Schizophrenia: An Evolutionary Defense Against Severe Stress


Schizophrenia: An Evolutionary Defense Against Severe Stress

The adrenochrome investigations into schizophrenia which I have pursued since 1952, and the recent important investigations into the relationship between heart, function and adrenalin transforming to adrenochrome, points to a connection between brain and cardiac disorder. I suggest there is a link between schizophrenia and some types of heart dysfunction, My hypothesis is that the biochemistry of schizophrenia has evolved in order to protect us against death from cardiac fibrillation during severe stress, but for one to two percent of the population this life saving mechanism leads to schizophrenia. The evidence for this idea has been forming slowly over the past 40 years, and is an outcome of the adrenochrome hypothesis of schizophrenia proposed by my colleague, Dr. H. Osmond, and myself.

The hypothesis can be presented as a series of equations.

A) Under normal conditions there is a balance between release of catecholamines and their conversion to their oxidized derivatives, and neither sets of compounds are produced to excess.

B) Severe stress leads to too much adrenalin and other sympathomimetic amines. Excessive concentration of adrenalin in heart muscle, oxidation of adrenalin in myocardium to adrenochrome, and to adrenolutin. Adrenochrome causes fibrillation and other cardiac pathology and dysfunction.

C) Leakage of adrenochrome and its derivatives such as adrenolutin into the blood and into the brain causing a toxic psychosis called schizophrenia.

D) Schizophrenia -- perceptual illusions and hallucinations combined with thought disorder. This was the definition used by Conolly.( 1) Psychiatry has recently started to use the same definition; they wrote, "a break with reality usually manifested as hallucinations, delusions, or a disruption in thought processes."

This reaction is accelerated by increasing the oxidative potential, i.e. by increasing the availability of factors which increase oxygenation or which increase oxidative enzymes or auto catalysts, and by decreasing the availability of factors which inhibit the reaction, i.e. the antioxidants. It will also be driven to excessive oxidation by inhibiting the enzymes which destroy adrenalin via non-phenolic pathways.

A. Severe Stress and Excessive Secretion of Adrenalin

The flight and fight mechanism deduced by Dr. Walter Cannon many years ago has served us well in understanding why the body suddenly secretes or releases copious amounts of adrenalin when we are threatened. Animals with the quickest and most aggressive response to threats would be most apt to survive and pass on their genes to their offspring. The flight-fight mechanism remains intact today, even though the nature of the threat has been completely altered, our bodies have not been changed very much over the past 50,000 years. Dr. Robert M. Sapolsky( 2) provides an excellent popular description of the effects of stress upon the various body systems and hormones. But there is very little discussion of the connection between these effects and the sympathomimetic amines and their derivatives.

Adrenalin is a very powerful toxic natural chemical which has important positive actions and many potentially toxic effects. One of the toxic effects is upon the heart. This has been known since 1905 when the first results were recorded that intravenous adrenalin caused carditis. The literature on the toxicity of adrenalin on the heart is well documented by Dhalla, Yates, Naimark, Dhalla, Beamish and Ostadal.( 3) In their summary they write, "It is well known that massive amounts of catecholamines are released from the sympathetic nerve endings and adrenal medulla under stressful situations. Initially, these hormones produce beneficial effects on the cardiovascular system to meet energy demands of various organs in the body and their actions on the heart are primarily mediated through the stimulation of the beta-adrenergic receptors-cyclic AMP system in the myocardium. However, prolonged exposure of the heart to high levels of catecholamines results in coronary spasm, arrhythmias, contractile dysfunction, cell damage and myocardial necrosis."

It is clear that no animal could have evolved unless it developed measures for moderating the effects of adrenalin and other sympathomimetic amines, and quenching them once the stressful event was over.

B. Excessive concentration of adrenalin in heart muscle combined with oxidation of adrenalin in myocardium to adrenochrome, and to adrenolutin. Adrenochrome causes fibrillation and other cardiac pathology and dysfunction. Adrenochrome is less toxic than adrenalin. It is removed by conversion into two main chrome indoles, adrenolutin which is toxic, causing psychotic changes similar to those caused by adrenochrome and 5,6 dihydroxy indole which is not. This requires the presence of anti-oxidants.

I will refer to adrenalin only but include all the other catecholamines such as noradrenalin and dopamine. In the same way, when I discuss adrenochrome I refer also to the other oxidized derivatives of the other catecholamines such as noradrenochrome and dopachrome.

Any animal that cannot eliminate adrenalin will quickly die from overdose of the adrenalin. There are two factors which will lead to an over-accumulation of adrenalin: ( 1) excessive release of adrenalin and too rapid absorption into myocardium; ( 2) slow removal of the adrenalin from the heart muscle and other tissues. But both factors may be operating simultaneously. The sudden death of a few cocaine users in a stressful situation could be an example of both factors in operation. The stress of the reaction induces excessive secretion of adrenalin, and the cocaine itself blocks the activity of two of the four enzymes which remove adrenalin. Two systems which do not lead to adrenochrome are blocked, thus throwing too much of the burden on the phenolase pathway and increasing adrenochrome production by auto-oxidation.

