the psychophysiology of cancer

The Journal of Asthma Research. Vol. 8, No. 2, December, 1970

The Psychophysiology of Cancer

A. HOFFER, M.D., PH.D., F.A.P.A., C.R.C.P. (C).

Introduction

When two distinct phenomena are correlated in time, it is tempting to con- sider that one may be the cause of the other. When a patient has cancer and a t the same time shows psychological changes, it is possible that (a) the psychological changes come from the patient’s knowledge he has a killing disease, (b) they result from direct changes in the body such as invasion of nerves, of brain or of other organs whose function is disrupted, (c) they come from toxins, hormones or other chemical messengers produced by the cancerous tissue, (d) they preceded the development of the cancer and may have increased the possibility of the tumor’s developing and growing more rapidly.

Psychological changes which result from knowing cancer is present are usually mild and very seldom lead to severe depression or suicide. When these changes are disturbing, simple counselling and/or psychotherapy may be adequate. I n any event these changes can be treated by physicians, with or without drugs. These changes do not properly belong in the psychophysiology of cancer, for they are not unique and probably not much different from reactions to other killing diseases.

Psychological changes which come from invasion of brain and nerves by the tumor fall within the field of the neurologist and neurosurgeon. They may also be omitted from consideration here.

The real province of the psychophysiology of cancer lies within the last two causal phenomena, i.e. the effect of cancerous toxins in producing mental changes, and the possibility that certain psychological attitudes or states increase the likelihood of cancer. Both these phenomena have been examined more and more seriously and intensively. Through interest in the psychophysiology of schizophrenia I have been led to a recent interest in cancer. I have found that approximately one-third of our cases with cancer secreted the mauve factor in the urine. [Irvine (1961, Hoffer and Mahon (1961), O’Reilly, Hughes, Russell and Ernest (1965), O’Reilly, Ernest and Hughes (1965).] This is the same factor found in many psychiatric patients and most often in schizophrenia. It is, therefore, possible that in certain cases of cancer, toxins are released which not only injure neurological tissue but also produce mental changes. The mauve factor may be a measure of these toxins.

Neurological Consequences of Cancer

According to Holt (1965), both Oppenheim (1888) and Nonne (1900) recognized nervous system changes in cancer patients in the absence of metastases, and they suggested its origin was toxic. There was then a long hiatus in these considerations until Denny-Brown (1948) described two cases of primary sim-

61

J A

sthm

a D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B M

ainz

on

10/2

5/14

For

pers

onal

use

onl

y.

62 A. HOFFER

ple degeneration of the dorsal root ganglion cells and primary degeneration of muscles associated with brorichiogenic carcinoma. He suggested that metabolic disorders led to these neurological changes. Brain, Daniel and Greenfield (1951) reviewed the literature which showed a high correlation between cancer and subacute cortical cerebellar degeneration that terminated in two years. The Purkinj e cells were specially vulnerable. About two-thirds of the cases had cancer. They added four more cases-two with cancer of the bronchia and one with ovarian cancer. All four also had mental changes which led to dementia in three. Heathfield and Williams (1954) added several more cases of bronchial carcinoma-one with mixed peripheral neuropathy, one with myopathic changes, one with an obscure myopathy and two with peripheral sensory neuropathy. Similar reports were made by Leigh and Meyer (1949), Lennox and Prichard (1950), Croft (1958), Charatan and Brierly (1956) , Henson, Russell and Wilkinson (1954) and Holt (1960). I n fact Holt (1960) reported that idiopathic neuropathy was sometimes a first sign of cancer.

Interest in the neuropathic propensities of cancer has grown very rapidly, and in a recent issue of Brain (1965) the majority of reports dealt with this matter. Croft and Wilkinson (1965) found the highest incidence of neuromyopathy with cancer of the lung and ovary. Cancer of the breast, colon and cervix produced about the same incidence as a control series. Fourteen per cent of lung cancer patients and 16 per cent of ovarian tumors showed these changes. Stomach and prostatic cancer had nine and six per cent incidence, but out of 162 patients with cancer neuromyopathy, about half had cancer of the lung.

The most frequent neurological change was neuromuscular neuromyopathy in 50 per cent. Next in frequency was mixed peripheral and primary myopathic disorder. Cerebellar disorders and myopathy were next most common. Sensory neuropathies were highly associated with lung cancer which was present in 75 per cent of cases. Henson, Hoffman and Urich (1965) reported five cases with encephalomyelitis. In only one were there mental changes. Lord Brain and Wilkinson (1965) reported an additional 19 cases; ten with lung cancer and five with ovarian cancer. All had subacute cerebellar degeneration. Eleven had mental changes, chiefly dementia. Oat cell cancer of lung seems to be more toxic than other forms. Dayan, Croft and Wilkinson (1965) compared 37 cases of neuromyopathy with lung cancer against 120 cases of lung cancer and no neuromyopathy. There was some association between oat cell cancer and sensory neuropathy or the encephalomyelitic form of neuromyopathy.

Psychological Consequences of Cancer

(a ) Neurotic Changes

Kowal (1955) reviewed the early hist,orical evidence which showed a relationship between emotional factors and cancer. This was noted in the 18th century. Subjects with cancer had frequently lost a significant person and suffered from despair and hopelessness. Kowal assumed the emotional factors were causal to the cancer. It does not seem likely that emotional factors could

J A

sthm

a D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B M

ainz

on

10/2

5/14

For

pers

onal

use

onl

y.

