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Adrenochrome Hypothesis
In 1952, Humphry Osmond joined me in Saskatchewan, bringing with him the observations he and John Smythies had made.6 They had compared the experiences induced in normal subjects by mescaline with the experiences schizophrenia induced in its victims. There were many remarkable similarities and, of course, differences. They realized that if a molecule as simple in structure as mescaline could produce an experience which mimicked something as complex as schizophrenia, a similar compound produced in the body could be the schizophrenic toxin. Using somewhat similar reasoning, Osmond and I induced non schizophrenic subjects to excrete a mauve factor when given LSD. Later, the same factor was identified as kryptopyrrole,7,8 and a rapid screening method was developed by Sohler, Hosztynska, and Pfeiffer.9 Pfeiffer, Sohler, Jenney, and Iliev described the syndrome pyroluria10 (which Hoffer, Osmond, and Mahon had termed malvaria11,12,13,14,15,16,17) and its treatment with large doses of pyridoxine and zinc. Kryptopyrrole is toxic.18,19
Mescalin is a methylated derivative of a phenylethylamine similar to adrenalin. Adrenalin became even more likely as a source when one of their subjects reported that deteriorated (discolored) adrenalin which had had inhaled for his asthma induced a mescaline type experience in him. They suggested that methylated derivatives of adrenalin played a role in the genesis of schizophrenia. This idea was brilliant, for it immediately provided a guide to the search for the elusive toxin. Until then (and since), most biochemists had devoted their research to examining body fluids of schizophrenics to find anything that could sort out patients from controls. The odds of finding such a substance from the thousands present in the body were and are very low.
But in 1952, the idea was too far in advance of biochemical technology. There were no methods for measuring these methylated derivatives, and none were being sought because it was “known” that methylation could not take place in the body.
The Osmond-Smythies hypothesis pointed toward methylated derivatives as a general class. With Osmond, I began to examine the literature for all known hallucinogens; fortunately, there were few: d-lysergic acid diethylamide, ibogaine and harmine, all indoles, mescaline, which was an amine which could be indolized, and pink adrenalin, whose structure remained unknown to us. Soon after, Prof. D. Hutcheon, a pharmacologist, joined the Saskatchewan Committee on Schizophrenia Research. He told us it was adrenochrome. Of the five hallucinogens, four were indoles and the fifth might become an indole. We now had another guideline. Search the body for an hallucinogen, an indole derived from adrenalin. Was it andrenochrome, adrenolutin, or one or more of their derivatives?20
From the beginning, the idea aroused an inordinate amount of rage among our psychiatric colleagues. Our first grant request from Ottawa was vetoed by Canada’s three most distinguished chairmen of departments of psychiatry. They were overruled by an outside referee, Prof. Nolan D.C. Lewis of Columbia University.
The adrenochrome hypothesis directed our attention to three main research areas. If the predictions derived from the hypothesis were confirmed, this would provide support for the hypothesis. Naturally, adrenochrome or its derivatives must be formed in the body, either only in schizophrenics, which would make this disease unique, or in everyone but to a greater degree in schizophrenics. It would also follow that adrenochrome would be hallucinogenic. Finally, it would follow that reversing the reaction, i.e. preventing the formation of adrenochrome, would be therapeutic.
To examine the first idea we assembled a small team of chemists led by Dr R.A. Heacock.21,22 We discovered how to synthesize crystalline adrenochrome that was stable at room temperature and also its derivative, crystalline adrenolutin. Our group was the first to have available pure adrenochrome, but we were not able to isolate and crystallize it from body fluids. In our book, The Hallucinogens (Hoffer and Osmond, 1967), we summarized the evidence that showed all the conditions essential for the formation of adrenochrome were present.23 These include the substrate, the catecholamines, the enzymes and catalysts necessary for oxidation, and the products of oxidation, the melanins. These are chrome indole polymers.
