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Meprobamate in Psychiatric Disorders
Meprobamate in Psychiatric Disorders JOSEPH C. BORRUS, M.D.*
MEPROBAMATE, more popularly known under the trade names of Miltown and Equanil, has been in general use since April 1955. Prior to this, it was used experimentally for over two years by many investigators including Selling, Berger, Hendley et al., Lamere and Borrus. 1- 6 The wide general acceptance of meprobamate in such a short period of time points up two very interesting features of this preparation. The first of these is that the medicament seems to be upholding its earlier promise as an adjunct in the relief of anxiety and tension states. Secondly, it emphasizes, in particular, the tremendous need for some form of ataraxic to help cushion the central nervous system from the intense pressures of everyday living. The search for such a buffer has been a continuous one which dates back to Aristotle and some of the earlier observations of the Egyptians, Phoenicians and Persians. The increased tempo of modern society has greatly enhanced the need to either support the individual by reducing the multitude of stimuli entering consciousness by medication, or to re-educate the individual's nervous system to adapt better by means of psychiatric treatment either in the form of psychotherapy or psychoanalysis. Experience has shown that more often a combination of therapies is the answer. The general practitioner and the internist will combine medication with supportive psychotherapy. The psychiatrist will also make use of medication along with his deeper interpretive and integrative approach to psychotherapy, while the analyst may attempt to utilize his free associative techniques almost entirely. In each instance, the method of choice will depend upon the patient's present condition and his personality as well as the physician's own prior experiences in dealing with his patients and the kind of situations which he encounters. Formerly, medicaments such as bromides, barbiturates, chloral hydrate and paraldehyde were the chief aids of the physician where sedatives were necessary. Today, the ataraxics have supplanted these. Meprobamate is one of these ataraxics.
* Neuropsychiatrist, Attending Staffs, Middlesex General and St. Peter's General Hospitals; Consulting Psychiatrist, Middlesex County Rehabilitation and Polio Hospital, New Brunswick, New Jersey. 327
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328 I>IIARMACOLOG Y
Meprobamate, chemically, is a 2-Inethyl-2-n-propyl-l,:3-propanediol dicarbamate which has a characteristic bitter taste and is a straight chain aliphatic compound. It has a muscle-relaxant action, some anticonvulsive properties, and fear, anxiety and tension relieving properties. The muscle-relaxing effects involve primarily the voluntary skeletal muscles, yet even in very large doses it does not appear to affect the diaphragm so that respiration remains free. This, in essence, vvould seem to provide an additional margin of safety in the use of this drug. The anticonvulsant action of this 111edication is observed in its opposing the action of Metrazol and strychnine induced seizures. 2 , 6 In this respect, it has proved more effective than some of the barbitura~es, Inephenesin and in some instances, trimethadione. l"he reduction of fear, aggressiveness, hostility, tremulousness and the development of a greater sense of well-being ,vere noted first upon observations on animals and then in clinical studies both in hospitals 2 and in private practice. I , 4, 5, 7 The rationale for any therapy depends first upon its site and mode of action and, secondarily, upon its effectiyeness. 'rhe action of meprobaIllate as reported in the literature 2 , 3 seems to be on the interneuronal circuits where it acts as a blocking agent. Investigators have shovvn that where single reflex arcs are concerned (no interneurones) the drug has no effect, whereas with more complicated circuits involving lnany interneurones these reflex actions tend to be reduced or abolished by the medicine. There is also a central effect, which appears to be selective, on the thalamus. This was demonstrated by electrical recordings taken from the thalamus during the administration of meprobamate in low dosage. 3 , 8 Much higher dosages were necessary to produce subcortical and cortical changes. Berger2 , 9 raises the question of the interneuronal blocking of the drug in reducing son1e of the cortical thalamic impulses, hence relieving and calming some of the physiologic components of anxiety. By carrying this line of thinking a little further, it may be possible to compare the effects of meprobaluate vvith those of the various neurosurgical procedures such as a subcortical undercutting of the frontal association pathways as was developed in the prefrontal and supraorbital lobotolnies and the analogous effects that are obtained by thalamotomy as advocated by Wycis and Spiegel. This is still conjectural, but the drug has the advantage of being a temporary blocking agent, i.e., it temporarily modifies the number of incoming stimuli and, as the individual regains better control of his emotional reactions, is no longer needed. With actual surgery, of course, changes are brought about vvhich become unalterable. Meprobamate seeIns to have little or no effect on the autonomic system per se nor does it either produce, or change the responses to, cholinergic, adrenergic or histamine effects. The absence of specific autonomic
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effects therefore makes for greater acceptance by the patient, since he need not fear the development of unwanted somatic changes. METIIOD OF USE
