DIMETHYL SULFOXIDE IN THE TREATMENT OF MENTAL PATIENTS

Eduardo Ramirez Labomtorio de Investigaciones Psiquicitricas

and

Segisfredo Luza Chtedm de Psiquiatria, Facultad de Medicina

Universidad Peruana "Cayetano Heredia, " Lima, Peru

Dimethyl sulfoxide (DMSO) was synthetized by Alexander Saytzeff' in 1867. It is a versatile chemical compound, the simplest member of the alkyl sulfoxides group, its chemical formula being: CH3-SO-CH3. It is an oily, colorless organic liquid, with a slight sulphurlike smell and a faintly bitter taste. I ts molecular weight is 78.13; minimal specific gravity, 1.08 a t 25OC; melting point, 18.4"C; and boiling point, 188-190°C (760 mm Hg). It is strongly hygroscopic and quite polar. DMSO mixes in water in any propor- tion. It is a powerful solvent, able to dissolve many organic compounds (ex- cept saturated aliphatic hydrocarbons) and many inorganic salts. It is com- patible with most common organic solvents. DMSO can be considered as a neutral and stable compound. Its main industrial uses are: (1) as a solvent for resins, synthetic fibers, pesticides, dyes, pigments, etc.; (2) as a reaction medium; and (3) as a chemical reactant for chemical synthesis. It is also be- ing used because of its other interesting qualities: its antifreeze properties, its humectancy, its dispersing ability and that of forming chelates with many inorganic salts.2

In biology, DMSO called for attention from the very beginning because of its remarkable quality of crossing through organic membrane^,^'^'^'^ car- rying along other dissolved s u b ~ t a n c e s ~ - ~ without apparently destroying the integrity of the Because of its wide range of qualities, DMSO is being used a t present, on a test basis, in agriculture as a solvent and insecticide, and as a carrier for antibiotics and It is also used as a preserver of live cells and tissues against freezing damage.g-'6 It is being tested as well as a tissue protector against the effect of radiation^.'^-^'

However, it was the research of Jacob and coworkers3'* that drew atten- tion to the possible use of DMSO in medicine. These authors pointed to its qualities as (1) a penetrant carrier; (2) a local analgesic agent; (3) an anti- inflamatory adjunct; (4) a bacteriostatic agent; (5) a diuretic; (6) a tran- quilizer; and (7) a potentiator of other compounds. Following these investi- gations, DMSO was used by dermal application, with initial promising results in the treatment of the following diseases: acute musculoskeletal injuries, acute and chronic subacromial bursitis, rheumatoid arthritis, osteoarthritis, gouty arthritis, Dupuytren c ~ n t r a c t u r e , ~ ' - ~ ~ post-traumatic and post-

655

656 Annals New Y ork Academy of Sciences

operative “intractable” pain, post-amputation phantom pain, tic doulou- reux, post-mastectomy lymphedema of the upper extremity, superficial second- and third-degree bums, trigeminal neuralgia, acute and chronic sinus- itis, peripheral arterial insufficiency, pulmonary emphysema, meconium ileus, acne, pruritus ani and vulvae, headache, cutaneous manifestations of generalized scleroderma,28 and acute inflammatory eye diseases.

PHARMACOLOGIC EFFECTS, FATE, AND TOXICITY OF DIMETHYL SULFOXIDE

25

26 27

29

DMSO has a remarkable capacity for penetrating organic membranes, including the skin, without apparently destroying their It also easily penetrates and goes through the brain. Gordy has detected S35 in the CSF following intravenous injection of labelled DMSO in dogs.26 We have observed that it easily goes from CSF to the blood. Intrathecal injection of diluted DMSO (3 per cent) produces, after about 30 minutes, the characteristic odor of the compound in the patient’s breath.38 DMSO has adren~lythic,~’ slight anti~holinergic,~~ anti-inflammatory, local analgesic, bacteriostatic, local histamine-liberating,7 and diuretic (water diuresis) properties, as well as