Recently, Hegedus, Kuttab, Altschule and Nayak demonstrated the presence of a particular type of melanin, rheomelanin, in serum.24 It is made from adrenochrome. Most melanins are made from tyrosine and require the enzyme tyrosinase. However, reddish neuromelanins are present in the brain even in albinos. They are found in areas of the brain rich in noradrenalin, adrenalin, dopamine, and serotonin. These chrome indoles may also be formed from aldehydes formed by amine oxidase. These amines may be metabolized by three pathways, but the chrome indoles may come from any one of these pathways. A deficiency of amine oxidase or a surplus of amines would force the amines more directly into the indole pathway. Areas richest in these amines would be most apt to accumulate neuromalinins.
Serotonin interacts with catecholamines and may modulate the oxidation of adrenalin to adrenchrome. VanderWende and Johnson reported that substantia nigra and caudate nucleus were high in dopamine and serotonin.25 Dopamine is in the soluble fraction and serotonin is bound. An excessive release of or failure to bind serotonin would lead to a reduction in formation of melanin. Less melanin is found in Parkinsonism disease. When the concentration of serotonin is lower than the concentration of adrenalin, adrenochrome formation is accelerated. When the ratio is reversed, oxidation is inhibited. VanderWende and Johnson point out both must be measured.26 The ratio is critical. At normal ratios no adrenochrome is formed. When too little serotonin is present, formation of adrenochrome is accelerated.
The amount of amine oxidized to aminochromes is less important than the time during which oxidation occurs. Even a slight conversion will be pathological if long continued and if detoxifying measures are defective. The ratio of amount formed to amount inactivated is critical. If the body lacks antioxidants (free radical scavengers) more adrenochrome will be formed. Increased quantities of melanin would accumulate in all areas where melanin is normally deposited and in some where it is not. Hair and skin should be darker and in many schizophrenics this darkening is quite evident. One of my female patients deposited a yellow-brown pigment in her fingernails and toenails. As she recovered, a clear area appeared in every nail as new, normal nails grew. The demarcation between distal discolored nail and proximal clean nail was the same in every nail. Deposition of melanin had stopped simultaneously in each nail. Chronic schizophrenics do not develop gray hair as often and do develop pigment in their skin as do pellagrins, especially when treated with chlorpromazine, in sun exposed areas. The relation of pigment in schizophrenic brains relative to normal brains is not known.
A small number of schizophrenics treated with vitamin B-3 go through a phase when melanin is deposited in their skin, particularly in the flexor surfaces. It resembles an old suntan, which begins to fade. The discoloration of skin is not pathological. Parsons also saw this in a few patients treated with niacin for hypercholesterolemia.27 He described it as a localized, velvety thickening and tanning of the skin. It is not acanthosis nigricans, a term used by Lipton et al,28 who erroneously concluded this after misreading a paper published by Wittenborn, Weber, and Brown.29 The discolored skin is easily removed by gently rubbing the wet skin. It leaves normal skin underneath. It proves excess melanin is deposited in skin, primarily in schizophrenics. No cases were reported by the coronary study on thousands of patients.
Modern scientists investigating melanin no longer dispute its source. Barr, in his thorough review of the evidence, concluded the melanins play a unique and most important role in growth and development.1 Others are convinced adrenochrome plays a most important role in heart function.30,31,32 Old age pigment accumulates in heart muscle at a rate of 1/2 % of the cell volume per decade, and older people may contain 10% of pigment by volume in their cells.33 Others discuss the oxidative pathways of catecholamines in the formation of neuromelanins and cytotoxic quinines.34,35 Dopamine and 6 hydroxydopamine are toxic after they are converted into their chrome indoles.
Melanin is a remarkably versatile substance; for example, it is a very efficient photon absorbing molecule that responds also to sound. This is why it is present in skin, eyes, and the inner ear. Maybe this is how the day/night light ratio controls mood in some cyclothymic individuals. It is a free radical scavenger binding organic and metallic molecules. Metals bound to melanin as hair and skin are shed, much as deciduous trees eliminate unwanted minerals by dropping their leaves. It is an organizing substance present at ever stage from the oocyte into the highly pigmented neural crest from which it is dispersed to the central nervous system and the autonomic nervous system. In the growing rat, neuromelanin reaches a stable adult level in 30 days, while dopamine and noradrenalin increase from day 1 to day 60. Neuromelanin is not a metabolic waste-basket.