Meprobamate is prepared as a 400 mg. tablet, which is the only form and strength available as of this writing. The favored dosage is one tablet four times a day after nleals, vvith the fourth tablet being taken at bedtime. l'hen, depending upon its effectiveness at this dosage level, it may either be increased to two tablets four tilnes a day, or reduced to meet the individual patient's need. As a rule, ambulatory patients will rarely require more, but occasionally as many as ten to twelve tablets daily will be needed where a great deal of restlessness and agitation are part of the symptomatology. The optimum dosage can be determined within a period of about two weeks. While it is possible to maintain a patient on medication indefinitely, in most cases the physician will begin to reduce the dosage as the patient improves or the patient himself will spontaneously reduce the amount of medication with the statement, "I felt so good that I forgot to ,fake the medicine at times." Actually the dosage can be reduced gradually or abruptly with no untoward effects in the average dosage range mentioned above. Whenever depression vvas an associated feature of the over-all condition of the patient, 5 mg. of one of the amphetaluines taken along with the meprobamate has alleviated this distressing feature. Also in seriously disturbed patients, the combination of two tablets of meprobamate and a 50 mg. tablet of chlorpromazine taken four times a day has been effective in relieving severe, distressing anxiety symptoms and even psychotic manifestations. It has been my experience that if a patient does not respond to this combination, then hospitalization is required. This apparently has also been the experience of others. 7, 10 Just as with all the other ataraxics developed thus far, meprobamate appears to have no effect on the pure endogenous depressions or on the manic-depressive depressions where strong guilt feelings and feelings of unworthiness, hopelessness and futility are paramount. Whenever meprobamate is used as a sleep-inducing preparation, the patient will generally respond quite favorably to two tablets taken about 15 minutes before bedtime. INDICATIONS AND RESULTS
Meprobamate has shown great effectiveness in anxiety and tension states, phobias, tension headaches, psychosomatic disorders, insomnia, premenstrual tension, neurodermatitis and behavior disorders. It has been less effective but still quite helpful in ambulatory schizophrenia, posttraumatic neuroses, petit mal epilepsy, muscle spasms (of various etiologies) and cerebral palsy.
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Anxiety and Tension States
Anxiety in one form or another, and in varying degree, accompanies practically all illness. Every physician, whether he be in general or specialty practice, is familiar with the need to reassure his patient about his illness and to allay his fears and concern relating to it. This is as true of a minor one such as simple paronychia as of a more serious, complicated surgical or cardiac condition. Anxiety, moreover, is not associated solely with physical or mental illness but may well become a part of one's everyday living. The loss of a loved one, the disappointment in failing to obtain a sought-for promotion or job, the need to match wits with a competitor or the need to address large groups, or the feelings of resentment to others, are but a few of the daily stress situations which human beings face that often produce anxiety. The anxiety which the physician and psychiatrist sees is usually exemplified by certain emotional and physiological changes within the individual. The anxious and tense person expresses a vague sense of uneasiness with a feeling of impending disaster. In addition, he complains often of palpitations, tremulousness, hyperhidrosis, coldness of the extremities, dryness of the mouth and a tightness or fluttering within the chest or abdomen. This is the usual pattern of an anxiety reaction or tension state and it can be extremely incapacitating to the possessor, whatever the underlying etiology. In some instances, a precipitating cause will have been a recent traumatic experience. In other cases the anxiety is but an outward expression of a more deep-seated earlier established pattern with either guilt or hostility precipitating the anxiety. Whatever the cause may be, the uniformly favorable response to meprobamate of 60 to 90 per cent 5 • 7. 9 of these patients establishes this drug as a welcome adjunct to the armamentarium not only of the general practitioner, the internist and others in the various fields of medicine, but also of the psychiatrist. For the former, meprobamate may help tide a patient over an acute disturbance following a recent emotional trauma. For the latter, it will help to ease some of the patient's symptoms and thereby make him more amenable to whatever psychotherapeutic procedures may be necessary. Improvement following meprobamate is usually characterized by lessened irritability, a general sense of well-being, a decrease in morbid preoccupation with symptoms generally, a greater ability to concentrate, a greater sense of relaxation and a return to both a more active social life and to a more productive career economically. Improvement will generally commence within a few days after the start of treatment. Phobic States
These are closely related to anxiety and tension states so far as physiological changes are concerned. However, instead of an ill-defined