THE PSYCHOPHYSIOLOGY OF CAXCER 63

play a major causal role, although there is no longer room for doubt that the cancer can cause mental changes. Eighteenth century physicians should have seen significant associations more frequently than we do today because diagnosis was then more difficult, and tumors would be present much longer before they were diagnosed. The effect of cancer-induced toxins would, therefore, be more obvious. Furthermore, mental changes present as a result of a slow-growing tumor would produce mental changes before the tumor was recognized and could be given a causal interpretation.

LeShan and Worthington (1955) compared 152 subjects with cancer with 125 subjects not sick, or ill, with other illnesses. They used the Worthington Per- sonal History as the main instrument for measuring neurotic changes.

Loss of an important relationship before diagnosis was found in 72 per cent of cancer cases and in 12 per cent of controls. Inability to express hostility to others was present in 47 per cent of cancer cases and in 25 per cent of controls, while guilt and/or anxiety over death of a parent was present in 38 per cent of cancer cases against 11 per cent of controls. These authors ran a double blind experiment where 28 records (15 cancer and 13 controls) were diagnosed from the record. They made 24 correct predictions. This could have arisen by chance in one out of 10,000 cases.

LeShan and Worthington (1956) enlarged the series to 250 cases. The results were the same. Further studies were reported by LeShan (1959), LeShan and Reznikoff (1960) and LeShan and Worthington (1956, 1956a). LeShan and Worthington (1956b) made certain predictions on the basis of their earlier investigations. The first one was that the cancer rate in women should be related to their marital state-increasing from single to married to divorced to widowed women. In 1929-31 in U.S.A. the cancer mortality rates for these classes of women were 61, 138, 176 and 527 respectively. They made four other predictions and data were reported which supported them all. These were: (1) married individuals with children should have lower cancer mortality rates, (2) second generation Americans should have a higher rate, (3) countries a t war in which the population was in agreement with war aims should have lower rates, whereas if there was widespread disagreement over war aims the rates should be increased, (4) simple, hebephrenic and catatonic schizophrenics should have less, and paranoid schizophrenics more cancer.

LeShan (1961) isolated a factor present primarily in patients dying with cancer. Out of 18 patients with cancer, 16 had severe despair. This was present in one out of 15 mentally ill patients. Despair was defined as a bleak hopelessness about ever achieving any meaning, zest or validity in life. The subject felt alone, and when despair was deep, could neither love nor hate and could not relate to others. Despair contained three components: (1) a lack of any belief that outside objects could bring satisfaction, (2) absence of faith in development, (3) absence of belief that any action taken by the patient could ease his loneliness. LeShan believed despair accelerated tumor growth.

Kissen (1964) determined personality of three groups of patients by means of the Maudsley Personality Inventory. Low scores suggest the absence of anxiety

J A

sthm

a D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B M

ainz

on

10/2

5/14

For

pers

onal

use

onl

y.

64 A. HOFFER

or tension; this, the author suggested, showed that low scorers had fewer outlets for release of emotional tension. There was a tendency for lung cancer cases t o score low. The mortality rate was also higher for low scores.

Earle (1962) tried to corroborate the findings of LeShan and his colleagues. The Worthington Personal History test was given double blind to 54 cases of cancer and 35 controls who were normal. There were significant differences in 17 out of the 38 questions. Cases with cancer had a mean score of 15.8, while the controls’ mean score was 9.6 (P < .01). Earle repeated this study on a second group of 44 with similar results. Thus Earle’s findings were corroborative, but Earle could not accept a primary causal relationship and suggested these changes arose simply from being ill. The main criticism was that there was no known intermediate between physiological and psychological factors. This was recognized by LeShan (1960) , who reported, “Another research problem is the complete lack of theory as to intervening variables between psyche and cell.”

( b ) Psychotic Changes The coincidence between lung cancer and psychosis is not rare and has been

mentioned in the literature frequently. Cancer specialists know they should examine the lungs when a middle-aged man becomes psychotic. Brain, Daniel and Greenfield’s (1951) four cases all had mental changes leading to dementia in three. Charatan and Brierly (1956) reported three cases of bronchial cancer who were also psychotic. In two, the psychotic symptoms preceded the symptoms of cancer, and in one they occurred fourteen months after the initial hemoptysis. The clinical picture resembled a toxic confusional psychosis with lucid intervals. Lord Brain and Wilkinson’s (1965) series of 19 cases contained 11 who had mental changes, chiefly dementia. In Henson, Hoffman and Urich’s (1965) series of five, onc was said to be in a dilapidated mental state with poor memory.

Metastases from lung cancer frequently grow in the brain. Galluzei and Payne (1956) found that in 30 per cent of their cases this occurred. Therefore, when a patient with lung cancer becomes psychotic, it is often assumed that secondaries are already present in the brain. Warren and Gates (1964) found a lower incidence of brain metastases. Out of 368 cases of primary lung cancer, cerebral metastases occurred in 10 per cent. Perhaps earlier diagnoses in the 1960’s has led to reduction in cerebral metastases.

This was the natural conclusion in the case reported by Hoff er (1965) when, in fact, no metastases were present. None of the three cases reported by Chara- tan and Brierly (1956) had cerebral metastases. I n a clinicopathological confer- ence reported in British Medical JozLrnal, 1: 1492-1495, 1964, a 63-year old woman had mental changes thought to arise from cerebral metastases from lung cancer. In the mental hospital she was co-operative but agitated and verbose, and had flight of ideas and disorientation. But a t autopsy no metastases were found in the brain. This patient had an oat cell cancer of right upper lobe bronchus with secondaries in lung, liver, spleen and adrenals. The presence

J A

sthm

a D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B M

ainz

on

10/2

5/14

For

pers

onal

use

onl

y.