There are three types of melanin: (1) eumelanins, derived from tyrosine, black-brown in color as seen in skin; (2) neuromelanin, derived from catecholamines, from serotonin and from melatonin; and (3) phaemelanins, which contain cysteine and gluthathione and are red, yellow, green, blue or violet.
The oxidizing enzymes are tyrosinase, peroxidase, and monoamine oxidase. The latter deaminates amines and indole amines to aldehydes, which form melanins. Auto-oxidation also occurs, catalyzed by copper and iron. The type of melanin varies with the site. In substantia nigra, dopamine is the major source. In the locus coeruleus, noradrenalin, and in the diffuse brain stem raphe system, serotonin is the chief precursor. These melanins are found in strategic, highly functional areas of the brain. I am puzzled how theorists who support the dopamine hypothesis of schizophrenia can ignore one of the most important and most toxic metabolites, dopachrome, and its melanin.
Absolute proof of a substance is present in the body is to extract that substance and to prove it is identical with a synthetic substance of know structure, or to convert it in the body into a stable derivative which can be crystallized and identified. The body has, in fact, carried out the second step and whenever we extract melanin we are proving the presence of adrenochrome in the body, even if it has a transient life.
Hegedus and Altschule, in a series of reports, concluded that adrenalin, adrenochrome, and adrenolutin incubated in blood formed rheomelanins and hemolyzed erythrocytes.36,37,38 They concluded the indole pathway was available in blood, and, even more, that erythrocytes from schizophrenics were abnormally susceptible to the hemolytic effect of rheomelanins or precursors formed from aminochromes. Blood contains cells that metabolize adrenalin to adrenochrome as the major pathway.
Matthews, Hallett, Henderson and Campbell reported that over 80% of the adrenalin was oxidized to adrenochrome by polymorphonuclear leukocytes stimulated by latex beads or by the peptide N formylmetleuphe.39 Oxidation began in 5 minutes and continued for 4 hours. This was the favored pathway over amine oxidase and catechol O methyltransferase. They also found that serum from patients drawn after myocardial infarction induced more oxidation than control serum. This provides a cellular mechanism for adrenochronme formation in inflammatory conditions. Perhaps the oxidized catecholamine free radicals are use to destroy bacteria. Adrenochrome is also an antimitotic poison.
It is likely the proportion of catecholamines converted to aminochromes varies enormously from 1% to 2% to over 80%, depending upon the tissues where this oxidation occurs. In the synapse this oxidation is dangerous, as quinines, an intermediate, are toxic. Liang, Plotsky and Adams found that 6 hydroxy dopamine reacts with central nervous system tissue in vivo to form paraquinone.40 Tse, McCreery and Adams reported catecholamines were oxidized in vitro using conditions comparable to human brain,41 and Cheng suggested that paraquinone from 6 hydroxy dopamine was an important toxin causing destruction of neural tissue.42 Is adrenochrome formation a way of removing more toxic paraquinones? It is possible the aminochromes, once formed, increase the formation of more by inhibiting catechol O methyl transferase.43
The adrenalin/adrenochrome pathway has become an important are for study in heart disease. Yates, Beamish and Dhalla, Beamish, Dhillon, Sinsal and Dhalla, and Yates, Taam, Sinsal, Beamish and Dhalla showed adrenochrome is partly responsible for myocardial necrosis and failure following massive injection of adrenalin.44,30,45 Sulfinpyrazone (Anturan) was reported by the Anturan Reinfarction Trail investigators to decrease cardiac mortality after the first infarction. It does so by abolishing adrenochrome induce arrhythmias.
Altieri and Inchiosa reported adrenochrome was a potent inhibitor of myosin, actomyosin and myofibrillar ATPase at physiological levels and pH.46 There was no effect on cerebral cortex ATPase. It is formed in smooth muscle and is part of the mechanism by which adrenalin relaxes certain smooth muscles.