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sense of uneasiness, we see a more specific fear as the predominant symptom. This may be observed as a fear of dying, or fear of cancer, insanity, heart disease, tuberculosis, etc. These people are extremely perturbed. They show evidence of extensive agitation and restlessness and may become so distraught as to refuse to leave their homes, will stop working, will be unwilling to drive a car and even refuse to remain home alone. The man who must have a member of his family accompany him to his place of business or the housewife who frantically calls her husband home from work because of her fear of dying, are both familiar stories to the practicing physician. Since this creates not only economic hardships, but also severly limits the usefulness of these people both at work and at home, quick relief is needed. Meprobamate has proved of value in phobic states by relieving the intensity of the fears as well as the paralysis of action that these fears evoke, although it does not relieve the actual fears themselves. This will come later as the patient gains a better understanding of the dynamics of his illness. Studies by Lasagna,10 Selling,7 Osinski,11 Hollister et al. 12 and others have illustrated how much more effective and more gratifying have been the results of treatment of these states with meprobamate than with some of the other medications such as barbiturates, paraldehyde, mephenesin and some of the other ataraxics as chlorpromazine and reserpine. This has been especially true in private practice where these conditions are seen most commonly. Throughout the author's experience, wherever depression was the outstanding feature of the anxiety or phobic state, a combination of one of the amphetamines along with the meprobamate was often sufficient to break through this depression and ameliorate the over-all condition, thereby often reducing the need for electroconvulsive treatment. Headaches
Headaches are a frequent accompaniment of almost every tension state. Studies by Wolf and others have emphasized the stretching of tissue and the change in the size (caliber) of blood vessels as the primary etiologic factor in headaches. However, we frequently see headaches that are the result of constant, almost unremitting contraction of the posterior muscles of the neck, often described by the patient as a tightness in the back of the head and neck. This type of nuchal headache as well as the frequent complaint of a "tight band around my head" or compression headache is usually a part of a more deep-rooted pattern of neurosis. Consequently, here too a favorable response to meprobamate would be expected and this has actually been observed. 9 The absence of any significant blood pressure reducing effect has permitted the use of meprobamate in headaches of hypertensive origin. Of further interest to the psychiatrist has been the report of a reduction
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of post-electroshock headaches by the use of meprobamate one hour prior to treatment. 13 Whether this is a direct result of some reduction in anxiety preliminary to treatnlent or whether this is due to the musclerelaxing effects of the drug has not been clearly explained. Insolllnia
Insomnia in one form or another is perhaps one of the commonest COlnplaints met by the physician irrespective of his type of practice. This may occur either as an inability to fall asleep upon retiring, or the awakening after a brief period of perhaps one to two hours of sleep and then finding it impossible to return to sleep. In both of these situations, meprobamate has shown considerable effectiveness. 5 , 7,10,11,12 If it is taken during the day, the patient will often be sufficiently relaxed that normal sleep will ensue vvithout medication. On the other hand, if this is not sufficient, then the addition of one or t\VO tablets taken 15 minutes before retiring will solve the problem of the patient who finds it difficult ~o fall asleep. By the same token, a similar dose taken upon awakening during the early morning hours will bring a return of sleep \vithout producing any drowsiness the following day. Presumably meprobamate acts by relieving tension and anxiety, since electroencephalographic studies do not show the characteristic pattern of a barbiturate type of sleep. Patients tend to report a fairly restful sleep without the morning depression and sluggishness seen following barbiturates. In addition, there is apt to be very little dreaming although this seems to be more dependent upon the individual's personality pattern and the degree of anxiety under which he is living at the time. In the severe agitated depressions, however, meprobamate has proved ineffective both as a sleep-inducing preparation and as a euphoriant.
The Psychoses 'I'he author's experience with the use of meprobamate in the psychoses, manic-depressive and schizophrenic, while it may have been somewhat limited (under 100 cases), nevertheless is sufficient to indicate that meprobamate has limited value here. Pennington,14 hovvever, in a study of the effects of various ataraxics on the psychoses, reported favorable results with very large doses in a hospital setting. Such large doses (12 to 25 tablets daily) would not be warranted or even feasible in ordinary private practice where a patient may be under observation only once or twice a week, and the expense to the patient would be a deterrent. The use of meprobamate in ambulatory schizophrenics was somewhat more encouraging, and since this type of patient is more apt to be seen in everyday practice a trial on meprobamate 111ay be \vorthwhile.