Evolution has created four main pathways for degrading adrenalin with an additional auto-oxidation pathway. These four pathways require enzymes, but there is a fifth way, auto-oxidation, in the presence of known oxidizers such as iron or copper, and in the absence of antioxidants such as vitamin C and vitamin E. The five pathways for dealing with adrenalin are the culmination of millions of years of evolution. The best example of the auto-oxidation is the spontaneous conversion of adrenalin to the red colored adrenochrome when it is allowed to stand in solution in contact with oxygen.

The first pathway requires phenolases, ie. enzymes which oxidize catecholamines to adrenochrome (chrome, indoles or colored indoles). Adrenochrome is almost a free radical and is rapidly changed to adrenolutin and other indoles in the blood. It must have a very short half-life in blood.( 4) The phenolase pathway is the major one in the heart. Up to 80% of the adrenalin absorbed by myocardial tissue is converted into adrenochrome. It is also the major pathway in polymorphonuclear leucocytes( 5) and is therefore a factor in inflammations. In the rest of the body it may comprise a minor pathway, but other tissues of the body have not been examined very thoroughly. The controversy over the formation of adrenochrome in the body is reviewed by Hoffer and Osmond.( 6,7)

Two pathways (the second and third) require the enzymes amine oxidase and catechol-0-methyl transferase. The new products formed are aldehydes, not indoles such as adrenochrome. This is the pathway which has been studied very intensively in psychiatry, but this research has been largely of little value, both in determining the cause or aiding in the treatment of schizophrenia. The fourth pathway requires the minor enzyme phenolsulfotransferase. Other enzymes which oxidize adrenalin are xanthine oxidase, heart muscle cytochrome C oxidase, cytochrome C and methamyoglobin.

One catecholamine, dopamine, has been studied quite intensively and is enshrined in psychiatric research as the dopamine hypothesis.(8) But no attention has been given to one of the end products of dopamine metabolism, dopachrome, as if the molecule simply bounced back and forth unaltered within the synapse between receptor and the nerve terminal from which it originated.

The presence of these potent, highly reactive substances has finally been firmly established by Dhalla, Ganguly, Rupp, Beamish and Dhalla,(9) Matthews, Henderson and Campbell.( 5) Matthews et al. write, "We have demonstrated the presence of an adrenalin oxidase in serum during the days following acute myocardial infarction. Furthermore we have extracted a compound which was precisely equivalent to adrenochrome on hplc (high pressure liquid chromatography) analysis from the synovial fluid of patients with rheumatoid arthritis." Dhalla et al. published a method for measuring the amount of adrenolutin in plasma. Administration of different catecholamines as well as adrenochrome and adrenolutin in rats also increased the level of adrenolutin in plasma. Adrenolutin was found to be present in plasma in other species including dog, rabbit and pig. High levels of adrenolutin, which may represent total concentration of aminolutin in plasma, suggests the presence of an efficient mechanism for the oxidation of catecholamines under in vivo conditions. Another derivative of adrenochrome is 5,6 dihydroxy N methyl indole (leuco adrenochrome). This compound has anti-tension or anti-anxiety properties. See Hoffer and Osmond(10).

Matthews, Henderson and Campbell( 5) found that the percentage conversion of adrenalin to adrenochrome markedly increased as the concentration of adrenalin decreased. This suggests that the ability to detoxify adrenalin by the adrenochrome pathway is restricted to conditions where the production of adrenalin is relatively low. As the amount of adrenalin increases the other pathways (mono amino oxidase and catechol-0-methyl transferase) come into play and help remove the adrenalin. But with excessive amounts the adrenalin is auto-oxidized again, leading to adrenochrome and other free radical molecules. It is probable the body has evolved a series of reactions for dealing with adrenalin and other catecholamines as follows:

Under resting conditions small amounts of adrenochrome are formed and circulates in the blood as adrenolutin since adrenochrome is too unstable to remain very long in the blood. This is a condition of little stress, e.g. when sleeping and when relaxing during the day free of unusual anxiety or depression. In the synapse adrenalin loses one electron and becomes oxidized adrenalin. In the presence of NAD it regains the electron to reconstitute the original adrenalin. If there is a deficiency of nicotinamide adenine dinucleotide (NAD), the oxidized molecule loses another electron to become adrenochrome. This last reaction is irreversible. Oxidized adrenalin is a free radical and adrenochrome shares many of the properties of free radicals. This reaction is controlled by the oxidizing enzymes chiefly in heart and in leucocytes and in inflamed tissues, but perhaps in other tissues not examined yet. The major antioxidants vitamin C, vitamin E and selenium probably play major roles, as does NAD. Another main derivative of adrenochrome is leuko-adrenochrome which is not toxic.
Under conditions of increased secretion of adrenalin the adrenochrome enzyme pathways becomes saturated and the non-adrenochrome pathways come into play forming aldehydes and other non-aminochrome substances. This would be characteristic of moderate stress or of severe short-lived stress that most of us have to endure most of our lives. There are many known pathways for changing adrenalin and removing its toxic properties on heart and on blood pressure, indicating how essential is the rapid detoxification of adrenalin. These are: ( 1) mono amine oxidase -- the end product is 3,4 dihydroxy phenylhydroxyacetaldehyde; inhibitors of this enzyme include cocaine, histamine, ephedrin, adrenochrome, caffeine, amphetamine, nicotine, harmine, antabuse, LSD, hyperbaric oxygen; ( 2) 0-methyl-transferase -- the end product is 3-methoxy-4 hydroxy mandelic acid; ( 3) phenol sulfotransferase -- the end products are sulfates; cocaine is an inhibitor of this reaction; ( 4) other enzyme systems and molecules. Most of the adrenalin released into the synapses is rapidly reabsorbed. The rest must be metabolized quickly.
Under severe and prolonged stress none of the enzymatic pathways would be adequate to deal with the huge amount of adrenalin and the final mechanism would come into play -- auto oxidation in the cell compartments where the concentration rose the most. Auto-oxidation might be the major pathway under these conditions. This would give rise to many other free radicals such as orthoquinones and indolic catechols.(11) Ferritin and copper catalyze the auto-oxidation of the catecholamines.
Anything which increases the production of adrenochrome will increase cardiac pathology. This will result from major and long prolonged stress. It will also come about when the mechanisms for removing adrenalin are distorted by drugs or other conditions and from a deficiency of antioxidants. Thus pyrogallol, a catechol-0-methyl transferase inhibitor, increased the severity of heart lesions.