Both in the ability to carry other compounds through membranes. vitro and in high concentrations, DMSO blocks nervous ond duct ion.^^ It is also being reported that this compound does not alter the 0 2 consumption of rats’ liver, brain, and hemi-diaphragm, and that according to the concentra- tion involved it inhibits in vitro the action of several enzymes (urease, trypsin, and chemotrypsin) .33 In vitro it also reduces osmotic resistance of erythro- cytes and produces a certain amount of hemolysis in low concentrations. In high concentrations, it inhibits blood coagulation in ~ i t r o ~ ~ and increases gastric hemorrhage in rats.31 Reports about a possible potentializer effect of DMSO on other compounds are in ~ o n f l i c t . ~ ’ ~ ’ ~ ~ ’ ~ ~ ’ ~ ~

DMSO is quickly changed in the organism into dimethyl~ulf ide~~ and in this way it is eliminated through the lungs (3 per cent),45 the skin, urine and feces, giving the patient a certain special odor, which sometimes has been com- pared with that of sea food or fish. The main metabolite of DMSO is dimethyl- ~ u l f o n e , ~ ~ ’ ~ ~ which is mainly eliminated through the urine and in a smaller proportion through the feces.

DMSO shows a very low toxicity. Test animals tolerate rather high doses administered through all the usual ways, both in acute and chronic administra- tions during a long period, and the LD50 is extremely high for all tested

DMSO shows a highly alkaline pH, about 11.6. I t is very hygroscopic (it absorbs 70 per cent of its own weight of air humidity at 20°C and 65 per cent relative humidity),35 and it generates heat when it mixes with water (60 cal. per gram a t 20°C).23 Because of all this, when this compound is given undiluted and in high doses, it violently absorbs water in and around the area of application, producing the sensation of pain, heat, or burn- ing. It seems abundantly clear that due of this quality and the high pH of

26

3,4,6.7,31

33

animals.23.25.35-42

Ramkez & Luza: In Mental Patients 657

DMSO, all the adverse signs and symptoms described 60 far in animals were present when they were given high doses of the product undiluted or in high concentrations. Some of the authors describing these toxic effects underline that these results did not appear when the product had been d i l ~ t e d . ~ ~ ’ ~ ~ ’ ~ ~

Dimethyl sulfoxide has been well tolerated by humans in 90 and 100 per cent concentrations, in doses of 5 to 60 ml per day and administered by dermal application, either in acute or months-long treatment.7’23-25 So far, no case has been described involving serious intolerance or toxicity due to short- or long-term use of DMSO through dermal application.

DIMETHYL SULFOXIDE IN MENTAL CASES As previously mentioned, Jacob and c o - a ~ t h o r s ~ ’ ~ described tranquilizing

effects of DMSO in animals and also in humans to whom the compound had been administered by dermal or intranasal application.27 Nevertheless, a number of other researchers who gave DMSO to animals and by dermal appli- cation to a significant number of patients, either do not mention that

or deny it.7 On the other hand, it has been noticed that DMSO produces in some patients increased fatigue and lethargy (17 cases out of 548 under treatment), and these symptoms would be related with dosage and length of treatment.23

The studies we carried out in administering DMSO to various test animals in different concentrations and also undiluted, and by several ways of applica- tion, do not prove that this compound has tranquilizer (sedative, cataleptic, or antianxiety) effects in animals.38 Only when toxic doses are being used, as

can generalized depression and de- other researchers have observed, creased motor activity be observed. These symptoms could not be interpreted as a tranquilizing effect of the compound.

In spite of this negative experience regarding any tranquilizing effect of DMSO in animals, we decided to test the compound in mental cases, because we wanted to test, in some way, the theory of one of us ram ire^),^^ that the antipsychotic effect of the phenothiazine tranquilizers is related to the sulphur atom on 9 position in the phenotiazine ring of these compounds.

We had completed a great many toxicity tests of DMSO in different animals-varying the concentration, dosage and way of adrnini~tration~~- before we undertook the clinical study in normal human volunteers. The tests were repeated with these subjects, who received the compound in differ- ent concentrations, doses, and ways of administration. We concluded that concentrations of 50 and 80 per cent and the intramuscular way of administra- tion could be the most useful for testing mental patients.

effeCt23,36,41

28,36,41

38

MATERIALS AND METHODS

DMSO was given to 42 mental patients grouped as follows: (a) 25 schizo- phrenic patients (14 acute and 11 chronic cases); (b) four manic depressive psychotics in the manic state; (c) four cases of alcoholic psychoses; (d) four

658 Annals New Y ork Academy of Sciences

obsessive-compulsive neuroses cases; and (e) five with severe anxiety states. Schizophrenic Patients

Twenty five patients were treated, 14 of them acute and 11 chronic with more than 10 years of disease. Nineteen were males and six females. The average for the male group was 27 years 4 months and for the female 25 years 5 months.