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Alcoholislll and Drug Addiction
All of the ataraxics and tranquilizers have been utilized at one time or another both in the treatment of the acute phases of alcoholism and drug addiction as well as in combating the withdrawal symptoms and after-effects of the drying-out period. Meprobalnate has been reported of only slight value in the acute phases of alcoholism and drug addiction. However, it has been observed of very definite value in relieving alcoholic jitters, restlessness, apprehension, guilt feelings and sleeplessness. l"'himann and Gauthier 15 and others 4, 7 all conclude in their respective studies that meprobamate ful£111s the function of an ideal relaxant in the subacute withdrawal stages of alcoholism. It helps the patient remain off alcohol following the withdrawal and aids him to adjust better to the stress and emotional tension of work and family afterwards. ~Finally, the absence of autonomic effects and the absence of increasing depression for patients who are already depressed, as well as the lack of habituation all together increase the value of meprobamate in the follow-up treatment of alcoholisIll. In all of the studies thus far reported, the sIllall number of eases involving the use of meprobalnate in drug addiction makes it impossible to evaluate adequately its efficacy in this condition. It is apparent that considerably more work will have to be done with drug addicts treated with meprobamate before a more positive opinion can be rendered. Psychosolllatic Conditions
The major uses for meprobamate have already been discussed. However, there have been reported cases in fields somewhat related to psychiatry wherein meprobamate has likewise been of some value. IJerhaps here, too, the action of this medicament in relieving anxiety and tension has been the major contribution. l-'he gastric distress unrelated to ulcer or organic disease, menstrual stress 14 in women who experience tension prior to and during the menstrual flow, neurodermatitis where the emotional aspects are particularly annoying, idiopathic anogenital pruritus,16 allergic reaction, behavior disorders in children and petit mal epilepsy 17 constitute this group. In epilepsy, favorable results \vere reported in the idiopathic petit mal type, but the drug has been of little or no actual value in grand mal epilepsy. When it was effeetive in petit mal, the absence of toxicity increased its value over trimethadione whenever it could be used satisfactorily. l\feprobamate has also been reported of value in cases where 11luscle spasm is a factor. This would be in keeping with its properties as a striated muscle relaxant. Hence, it ,vould be worth a trial in such conditions as ,vryneck, torsion spasm, cerebral palsy, especially where athetosis is a Inajor disturbance, and perhaps in the Inuscle spaSln of acute poliomyelitis. My own experience in these conditions has been somewhat
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limited so I cannot evaluate these results critically but report them for general information and for further investigation. HABITUATION; WITHDRAWAL SYMPTOMS
As with most medications, especially sedative relaxants, the problem of habituation is of utmost concern. The desire, particularly of a dependent person, to rely upon some medication to solve all of his problems, or to shut himself off from the rest of the world in a state of complete sleep or dreamy tranquility, is what has made narcotics, alcohol and barbiturates so popular. With these preparations, habituation and addiction take place readily and unfortunately all too frequently. Thus far, there has been little evidence of actual habituation to meprobamate. Among the men who have used it extensively during the past three years, no real tolerance has been observed, although on occasion some individuals will be reluctant to discontinue its use. The vast majority of patients, perhaps 75 to 85 per cent in my own experience and that of others, will discontinue using meprobamate as they begin to feel better. The remaining 15 to 25 per cent will discontinue gradually at the physician's suggestion. This is especially true at the onset when he outlines to the patient that the primary goal of the therapy is to help him reach a point where he feels well and requires no further medication. My own observations have further shown that in a few instances, approximately 1 per cent, a strong dependence upon meprobamate will take place with a definite reluctance to give up the drug. This usually occurs in extremely dependent, emotionally immature persons who will grasp upon any means to maintain themselves free of their inner tension. These patients will usually require considerable psychotherapy pointing out this dependency before they will forego the use of the medicine. Once, however, they gain this understanding and much of their anxiety has been dispelled, they are only too happy to stop the use of it (even if only for the financial saving). Generally, this has been the experience of other investigators in this field as well. In all of the literature thus far released that has come to my attention, only one case of possible u'ithdrawal symptoms has been reported. This was reported by Lemere 18 and involved a patient taking 16 tablets daily for one month. This patient had one convulsive seizure ten hours after he had abruptly discontinued the use of the drug. He then had no further difficulty. It is not at all unusual to observe some reaction where very large doses of a depressant are taken and then stopped abruptly. The abrupt withdrawal of Dilantin Sodium in epileptics, for instance, may precipitate seizures. Similar reactions have been reported after sudden withdrawal of alcohol and barbiturates. This suggests that a physiological dependence may develop in some people. On the other hand, Pennington,t4 who used doses as large as 12 tablets of meprobamate twice daily, noted no such untoward effect. Again, this may have