Antioxidants protect against the effect of free radicals. Free radicals are formed with adrenochrome when catecholamines are oxidized. Vitamin E protected rat hearts against damage, while on the contrary, vitamin E deficiency made them more sensitive. Other antioxidants are vitamin C, and coenzyme Q10. Vitamin B-3 is also involved since the NAD system, of which vitamin B-3 is a major component, plays a role in the oxidation of adrenalin first to oxidized adrenalin and then to adrenochrome.(12) Cocaine abuse, according to Beasley(13) is associated with myocardial infarction arrhythmias, transient severe hypertension, stroke and seizures. Cocaine abusers also suffer from nutritional deficiencies including vitamin B-6, vitamin B-1 and ascorbic acid.

C) Leakage of adrenochrome and its derivatives such as adrenolutin into the blood and into the brain

Th oxidized products of adrenalin metabolism are circulating in the blood. It is likely the major source is from the heart which is the largest organ in the body which can make adrenochrome and its derivatives. The largest organ which detoxifies catecholamines is the skin. The end product is melanin derived from tyrosine. Melanin is a complicated polymerized molecule made from chrome indoles.

Adrenochrome can be transferred across the blood-brain barrier. In our early experiments with adrenochrome we were able to show the psychological effects of adrenochrome given parentally, see Hoffer and Osmond.( 6) It is highly probable it is transferred. In addition it can be made in the brain at the synapses from the catecholamines. The pigment in the red nucleus is an adrenalin-derived melanin which must have gone through the adrenochrome pathway. It cannot come from tyrosine since it is also present in albinos who lack tyrosinase, the enzyme which converts tyrosine into black melanin.

D) Schizophrenia

The adrenochrome hypothesis of schizophrenia has been reviewed many times.( 6) We suggested that an increased conversion of adrenalin to adrenochrome was one of the causes of schizophrenia, basing this conclusion on our findings that adrenochrome and adrenolutin are hallucinogens, that they could be made in the body, and that reversing or preventing the reaction was therapeutic for schizophrenia. We used large doses of vitamin B-3 and ascorbic acid. Over the past five years it has been reinforced by the final proof that adrenochrome is formed in the body (Dhalla, Ganguly Rupp, Beamish and Dhalla).(8) What still remains is to show the relation between adrenochrome (or adrenolutin) levels and the schizophrenias, using the accurate methods developed by this group. The first recent tentative moves to look at the adrenochrome hypothesis by psychiatrists appeared in a report by Cadet and Lohr(14) who concluded, "After a review of the possible neurotoxic effects of free radicals formed during states of high dopamine turnover, we postulate that the neuronal damage caused during these episodes might form the substrate of a comprehensive hypothesis that could potentially explain the protean findings in the group of schizophrenias and the progression of the syndrome, in some patients, to the so-called schizophrenic defect state." Dopamine is one of the catecholamines and the free radicals are either adrenochrome or other free radicals formed during its synthesis. Since these two authors were totally unaware of our adrenochrome hypothesis originally reported in 1954,(*) I wrote and told them that I thought their hypothesis was a very good one. I added I had also considered it was a very good one when we first published it many years before. I received no reply. The word adrenochrome does not appear in their paper, as if it were poison.

The Role of Antioxidants

Antioxidants protect both heart and brain against the toxic effects of adrenochrome and similar chrome indoles by decreasing their formation.

A) Niacin

Niacin is an antidote against d-lysergic acid diethylamide(15) (LSD) and against adrenochrome. It reverses the effect of adrenochrome on the electroencephalogram in human subjects,(16) and reverses the psychotomimetic effects of adrenochrome when injected intravenously into human subjects.( 6) It is also a safe and effective therapeutic agent in the treatment of the schizophrenias and several other psychiatric diseases. It is one of the main elements of orthomolecular psychiatric treatment. Every physician who has duplicated the niacins-chizophrenia studies has corroborated our earlier findings. However, the treatment is not accepted because it was introduced during the wrong paradigm, the paradigm of vitamins as prevention only. For a full discussion see the following reports.(17)

B) Ascorbic acid

Vitamin C is nature's most effective water-soluble antioxidant. We began to treat our schizophrenic patients with it in 1952 because we thought its antioxidant properties would decrease the conversion of adrenalin to adrenochrome.