Most of the 14 acute schizophrenic patients (eight paranoid and six catatonic-paranoid) were excited. Four were in obvious states of agitation and showed serious disturbance of the ego conscience, harm and persecu- tion ideas, and auditory and visual hallucinations. Two of them were taken with hands-bound into the hospital; and when received in the admission ward, one of them crashed the window panes, shouting that the devil was chasing him. During the following days, he remained in bed, his eyes closed and mak- ing stereotypic gestures. His conduct was completely disorganized. The other patient would run along the corridors and bang the doctor’s door, shout- ing: “I am dying, I am dying; forgive me doctor, help ma, they are killing me.” The third patient showed conscience disturbances, lack of orientation in time and space and incongruous conduct. He used to lie on the floor or tear out the bed clothes, and he sometimes attempted to sleep on the wire surface of the bed, covering himself with the mattress. His legs showed many injuries caused by his own actions, and he suffered from auditory and cenesthesic hallucina- tions. Finally, the fourth patient, a woman of 20, entered the hospital in a state of clear agitation. She suffered from false recognition and mystical hallucinations, was an exhibitionist, and attempted to undress herself in order to “give God a child.” Shortly before, she had tried to commit suicide with overdoses of digitalis.

The 11 chronic patients were seven paranoiacs, two catatonic-paranoiacs and two hebephrenics with active symptoms: hallucinations, harm and per- secution ideas, desire for isolation, inhibitions and psychomotor retardation, as well as episodic aggressiveness or refusal to have any emotional contact with the rest of patients. Four of them, being under conventional therapy as outpatients, were hospitalized for acute episodes, and seven were very dete- riorated patients with uninterrupted hospitalization for more than six years. These last patients had a common background in the fact that they had been unsuccessfully treated with insulin, electroshock, and phenothiazine drugs (equivalent to an average of 300 mgs. of chlorpromazine a day) for more than four years. One of the patients had been deprived of his legal capacity, and when he began treatment he showed mental disintegration and false personification (he claimed to be Marie Antoinette), and he also had several motor stereotypiae, including verbigeration, and he remained in isolation, completely careless in his personal grooming. Another case had been jailed a number of times for attacking passers-by and even his own father. He showed auditory hallucinations and was also extremely untidy.

Ramhez & Luza: In Mental Patients 659

Patients with Manic Depressive Psychoses Four patients in the manic phase were treated. They suffered from psycho-

motor agitation for 15 days on the average, verbosity, megalomaniac ideas, flow of ideas, and insomnia. One of them used to fight in his ward, tearing out the bed clothing and causing a great deal of trouble because of the noise he made and because of his psychomotor agitation. On one occasion, another patient punched him in the mouth because of the tumult he was causing. Out of the four patients, three were men averaging 33 years 5 months in age; and the woman was 22. The four patients had suffered previously from episodes of the same kind lasting approximately three months and receding after intensive treatment with tranquilizing drugs and electroshock therapy. One of the patients had to be given uncommonly large quantities of parenteral barbitu- rates to control his destructive impulses. Patients Suffering from Alcoholic Psychoses

Two of the patients showed symptoms of alcoholic hallucinosis, and the other two were in the delirium tremens state. All four (three males and one female) had records of previous hospitalization due to the same causes. When treatment began, they showed severe apprehensive tendencies and auditory hallucinations. Patients Suffering from Anxiety

Nine patients (six male and three female) were treated, out of whom four suffered from obsessive compulsive neuroses and five from various types of severe anxiety reactions. The first four were young, averaging 21 years 5 months in age, and had shown obsessive ideas and intense anxiety for as long as a year. One of them, an engineering student, had been forced to abondon his studies. The symptomatology of this patient was characterized by homosexual ideas and doubts. He was afraid that he might introduce through the anal orifice every long and pointed object he could find; on the street he was afraid of becoming the victim of a sex aggression; and he suffered from the idea of being judged as a homosexual in spite of the fact that he had never had any such experience. When treatment was started, he was extremely anxious and revealed frustration because no previous treatment had improved his condition. Another patient showed compulsive walking; on one night he walked 30 km. At the same time, he thought that he could not walk properly and that people were observing him.