T H E PSYCHOPHYSIOLOGY OF CANCER 65

of psychotic symptoms in the absence of clear neurological changes is, therefore, not pathognomonic of secondaries in the brain.

Lewis (1936) examined the relationship of cancer to various forms of schizophrenia. The subgroups catatonia and hebephrenia frequently had atrophy of tissue, hypoplasia and fibrosis, but rarely had cancer. On the other hand, paranoid schizophrenics frequently had hypertrophy, hyperplasia and cancer. Lewis suggested that cancer was a form of paranoia a t the cellular level. These interesting findings were corroborated by Scheflen (1951) on an entirely different group. He examined all records of patients dying between 1928 and 1942 at Worcester State Hospital. The cancer death rate was very high for paranoid schizophrenia. Between ages 45 and 54 i t was four times the expected rate from the normal population, and between ages 55 and 64 i t was twice the expected rate. It also occurred at an earlier age in paranoids. But catatonics and hebe- phrenics had less than the expected death rate, as did senile depressions.

Hormonal Consequences of Cancer

It is well established that cancers can produce many endocrine disturbances. Lipsett, Odell, Rosenberg and Waldmann (1964) reported the following changes -Gushing's Syndrome, hyperserotoninemia and precocious puberty. The hormones involved respectively were adrenocorticotrophin, parathormone, insulin, thyrotrophin, vasopressin, serotonin, and gonadotrophin. Bower, Mason and Forsham (1964) reported a case of bronchiogenic carcinoma with inappropriate antidiuretic activity in plasma and in the tumor. Sullivan and Rona (1964) discussed these systemic effects of nonendocrine tumors. Neurological and mental changes were also noted in association with cancer of lung, ovary, uterus, prostate, rectum and breast. Kissen (1962) compared 212 cases of lung cancer with 246 non-cancer controls. Peptic ulcer occurred more frequently in cancer cases between ages 45 and 64. The frequency of non-articular rheumatism, neurosis and dermatitis was also increased. Conditions occurring infrequently were diabetes mellitus, hypertension, rheumatoid arthritis, asthma, angina, coronary thrombosis, colitis, eczema, psoriasis, urticaria and acne vulgaris. Taylor and Siemsen (1965) presented a case of bronchiogenic carcinoma which simu- lated hyperparathyroidism preoperatively. Typical biochemical changes such as hypophosphatemia, hypercalciuria, increased phosphate clearance, decreased tubular reabsorption of phosphorus and abnormal rapid calcium infusion test were present. The patient was also mentally disturbed. After removal of the cancer the biochemistry became normal.

Malvaria Irvine (1961) found that schizophrenic patients excreted a substance in urine

which stained mauve with Ehrlich’s reagent on paper chromatograms. Hoffer and Mahon (1961) a t the same time corroborated this report using a slightly different purification method. Both methods were highly correlated and measure nearly the same thing. The Irvine method contains slightly more material and

J A

sthm

a D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B M

ainz

on

10/2

5/14

For

pers

onal

use

onl

y.

66 A. HOFFER

may show traces of material when the Hoffer and Mahon (1961) method shows none. This method was used by O’Reilly, Hughes, Russell and Ernest (1965) and O’Reilly, Ernest and Hughes (1965) in their investigation of the mauve factor.

O’Reilly, Ernest and Hughes examined urine from 850 subjects. At Saska- toon, Hoffer (1965) exa.mined urines from about 850 subjects a t a different hospital over a period of five years. The results are shown in Table 1.

The two normal subjects in the Hoffer series include one university student completing his Master’s degree in science, and a girl aged 4. The boy had two sisters, of whom one was normal and negative; and the other, suffering from anxiety and hysteria, was positive. He had one brother with schizophrenia and alcoholism who was positive. The normal subject did not feel normal, as he had always felt different and cut off from his friends. He often felt impelled to say inappropriate things in company which he later regretted. The normal girl had two siblings, an older brother with juvenile schizophrenia who was positive, and an older sister with a behavioral problem who was positive. As far as her parents could tell, she was normal.

In a recent survey, twenty-seven families with one member malvarian were examined for the mauve factor. Information was obtained for each member of the family tested. The diagnostic description of each case is shown in Table 2.

TABLE 1 Incidence of Malvaria

Group

Normal Physically I11

(a) Adults (b) Children (c) Cancer

(a) Adults (b) Children

Mentally Retarded

Neuroses Depressions Alcoholics Personality Problems Emotionally Disturbed Chi1

dren Schizophrenia

(a) Untreated (b) Treated-No response Recovered

Autistic Children Organic Brain Disease

Hoffer (1965)

Total lumber ___

52

22

34

21 32

107 65 84 65

244 148 96 76

5 22 -

~

Jumber iositive

2

2

13

1 12 41 21 32 22

155 111 44 21 0 5

O’ReiIly (1965) __ Total

number __

18

277 134 112

41 127 49 86 49

SG

28 -

__ rumbe ositivi

2

33 16 30

13 60 18 45 12

45

8 -

Total __

Tumber

70

299 134 146

21 32

148 192 133 151 49

330 148 96 76 5

50 -

__

Positive __

4

35 16 43

1 12 54 81 50 67 12

200 111 44 21 0 13 -

Per Cent Pos.