The oxidation of the catecholamines to their chrome indoles is inhibited or decreased by the presence of ample supplies of the main antioxidants of the body and the toxicity of normal amounts of adrenochrome converted to adrenolutin is prevented by NAD. Thus the three main defense mechanisms against excessive formation of these indoles are vitamin C, the major watersoluble anti-oxidant, vitamin E, the major surface or fat-soluble antioxidant, and vitamin B-3. There are probably other antioxidant defense mechanisms including coenzyme Q10 and selenium. The first defense mechanism was eroded after we lost the ability to make vitamin C in our bodies and we moved from a diet rich in this vitamin to the usual subclinical scorbutic diet of most of the human population. The ascorbic acid-rich diet which we left was also rich in vitamin E compared to our modern diets. This has eroded the second major defense agent excessive oxidation. The third defense mechanism, ample amounts of vitamin B-3 was removed with the major deterioration of modern food which has occurred within the past 200 years. Pellagra is one of the best examples of this. At one time a quarter of the admissions to southern mental hospitals were pellagrins. Schizophrenia was rarely described before 1800 A.D. Over the past 200 years it has become one of the major disease problems in all industrialized countries. To sum up this argument, the genetic disease hypoascorbemia, and the gradual change of our food supply to a diet low in vitamin C, vitamin E and vitamin B3 has made it impossible for the schizophrenic patients to take advantage of the beneficial defense mechanism against overproduction of adrenochrome and its derivatives.

Schizophrenia and Stress

Huxley, Mayr, Osmond and Hoffer(18) presented the hypothesis that schizophrenia involves a genetic morphism. Sir Julian and Professor E. Mayr had independently arrived at the same conclusion. We wrote, "The high frequency of schizophrenia cannot be maintained by mutation alone, and is evidence of a balanced morphism. The fertility (reproductive fitness) of schizophrenics is only about 70% of that found in socio-economically comparable normals. The incidence of the disease would therefore be rapidly reduced to the level where it is maintained by mutation alone, unless its selective disadvantages of lower viability and fertility were compensated by some selective advantage. The physiological advantages are high resistance to surgical and wound shock, to otherwise dangerous concentrations of insulin and other hormones, histamine etc. and to various allergies and infections." Hoffer and Osmond discussed this further.

There is no overall advantage in having schizophrenia, in being sick. The advantage arises from having some of the genes of schizophrenia which do not express themselves by causing the disease, i.e. in the first order relatives of the patients. Parents, children and siblings of schizophrenics will have the advantages as will the recovered patients. I have observed that these advantages are in both physical and intellectual areas. When other psychiatrists begin to examine the patients and their relatives for these positive attributes, I have no doubt they will come to the same conclusion.

Stress is a factor in precipitating the illness in people who have the genetic apparatus for making them sick. This is the conclusion of Yatkin and Labban.(19) They write, "The results of this study demonstrate that traumatic war events can be regarded as of primary importance for risk factors in triggering the onset of schizophrenia." The individual is not able to deal with the increased stress because he is not able to make enough vitamin B-3 from tryptophan, or from a deficiency of this amino acid as in pellagra.

If this hypothesis is correct, it follows that the two main components of biochemical treatment of the schizophrenias must be to decrease the biochemical effects of stress, i.e. decrease the secretion of sympathomimetic amines, and to use ample quantities of the antioxidants. Niacin and ascorbic acid have been examined most thoroughly. Vitamin E has received a little attention. The other natural antioxidants have not been investigated for their potential therapeutic properties. It would be very interesting to examine beta carotene and selenium.

The Final Common Chemical Pathway

This hypothesis represents the final common pathway in the production of the schizophrenias. Orthomolecular psychiatrists were the first to recognize that a large number of conditions will lead to one or more of the schizophrenic syndromes.(20) But no matter what the precipitating factor, the syndrome, the final clinical pictures are similar. They include the perceptual and thought disorder symptoms combined with mood and behavioral changes. But the different syndromes will have different clinical courses and will require specific treatment to deal with the inciting causes as well as dealing with the final common pathway, the disorder of amine metabolism. These precipitating factors impinge upon the adrenalin converted to adrenochrome transformation by driving the reaction from adrenalin to adrenochrome and on. For a detailed discussion of these and many other factors, see Hoffer and Osmond.( 6)

1) Factors which drive the adrenalin transformed to adrenochrome reaction.

a) Deficiency of NAD. Adrenalin loses one electron becoming an unstable oxidized adrenalin. In the presence of adequate concentrations of NAD and NADH it is reduced to adrenalin, the original molecule. But in the absence of NAD it loses a second electron to become adrenochrome which is no longer reducible to adrenalin. Thus a deficiency of NAD leads to an increase in the production of adrenochrome and its derivatives.The most common reason for the deficiency of NAD is a deficiency of vitamin B-3 as in pellagra, or a dependency where for reasons unknown, much more vitamin B-3 is required. Pyridoxine is required for the conversion of some of the tryptophan to NAD. With a deficiency of pyridoxine pellagra symptoms will also appear.