Wortsman, Frank and Cryer recorded extraordinarily high plasma levels of adrenalin in patients resuscitated from cardiac arrest.47 Adrenalin levels rose 300 times while noradrenalin rose 10 times. Increases also occur in hypoglycemia and hemorrhagic shock.
The exact connection between schizophrenia and oxidized catecholamine metabolites has not been studied. It is unlikely they are specific to schizophrenia, most likely due to a combination of factors, such as a deficiency of reducing substances or antioxidants, an excess of oxidizing metals or enzymes, and an overload of catecholamines. The increased amount of adrenochrome and like substances cannot be detoxified fast enough, leading to an accumulation of adrenochrome and its metabolites. One does not even need to postulate higher concentrations of adrenochrome will be found. The increased amount of adrenochrome may be removed or destroyed just as quickly, leaving damaged molecules or an accumulation of its metabolites such as melanin. The oxidation of activated adrenalin at the synapse will destroy the receptors. This is why dopamine is toxic. If dopamine were stabilized so it could not be oxidized to dopachrome, it is doubtful that it would destroy neuron receptors. The destruction occurs by the interaction between the oxidized aminochrome and the chemicals on the surface of the receptors. Walaas and Walaas have shown that the oxidation of adrenalin to adrenochrome is accelerated in synapses when there is a deficiency of vitamin B-3 as nicotinamide adenine dinucleotide.49
Niacin is a broad-spectrum hypocholesterolemic substance that decreases cholesterol,50 (, triglycerides, low density and very low density lipoprotein cholesterol, and elevates high density lipoprotein cholesterol. A huge coronary drug study (1975) compared five substances: placebo, estrogen, thyroid, clofibrate, and niacin.51 Patients were treated for 9 years, the study ending in 1976 or so.Niacin, at the end of the study, was superior to the other four treatments, but there was no difference in the death rate. The state of the patients was reexamined beginning in 1982. Recently, Canner reported that niacin decreased the death rate by 11%.52 Clofibrate and placebo were the same and estrogen and thyroid had increased it and had been discontinued during the original study. What was surprising was this beneficial effect even after treatment was discontinued many years before. In sharp contrast, Dr E. Boyle found that his patients on niacin continually for 10 years after their first coronary suffered only 10% mortality rather than the expected 90%.53 Niacin could prevent the excessive formation of adrenochrome and would antidote the toxic effect of adrenochrome on myocardial tissue, much as it antagonized the cerebral arrhythmia measured on the electroencephalograph when adrenochrome was given intravenously.
Mescalin is a methylated derivative of a phenylethylamine similar to adrenalin. Adrenalin became even more likely as a source when one of their subjects reported that deteriorated (discolored) adrenalin which had had inhaled for his asthma induced a mescaline type experience in him. They suggested that methylated derivatives of adrenalin played a role in the genesis of schizophrenia. This idea was brilliant, for it immediately provided a guide to the search for the elusive toxin. Until then (and since), most biochemists had devoted their research to examining body fluids of schizophrenics to find anything that could sort out patients from controls. The odds of finding such a substance from the thousands present in the body were and are very low.
But in 1952, the idea was too far in advance of biochemical technology. There were no methods for measuring these methylated derivatives, and none were being sought because it was “known” that methylation could not take place in the body.
The Osmond-Smythies hypothesis pointed toward methylated derivatives as a general class. With Osmond, I began to examine the literature for all known hallucinogens; fortunately, there were few: d-lysergic acid diethylamide, ibogaine and harmine, all indoles, mescaline, which was an amine which could be indolized, and pink adrenalin, whose structure remained unknown to us. Soon after, Prof. D. Hutcheon, a pharmacologist, joined the Saskatchewan Committee on Schizophrenia Research. He told us it was adrenochrome. Of the five hallucinogens, four were indoles and the fifth might become an indole. We now had another guideline. Search the body for an hallucinogen, an indole derived from adrenalin. Was it andrenochrome, adrenolutin, or one or more of their derivatives?20
From the beginning, the idea aroused an inordinate amount of rage among our psychiatric colleagues. Our first grant request from Ottawa was vetoed by Canada’s three most distinguished chairmen of departments of psychiatry. They were overruled by an outside referee, Prof. Nolan D.C. Lewis of Columbia University.