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been due to gradual withdrawal although she did not say explicitly. Certainly with the average dosages (four to eight tablets daily), even sudden discontinuance of medication showed no untoward effect. Lemere further stated in his most recent report that true addiction, in the full sense of the word, did not occur since there was no build-up of tolerance wherein increasingly larger amounts are required to produce the same effect. He did, however, believe that some patients experience slight withdrawal symptoms in the form of nervousness and jitters. He further stated that, "Thus far, the benefits of meprobamate far outweigh the problems produced by the relatively infrequent abuse of this drug." OVERDOSAGE
Overdosage, accidental or deliberate (suicidal), thus far has not been much of a problem because of the low toxicity of meprobamate. Selling has reported one patient taking 50 tablets within a 24 hour period, and a second one who took an even larger amount. Both became quite somnolent and a slowing of pulse rate was noted. However, both were easily roused by a combination of black coffee and forced physical activity (walking around). A 10 to 12 hour period of sleep followed at which time they awoke without apparent after-affects. Other reports14 , 17 of deliberate overdosage have been similar. Within the realms of my own experience, I had two patients who had ingested between 20 to 30 tablets at one time, but in each instance gastric lavage within an hour mitigated much of the effect, so that these patients suffered nothing more than an increased period of drowsiness for a six to eight hour period and had no further after-effect. Thus, it is reasonable to conclude that stimulants in the form of caffeine and perhaps Metrazol, as well as physical activity, would counteract the effects of overdosage. MEPROBAMATE IN COMBINATION
Mention has already been made of the occasional combination of the amphetamines with meprobamate where depression has been a major feature along with the anxiety. A 5 mg. tablet of dextro-amphetamine or metamphetamine taken along with meprobamate in the morning and afternoon doses has helped to dispel the depression and permit the patient to deal more effectively with his anxiety. A second preparation which has been found effective in combination with meprobamate is chlorpromazine. In unusually severe anxiety states in which tremendous restlessness and agitation are prominent and hospitalization is not desired and could possibly be avoided, this combination has proved effective, whereas each preparation alone has failed to produce the desired results. Two tablets of meprobamate and two 25 mg. tablets of chlorpromazine, taken together four or five times a day, have enabled the patient to be carried in this fashion until the symptoms have subsided. Then the medication is reduced first to one tablet of each,
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four tinles a day, and further gradual reductions are made over a peri()d of three to six weeks with complete recovery and discontinuanee~~Fall Inedication. SIDE REACTIONS AND TOXICITY
Drou'siness is the principal, and almost the only, side effect.I, 5,7,10,11.,19 This ,vas complained of by approximately 50 per cent of the patients in my o\vn experience. However, this effect subsided rapidly after the first few days of treatment. As a rule, it was not even considered neeessary to reduce the dosage as this effect subsided spontaneously. Here, too, individual variations would enter into the picture and, on rare occasions, amphetamine was added. In other instances, as already mentioned, amphetamine was added to alleviate symptoms of depression. An allergic reaction may occur after the first or second tablet is taken and is apt to be characterized by urticaria with either a macular type of eruption or the raised eruption of giant hives with intense itching. }1'ever, angioneurotic edema, fainting and bronchial spasms were other forms of allergy noted. On the whole, allergic reactions were observed in about 1 per cent of the patients treated. Treatment for the allergic reactions consisted first in stopping the medication, then the use of antihistamines every four hours and of epinephrine and even hydrocortisone where this seemed necessary. In every instance of an allergic reaction, once the drug was discontinued recovery followed promptly either with or without the use of the other preparations, and no further untoward effects were observed either objectively or subjectively or were reported by the patient. Laboratory studies thus far have failed to reveal any evidence of unfavorable effects on the blood, kidneys or liver. No evidence of anemia, leukopenia, albuminuria, glycosuria or other alterations of the blood or urine have been reported even after use of the medication daily for a year or longer. SUMMARY AND CONCLUSIONS
