The Adrenochrome Hypothesis of Schizophrenia

“Working in a psychiatrically innovative environment created by the government of saskatchewan, canada, abram hoffer and humphry f. osmond enunciated the adrenochrome hypothesis for the biogenesis of schizophrenia in 1952, slightly later proposing and, apparently, demonstrating, in a double-blind study, that the symptoms of the illness could be reversed by administering large doses of niacin. after placing the hypothesis within its ideological framework, the author describes its emergence and elaboration and discusses the empirical evidence brought against it. hoffer’s idiosyncratic diagnostic procedures, especially his creation and use of a supposed biochemical marker for schizophrenia, are examined. the author argues that hoffer’s conceptualization of schizophrenia, as well as his treatment approach, depended on a tautology. following david healy, the author treats the adrenochrome hypothesis as a version of a transmethylation theory, thus incorporating it into mainstream psychopharmacology.”

“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.”

“The hypothesis is presented, based on the chemical structure of neuromelanin, that one of its functions in the catecholamine neurons in the brain is to protect the cell against toxic quinones (such as dopaminochrome and noradrenochrome, or their dihydroxy isomers) produced from the catecholamines dopamine and noradrenaline (and possibly adrenaline) during the course of prostaglandin synthesis by the enzyme prostaglandin h synthetase, or possibly by spontaneous oxidation. one aminochrome-adrenochrome-has been shown to be neurotoxic and to have psychotomimetic properties in humans. depending on the site of production these compounds may be involved in the pathogenesis of parkinson’s disease or schizophrenia.”

“Now that definitive direct evidence has been obtained that oxidized metabolites of catecholamines – aminochrome (derived from dopamine) and related compounds – occur in the human brain the question this paper explores is what is their function there, if any. they are precursors of neuromelanin and are formed inter alia by co-oxidation by prostaglandin h ’synthase during the synthesis of prostaglandin h from arachidonic acid. their further metabolism by nahpd-cytochrome p450 reductase forms the highly neurotoxic o-semiquinone together with free oxygen radicals. the defenses against these orthoquinones (o-quinones) and o-semiquinones (which include reduction, o-methylation, 5-cysteinylization, glutathione conjugation, conversion to the o-hydroquinone, and neuromelanin formation), and their possible status in schizophrenia, are reviewed. this system is closely linked with glutamate neurotoxicity because glutamate receptors activate pgh synthase and because dopamine toxicity is mediated by these o-quinones acting on nmda receptors. interactions between glutamate and dopamine neurotoxicity are explored, including a possible role for the redox properties of catecholamines. the hypothesis is presented that some of the demonstrated cellular damage in the schizophrenic brain may be mediated by catecholamine o-quinones. the significance of the evidence from previous studies carried out 40 years ago, that a closely related catecholamine o-quinone – adrenochrome – has psychotomimetic properties in humans and behavior disrupting properties in animals, is reviewed in the light of these recent findings.”

“Osmond and smythies (1952) have given reasons for reviving the view originally put forward by bleuler (1950) that schizophrenia is essentially a disorder of metabolism, and have suggested that some substance chemically related to mescaline might be the causative agent. hoffer, osmond and smythies (1954) have begun an investigation of this hypothesis and have found that adrenochrome, an oxidation product of adrenaline which is probably a normal intermediate metabolite, has active hallucinogenic properties. these authors do not regard adrenochrome as being unquestionably the toxic agent in schizophrenia, but suggest that it or some closely related substance, having the indole ring and derived from adrenaline, is involved. they also advance the opinion that the metabolic fault consists of an overproduction of adrenochrome or similar substances. such a view necessarily implies either overproduction of adrenaline or a blocking of one or more of the paths of adrenaline detoxification in the body which do not lead through adrenochrome. as adrenaline is derived from tyrosine the hypothesis is essentially one of abnormal tyrosine metabolism. from this hypothesis certain deductions can be made.”

“This is an up-to-date account of the present status of biochemical theories and experiments as they concern schizophrenia. briefly, reference is made to the controversy of psychogenic vs biochemical aetiology of schizophrenia. in pointing to kalimann’s data of genetic factors involved in this disease, it is concluded that a predisposing genetic factor is clearly demonstrated as playing an important role in the aetiology of schizophrenia. owing to the fact that the genes are supposedly responsible for the production of specific enzymes, it would appear reasonable to look for disturbances of metabolism and, in particular, enzyme dysequilibrium in schizophrenic patients. phenylpyruvic acid oligophrenia is cited as an interesting prototype of such genetically induced abnormalities of enzyme-regulated metabolism. one line of investigation is pursuing the role of amines which play a role in brain function. osmond and smythies have been impressed by the structural similarity of mescaline and adrenaline and have developed a theory according to which adrenochrome or, as hoffer and osmond have stated more recently, adrenolutin, i. e. some intermediate metabolites of adrenaline, are the toxic substances responsible for the schizophrenic phenomena. most of these metabolites are destroyed in the body by monoamine oxidase and by a copper-containing blood enzyme, caeruloplasmin. akerfeldt’s test which is based on the oxidation of n,n-dimethylparaphenylenediamine is positive in schizophrenia but not specific since it is also positive in pregnancy, malignancies and other diseases. the author has observed 8 patients who were adrenalectomized 7 yr. ago. this must have resulted in considerable reduction of adrenaline production but did not alter the schizophrenic pathology and thus does not support the hypothesis of adrenaline or its breakdown products as being the major aetiological factor in schizophrenia. heath and his collaborators have been able to separate a fraction from schizophrenic serum which they named taraxein which is a protein extract and which in the hands of heath and his group has consistently produced schizophrenia-like symptoms when it was injected into normal volunteers. heath believes that this particular protein fraction is the specific toxic substrate of schizophrenia. his findings, however, could not be confirmed so far by other workers who have repeated his experiments. winter and flataker observed that the climbing behaviour of rats was significa…”