6

12 12 30

5 37 37 42 30 31 24

61 75 46 29 0

26

J A

sthm

a D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B M

ainz

on

10/2

5/14

For

pers

onal

use

onl

y.

THE PSYCHOPHYSIOLOGY OF CANCER 67

Physically Schizo- Depression Neuroses Diagnosis Ill phrenia _ _ _ _ _ _ _ _ _ _ ~ ~ ~ ~

Malvarian 1 22 6 5 Nonmalvarian 0 4 3 2

TABLE 2 Comparative Psychopathology of Malvarians and

Nonmalvarians in 27 Families

Behavioral Mentally Changes Retarded hTormal

8 2 2 3 3 38

It is clear that the major psychopathology was found among the malvarian group. The 46 malvarians had only two members (already described) who were classed as normal. The 53 nonmalvarians contained 38 who were normal, i.e. free of symptoms and signs and functioning well a t school or in the community. Only 22 of the malvarians (48 per cent) were schizophrenic, but a large number of the neurotic and behavioral subjects were children who had not yet entered the critical period for developing schizophrenia, i.e. after puberty. Excluding the original target member used to select the families, 30 per cent of the first order relatives were malvarian.

Hoffer and Osmond (1962, 1963) used this objective laboratory test as the diagnostic criterion for a condition termed malvaria. This was an attempt to define homogeneous psychiatric groups by a laboratory test instead of by clinical criteria, which are often vague and imprecise. Hoffer and Osmond (1963) compared 104 consecutive malvarians against 75 control nonmalvarians. A detailed and careful examination of the retrospective clinical records showed the following differences.

The HOD test was a card-sort test developed by Hoffer and Osmond (1961) for measuring those clinical changes commonly used in diagnosing schizophrenia. High scores indicate abnormal clinical signs are present.

Hoffer and Osmond’s (1963) data suggested that as a group, malvarians resembled schizophrenics more closely than any other group, while nonmalvarians resembled neuroses more than any other group. O’Reilly, Hughes, Russell and Ernest (1965) found significant differences between malvarians and nonmalvarians in thought disorder. They did not use the HOD test. O’Reilly, Ernest and Hughes (1965) concluded that the “incidence of malvaria appears to rise with the severity of the emotional disturbance.”

It is, therefore, clear that any person having malvaria is more likely to have emotional and psychiatric difficulties than a nonmalvarian.

O’Reilly, Ernest and Hughes (1965) reported that out of twenty-two cases with cancer, eleven were positive. Since then they have enlarged the series as is shown in Table 1. I n Saskatoon, out of 34 cases of cancer, 13 were malvarian. The location of the cancer and the incidence of malvaria is shown in Table 4.

None of the cancer cases in the Moose Jaw (O’Reilly) or Saskatoon (Hoffer) series were examined psychiatrically with one exception. Therefore, it is impossible to know whether minor or neurotic differences were present. Only two from Saskatoon showed major psychiatric differences. They will be described later.

J A

sthm

a D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B M

ainz

on

10/2

5/14

For

pers

onal

use

onl

y.

65 A. HOFFER

Malvarian

Per Cent Abnormality Present

TABLE 3 Comparison of Malvarians and Nonmalvarians

Nonmalvarian

Per Cent

Depression Perception Paranoid Total

Perception Visual Auditory

Thought Content Process

Inappropriate Depressed

Seclusive Inappropriate Overactive

Mood

Activity

7.9 10.0 3.9

55.0

33 29

69 30

33 64

18 37 27

~ -~

Site of Cancer

Lung Before treatment After treatment

Ovary and uterus GI tract and prostate Breast and cervix All other cancers

7 4

29 4

8 58

3 9 9

Number Positive

7 0 5 9 7 8

TABLE 4 Site of Cancer and Incidence of Malvaria

5.5 3.7 2.1

25.6

Number Negative

1 4 2

24 12 19

Per Cent Positive

87 71 27 37 29

Detailed examinations for neurological changes were not made for the majority of cases. But it can be concluded that no major psychiatric disorders were present in the cancer malvarians. The work from O’Reilly’s laboratory showed that cancer cases do not secrete mauve factor continually. A series of tests on the same patients with cancer showed that some might be positive only a few days. It is likely cancer patients were intermittent secretors of mauve factor. In sharp contrast, work by Irvine (1961) at North Battleford, by Osmond (1960) at Weyburn, and in Saskatoon showed that malvarian schizophrenics as a rule

J A

sthm

a D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B M

ainz

on

10/2

5/14

For

pers

onal

use

onl

y.


remained malvarian up to three years, unless there was a major change in their clinical state. It would seem that intermittent malvaria is not as sinister as continuous malvaria. We can not guess how long malvaria must be present before mental changes appear, but our data suggests it must be present a t least six months before other changes appear. The majority of cancer malvarians probably do not have it so long.

The two cancer malvarians from Saskatoon who were mentally ill were interesting. One had a period of about one day following surgery when he was very disturbed mentally, practically in a delirium. The other case, Mr. A. C., will be described in detail; see Hoffer (1965).