From a psychiatric standpoint, lneprobamate has proved to be of great benefit in anxiety and tension states, phobias, tension headaches, some psychosomatic disorders, insomnia either alone or as a feature of one of the aforementioned, alcoholism, premenstrual tension, neurodermatitis and behavior disorders. It has been less effective but still somewhat helpful in ambulatory schizophrenics, conversion and obsessive compulsive neuroses, petit mal epilepsy, muscle spasms and neurologic disorders including cerebral palsy. It is both a tranquilizer and muscle relaxant and seems to exert its effect upon the thalamus. Side eff~cts except for drowsiness are infrequent and are easily controlled. Even the latter subsides after the first
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fevv days of treatment. The drug is virtually. free of habituation and addictive properties, and does not have hypotensive or depressive effects. Perhaps the greatest value of llleprobamate lies in its use as an adjunct in psychotherapy. This is equally true -vvhether the psychotherapy is primarily supportive (suggestion, re-education and reassurance), as eornnlonly utilized by the general practitioner, or the deeper interpretive and free association approach of the psychiatrist. REFERENCES 1. Selling, L. S.: Clinieal Study of a New Tranquilizing Drug. J.A.M.A. 157: 15~)4, 1955. 2. Berger, F. M.: Pharmaeologieal Properties of 2-Methyl-2-n-propyl-1,3-propanediol Dicarbamate (Miltown), a New Interneuronal Blocking Agent. J. Pharmacol. & Exper. Therap. 112: 413, 1954. 3. Hendley, C. D., Lynes, T. E. and Berger, F. M.: Effect of 2-Methyl, 2-n-propyl1,3-propanediol Dicarbamate (Miltown) on Central Nervous System. Proc. Soc. Exper. BioI. & Med. 87: 608, 1954. 4. Lemere, F.: New Tranquilizing Drugs. Northwest Med. 54: 1098, 1955. 5. Borrus, J. C.: Study of Effect of Miltown (2-Methyl-2-n-propyl-1, 3-propanediol Dicarbamate) on Psychiatric States. J.A.M.A. 157: 1596, 1955. 6. Berger, F. 1\1.: Anticonvulsant Activity of 2,2-Disubstituted-1,3-propanediols in Electroshock Seizures. Proc. Soc. Exper. BioI. & Med. 78: 277, 1951. 7. Selling, L. S.: A Clinical Study of 1Vliltown, a New Tranquilizing Agent. J. Clin. & Exper. Psychopath. & Quart. Rev. Psychiat. & Neurol. 17: 7, 1~)56. 8. Hendley, C. D., Lynes, T. E. and Berger, F. M.: Effect of 2-Methyl-2-n-propyl1,3-propanediol Dicarbamate (Miltown) on ElectricaJ Activity of the Brain. Fed. Proc. 14: 351, 1955. 9. Berger, F. M.: Meprobamate: Its Pharmacologic Properties and Clinical Uses. Internat. Rec. of Med. & Gen. Pract. Clin. 169: 184, 1956. 10. Lasagna, L.: A Study of Hypnotic Drugs in Chronically Hospitalized Patients. J. Chron. Dis. 3: 122, 1956. 11. Osinski, W. A.: Treatment of Anxiety States with Miltown. Submitted for publication, 1956. 12. Hollister, L. E., Stannard, A. N. and Drake, C. F.: Treatment of Anxious Patients with Drugs. Am. J. M. Se. In press, 1956. 13. ThaI, N.: Premedication for Electroshock Treatment (Effect of Meprobamate in 120 Psychotic Patients). Dis. Nerv. System 17: 3, 1956. 14. Pennington, V. M.: Effects of Six Ataraxics in Neuropsychiatric Patients. Paper read at Academy of Psychosomatic Medicine Meeting, New York City, October 6-8, 1955. 15. Thimann, J. and Gauthier, J. W.: Miltown as a l'ranquilizer in Treatment of Alcohol Addicts. Quart. J. Stud. Alcohol 17: 19, 1956. 16. Sokoloff, O. J.: Use of Meprobamate (Miltown) as an Adjunct in the Treatment of Anogenital Pruritus. Arch. Dermat. & Syph. In press, 1956. 17. Perlstein, M. A.: Use of Meprobamate (Miltown) in Convulsive and Related Disorders. J.A.M.A. 161: 1040, 1956. 18. Lemere, F.: Drug Habituation (Correspondence). J.A.M.A. 160: 1431, 1956. 19. Fabing, H. D.: The Ataractic Drugs: Their Uses and Limitations in Psychiatry. Am. Professional Pharmacist 22: 413, 1956. 184 Livingston Avenue New Brunswick, New Jersey
MEPROBAMATE, more popularly known under the trade names of Miltown and Equanil, has been in general use since April 1955. Prior to this, it was used experimentally for over two years by many investigators including Selling, Berger, Hendley et al., Lamere and Borrus. 1- 6 The wide general acceptance of meprobamate in such a short period of time points up two very interesting features of this preparation. The first of these is that the medicament seems to be upholding its earlier promise as an adjunct in the relief of anxiety and tension states. Secondly, it emphasizes, in particular, the tremendous need for some form of ataraxic to help cushion the central nervous system from the intense pressures of everyday living. The search for such a buffer has been a continuous one which dates back to Aristotle and some of the earlier observations of the Egyptians, Phoenicians and Persians. The increased tempo of modern society has greatly enhanced the need to either support the individual by reducing the multitude of stimuli entering consciousness by medication, or to re-educate the individual's nervous system to adapt better by means of psychiatric treatment either in the form of psychotherapy or psychoanalysis. Experience has shown that more often a combination of therapies is the answer. The general practitioner and the internist will combine medication with supportive psychotherapy. The psychiatrist will also make use of medication along with his deeper interpretive and integrative approach to psychotherapy, while the analyst may attempt to utilize his free associative techniques almost entirely. In each instance, the method of choice will depend upon the patient's present condition and his personality as well as the physician's own prior experiences in dealing with his patients and the kind of situations which he encounters. Formerly, medicaments such as bromides, barbiturates, chloral hydrate and paraldehyde were the chief aids of the physician where sedatives were necessary. Today, the ataraxics have supplanted these. Meprobamate is one of these ataraxics.