Increased adrenochrome formation in the synapse would play havoc with the transmission of signals by binding with receptor sites on the neuron. It is a synaptic inhibitor as are LSD and other hallucinogens.(21) Bindoli et al.(10) speculated that noradrenochrome formed in the synapse by autooxidation could combine with acetylcholine, thus establishing a short circuit between the adrenergic and cholinergic pathways. Galzigna(22) had suggested this could cause the mental symptoms.

b) Allergic reactions -- Somatic allergy symptoms such as eczema, rashes, and others are not as common in schizophrenic patients. They can also tolerate large quantities of histamine.( 5)

Both adrenalin and adrenochrome are antihistamines. Adrenalin is used to protect against anaphylactic shock. Adrenochrome has 4% of the antihistaminic activity of pyrilamine.( 6) Adrenolutin present in the blood in normal amounts could be another protective mechanism against allergic reactions. I have studied several patients where there was a clear relationship. When they were very ill they had no somatic allergic reactions but when they had recovered they suffered a recurrence of allergic reactions they had had before. A female patient recovered with the use of nicotinaminde 3g daily. But her eczema came back so strong she stated she preferred to have some of the schizophrenia rather than the eczema and itching. I decreased the nicotinamide to 500 mg, three times daily. Her eczema vanished and her paranoid ideas came back to a small degree. She was content with the trade-off.

Foods and other chemicals can induce the schizophrenic reaction. I have fasted (water only) over 200 patients for four days or more to determine whether they were allergic. These were patients whose response to megadoses of vitamin B-3 was not adequate. They were all better after the fast and most were normal. When they then ate the foods that they were allergic to they promptly became psychotic. It can be turned off and on as simply as by giving volunteers LSD. I suggest the allergic reaction calls for the continued secretion of adrenalin, a higher level of aminochromes in the blood and the perpetuation of the psychosis, After the offending foods are removed this mechanism is not needed as much, there is a decrease in the aminochrome levels and the psychosis is no longer present.

c) The hallucinogens -- Many of the hallucinogens are indoles thus resembling adrenochrome in structure, and many are similar. An example of the first is d-lysergic acid diethylamide (LSD) and of the latter is amphetamine and the methylenedioxy amphetamines, (MDA). LSD does not always cause the typical hallucinogenic reaction. During our research with psychedelic therapy for alcoholics using LSD(23) we had many patients whose only response to 200 micrograms of LSD was severe anxiety and tension. We would then double the dose to 400mcg but even then a few did not react. This means that LSD in itself is not an hallucinogen but it must create the reactions in the body which do produce the typical psychiatric reaction. A few patients were given adrenochrome intravenously three hours after they had been given the LSD and had not reacted. Within a few minutes after the injection they went into the usual type of reaction with perceptual changes and thought disorder.( 6) Hoagland, Rinkel and Hyde(24) suggested that LSD might owe its psychotomimetic properties to a disturbance of adrenalin metabolism.(7) It is likely that LSD increases the formation of adrenochrome and that the usual reaction results from the activity of both LSD and adrenochrome. When the body cannot make enough adrenochrome the LSD by itself causes a lot of anxiety and tension. Injecting adrenochrome allows the full experience to develop. Perhaps it does so by inhibiting amine oxidase and catechol-0-methyl transferase. The excess adrenalin would then be changed into adrenochrome by auto-oxidation in the synapse.

Amphetamines are similar in structure to adrenalin. But it may also act by increasing adrenochrome levels. It has been reported that amphetamines displace dopamine from its vesicular stores into the cell where auto-oxidation can occur, forming dopachrome.(25)

d) Increasing oxidation by fever, hyperbaric oxygen and copper. Fever increases the rate of the chemical reactions in the body. Every ten degrees rise in temperature doubles the rate. Thus a fever of 104øF can have an appreciable effect. The association between high fever and delirium is not rare. While a delirium is not schizophrenia, it is sometimes difficult to distinguish them. Hyperbaric oxygen is also known to increase perceptual problems.( 6) Hyperbaric oxygen is much less toxic for animals after the adrenal glands were removed, while injecting adrenalin increased toxicity.( 6) Copper increases the rate of autocatalytic reactions. The association between increased blood copper (and decreased zinc levels) i s not strong, but several studies have linked them. Penicillamine, a powerful copper chelator, has been used to assist in the treatment of schizophrenia. In 1954 I saw an unusual response of a schizophrenic patient to penicillin. She had not responded to any treatment including ECT. I gave her penicillin for an infection of her wrist. Within five days there was a substantial improvement. Shortly after that penicillamine, a derivative from penicillin became available and I incorporated that into the treatment program I was then developing. I gave it to my treatment failures. In 1960 in "The Chemical Basis of Clinical Psychiatry,"(9) I described four treatment failures who responded when penicillamine was added. They were given ECT, niacin, 3 grams daily, ascorbic acid 3 G daily and penicillamine 2 G daily for up to two weeks. They had not responded to the same treatment without the penicillamine. Of the four, three became normal and one much improved.

Another childhood schizophrenic was treated by his father against the wishes of his psychiatrist.(26) His father, a physician, called me in 1960. He told me his son age 12, had just been declared hopelessly ill by a professor of psychiatry and he had been advised to commit him to a mental hospital and to forget about him. He immediately began a search of the local medical library and ran across our first 1957 publication. I suggested he start him on niacin 3 grams daily. These large dose tablets were not commercially available then. However he was able to persuade Kirkman Laboratories in Oregon to make him a batch containing 500 mg. But the psychiatrist in charge refused to give the pills to his patient claiming that he had tried them before and it had not worked and secondly, that it would "fry his brains."(27) Both statements were lies. The physician then began to feed his son jam sandwiches every day containing the niacin. He did this while they were walking in the grounds of the university hospital. After 6 weeks the boy told his father he wanted to go home. He was discharged, remained well for 18 months. He was able to complete grade 12 in the USA top 5 percentile. His father had asked me how long he should remain on the vitamin. I suggested that one year might be adequate. To be on the safe side he was on for 18 months. But after the vitamin was stopped he relapsed. When the vitamin was resumed he did not respond. I then suggested he add penicillamine 2g daily until he had some side effects. He was on it for several weeks. He became well and has remained normal. He became a research psychiatrist.

