and their metabolites in rats. Life Sci 913–920Google Scholar
  10. Childs E, de Wit H (2006) Subjective, behavioral and physiological effects of acute caffeine in light, nondependent caffeine users. Psychopharmacology (Berl) 185(4):514–523CrossRefGoogle Scholar
  11. Childs E, Hoffoff C, Deckert J et al (2008) Association between ADORA2A and DRD2 polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology 33:2791–2800PubMedCrossRefGoogle Scholar
  12. de Wit H, Griffiths RR (1991) Testing the abuse liability of anxiolytic and hypnotic drugs in humans. Drug Alcohol Depend 28:83–111PubMedCrossRefGoogle Scholar
  13. Dorfman L, Jarvik M (1970) Comparative stimulant and diuretic actions of caffeine and theobromine in man. Clin Pharmacol Ther 11:869PubMedGoogle Scholar
  14. Drouillard D, Vesell E, Dvorchik B (1978) Studies on theobromine disposition in normal subjects. Alterations induced by dietary abstention from or exposure to methylxanthines. Clin Pharmacol Ther 23:296PubMedGoogle Scholar
  15. Fan J, McCandliss BD, Fossella J, Flombaum JI, Posner MI (2005) The activation of attentional networks. NeuroImage 26:471–479PubMedCrossRefGoogle Scholar
  16. Ferré S (2008) An update on the mechanisms of the psychostimulant effects of caffeine. J Neurochem 105:1067–1079PubMedCrossRefGoogle Scholar
  17. Fischman MW, Foltin RW (1991) Utility of subjective-effects measurements in assessing abuse liability of drugs in humans. Br J Addict 86:1563–1570PubMedCrossRefGoogle Scholar
  18. Frary CD, Johnson RK, Wang MQ (2005) Food sources and intakes of caffeine in the diets of persons in the United States. J Am Diet Assoc 105:110–113PubMedCrossRefGoogle Scholar
  19. Fredholm BB (2007) Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ 1315–1323Google Scholar
  20. Fredholm BB, Bättig K, Holmén J, Nehlig A, Zvartau EE (1999) Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 51:83–133PubMedGoogle Scholar
  21. Freedman ML, Reich D, Penney KL, McDonald GJ, Mignault AA, Patterson N, Gabriel SB, Topol EJ, Smoller JW, Pato C, et al. (2004) Assessing the impact of population stratification on genetic association studies. Nat Genet 388–393Google Scholar
  22. Haertzen CA (1966) Development of scales based on patterns of drug effects, using the Addiction Research Center Inventory (ARCI). Psychol Rep 163–194Google Scholar
  23. Hart AB, de Wit H, Palmer AA (2012) Genetic factors modulating the response to stimulant drugs in humans. Behavioral Neurogenet 12:537–577CrossRefGoogle Scholar
  24. Heim F, Ammon HPT (1969) Caffeine and other methyl xanthines. Schattauer-Verlag, StuttgartGoogle Scholar
  25. Johanson CE, Uhlenhuth EH (1980) Drug preference and mood in humans: d-amphetamine. Psychopharmacology 71:275–279PubMedCrossRefGoogle Scholar
  26. Lelo A, Birkett D, Robson R, Miners J (1986) Comparative pharmacokinetics of caffeine and its primary demethylated metabolites paraxanthine, theobromine and theophylline in man. Br J Clin Pharmacol 22:177PubMedCrossRefGoogle Scholar
  27. MacLeod JW, Lawrence MA, McConnell MM, Eskes GA, Klein RM, Shore DI (2010) Appraising the ANT: psychometric and theoretical considerations of the Attention Network Test. Neuropsychology 24:637PubMedCrossRefGoogle Scholar
  28. McNair DM, Lorr M, Droppleman LF (1971) Profile of mood states (POMS). Educational and Industrial Testing Service, San DiegoGoogle Scholar
  29. Mitchell ES, Slettenaar M, vd Meer N, Transler C, Jans L, Quadt F, Berry M (2011) Differential contributions of theobromine and caffeine on mood, psychomotor performance and blood pressure. Physiol Behav 104:816–822PubMedCrossRefGoogle Scholar
  30. Moffat A (1986) Clarke's isolation and identification of drugs, 2nd edn. Pharmaceutical Press, LondonGoogle Scholar
  31. Mumford GK, Evans SM, Kaminski BJ, Preston KL, Sannerud CA, Silverman K, Griffiths RR (1994) Discriminative stimulus and subjective effects of theobromine and caffeine in humans. Psychopharmacology (Berl) 115:1–8CrossRefGoogle Scholar
  32. Mumford GK, Benowitz NL, Evans SM, Kaminski BJ, Preston KL, Sannerud CA, Silverman K, Griffiths RR (1996) Absorption rate of methylxanthines following capsules, cola and chocolate. Eur J Clin Pharmacol 51:319–325PubMedCrossRefGoogle Scholar