The five remaining patients showed anxiety related to conflictive situa- tions as well as feelings of inability and inferiority. Several of them suffered also from symptoms of the autonomic nervous system such as wet hands, blush trend, headache etc.

Drug, Dosage and Method of Administration

In the current clinical study we used dimethylsulfoxide, pharmaceutical grade, in 50 and 80 per cent w/v concentrations, diluted in saline in 5 ml. vials

660 Annals New York Academy of Sciences

for intramuscular administration. Although DMSO seems to be active and well tolerated through oral and parenteral administration, it seemed to be less potent through oral administration even when the undiluted doses were the same. Therefore, it was decided to treat the patients intramuscularly. Most treatments began with an 80 per cent vial two to three times a day. In the most disturbed cases, it was necessary to use up to five vials a day. With patients showing mild or less intense symptoms, as was the case with patients suffering from anxiety, only one or two vials a day were used. Patients with agitation received normal doses of barbiturates as well during the first days of DMSO treatment. As symptoms began to improve, treatment was changed to the 50 per cent concentration.

Before starting therapy with DMSO, all previous types of treatment were stopped for a t least a week in the chronic patients. All patients were examined both medically and psychiatrically, and the following laboratory tests were completed: hemogram, hemoglobin, platelets, fasting blood sugar, BUN, cholesterol, prothrombin time, total protein, A-G ratio, alkaline phosphatase, direct and total bilirubin, cephalin flocculation, thymol turbidity, Takata-Ara test, and complete urine analyses. All these tests were repeated initially once a week and then every two weeks or monthly, as treatment proceeded. In a few instances ECG, EEG, and cerebrospinal fluid tests were performed as well, both before and during treatment.

Finally, the above examinations were periodically repeated after treatment was completed. All patients received complete ophthalmologic examination after treatment was finished.

The action of the drug was evaluated through clinical procedures, by examining the patients from the psychopathologic standpoint and by apprais- ing each patient’s conduct.

Because of the characteristic odor of the drug and of the patient under treatment, clinical control tests with placebo or with the blind and double- blind methods proved to be impossible, however desirable this would have been. This was also the experience of other authors intending the same.23 Therefore, in order to control the therapeutic action of the drug under study, we have compared the average hospitalization period of acute cases treated with DMSO with that of acute patients not receiving DMSO but having diagnoses as close as possible to those under test.

The control group was comprised of 16 patients, divided as follows: seven acute schizophrenic patients (five men, two women) ; two suffering from manic- depressive psychoses in the manic state; three from alcoholic psychoses, and four from severe anxiety reactions. The patients belonging to this control group received the psychiatric treatment in current use: insulin coma, electro- shock therapy, phenothiazines, minor tranquilizers and sedative barbiturates.

Ramhez & Luza: In Mental Pat ients 661

RESULTS Schizophrenic Patients

The 14 acute patients responded better to this form of treatment than the chronic patients. In these acute patients the most noticeable effect was the amelioration of the agitation state; the state began to decrease from the very first few doses, and this was particularly true with the six catatonic-paranoid patients who entered the hospital in a great state of agitation. In the eight paranoiacs, the improvement was better a t the conduct level, that is in connec- tion with symptoms of distrust and seclusion, except in the case of an agitated woman, whose psychomotor agitation improved first. After that, an improve- ment was noted in the other psychotic symptoms. In succession, the ego conscience disturbances, hallucinations, stereotypia and paranoid ideas of harm and persecution were the symptoms more favorably affected by the drug.

The 14 patients were discharged from the hospital within 45 days. Of this group three had achieved complete recovery 15 days after they entered the hospital. One of them said: “I have been out of my mind. I dont know what happened to me. I wonder what my children are going to say.” The psychoses of the 11 remaining patients receded in a longer period.