* Neuropsychiatrist, Attending Staffs, Middlesex General and St. Peter's General Hospitals; Consulting Psychiatrist, Middlesex County Rehabilitation and Polio Hospital, New Brunswick, New Jersey. 327
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328 I>IIARMACOLOG Y
Meprobamate, chemically, is a 2-Inethyl-2-n-propyl-l,:3-propanediol dicarbamate which has a characteristic bitter taste and is a straight chain aliphatic compound. It has a muscle-relaxant action, some anticonvulsive properties, and fear, anxiety and tension relieving properties. The muscle-relaxing effects involve primarily the voluntary skeletal muscles, yet even in very large doses it does not appear to affect the diaphragm so that respiration remains free. This, in essence, vvould seem to provide an additional margin of safety in the use of this drug. The anticonvulsant action of this 111edication is observed in its opposing the action of Metrazol and strychnine induced seizures. 2 , 6 In this respect, it has proved more effective than some of the barbitura~es, Inephenesin and in some instances, trimethadione. l"he reduction of fear, aggressiveness, hostility, tremulousness and the development of a greater sense of well-being ,vere noted first upon observations on animals and then in clinical studies both in hospitals 2 and in private practice. I , 4, 5, 7 The rationale for any therapy depends first upon its site and mode of action and, secondarily, upon its effectiyeness. 'rhe action of meprobaIllate as reported in the literature 2 , 3 seems to be on the interneuronal circuits where it acts as a blocking agent. Investigators have shovvn that where single reflex arcs are concerned (no interneurones) the drug has no effect, whereas with more complicated circuits involving lnany interneurones these reflex actions tend to be reduced or abolished by the medicine. There is also a central effect, which appears to be selective, on the thalamus. This was demonstrated by electrical recordings taken from the thalamus during the administration of meprobamate in low dosage. 3 , 8 Much higher dosages were necessary to produce subcortical and cortical changes. Berger2 , 9 raises the question of the interneuronal blocking of the drug in reducing son1e of the cortical thalamic impulses, hence relieving and calming some of the physiologic components of anxiety. By carrying this line of thinking a little further, it may be possible to compare the effects of meprobaluate vvith those of the various neurosurgical procedures such as a subcortical undercutting of the frontal association pathways as was developed in the prefrontal and supraorbital lobotolnies and the analogous effects that are obtained by thalamotomy as advocated by Wycis and Spiegel. This is still conjectural, but the drug has the advantage of being a temporary blocking agent, i.e., it temporarily modifies the number of incoming stimuli and, as the individual regains better control of his emotional reactions, is no longer needed. With actual surgery, of course, changes are brought about vvhich become unalterable. Meprobamate seeIns to have little or no effect on the autonomic system per se nor does it either produce, or change the responses to, cholinergic, adrenergic or histamine effects. The absence of specific autonomic
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effects therefore makes for greater acceptance by the patient, since he need not fear the development of unwanted somatic changes. METIIOD OF USE
Meprobamate is prepared as a 400 mg. tablet, which is the only form and strength available as of this writing. The favored dosage is one tablet four times a day after nleals, vvith the fourth tablet being taken at bedtime. l'hen, depending upon its effectiveness at this dosage level, it may either be increased to two tablets four tilnes a day, or reduced to meet the individual patient's need. As a rule, ambulatory patients will rarely require more, but occasionally as many as ten to twelve tablets daily will be needed where a great deal of restlessness and agitation are part of the symptomatology. The optimum dosage can be determined within a period of about two weeks. While it is possible to maintain a patient on medication indefinitely, in most cases the physician will begin to reduce the dosage as the patient improves or the patient himself will spontaneously reduce the amount of medication with the statement, "I felt so good that I forgot to ,fake the medicine at times." Actually the dosage can be reduced gradually or abruptly with no untoward effects in the average dosage range mentioned above. Whenever depression vvas an associated feature of the over-all condition of the patient, 5 mg. of one of the amphetaluines taken along with the meprobamate has alleviated this distressing feature. Also in seriously disturbed patients, the combination of two tablets of meprobamate and a 50 mg. tablet of chlorpromazine taken four times a day has been effective in relieving severe, distressing anxiety symptoms and even psychotic manifestations. It has been my experience that if a patient does not respond to this combination, then hospitalization is required. This apparently has also been the experience of others. 7, 10 Just as with all the other ataraxics developed thus far, meprobamate appears to have no effect on the pure endogenous depressions or on the manic-depressive depressions where strong guilt feelings and feelings of unworthiness, hopelessness and futility are paramount. Whenever meprobamate is used as a sleep-inducing preparation, the patient will generally respond quite favorably to two tablets taken about 15 minutes before bedtime. INDICATIONS AND RESULTS
Meprobamate has shown great effectiveness in anxiety and tension states, phobias, tension headaches, psychosomatic disorders, insomnia, premenstrual tension, neurodermatitis and behavior disorders. It has been less effective but still quite helpful in ambulatory schizophrenia, posttraumatic neuroses, petit mal epilepsy, muscle spasms (of various etiologies) and cerebral palsy.