  33. Posner MI, Peterson SE (1990) The attentional system of the human brain. Ann Rev Neurosci 25–42Google Scholar
  34. R Development Core Team (2012) R: A language and environment for statistical computing. R Foundation for Statistical Computing Vienna, AustriaGoogle Scholar
  35. Reeves DL, Bleiberg J, Roebuck-Spencer T, Cernich AN, Schwab K, Ivins B, Salazar AM, Harvey SC, Brown FH, Warden D (2006) Reference values for performance on the Automated Neuropsychological Assessment Metrics V3.0 in an active duty military sample. Mil Med 171:982–994PubMedGoogle Scholar
  36. Robinson GA, Butcher RW, Sutherland EW (1967) Adenyl cyclase as an adrenergic receptor. Ann N Y Acad Sci 703–723Google Scholar
  37. Rogers PJ, Hohoff C, Heatherley SV, Mullings EL, Maxfield PJ, Evershed RP, Deckert J, Nutt DJ (2010) Association of the anxiogenic and alerting effects of caffeine with ADORA2A and ADORA1 polymorphisms and habitual level of caffeine consumption. Neuropsychopharmacology 35:1973–1983PubMedCrossRefGoogle Scholar
  38. Ruxton C (2008) The impact of caffeine on mood, cognitive function, performance and hydration: a review of benefits and risks. Nutr Bull 33:15–25CrossRefGoogle Scholar
  39. Schindler CW, Karcz-Kubicha M, Thorndike EB, Müller CE, Tella SR, Ferré S, Goldberg SR (2009) Role of central and peripheral adenosine receptors in the cardiovascular responses to intraperitoneal injections of adenosine A1 and A2A subtype receptor agonists. Br J Pharmacol 144:642–650CrossRefGoogle Scholar
  40. Shi D, Daly JW (1999) Chronic effects of xanthines on levels of central receptors in mice. Cell Mol Neurobiol 719–932Google Scholar
  41. Smit HJ (2011) Theobromine and the pharmacology of cocoa. Handb Exp Pharmacol 200:201–234PubMedCrossRefGoogle Scholar
  42. Smit HJ, Blackburn RJ (2005) Reinforcing effects of caffeine and theobromine as found in chocolate. Psychopharmacology 181:101–6Google Scholar
  43. Snyder S, Katims J, Annau Z, Bruns R, Daly J (1981) Adenosine receptors and behavioral actions of methylxanthines. Proc Natl Acad Sci U S A 78:3260–3264PubMedCrossRefGoogle Scholar
  44. Svenningsson P, Nomikos GG, Fredholm BB (1999) The stimulatory action and the development of tolerance to caffeine is associated with alterations in gene expression in specific brain regions. J Neurosci 19:4011–4022PubMedGoogle Scholar
  45. Tarka SM, Cornish HH (1982) The toxicology of cocoa and methylxanthines: a review of the literature. CRC Crit Rev Toxicol 9:275–312CrossRefGoogle Scholar
  46. The Hershey Company (2012) Chocolate and caffeine. Hershey Company, PennsylvaniaGoogle Scholar
  47. Theocorp Holding Company LLC (2010) GRAS exemption claim for theobromine (3,7-dimethylxanthine) summary of data concerning the safety and GRAS determination of theobromine (3,7-dimethylxanthine) for use as an ingredient in specified foodsGoogle Scholar
  48. UK Joint Food Safety and Standards Group (1998) Survey of caffeine and other methylxanthines in energy drinks and other caffeine-containing products Food Surveillance Information Sheet. Joint Food Safety and Standards Group, LondonGoogle Scholar
  49. van den Bogaard B, Draijer R, Westerhof BE, van den Meiracker AH, van Montfrans GA, van den Born BJH (2010) Effects on peripheral and central blood pressure of cocoa with natural or high-dose theobromine: a randomized, double-blind crossover trial. Hypertension 56:839–846PubMedCrossRefGoogle Scholar
  50. Wechsler D (1958) The measurement and appraisal of adult intelligence, 4th edn. Williams & Wilkins, BaltimoreCrossRefGoogle Scholar
  51. Wesensten NJ, Killgore WDS, Balkin TJ (2005) Performance and alertness effects of caffeine, dextroamphetamine, and modafinil during sleep deprivation. J Sleep Res 14:255–266PubMedCrossRefGoogle Scholar
  52. Yang A, Childs E, Palmer AA, de Wit H (2010) More on ADORA. Psychopharmacology (Berl) 212:699–700CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Matthew J. Baggott
    • 1
  • Emma Childs
    • 1
  • Amy B. Hart
    • 1
  • Eveline de Bruin
    • 2
  • Abraham A. Palmer
    • 1
  • Joy E. Wilkinson
    • 3
  • Harriet de Wit
    • 1
  1. 1.University of ChicagoChicagoUSA
  2. 2.Unilever R&D VlaardingenVlaardingenThe Netherlands
  3. 3.Unilever R&D ColworthColworthUK

Personalised recommendations