As for the 11 chronic cases, the seven very deteriorated patients showed cessation of the agitation state and also a favorable change in conduct. As a matter of fact, a rapid decrease in restlessness and autism was noted. As the doses were being increased, distrust, seclusion, negative attitudes and lack of communication, as well as stereotypia decreased in both intensity and fre- quency. This improvement was specially noted in a patient who had been suffering from his disease for 14 years: two weeks after the treatment started, be became approachable and began to talk, giving clear answers about his background and, generally speaking, showing a recovery in alertness, as opposed to the lack of mental coordination he had displayed during the preceding 14 years. At present, he keeps himself busy as a typist in the ward, and apparently he has been able to maintain his manual and intellectual capacity. The same could be said about his proper social behavior. Before treatment began, the patient used to eat directly from the dishes, using no cutlery and spilling the food on his clothes. He himself decided to use forks, spoons, etc. In addition, he is now a neat and tidy man.

The remaining six chronic patients also improved so far as conduct is concerned. This was especially true of two who, due to the cessation of the previous treatment 10 days in advance of the DMSO test, became aggressive and had to be commited to strict seclusion for a number of days. The improve- ment of these patients made them capable of doing some occupational therapy later on. None of these patients was discharged from the hospital. The im- provement achieved during the first two weeks of treatment did not increase although DMSO treatment was uninterrupted for two to six months.

The four long-term chronic schizophrenics, hospitalized for acute episodes,

662 Annals New York Academy of Sciences

showed a complete remission and were discharged from the hospital. They responded faster to DMSO treatment than to conventional therapy. Their mean hospitalization time was shorter with DMSO treatment as compared with similar previous acute episodes of these patients or with other similar chronic schizophrenics treated as inpatients with conventional therapy.

All the above could encourage us to remark that out of the 25 schizophrenic patients, the 14 acute and four chronic cases did reach complete remission and were discharged from the hospital. The remaining seven chronic cases showed decrease of the agitation episodes and were able to cooperate to the extent of making occupational therapy possible. Patients Suffering fmm Manic-Depressive Psychoses

Following the trend of the cases described thus far, the four patients diagnosed as manic-depressive psychotics showed a remarkable improvement with regard to the agitation state. Gradually they became more tranquil, a t the same time decreasing their verbosity and megalomaniac ideas. Under DMSO treatment, the manic phase became shorter and less intense than the previous episodes manifested by the same patients. Patients with Alcoholic Psychoses

These four patients showed a noticeable improvement from the beginning of treatment. In fact, restlessness decreased after the first few days, in spite of the fact that hallucinations remained, specially in both cases suffering from alcoholic hallucinosis; later on, these symptoms decreased in intensity and frequency, until they completely disappeared.

1 2

1. - Acute schyrophrenia 2 . - Mania 3 . - Anxiety states

p$l 3

DMSO : Dirnethylsulfoxide therapy

S P T : Standard Psychiatric Therapy

FIGURE 1. Hospitalization time of acute mental inpatients treated with DMSO and with conventional therapy.

Ramirez & Luza: In Mental Patients 663

Patients Suffering from Anxiety States The anxiety states, associated with bioneuroses and psychoneuroses also

benefited from the drug. Doses from one to two vials a day caused decrease in the anxiety symptoms, which are so characteristic of those states. This was particularly true so far as obsessive-compulsive patients were concerned. Patients said that they felt calm, that ideas did not upset them as before, that they were able to overcome their obsessive compulsions and that finally they were able to act in a more spontaneous way.

Inpatient treatment at hospital was shorter for the 31 acute cases treated with DMSO than for the 16 acute patients of the control group treated with conventional therapy, as it is shown in the following figure.

Dimethyl Sulfoxide Tolerance

All treated patients tolerated DMOS well. There was no serious allergic reaction, nor intolerance or toxicity. Symptoms of dependence on the drug or addiction to it were not observed. Insomnia was a symptom noticed rather frequently in the patients, especially those suffering from agitation. At least partially, it seemed to be a symptom caused by the disease proper and also by the drug. It was controlled with hypnotic barbiturates. Insomnia was present only during the first days of treatment and disappeared as patients became calm.