Case History of Mr. A.C. Mr. A.C., aged 73, a distinguished and creative scientist, was admitted to

hospital, September 1963. A bronchiogenic carcinoma was found. Shortly after admission he became depressed. This was considered appropri-

ate to his condition and his awareness of the diagnosis. But he also developed a marked change in personality. His depression deepened, he became confused and his behavior became irrational. He was given a series of radiation therapy to his chest. Surgical intervention was ruled out because the psychiatric changes suggested that metastases were present in the brain. He continued to deteriorate and when it was impossible to nurse him on the medical ward, he was trans- ferred to the Psychiatric Department. By this time he was clearly psychotic. He was confused and disoriented and within a few days had visual and auditory hallucinations. There was a marked impairment in his thought process with poor concentration, blocking, bad memory, etc. His thought content was abnormal. He was delusional, irrational, and had no insight or judgment and showed marked general intellectual deterioration. He was also depressed, but this mood fluctuated widely. The MMPI showed gross impairment of intellectual and perceptual qualities of an organic nature. Intellectual skills related to visual motor functions were almost totally absent. The diagnosis was organic brain syndrome and his prognosis was very poor.

He was discharged February 15, 1964, improved, but his behavior at home was no better; and his wife, with a female assistant, was unable to cope with him. He was readmitted to the psychiatric ward again on March 3, much the same, if not worse than he had been on his previous admission. His wife reported he had been very restless a t night, disoriented, very weak and had become worse. His admission note contained the phrase “Progressive deterioration makes the prognosis poor.” On March 11, terminal care by the Cancer Clinic was authorized. The reason for admission was not to cure his mental condition but to hold him while a nursing home was located where he could be nursed until he died.

Shortly after his second admission his urine was examined, on March 18, 1964, and it was found he excreted large quantities of mauve factor. Because nicotinic acid had been so valuable in treating schizophrenia, malvaria and senile confusional conditions, he was started on it a t a dose of one gram three

J A

sthm

a D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B M

ainz

on

10/2

5/14

For

pers

onal

use

onl

y.

70 A. HOFFER

35

Malvarian 23 Nonmalvarian 57

times each day. He was given 3 grams of ascorbic acid as an adjunct. Within 24 hours he was mentally much improved and three days later he was discharged to his home. A few days later he was mentally normal, but he had only a vague recollection of his psychosis. He continued to take these two vitamins and remained mentally normal but physically weak until he died 948 days after beginning vitamin intake, and 34 months after the diagnosis of bronchiogenic cancer was first established. The last radiological examination showed that there was no recurrence of the cancer. Cause of death was probably coronary disease. Unfortunately no autopsy was performed.

In the spring of 1964, when the initial test period on the Saskatoon cancer cases was completed, one of us (AH) predicted that malvarian cancer cases would have a better prognosis than nonmalvarian cases. This prediction was based upon the hypothesis that mauve factor came from a mitotic or growth inhibitor released by tissues defending themselves against the tumor. This was in agreement with the observation that cases with the more severe forms of schizophrenia who have a high frequency of malvaria have cancer more rarely than controls.

On December 31,1965, the status of 34 cases was determined. The results are shown in Figure 1.

A comparison of the mean duration of life in days after the urine test was done is shown in Table 5. Since the exact onset date of illness is unknown, this

1 Numberdays alive average 1 2 3

______ 647 297

23 23 15 24 5 5 10

NON-MALVARIA I N.21

I A /- N.13

20- 0 I00 200 300 400

DAYS AFTER TESTING URINE

FIG. 1. Possible relationship between malvaria and prognosis of some patients having cancer.

J A

sthm

a D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B M

ainz

on

10/2

5/14

For

pers

onal

use

onl

y.

THE PSYCHOPHYSIOLOGY O F CANCER 71

seems fair, as no bias is involved. All patients were in hospital for diagnosis and/or treatment.

In the Hoffer series the malvarians lived much longer and fewer died. I n the O’Reilly series there was no significant difference in mortality, but the malvarians lived on the average 40 days (10 per cent) longer. The composition of the groups was, of course, much different; and much larger groups would need to be investigated. The data supports the proposition that malvarians have a slightly better prognosis. Controlled studies with comparable treatments on comparable cancer cases are required.

Hypothesis-The Missing Link The data lead to the hypothesis that malvaria in cancer is a measure of the

biochemical defenses against cancer. Without going into elaborate detail, I suggest that the system adrenaline to adrenochrome (and/or noradrenaline to noradrenochrome or dopamine to dopachrome) is involved in the mechanisms for controlling and containing growth.

Adrenochrome is a very powerful antimitotic substance, [Lettre (1954), Gel- fant (1960), Bullough and Laurence (1960), Bullough (1952, 1955)], whereas adrenaline unchanged has no effect on cell division. Bullough (1955) reported that in vivo both adrenaline and adrenochrome were equally effective in reduc- ing epidermal mitosis. However, in vitro adrenaline had no activity while adrenochrome was as active as it was in vivo. This suggested that adrenaline acted as an in vivo mitotic inhibitor by being converted into adrenochrome. Bullough and Rytomaa (1965) developed a chalone theory of carcinogeneses. Some tissues contain substances which depress mitotic activity. These substances are termed “chalones” and each one is apparently tissue specific. They have been found for liver, kidney, epidermis, granulocytic tissue and erythro- cytes. According to Bullough and Rytomaa, epidermal chalone is not fully functional and requires adrenaline to make it fully operative. This explains the diurnal mitotic rhythm.