In 1965 in a NATO Advanced Study Institute held at Drammen, Norway August 2-14, 1965, I reported "We gave 2 g of penicillamine per day for 10 to 20 days to patients who had not responded to any previous therapy including niacin, electro convulsive therapy and tranquilizers. Since these studies began we have treated about 20 and of these one-half have been salvaged and are well. This is a controlled study since each subject had not responded to a series of therapeutic efforts and natural remission occurring within the period of penicillamine therapy is much less likely. In half the cases a slight fever and faint rash occurred at 6 to 7 days. It was usually followed by remarkable improvement within 24-48 hours. The slight temperature elevation was a signal to discontinue medication and the temperature was normal next morning. The followup period is now 78 years." These patients remained on the vitamin therapy.(28) The use of penicillamine is described in How to Live with Schizophrenia.

But penicillamine has another property. It changes adrenochrome into 5,6 dihydroxy N-methyl indole, also called leucoadrenochrome. This is a nontoxic indole which Osmond and I found had good anti-tension properties.(9) This may be another explanation of its therapeutic properties. Decreasing copper levels will decrease the formation of adrenochrome by autocatalytic oxidation and removal of the adrenochrome into an innocuous indole will further lessen the amount of this hallucinogen in the body.

e) Monoamine Oxidase Inhibitors. The most commonly used monoamine oxidase inhibitors are three of the older antidepressants, tranylcypromine (Parnate), isocarboxazid (Marplan) and phenelzine (Nardil). These compounds are euphorients, stimulants and hallucinogens. I have had most experience with parnate and have seen a major transient psychosis produced by large doses of this antidepressant. This is not surprising since it does block one of the main pathways of adrenalin metabolism and forces the autooxidation of adrenalin into adrenochrome. It is also similar in structure to the catecholamines. The psychosis promptly vanished when the parnate was discontinued.

2) Factors which suppress the formation of adrenochrome or remove it from circulation.

Several well-known antioxidants are being investigated for their therapeutic properties: vitamin E against cardiovascular disease, beta carotene and selenium for their anti-cancer properties, and vitamin C for a large number of clinical uses. Only vitamin C has been studied intensively for the treatment of schizophrenia. These originated in our research in Saskatchewan in 1952. I have found vitamin C to be very helpful in controlling severe anxiety and tension in schizophrenic patients and in decreasing the incidence of relapses which may occur after a virus episode such as the flu. We discussed the relationship between vitamin C deficiency and schizophrenia.(29) The beneficial effect of vitamin C was confirmed by Kanofsky and Lindenmayer.(30) They gave 2-6 grams per day of ascorbic acid to 21 long-term neuroleptic refractory schizophrenic inpatients along with the medication for one month. In several, definite clinical improvement was noted by the treating staff and in most cases by the patients as well. One who had been floridly psychotic at the beginning of the treatment achieved full remission within 2 weeks. A response rate of 33% for this type of chronic refractory patient is very good. Perhaps if they had used even higher doses, up to the sub-laxative level, they might have seen additional responses. There have been a few studies using vitamin E to reverse the tardive dyskinesia induced by tranquilizers but the results are equivocal. These studies did not aim at any general improvement in the psychotic state. There is some evidence that selenium may have a therapeutic role.(31) All the antioxidants should be examined to determine which ones have the greatest therapeutic usefulness. Coenzyme Q10 was found to enhance memory and attention in a small series of chronic schizophrenic patients.(32) The ten subjects were on clozapine or haldol. This may mean that the impairment of these cognitive functions by these drugs is partially reversed by Q10, 300 mg daily.

There is thus very robust evidence that driving the adrenalin adrenochrome reaction toward adrenochrome is a causal factor in producing schizophrenia and inhibiting or reversing the reaction is therapeutic.

Normal people will produce a more or less constant amount of adrenalinoxidized derivatives with slight increases during stress and decreases when relieved of stress. In schizophrenics I suggest that there is an increase in the amount of adrenochrome and its derivatives. This may cause paranoid or other psychotic ideas which can be suppressed for long periods of time. If they are exposed to severe prolonged stress either from psychosocial stresses (being fired, being rejected, etc.), there will be a major increase in adrenalin production, overwhelming the ability of the enzymes to cope and the overload into auto-oxidation will begin. The increased production of adrenochrome will then interfere with brain synaptic transfer of signals and cause schizophrenia. Schizophrenia may thus be considered a failure of the enzymatic degradation of adrenalin, forcing the body to use auto-oxidation to prevent death from the excess adrenalin.

The interference with the synaptic mediators caused by the adrenochrome and other chrome indoles produces the perceptual distortions and thought disorder as do the hallucinogens. This is described in our book How to Live with Schizophrenia.