Intramuscular injections with 80 per cent DMSO produced pain or a feeling of heat in the area, lasting for some minutes. Intramuscular administration of this compound in doses and concentrations as described, in short- or long-term treatment lasting for months, did not produce noticeable irritation at the site of injection. Treatment with DMSO did not produce important changes in weight, pulse, blood pressure or temperature, either in acute or chronic admin- stration. Some patients showed polyurea (water diuresis) , polydipsia and some diaphoresis. These symptoms appeared with different degrees of intensity and were more constant and pronounced when higher doses were used.

In short- or long-term administration, DMSO has not produced autonomic symptoms, motor alterations, or muscle relaxation. This enabled some patients to continue their treatment at an appropiate time as ambulatory cases. Parkinson-like syndrome has not been observed. The laboratory tests during and after treatment show results within the normal range.

No treated patient showed ophthalmological changes or lenticular opacities that could be attributed to DMSO treatment.

DISCUSSION

Clinical results presented in this paper show that DMSO has a significant antipsychotic effect. Psychomotor agitation and anxiety are the symptoms best improved by treatment. With such therapy, the patient becomes calm and is gradually able to liberate himself from the psychotic or severe-neurotic

664 Annals New York Academy of Sciences

symptoms. DMSO has a moderate sedative action. I t does not produce mental clumsiness, drowsiness or hypnotic effects. Nevertheless, it favors normal sleep in patients suffering from no major overexcitement. DMSO a t the same time has a clear psycho-stimulant action; without producing overstimulation or euphoria. It increases conscience clearness and alertness, and levels the pa- tient’s mood. Because of these changes the patient is better able to cope with reality. This is most noticeable in chronic apathetic and environmentally disconnected cases. Contrary to antidepressant drugs and stimulants of the central nervous system, DMSO acts favorably on autism, steriotypiae and lack of energy. Thus, it improves the patient’s conduct and sociability, making psychotherapy and occupational therapy a lot easier. The antipsychotic effect of DMSO is rapid. According to the intensity of the case, it can be observed between the first and seventh days of treatment.

The effect of DMSO on psychiatric patients could be described as one of mental stabilization. Of all known tranquilizers, we would say that this one is most deserving of the term ataractic. Among other things, it differs from phenothiazine compounds in showing no marked sedative or hypnotic action in high doses, in spite of its antipsychotic effect. The sedative action of DMSO is mild and could be compared with that of the so-called minor tranquilizers. Because of this, patients with intense psychomotor excitement and aggresive or destructive conduct have been treated during the first days with hypnotic barbituratesin addition to DMSO. I t is a well-known fact that these com- pounds do not have any antipsychotic action. In order to discard the possibil- ity that the observed antipsychotic effect of DMSO might be due to a mere potentialization of barbiturates in some very dangerous patients, we carried out for two weeks a treatment with barbiturates alone. When no improvement was noted, DMSO treatment was added. When patients were not dangerous, in spite of their intense psychomotor agitation, DMSO alone was used. It is pos- sible that the combination of DMSO and the major tranquilizers now in current use would produce results more quickly and effectively.

Complete remission of acute patients and of the chronic schizophrenics with acute episodes treated with DMSO persists thus far. The first treated case has shown no relapses for as long as a year after completing treatment. The last of these patients has only been followed for a period of four months, without further treatment or relapse. Improvement of the seven chronic schizophrenic patients-all of them in a very serious condition and with more than six years as hospital inpatients-lasted from one to four weeks after completing the initial treatment. When they relapsed and DMSO was re- sumed, they respond in the same way, and their reaction was equally favor- able. This fact suggests that DMSO does not produce tolerance.

Dimethyl sulfoxide is therefore a very interesting drug, so far as psychiatry is concerned, because its very simple molecule produces a t the same time antipsychotic, sedative and psycho-stimulant effects.

I t is probable that the mental equilibrium produced by DMSO in normal

Ramirez & Luza: In Mental Pat ients 665

subjects and mental patients would derive to a certain extent from its properties of changing the permeability of the organic membrane. Since CNS is considered from the neuro-chemical viewpoint as a system of superimposed membranes, and since it is thought that some of the phenothiazines act in the way of changing the permeability of the membrane, we think that DMSO may change the permeability of the blood-brain barrier, the neuronal or the vesicle membrane. Thus, it would permit CNS function closer to normality.