In sleeping mice, when output is low, there is insufficient adrenaline to main- tain the chalone-adrenaline complex, and mitosis increases. When the mice wake up, adrenaline secretion increases, the complex reforms, and the mitotic rate falls. Similar diurnal changes have been found in 15 other tissues. Bullough and Rytomaa state: “It is commonly believed that the initial damage, which creates the incipient tumour cell, is permanent and irreversible. Since even within the one tissue this damage may lead to very different types of tumours, it is clear that it must be variable, both quantitatively and qualitatively. However, in all cases it must include damage to the mitotic and functional homeostatic mechanism. If this results in a failure to respond to the chalone that is present, then the damaged cells would be expected to lose immediately their ability to function as part of the tissue, to commence unhindered mitotic activity, and to form a rapidly growing malignant tumour. If, however, the damage results in a failure to synthesize chalone, then nothing a t all may happen since the damaged cell, being embedded in a mass of normal cells, should continue to

J A

sthm

a D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B M

ainz

on

10/2

5/14

For

pers

onal

use

onl

y.

72 A. HOFFER

be controlled by the chalone which i t receives from these normal cells. In this way, it may remain relatively quiescent for a long time. Indeed, no tumour may develop a t all until, as a result of slow proliferation, the damaged cell gives rise to a group of abnormal descendant cells which is so large (perhaps about 1 mm. diam.) that its central region is beyond the effective range of the inward-dif- fusing chalone.”

The length of this period of quiescence must normally be a matter of chance, but it is evident that it should be shortened in any situation, such as adrenalectomy or tissue change that tends to weaken the chalone mechanism in the surrounding tissue. It is now well known that both adrenalectomy and tissue damage do indeed have this effect and, as would be expected, so also do the mitogenic hormones and possibly the proteins. Conversely, the period of quiescence should be lengthened by any situation, such as stress, that strengthens the chalone mechanism, and, indeed, one of the most potentially significant obser- vations in the whole history of cancer research is that in mice stressed by partial starvation the period of tumour cell quiescence may be so prolonged that cancer never develops a t all. Thus adrenaline increases the operating efficiency of the chalone system and in its absence, failure of the system would increase the chance of tumour growth. But if the adrenaline must first be converted into adrenochrome, then the reaction adrenaline into adrenochrome becomes rate limiting, and increased adrenaline production would improve the chalone system efficiency only if the conversion into adrenochrome was also increased. Bullough and Rytomaa’s scheme would then become

adrenaline + chalone (adrenochrome)

There are, indeed, model proteins in which this change occurs. Thus Walaas, Walaas and Haavaldsen (1963) found that adrenaline reacted with ceruloplasmin. The interaction of adrenaline with CuII ions in the ceruloplasmin made it autoxidizable due to the formation of semiquinones. In the presence of oxygen the free radicals are dehydrogenated and indolyzed. This occurred much more readily with adrenaline than with noradrenaline.

Walaas and Walaas (1965) proposed the hypothesis that similar changes occurred a t the post synaptic site of the synapse.

If adrenochrome plays a role, stress would decrease mitoses only if adrenochrome could be formed, and could be particularly helpful in preventing tumour development when excessive quantities of adrenochrome could be formed. Hoffer, Osmond and Smythies (1954) , Hoffer (1964) , proposed the hypothesis that adrenochrome was involved in the production of schizophrenia. If schizophrenics have increased quantities of adrenochrome they would be capable of using stress particularly well in suppressing cancer. Perhaps this is the explana- tion for the decreased incidence of cancer in the three severer forms of schizophrenia, for all schizophrenics in mental hospitals are under stress. On the other hand, stress might not work in the same way in normal people. Perhaps adrenaline unconverted to adrenochrome might be a mitotic stimulant, and this could

J A

sthm

a D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B M

ainz

on

10/2

5/14

For

pers

onal

use

onl

y.


account for LeShan’s findings that long continued milder stresses increased the incidence of cancer. Recently Garson (1965) described seven cases from his practice where cancer developed very soon after severe prolonged psychological stress. The first patient, a dedicated Communist, was suddenly forced to change his ideas about the last years of Stalin’s life. Eight months later he had a rectal cancer. I n the second case, a business man was severely depressed for one year when forced out of his business which he had worked hard to establish. He died of bronchial cancer within one year. An additional five similar cases were described. Garson believed that the stress and anxiety in the seven materially accelerated tumour development and growth. It was his impression that in 80 per cent of carcinoma sufferers, there was more than the usual degree of worry and stress. In his non-cancer cases, fewer than 10 per cent had this degree of anxiety.

The chemical nature of the mauve factor is unknown. It appears to be a pyrrole, [Irvine (1961)l and has been produced in a few animals and in one human by feeding tyrosine. It is possible it is a derivative of adrenochrome formed by the fracture of the benzene portion of the molecule. This kind of reaction occurs in melanin formation, Nicolaus (1962). Malvarians should form more adrenochrome than nonmalvarians. The presence of malvaria in cancer cases could indicate an increased release of adrenochrome which would inhibit tumour growth and to an increased incidence of neurological and psychiatric changes. Croftland, Wilkinson (1965) found the highest incidence of neuromy- opathies in lung and ovarian tumours. Fourteen per cent of lung tumour cases and 16 per cent of ovarian cancers had serious neuromyopathic changes. Simi- larly, in Brain and Wilkinson’s (1965) series of 19 with subacute cerebellar degeneration, 10 had lung cancer and 5 ovarian cancer. But according to Croft and Wilkinson (1965), breast, colon and cervical cancers produced only chance neuromyopathic changes. The lung, ovarian and uterine cancers had the highest incidence of malvaria while the other cases of cancer had significantly less.