The adrenochrome hypothesis directed our attention to three main research areas. If the predictions derived from the hypothesis were confirmed, this would provide support for the hypothesis. Naturally, adrenochrome or its derivatives must be formed in the body, either only in schizophrenics, which would make this disease unique, or in everyone but to a greater degree in schizophrenics. It would also follow that adrenochrome would be hallucinogenic. Finally, it would follow that reversing the reaction, i.e. preventing the formation of adrenochrome, would be therapeutic.
To examine the first idea we assembled a small team of chemists led by Dr R.A. Heacock.21,22 We discovered how to synthesize crystalline adrenochrome that was stable at room temperature and also its derivative, crystalline adrenolutin. Our group was the first to have available pure adrenochrome, but we were not able to isolate and crystallize it from body fluids. In our book, The Hallucinogens (Hoffer and Osmond, 1967), we summarized the evidence that showed all the conditions essential for the formation of adrenochrome were present.23 These include the substrate, the catecholamines, the enzymes and catalysts necessary for oxidation, and the products of oxidation, the melanins. These are chrome indole polymers.
Recently, Hegedus, Kuttab, Altschule and Nayak demonstrated the presence of a particular type of melanin, rheomelanin, in serum.24 It is made from adrenochrome. Most melanins are made from tyrosine and require the enzyme tyrosinase. However, reddish neuromelanins are present in the brain even in albinos. They are found in areas of the brain rich in noradrenalin, adrenalin, dopamine, and serotonin. These chrome indoles may also be formed from aldehydes formed by amine oxidase. These amines may be metabolized by three pathways, but the chrome indoles may come from any one of these pathways. A deficiency of amine oxidase or a surplus of amines would force the amines more directly into the indole pathway. Areas richest in these amines would be most apt to accumulate neuromalinins.
Serotonin interacts with catecholamines and may modulate the oxidation of adrenalin to adrenchrome. VanderWende and Johnson reported that substantia nigra and caudate nucleus were high in dopamine and serotonin.25 Dopamine is in the soluble fraction and serotonin is bound. An excessive release of or failure to bind serotonin would lead to a reduction in formation of melanin. Less melanin is found in Parkinsonism disease. When the concentration of serotonin is lower than the concentration of adrenalin, adrenochrome formation is accelerated. When the ratio is reversed, oxidation is inhibited. VanderWende and Johnson point out both must be measured.26 The ratio is critical. At normal ratios no adrenochrome is formed. When too little serotonin is present, formation of adrenochrome is accelerated.
The amount of amine oxidized to aminochromes is less important than the time during which oxidation occurs. Even a slight conversion will be pathological if long continued and if detoxifying measures are defective. The ratio of amount formed to amount inactivated is critical. If the body lacks antioxidants (free radical scavengers) more adrenochrome will be formed. Increased quantities of melanin would accumulate in all areas where melanin is normally deposited and in some where it is not. Hair and skin should be darker and in many schizophrenics this darkening is quite evident. One of my female patients deposited a yellow-brown pigment in her fingernails and toenails. As she recovered, a clear area appeared in every nail as new, normal nails grew. The demarcation between distal discolored nail and proximal clean nail was the same in every nail. Deposition of melanin had stopped simultaneously in each nail. Chronic schizophrenics do not develop gray hair as often and do develop pigment in their skin as do pellagrins, especially when treated with chlorpromazine, in sun exposed areas. The relation of pigment in schizophrenic brains relative to normal brains is not known.
