The adrenochrome hypothesis of schizophrenia revisited

Abstract

This paper reviews the current status of the adrenochrome theory of schizophrenia. An account is first given of all the experiments in which adrenochrome was reported to induce psychotomimetic effects in normal volunteers. Then the evidence is presented that adrenochrome may actually occur in the brain as a metabolite of adrenaline in the C2 group of adrenergic neurons in the medulla, together with an account of current ideas of the function of these neurons in higher limbic functions. Lastly the recent evidence is reviewed that the gene for the enzyme glutathione S-transferase is defective in schizophrenia. This enzyme detoxifies adrenochrome.

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

References

  1. Carlsson, A., Waters, A. and Hansson, L.O. (1994) “Neurotransmitter aberrations in schizophrenia: new findings”, In: Fog, R., Gerlach, J. and Hemmingston, R., eds, Schizophrenia. An Integrated View (Munksgard, Copenhagen), pp 332–343.

    Google Scholar 

  2. Fornstedt, B., Brun, A., Rosengren, E. and Carlsson, A. (1989) “The apparent autoxidation rate of catechols in dopamine-rich areas of the brain increases with the degree of depigmentation of substantia nigra”, J. Neural. Trans. Park. Dis. Den. Sect. 1, 279–295.

    Article  CAS  Google Scholar 

  3. Gai, W.P., Geffen, L.B., Denoroy, L. and Blessing, W.W. (1993) “Loss of C1 and C3 epinephrine-synthesizing neurons in the medulla oblongata in Parkinson’s disease”, Ann. Neurol. 33, 357–367.

    PubMed  Article  CAS  Google Scholar 

  4. Gertz, H-J. and Schmidt, L.G. (1991) “Low melanin content of substantia nigra in a case of neuroleptic malignant syndrome”, Pharmacopsychiatry 24, 93–95.

    PubMed  Article  CAS  Google Scholar 

  5. Greiner, A.C. and Nicholson, G.A. (1965) “Schizophrenia-melanism”, Lancet ii, 1165.

    Article  Google Scholar 

  6. Grof, S., Vojtechovsky, M., Vitek, V. and Prankova, S. (1963) “Clinical and experimental study of central effects of adrenochrome”, J. Neuropsychiatr. 5, 33–50.

    Google Scholar 

  7. Harada, S., Tachikawa, H. and Kawanishi, Y. (2001) “Glutathione S-transferase M1 gene deletion may be associated with susceptibility to certain forms of schizophrenia”, Biochem. Biophys Res. Comm. 281, 267–271.

    PubMed  Article  CAS  Google Scholar 

  8. Herbert, H. and Saper, C.B. (1992) “Organization of medullary adrenergic and noradrenergic projections to medullary periacqueductal gray matter in the rat”, J. Comp. Neurol. 315, 34–52.

    PubMed  Article  CAS  Google Scholar 

  9. Hoffer, A. (1957) “Adrenochrome in blood plasma”, Am. J. Psychiat. 114, 0.

    Google Scholar 

  10. Hoffer, A., Osmond, H. and Smythies, J. (1954) “Schizophrenia: a new approach part 2”, J. Ment. Sci. 100, 29–45.

    PubMed  CAS  Google Scholar 

  11. Kaiya, H. (1980) “Neuromelanin, neuroleptics and schizophrenia”, Neuropsychobiology 6, 241–248.

    PubMed  Article  CAS  Google Scholar 

  12. Lew, J.Y., Matsumoto, Y., Pearson, J., Goldstein, M., Hokfelt, T. and Fuxe, K. (1977) “Localization and characterization of phenylethanolamine-N-methyltransferase in the brain of various mammalian species”, Brain Res. 119, 199–210.

    PubMed  Article  CAS  Google Scholar 

  13. Lindemann, E. (1935) “The psychopathological effects of drugs affecting the vegetative system”, Am. J. Psychiat. 91, 983–1008.

    Google Scholar 

  14. Macarthur, H., Westfall, T.C., Riley, D.P., Misko, T.P. and Salvemini, D. (2000) “Inactivation of catecholamines by superoxide gives new insights on the pathogenesis of septic shock”, Proc. Natl Acad. Sci. USA 97, 9753–9758.

    PubMed  Article  CAS  Google Scholar 

  15. Nagutsu, I., Ikemoto, K., Takeuchi, T., Arai, T., Karasawa, N., Fujii, T. and Nagatsu, T. (1996) “Phenylethanolamine-N-methyltransferase-immunoreactive nerve terminals afferent to the mouse substantia nigra”, Neurosci. Lett. 245, 41–44.

    Article  Google Scholar 

  16. Osmond, H. and Smythies, J. (1952) “Schizophrenia: a new approach”, J. Ment. Sci. 98, 309–320.

    PubMed  CAS  Google Scholar 

  17. Otake, K., Ruggiero, D.A. and Nakamura, Y. (1995) “Adrenergic innervation of forebrain neurons that project to the paraventricular thalamic nucleus in the rat”, Brain Res. 697, 17–26.

    PubMed  Article  CAS  Google Scholar 

  18. Rico, B. and Cavada, C. (1998) “Adrenergic innervation of the monkey thalamus; an immunohistochemical study”, Neuroscience 84, 839–847.

    PubMed  Article  CAS  Google Scholar 

  19. Rinkel, M. and Solomon, A.C. (1957) “Chemical theories of psychosis”, J. Clin. Exp. Psychopath. 18, 323–334.

    PubMed  CAS  Google Scholar 

  20. Schwartz, B.E., Sem-Jacobsen, C. and Petersen, M.C. (1956) “Effects of mescaline, LSD-25 and adrenochrome on depths electrograms in man”, Arch. Neurol. Psychiat. 75, 579–587.

    Google Scholar 

  21. Smythies, J. (1996) “On the function of neuromelanin” Proc. R Soc. London B 263, 487–489.

    Article  CAS  Google Scholar 

  22. Smythies, J. (1999) “The neurotoxicity of glutamate, dopamine, iron and reactive oxygen species: functional interrelationships in health and disease: a review” Neurotox. Res. 1, 27–39.

    PubMed  CAS  Article  Google Scholar 

  23. Smythies, J. and Galzigna, L. (1998) “The oxidative metabolism of catecholamines in the brain: a review”, Biochim. Biophys Acta 1380, 19–162.

    Google Scholar 

  24. Smythies, J.R., Morin, R.D. and Brown, G.B. (1979) “Identification of dimethyltryptamine and o-methylbufotenin in human cerebrospinal fluid by combined gas chromatography/mass spectrometry”, Biol. Psychiatr. 14, 549.

    CAS  Google Scholar 

  25. Szara, S., Axelrod, J. and Perlin, S. (1958) “Is adrenochrome present in the blood?”, Am. J. Psychiatr. 115, 162–163.

    PubMed  CAS  Google Scholar 

  26. Szatmari, A., Hoffer, A. and Schneider, R. (1955) “The effect of adrenochrome and niacin on the electroencephalogram in epilepsy”, Am. J. Psychiat. 111, 603–616.

    PubMed  CAS  Google Scholar 

  27. Taubman, G. and Jantz, H. (1957) “Untersuchung über die dem adrenochrom zugeschrieben psychotoxischen wirkungen”, Nervenartz 28, 485–488.

    Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to John Smythies.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Smythies, J. The adrenochrome hypothesis of schizophrenia revisited. neurotox res 4, 147 (2002). https://doi.org/10.1080/10298420290015827

Download citation

Keywords

  • Schizophrenia
  • adrenochrome
  • adrenaline
  • C1-C3 adrenergic nuclei
  • neuromelanin