Conclusion A high proportion of cases of cancer of lung, ovary and uterus have malvaria.

We suggest that the mauve factor is a derivative of a chemical substance, perhaps adrenochrome, which is released by the body to help control the cancer. As a result, a proportion of cancer cases, especially lung and ovary, will suffer mild and severe mental changes depending upon the severity and chronicity of their malvaria. This hypothesis suggests many fruitful avenues for research to (1) control the psychological and neurological sequelae of cancer by giving nicotinic acid and ascorbic acid in large doses to cancer malvarians who have had the major portion of their tumour removed by extirpation or destroyed by adequate radiation (2) strengthen the defenses against cancer by increasing production of adrenochrome and its safe derivatives, or by giving adrenochrome substitutes such as adrenochrome monosemicarbaaone.

1201 CN Towers Saskatoon, Saskatchewan, Canada.

J A

sthm

a D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B M

ainz

on

10/2

5/14

For

pers

onal

use

onl

y.

74 A. HOFFER

References

1. BOWER, B. F., MASON, D. M., AND FORSHAM, P. H. Bronchogenic carcinoma with inappropriate anti-diuretic activity in plasma and tumor, New Engl. J. Med. 271 ~934- 938, 1964.

2. BRAIN, LORD, CROFT, P. B., AND WILKINSON, M. Motor neurone disease as a manifesta- tion of neoplasm (with a note on the course of classical motor neurone disease), Brain 88:47%500, 1965.

3. BRAIN, W. R., DANIEL, P. M., AND GREENFIELD, J. G. Subacute cortical cerebellar degeneration and its relation to carcinoma, J . Neurol. Neurosurg. Psychiat. 14:59-75, 1951.

4. BRAIN, Lorn, AND WILRINSON, M. Subacute cerebellar degeneration associated with neoplasms, Brain 88 :465478, 1965.

5. BULLOUGH, W. S. Stress and epidermal mitotic activity. I. The effects of the adrenal hormones, J. Endocrinology 8:265-274, 1952.

6. -. Hormones and mitotic activity. In Vitamins and Hormones, Ed. Harris, R. S., Marrian, G. F., and Thimann, K. V., Academic Press Inc., New York, 1955, pp. 261- 292.

7. -, AND LAURENCE, E. B. The Control of Mitotic Activity in Mouse Skin, Exp. Cell Research 2l :394-405,1960.

8. -. The Control of Epidermal Activity in the Mouse, Proc. the Royal Society B.

9. BULLOUCH, W. S., AND RYTOMAA, T. Mitotic Homeostasis, Nature 206:573-578,1965. 151 :517-536, 1960.

10. CHARATAN, F. B., AND BRIERLEY, J. B. Mental Disorder Associated with Primary Lung Carcinoma, Brit. Med. J . 1 :765-768, 1956.

11. CROFT, P. B. Abnormal Responses to Muscle Relaxants in Carcinomatous Neuropathy, Brit. Med. J . 1 :181-187, 1958.

12. -, AND WILKINSON, M. The Incidence of Carcinomatous Neuromyopathy in Patients with Various Types of Carcinoma, Bruin 88:427434,1965.

13. DAYAN, A. D., CROFT, P. B., AND WILKINSON, M. Association of Carcinomatous Neuro- myopathy with Different Histological Types of Carcinoma of the Lung, Bruin 88: 43-48, 1965.

14. DENNY-BROWN, D. Primary Sensory Neuropathy with Muscular Changes Associated with Carcinoma, J . Neurol. Neurosurg. Psychiut. 11 :73-87, 1948.

15. EARLE, M. J. Psychosomatic Aspects of Cancer, An evaluation of the claim that psychological factors are causally associated with cancer. Report to Scientific Com- mittee. The Marie Curie Memorial Foundation. London, 1962.

16. GALLUZZI, S., AND PAYNE, P. M. Brain Metastases from Primary Bronchial Carcinoma; A Statistical Study of 741 Necropsies, Brit. J. Cancer. 10:408-414, 1956.

17. GARSIN, J. 8. Personal communication, 1965. 18. GELFANT, S. A Study of Mitosis in Mouse Ear Epidermis in Vitro, Exp. Cell Research

19. HEATHFIELD, K. W. G., AND WILLIAMS, J. R. B. Peripheral Neuropathy and Myopathy

20. HENSON, R. A., HOFFMAN, H. L., AND URICH, H. Encephalomyelitis with Carcinoma,

21. -, RUSSELL, D., AND WILKINSON, M. Carcinomatous Neuropathy and Myopathy,

22. HOFFER, A, Treatment of Organic Psychosis with Nicotinic Acid, DG. N e w . System

23. -. Unpublished report, 1965. 24. -, AND MAHON, M. The Presence of Unidentified Substances in the Urine of Psy-

21 :603415, 1960.

Associated with Bronchogenic Carcinoma, J . N e w . 77:122-137,1954.

Brain 88~449464, 1965.

Clinical and Pathological Study 77 :82-121, 1954.

26:35%360, 1965.

chiatric Patients, J . Neuropsychiat. 8:331-362,1961.

J A

sthm

a D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B M

ainz

on

10/2

5/14

For

pers

onal

use

onl

y.


25. -, AND OSMOND, H. The Relationship between an Unknown Factor (US) in Urine of

26. -. A Card-Sorting Test Helpful in Making Psychiatric Diagnosis, J . Neuropsychiat.

27. -. The Association between Schizophrenia and Two Objective Tests, Can. Med.