A small number of schizophrenics treated with vitamin B-3 go through a phase when melanin is deposited in their skin, particularly in the flexor surfaces. It resembles an old suntan, which begins to fade. The discoloration of skin is not pathological. Parsons also saw this in a few patients treated with niacin for hypercholesterolemia.27 He described it as a localized, velvety thickening and tanning of the skin. It is not acanthosis nigricans, a term used by Lipton et al,28 who erroneously concluded this after misreading a paper published by Wittenborn, Weber, and Brown.29 The discolored skin is easily removed by gently rubbing the wet skin. It leaves normal skin underneath. It proves excess melanin is deposited in skin, primarily in schizophrenics. No cases were reported by the coronary study on thousands of patients.
Modern scientists investigating melanin no longer dispute its source. Barr, in his thorough review of the evidence, concluded the melanins play a unique and most important role in growth and development.1 Others are convinced adrenochrome plays a most important role in heart function.30,31,32 Old age pigment accumulates in heart muscle at a rate of 1/2 % of the cell volume per decade, and older people may contain 10% of pigment by volume in their cells.33 Others discuss the oxidative pathways of catecholamines in the formation of neuromelanins and cytotoxic quinines.34,35 Dopamine and 6 hydroxydopamine are toxic after they are converted into their chrome indoles.
Melanin is a remarkably versatile substance; for example, it is a very efficient photon absorbing molecule that responds also to sound. This is why it is present in skin, eyes, and the inner ear. Maybe this is how the day/night light ratio controls mood in some cyclothymic individuals. It is a free radical scavenger binding organic and metallic molecules. Metals bound to melanin as hair and skin are shed, much as deciduous trees eliminate unwanted minerals by dropping their leaves. It is an organizing substance present at ever stage from the oocyte into the highly pigmented neural crest from which it is dispersed to the central nervous system and the autonomic nervous system. In the growing rat, neuromelanin reaches a stable adult level in 30 days, while dopamine and noradrenalin increase from day 1 to day 60. Neuromelanin is not a metabolic waste-basket.
There are three types of melanin: (1) eumelanins, derived from tyrosine, black-brown in color as seen in skin; (2) neuromelanin, derived from catecholamines, from serotonin and from melatonin; and (3) phaemelanins, which contain cysteine and gluthathione and are red, yellow, green, blue or violet.
The oxidizing enzymes are tyrosinase, peroxidase, and monoamine oxidase. The latter deaminates amines and indole amines to aldehydes, which form melanins. Auto-oxidation also occurs, catalyzed by copper and iron. The type of melanin varies with the site. In substantia nigra, dopamine is the major source. In the locus coeruleus, noradrenalin, and in the diffuse brain stem raphe system, serotonin is the chief precursor. These melanins are found in strategic, highly functional areas of the brain. I am puzzled how theorists who support the dopamine hypothesis of schizophrenia can ignore one of the most important and most toxic metabolites, dopachrome, and its melanin.
Absolute proof of a substance is present in the body is to extract that substance and to prove it is identical with a synthetic substance of know structure, or to convert it in the body into a stable derivative which can be crystallized and identified. The body has, in fact, carried out the second step and whenever we extract melanin we are proving the presence of adrenochrome in the body, even if it has a transient life.
Hegedus and Altschule, in a series of reports, concluded that adrenalin, adrenochrome, and adrenolutin incubated in blood formed rheomelanins and hemolyzed erythrocytes.36,37,38 They concluded the indole pathway was available in blood, and, even more, that erythrocytes from schizophrenics were abnormally susceptible to the hemolytic effect of rheomelanins or precursors formed from aminochromes. Blood contains cells that metabolize adrenalin to adrenochrome as the major pathway.
Matthews, Hallett, Henderson and Campbell reported that over 80% of the adrenalin was oxidized to adrenochrome by polymorphonuclear leukocytes stimulated by latex beads or by the peptide N formylmetleuphe.39 Oxidation began in 5 minutes and continued for 4 hours. This was the favored pathway over amine oxidase and catechol O methyltransferase. They also found that serum from patients drawn after myocardial infarction induced more oxidation than control serum. This provides a cellular mechanism for adrenochronme formation in inflammatory conditions. Perhaps the oxidized catecholamine free radicals are use to destroy bacteria. Adrenochrome is also an antimitotic poison.