It is very difficult to evaluate the therapeutic effects of a drug on mental diseases, and especially so in this case where it has not been possible to use a placebo for proper control. A drug that is administered for mental disorders requires a long and elaborate clinical study involving a great number of patients, in order to assess its efficiency, therapeutic spectrum and contraindi- cations, as well as its tolerance under long-term administration. Therefore we hope that this research will stimulate investigators and clinicians to study fur- ther the therapeutic possibilities of DMSO. According to this preliminary study the compound would seem to be useful in treating some serious mental diseases and would possibly offer a new approach in psycho-pharmacological research.

SUMMARY

Dimethyl sulfoxide (DMSO), a powerful industrial solvent, easily crosses through biological membranes and enters the brain. The reported properties of DMSO include tranquilizer effect, mild adrenergic- and cholinergic-blocking action, and local analgesia, together with a very low toxicity. After many tests on its pharmacological action and toxicity in animals and later in human vol- unteers, this compound was tested in mental patients by the intramuscular route. Preliminary results on 42 severely disturbed psychiatric patients showed DMSO to have antipsychotic and antianxiety properties. It produces emotion- al calm followed by relief of some psychotic and severe neurotic symptoms. The action of the drug differs from that of the so-called tranquilizers mainly in that it does not produce major sedation or central depressant action. On the contrary, DMSO produces some mild stimulant effect that makes patients more alert, sociable, and acceptable for psychotherapy and occupational therapy. It does not produce muscle relaxation, autonomic changes or ex- trapyramidal symptoms. DMSO seems to be useful in the treatment of patients with the following diagnoses: (1) overexcited states (acute schizo- phrenic reactions, manic phase of the manic-depressive psychoses, alcoholic phychoses, symptomatic psychoses) ; (2) some symptoms of the chronic psychoses (autism, stereotypia, negativism, abnormal behavior or the hebe- phrenic states) ; (3) severe neuroses (anxiety reactions, obsessives). Tolerance to the drug was judged good in all the treated patients by clinical and laboratory controls. Inpatient treatment a t hospital was shorter for the acute patients treated with DMSO, as compared with a similar control group treated with conventional therapy.

666 Annals New York Acadeny of Sciences

1. 2. 3.

4.

5.

6. 7. 8. 9.

10. 11. 12. 13. 14.

15. 16. 17. 18. 19.

20. 21. 22. 23.

24. 25.

26. 27. 28.

29. 30.

31.

32. 33.

34.

35.

36.

37.

38. 39.

40.

REFERENCES

SAYTZEFF, A. 1867. Ann. Chem. Pharm. 144 148-156. Crown Zellerbach Corp. 1964. Dimethyl sulfoxide (DMSO) Technical Bulletin. JACOB, S. W., M. BISCHEL & R. J . HERSCHLER. 1964. Curr. Therap. Res.

JACOB, S. W.. M. BISCHEL & R. J . HERSCHLER. 1964. Curr. Therap. Res.

JACOB, S. W., M. BISCHEL, G. A. EBERLE & R. J. HERSCHLER. 1964. Fed.

STOUGHTON, R. B. & W. FRITSCH. 1964. Arch. Derm. 90 512-517. KL1GMAN.A. M. 1965. Part. 1? JAMA 193796-804: Part. 2, JAMA 193923-928. SCHINCHETTI, S. & B. BORN. 1965. J. of Pharmac. sci. 54: 285. LOVELOCK, J . E. & M. W. H. BISHOP. 1959. Nature 183 1394-1395. ASHWOOD-SMITH, M. J. 1961. Nature 190 1204-1205. ASHWOOD-SMITH, M. J. 1961. Int. J. Rad. Biol. 3 41-48.

FARRANT, J. 1963. Biochem. Pharmacol. suppl. 12 248. SILVER, R. K., H. B. LEHR, A. S. GREENE & L. L. CORIELL. 1964. Proc. soc.