28. -. Malvaria, a New Psychiatric Disease, Acta Psychkt. Scand. 59:335-366, 1963. 29. -, -, AND SMYTHIES, J. Schizophrenia: A New Approach. 11. Results of a year’s

30. HOLT, G. W. Ischemic Neuropathy in Necrotizing Arteries, Neurology 10:43-50, 1960. 31. -. The Nervous System and Occult Cancer, Idiopathic Neuronal Dysfunctions and

32. IRVINE, D. Apparently Nonindolic Ehrlich Positive Substances Related to Mental

33. KISSEN, D. M. Personality and Lung Cancer, The Lancet 1 :216-217, 1964. 34. KOWAL, S. J. Emotions as a Cause of Cancer, The Psychoanalytical Review 42:217-227,

1955. 35. LEIGH, A., AND MEYER, A. Degeneration of Granular Layer of Cerebellum, J. Neurol.

Neurosurg. Psychiat. 12:287-296, 1949. 36. LENNOX, B., AND PRICHARD, S. Association of Bronchial Carcinoma and Peripheral

Neuritis, Quart. J. Med. 19:97-109, 1950. 37. LESHAN, L. Psychological States as Factors in the Development of Malignant Disease:

A Critical Review, J . Nut. Cancer Institute 22:1-18, 1959. 38. -. Some Methodological Problems in the Study of the Psychosomatic Aspects of

Cancer, J. Gen. Psychol. 63:309-317,1960. 39. -. A Base Psychological Orientation Apparently Associated with Malignant Dis-

ease, Psychiatric Quarterlv. 40. -, AND RENZNIKOFF, M. A Psychological Factor Apparently Associated with Neo-

plastic Disease, J . Abn. SOC. Psychol. 60:439-440, 1960. 41. -, AND WORTHINGTON, R. E. Personality as a Factor in the Pathogenesis of Cancer:

A Review of the Literature, Brit. J . Med. Psychol. 29:49-56, 1956. 42. -, -. Some Psychologic Correlates of Neoplastic Disease : A Preliminary Report.

J . Clin. Exp. Psychopath. 16:281-288, 1955. 43. -, -. Some Recurrent Life History Patterns Observed in Patients with Malignant

Disease, J. Nerv. Ment. Disease. 124:460-465, 1956. 44. -, -. Loss of Cathexis as a Common Psycho-dynamic Characteristic of Cancer

Patients: An Attempt a t Statistical Validation of a Clinical Hypothesis, Psychol. Reports 2:183-193, 1956.

45. LEWIS, N. D. C. Research in Dementia Praecoz. National Committee for Mental Hygiene, New York, 1936.

46. LYSETT, M. B., ODELL, W. D., ROSENBERG, L. E., AND WALDMANN, T. A. Humoral Syn- dromes Associated with Nonendocrine Tumors, Ann. Int. Med. 61 :733-756, 1964.

47. LETTRE, R. Drug Action on Cells in Vitro: Exhibition of a Motion Picture, Ann. New York Acad. Science 58~1085-1088, 1954.

48. NICOLAUS. R. A. Biogenesis of Melanins, Rassegna di Medicina Sperimentale 9:l-32, 1962.

49. O’REILLY, P. o., HUGHES, G., RUSSELL, S., AND ERNEST, M. The Mauve Factor. An Evaluation, Dis. N e w . Syst. 26:562-568, 1965.

50. -, ERNEST, M. AND HUGHES, G. The Incidence of Malvaria, Brit. J . Psychiat. 111:

51. OSMOND, H. Personal communication, 1960. 52. SCHEFLEN, A. E. Malignant Tumors in the Institutionalized Psychotic Population,

Subjects and HOD Test Results, J . Neuropsychiat. 2:363-368, 1961.

2:306-330, 1961.

Assoc. J. 87~641-646, 1962.

research, J . Ment. Sci. 100:29-45, 1954.

Multiple System Syndromes, Amer. J. Med. Sciences 260:86-102,1965.

Illness, J. Neuropsychiat. 2:292305, 1961.

741-744, 1965.

Arch. Neur. Psychiat. 66~145-155, 1951.

J A

sthm

a D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B M

ainz

on

10/2

5/14

For

pers

onal

use

onl

y.

76 A. HOFFER

53. SULLIVAN, J. D., AND RONA, G. Systemic Effects of Non-endocrine Tumours, Can. Med. Assoc. J . 91 :647-654,1964.

54. TAYLOR, D. M., AND SIEMSEN, A. W. Bronchogenic Carcinoma Simulating Hyperpara- thyroidism, Arch. Intern. M e d . 166:67-73, 1965.

55. WALAAS, O., AND WALAAS, E. Biochemical Aspects of Schizophrenia. General Aspects. The Molecular Basis of Some Aspects of Mental Activity, A NATO Advanced Study Institute, Oslo, 1965.

56. WALAAS, E., WALAAS, O., AND HAAVALDSEN, S. Spectrophotometric and Electron-spin Resonance Studies of Complexes of Catecholamines with Cu (11) Ions and the Interaction of Ceruloplasmin with Catecholamines, Arch. Biochem. and Biophys.

57. WARREN, S., AND GATES, 0. Lung Cancer and Mestatasis, Arch. Path. 78:467473, 1964. 100:97-109, 1963.

J A

sthm

a D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

B M

ainz

on

10/2

5/14

For

pers

onal

use

onl

y.

the psychophysiology of cancer

Documents