I have presented some of the biochemical and clinical evidence to support the adrenochrome-schizophrenia hypothesis, i.e. that schizophrenia has evolved too successfully in dealing with chronic and severe stress mediated by the release of adrenalin. The increased production of adrenochrome and similar chrome indoles, the final common chemical pathway, leads to the characteristic perceptual and thought disorder changes. In 1965 I suggested(33) "The hypothesis that I now propose is that when the reaction is driven too far, causing excessive formation of aminochromes, there will be an inhibition of synaptic transmission that will be expressed psychologically as disturbances in perception, thought and mood, including hallucinations of one or more of the sensory modalities."

Treatment should cover two main areas: ( 1) the reduction in the secretion of catecholamines, i.e. decrease stress by medication, by removing the inciting factors such as hallucinogenic drugs, allergens, toxic elements such as copper and iron when present to excess and infections, and psychosocial intervention including, if necessary, treatment in hospital; ( 2) decrease the formation of adrenochrome and similar chrome indoles using antioxidants such as ascorbic acid and vitamin E and others in optimum doses and using vitamin B-3 (niacin or niacinamide or in combination) in optimum doses to protect against the toxic effect of the chrome indoles on the brain.

(1.) Conolly J: An Inquiry Concerning the Indications of Insanity. (1830) Dawsons of Pall Mall, London, 1964.

(2.) Sapolsky RM: Why Zebras Don't Get Ulcers. W.H. Freeman and Co., New York, 1994.

(3.) Dhalla NS, Yates JC, Naimark B, Dhalla KS, Beamish E & Ostadal B: Cardiotoxicity of Catecholamines and Related Agents. Cardiovascular Toxicology. Second Edition. Ed. Daniel Acosta, Jr., Raven Press, Ltd. New York, 1992.

(4.) Hoffer A & Kenyon M: Conversion of Adrenaline to Adrenolutin in Human Blood Serum. Arch Neur Psychiatry 77:437-438, 1957.

(5.) Matthews SB, Henderson AH & Campbell AK: The Adrenoehrome Pathway: The Major Route for Adrenalin Catabolism by Polymorphonuclear Leucocytes. J. Mol. Cell Cardiol 17:339-348, 1985.

(6.) Hoffer A & Osmond H: The Hullucinogens. Academic Press, New York, 1967.

Hoffer A & Osmond H: The Adrenochrome Hypothesis and Psychiatry. J Orthomolecular Medicine 5:32-45,1990.

(7.) Hoffer A: Enzymology of Hallucinogens. Reprinted in Enzymes in Mental Health. Eds. JG Martin & B. Kisch, JB Lippincott Co., 1966.

Hoffer A: Dopamine, Noradrenalin and Adrenalin Metabolism to Methylated or Chrome Indole Derivatives: Two Pathways or One? J Orthomolecular Psychiatry 14:262-272, 1985.

Hoffer A: Oxidation-Reduction in the Brain. J Orthomolecular Psychiatry 12:292-301, 1983.

(8.) Carpenter WT & Buchanan RW: Schizophrenia. The New England Journal of Medicine, 330:681-690, 1994.

(9.) Dhalla KS, Ganguly PK, Rupp H, Beamish RE & Dhalla NS: Measurement of adrenolutin as an oxidation product of catocholamines in plasma. Molecular and Cellular Biochemistry 87:85-92, 1989.

(10.) Hoffer A & Osmond H: The Chemical Basis of Clinical Psychiatry. CC Thomas, Springfield, IL, 1960.

(11.) Bindoli A, Rigobello MP & Deeble DJ: Biochemical and toxicological properties of the oxidation products of catecholamines. Free Radical Biology & Medicine 13:391-405, 1992.

(12.) Walaas E & Walaas O: Oxidation of reduced phosphopyridine nucleotides by p-phenylenediamines, catecholamines and serotonin in the presence of ceruloplasmin. Arch Biochem Biophys 95:151-162, 1961.

Walaas O & Walaas E: In, "The Molecular Basis of Some Aspects of Mental Activity." A NATO Advanced Study Institute, Drammen, Norway, 1965.

(13.) Beasley J: Managing the Alcoholic. Medical Tribune, May 25, Page 20, 1989.

(14.) Cadet JL & Lohr JB: Free Radicals and the Developmental Pathobiology of Schizophrenic Burnout. Integr. Psychiatry 5: 40-48, 1987.

(*) There was no reference to any of the basic adrenochrome papers dealing with its possible formation in the body and with its psychological properties. However, even this paper was too radical for the National Institutes of Health, Washington, DC. The authors in a footnote write, "This article was written by the authors in their private capacity and does not necessarily reflect the views of the NIMH." The NIMH has been the leading critic and opponent to our adrenochreme hypothesis since 1954.

(15.) Agnew N & Hoffer A: Nicotinic Acid Modified Lysergic Acid Diethylamide Psychosis. J Ment Science 101:12-27, 1955.

(16.) Szatmari A, Hoffer A & Schneider R: The Effect of Adrenochrome and Niacin on the Electroencephalogram of Epileptics. Am J Psychiat 3:603-616, 1955.

(17.) Hoffer A, Osmond H, Callbeck MJ & Kahan I: Treatment of Schizophrenia with Nicotinic Acid and Nicotinamide. J Clin Exper Psychopathol, 18:131-158, 1957.

Hoffer A: Nicotinic Acid: An Adjunct in the Treatment of Schizophrenia. Am J Psychiat 120:171-173, 1963.