FARRANT, J. 1964. J. Pharm. Pharmacol. 16 472-483. BOUR0NCLE.B.A. 1964. J. Lab. Clin. Med. 64: 843-844. ASHWOOD-SMITH, M. J. 1961. Int. J. Rad. Biol. 3 101-103. ASHWOOD-SMITH, M. J. 1962. Int. J. Rad. Biol. 5: 201-202. VAN DER MEER, C., P. W. VALKENBURG & M. REMMELTS. 1963. Int. J. Rad.

SCHRODER, E. & R. HUBER. 1962. Acta Biol. Med. Germ. 9 62-66. ROSENBAUM. E. E. & S. W. JACOB. 1964. Northwest. Med. 63: 167-168 ROSENBAUM, E. E. & S. W. JACOB. 1964. Northwest. Med. 63: 227-229. ROSENBAUM, E. E., R. J . HERSCHLER, & S. W. JACOB. 1965. JAMA192

JOHN, H. 1965. Arzneimittel-Fomhung 11: 1298-1305. ROSENBAUM, W. M., E. E. ROSENBAUM & S. W. JACOB. 1965. Surgery 58

JACOB, S. W. Personal communication. JACOB, S. W. 1965. Headache 5: 78-81. SCHERBEL, A. L.. L. J . MCCORMACK & M. J. POPPO. 1965. Cleveland. Clin.

GORDON, D. 1965. I n Medical World News 6 27-29. CAUJOLLE, F.. M. D. CAUJOLLE & P. H. CHANH. 1964. Arch. Intern. Pharma-

Merck Sharp & Dohme Informational Bulletin on the pharmacology of di-

HERSCHLER, R. J. & S. W. JACOB. 1965. DMSO. Tappi 4 8 43a-46a. GERHARDS, E., H. GIBIAN & G. RASPE. 1965. Arzneimittel-Forschung 11:

DIX0N.R. L., R. H. ADAMSON, M. BEN & D. P. RALL. 1965. Proc. %c. Exp.

BROWN, V. K., J. ROBINSON & D. E. STEVENSON. 1963. J. Pharm. Pharmacol.

CAUJOLLE, F., D. CAUJOLLE, M. H. BOUYSSOC & M. M. CALVET. 1964. c. R. HIXON, 0. F. Toxicity studies with dimethyl sulfoxide (DMSO). Crown Zeller-

RAMfREZ, E., ef 01. Unpublished data. ROSENKRANTZ, H., Z. HEDIDIAN, H. SEAY & M. M. MASON. 1963. Cancer

Chemotherapy. Reports 31: 7-24. SOMMER, S. & G. TAUBERGER. 1964. Arzneimittel-Forsch. 14 1050-1053.

6 134-135.

6 193-198.

Proc. 23(2): 410.

DJERASSI, 1. &A. ROY. 1963. Blood 22: 703-717.

Exp. Biol. Med. 117: 65&660.

Biol. 6 151-155.

309-313.

258-266.

Quart. 32 47-56.

codyn. 152 491-495.

methylsulfoxide. 1966.

1295-1297.

Biol. Med. 118 756-.

15 688-692.

Acad. Sci. Pans 258: 2224-2226.

bach Corp., Report.

Ramliez & Luza: In Mental Patients 667

41. WILLSON, J. E., D. E. BROWN & E. K. TIMMENS. 1965. Toxicology and Applied

42. FEIMAN, H., M. BEN & R. LEVING. 1964. The Pharmacologist 6: 188-189. 43. RAMfREZ, E. 1966. V International Congress of Collegium Internationale Neuro-

44. DISTEFANO, V. & H. H. BORGSTEDT. 1964. Science 144 1137-1138. 45. KOLB, K. H., G. JANICKE, M. KRAMER, P. E. SCHULZE & G. RASPE. 1965.

46. WILLIAMS, K. I. H., K. S. WHITTEMORE, T. N. MELLIN & D. S. LAYNE.

47. BRAUDE, M. C. & R. R. MONROE. 1965. curr. Therap. Resp. 7: 502-509.

Pharmacology 7: 104-112.

Psychopharmacologicum, March 28-31, Washington, D. C., U. S. A.

Arzneimittel-Forschung 11: 1292-1295.

1965. Science 149 203-204.