It is likely the proportion of catecholamines converted to aminochromes varies enormously from 1% to 2% to over 80%, depending upon the tissues where this oxidation occurs. In the synapse this oxidation is dangerous, as quinines, an intermediate, are toxic. Liang, Plotsky and Adams found that 6 hydroxy dopamine reacts with central nervous system tissue in vivo to form paraquinone.40 Tse, McCreery and Adams reported catecholamines were oxidized in vitro using conditions comparable to human brain,41 and Cheng suggested that paraquinone from 6 hydroxy dopamine was an important toxin causing destruction of neural tissue.42 Is adrenochrome formation a way of removing more toxic paraquinones? It is possible the aminochromes, once formed, increase the formation of more by inhibiting catechol O methyl transferase.43
The adrenalin/adrenochrome pathway has become an important are for study in heart disease. Yates, Beamish and Dhalla, Beamish, Dhillon, Sinsal and Dhalla, and Yates, Taam, Sinsal, Beamish and Dhalla showed adrenochrome is partly responsible for myocardial necrosis and failure following massive injection of adrenalin.44,30,45 Sulfinpyrazone (Anturan) was reported by the Anturan Reinfarction Trail investigators to decrease cardiac mortality after the first infarction. It does so by abolishing adrenochrome induce arrhythmias.
Altieri and Inchiosa reported adrenochrome was a potent inhibitor of myosin, actomyosin and myofibrillar ATPase at physiological levels and pH.46 There was no effect on cerebral cortex ATPase. It is formed in smooth muscle and is part of the mechanism by which adrenalin relaxes certain smooth muscles.
Wortsman, Frank and Cryer recorded extraordinarily high plasma levels of adrenalin in patients resuscitated from cardiac arrest.47 Adrenalin levels rose 300 times while noradrenalin rose 10 times. Increases also occur in hypoglycemia and hemorrhagic shock.
The exact connection between schizophrenia and oxidized catecholamine metabolites has not been studied. It is unlikely they are specific to schizophrenia, most likely due to a combination of factors, such as a deficiency of reducing substances or antioxidants, an excess of oxidizing metals or enzymes, and an overload of catecholamines. The increased amount of adrenochrome and like substances cannot be detoxified fast enough, leading to an accumulation of adrenochrome and its metabolites. One does not even need to postulate higher concentrations of adrenochrome will be found. The increased amount of adrenochrome may be removed or destroyed just as quickly, leaving damaged molecules or an accumulation of its metabolites such as melanin. The oxidation of activated adrenalin at the synapse will destroy the receptors. This is why dopamine is toxic. If dopamine were stabilized so it could not be oxidized to dopachrome, it is doubtful that it would destroy neuron receptors. The destruction occurs by the interaction between the oxidized aminochrome and the chemicals on the surface of the receptors. Walaas and Walaas have shown that the oxidation of adrenalin to adrenochrome is accelerated in synapses when there is a deficiency of vitamin B-3 as nicotinamide adenine dinucleotide.49
Niacin is a broad-spectrum hypocholesterolemic substance that decreases cholesterol,50 (, triglycerides, low density and very low density lipoprotein cholesterol, and elevates high density lipoprotein cholesterol. A huge coronary drug study (1975) compared five substances: placebo, estrogen, thyroid, clofibrate, and niacin.51 Patients were treated for 9 years, the study ending in 1976 or so.Niacin, at the end of the study, was superior to the other four treatments, but there was no difference in the death rate. The state of the patients was reexamined beginning in 1982. Recently, Canner reported that niacin decreased the death rate by 11%.52 Clofibrate and placebo were the same and estrogen and thyroid had increased it and had been discontinued during the original study. What was surprising was this beneficial effect even after treatment was discontinued many years before. In sharp contrast, Dr E. Boyle found that his patients on niacin continually for 10 years after their first coronary suffered only 10% mortality rather than the expected 90%.53 Niacin could prevent the excessive formation of adrenochrome and would antidote the toxic effect of adrenochrome on myocardial tissue, much as it antagonized the cerebral arrhythmia measured on the electroencephalograph when adrenochrome was given intravenously.