Hoffer A & Osmond H: Treatment of Schizophrenia with Nicotinic Acid -- A Ten Year Follow-Up. Acta Psychiat Scand 40:171-189, 1964.

Hoffer A & Osmond H: How to Live with Schizophrenia. University Books, New York, NY, 1966. Also published by Johnson, London, 1966. Written by Fannie Kahan. New and Revised Ed. Citadel Press, New York, NY 1992.

Hoffer A: The Effect of Nicotinic Acid on the Frequency and Duration of Re-Hospitalization of Schizophrenic Patients; A Controlled Comparison Study. Int J Neuropsychiatry 2:234-240, 1966.

Hoffer A: Use of Nicotinic Acid and/or Nicotinamide in High Doses to treat Schizophrenia. Can J Psychiatric Nursing 76:5-6, 1966.

Hoffer A: Treatment of Schizophrenia with a Therapeutic Program Based Upon Nicotinic Acid as the Main Variable. Molecular Basis of Some Aspects of Mental Activity, Vol. II. Ed. O Walaas, Academic Press, New York, 1967.

Hoffer A: Megavitamin B-3 Therapy for Schizophrenia. Can Psychiatric Ass J 16:499-504, 1971.

Hoffer A: Mechanism of Action of Nicotinic Acid and Nicotinamide in the Treatment of Schizophrenia. In, Orthomolecular Psychiatry, Eds. Dr. Hawkins and Linus Pauling. W.H. Freeman and Co., San Francisco, 1973.

Hoffer A & Osmond H: In Reply to The American Psychiatric Association Task Force Report on Megavitamin and Orthomolecular Therapy in Psychiatry. Canadian Schizophrenia Foundation, Regina, SK, now Toronto, ON, Canada. Aug. 1976.

Hoffer A: Chronic Schizophrenic Patients Treated Ten Years or More. J. Orthomolecular Medicine, 9:7-37, 1994.

(18.) Huxley J, Mayr E, Osmond H & Hoffer A: Schizophrenia as a Genetic Morphism. Nature 204:220-221, 1964.

(19.) Yatkin US & Labban S: Stress and Schizophrenia. Y. of Psychological Nursing, 30:29-32, 1992.

(20.) Pfeiffer CC: Mental and Elemental Nutrients. Keats Publishing Inc. New Canaan, CT, 1975.

(21.) Marrazzi AS: Psychosis as a Function of Disturbed Chemical Regulation of Cerebral Synaptic Transmission. Chemical Concepts of Psychosis, M. Rinkel and H.C.B. Denber, McDowell Obolensky, New York, 1958. Marrazzi AS & Hart ER: An Electrophysiological Analysis of Drugs Useful in Psychotic States. H.E. Himwich Pub #46, American Associations for the Advancement of Science, Washington, DC, 1957.

(22.) Galzigna L: Molecular interactions in the phenomenology of the onset of mental illness. Chem Biol Interact, 7:1-9, 1973.

(23.) Hoffer A & Osmond H: New Hope for Alcoholics, University Books New York 1966. Written by Fannie Kahan.

(24.) Hoagland H, Rinkel M & Hyde. Adrenocortical function and urinary phosphate excretion. AMA Arch. Neur. Psychiatry 73:100-, 1955.

(25.) Fuller RW, Hemrick-Lueke SK: Further studies on the long-term depletion of striatal dopamine in iprindole-treated rats by amphetamine. Neuropharmacology 21:433438, 1982.

(26.) Hoffer A: Five California Schizophrenics. J Sehizophrenia 1:209-2209, 1967. This report initiated an attempt by the American Psychiatric Association to censor our work and to prevent publication of the results of treatment they did not consider acceptable. After Dr. Osmond and I met with them in the early 1970's in Washington, D.C. they told us they would let us have their decision. We have still not heard from them.

(27.) He was referring to the cutaneous flush caused by niacin at the onset of treatment. There is only slight evidence that there is any dilatation of the visceral, internal, vessels.

(28.) Hoffer A: Molecular Basis of Some Aspects of Mental Activity, Vol. II. Ed. O Walaas, Academic Press, New York, 1967.

(29.) Hoffer A & Osmond H: Scurvy and Schizophrenia. Dis Nerv Syst 24:273-285, 1963.

(30.) Kanofsky JD & Lindenmayer JP: Ascorbate: An Adjunctive Treatment for Schizophrenia. Journal American College of Nutrition, 8:425, 1989.

(31.) Fester HD: The geography of Schizophrenia: possible links with selenium and calcium deficiencies, inadequate exposure to sunlight and industrialization. Journal off Orthomolecular Medicine 3:135-140, 1988.

Berry T: Selenium deficiency and clinical findings in Schizophrenia: a common thread. Journal of Orthomolecular Medicine 8:21-24, 1993.

(32.) Elkashef AM, Gold J, Folkers K & Wyatt RJ: The Effect of Coenzyme Q10 on the Cognitive Functions in Patients with Schizophrenia. The Institute for Biomedical Research, The University of Texas at Austin, Austin, Texas 78712-1167, 1994.

(33.) Hoffer A: Treatment of Schizophrenia with a Therapeutic Program Based Upon Nicotinic Acid as the Main Variable. Molecular Basis of Some Aspects of Mental Activity, Vol. II. Ed. O Walaas, Academic Press, New York, 1967.

Townsend Letter for Doctors & Patients.


By Abram Hoffer

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