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Anxiety and Tension States
Anxiety in one form or another, and in varying degree, accompanies practically all illness. Every physician, whether he be in general or specialty practice, is familiar with the need to reassure his patient about his illness and to allay his fears and concern relating to it. This is as true of a minor one such as simple paronychia as of a more serious, complicated surgical or cardiac condition. Anxiety, moreover, is not associated solely with physical or mental illness but may well become a part of one's everyday living. The loss of a loved one, the disappointment in failing to obtain a sought-for promotion or job, the need to match wits with a competitor or the need to address large groups, or the feelings of resentment to others, are but a few of the daily stress situations which human beings face that often produce anxiety. The anxiety which the physician and psychiatrist sees is usually exemplified by certain emotional and physiological changes within the individual. The anxious and tense person expresses a vague sense of uneasiness with a feeling of impending disaster. In addition, he complains often of palpitations, tremulousness, hyperhidrosis, coldness of the extremities, dryness of the mouth and a tightness or fluttering within the chest or abdomen. This is the usual pattern of an anxiety reaction or tension state and it can be extremely incapacitating to the possessor, whatever the underlying etiology. In some instances, a precipitating cause will have been a recent traumatic experience. In other cases the anxiety is but an outward expression of a more deep-seated earlier established pattern with either guilt or hostility precipitating the anxiety. Whatever the cause may be, the uniformly favorable response to meprobamate of 60 to 90 per cent 5 • 7. 9 of these patients establishes this drug as a welcome adjunct to the armamentarium not only of the general practitioner, the internist and others in the various fields of medicine, but also of the psychiatrist. For the former, meprobamate may help tide a patient over an acute disturbance following a recent emotional trauma. For the latter, it will help to ease some of the patient's symptoms and thereby make him more amenable to whatever psychotherapeutic procedures may be necessary. Improvement following meprobamate is usually characterized by lessened irritability, a general sense of well-being, a decrease in morbid preoccupation with symptoms generally, a greater ability to concentrate, a greater sense of relaxation and a return to both a more active social life and to a more productive career economically. Improvement will generally commence within a few days after the start of treatment. Phobic States
These are closely related to anxiety and tension states so far as physiological changes are concerned. However, instead of an ill-defined
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sense of uneasiness, we see a more specific fear as the predominant symptom. This may be observed as a fear of dying, or fear of cancer, insanity, heart disease, tuberculosis, etc. These people are extremely perturbed. They show evidence of extensive agitation and restlessness and may become so distraught as to refuse to leave their homes, will stop working, will be unwilling to drive a car and even refuse to remain home alone. The man who must have a member of his family accompany him to his place of business or the housewife who frantically calls her husband home from work because of her fear of dying, are both familiar stories to the practicing physician. Since this creates not only economic hardships, but also severly limits the usefulness of these people both at work and at home, quick relief is needed. Meprobamate has proved of value in phobic states by relieving the intensity of the fears as well as the paralysis of action that these fears evoke, although it does not relieve the actual fears themselves. This will come later as the patient gains a better understanding of the dynamics of his illness. Studies by Lasagna,10 Selling,7 Osinski,11 Hollister et al. 12 and others have illustrated how much more effective and more gratifying have been the results of treatment of these states with meprobamate than with some of the other medications such as barbiturates, paraldehyde, mephenesin and some of the other ataraxics as chlorpromazine and reserpine. This has been especially true in private practice where these conditions are seen most commonly. Throughout the author's experience, wherever depression was the outstanding feature of the anxiety or phobic state, a combination of one of the amphetamines along with the meprobamate was often sufficient to break through this depression and ameliorate the over-all condition, thereby often reducing the need for electroconvulsive treatment. Headaches
Headaches are a frequent accompaniment of almost every tension state. Studies by Wolf and others have emphasized the stretching of tissue and the change in the size (caliber) of blood vessels as the primary etiologic factor in headaches. However, we frequently see headaches that are the result of constant, almost unremitting contraction of the posterior muscles of the neck, often described by the patient as a tightness in the back of the head and neck. This type of nuchal headache as well as the frequent complaint of a "tight band around my head" or compression headache is usually a part of a more deep-rooted pattern of neurosis. Consequently, here too a favorable response to meprobamate would be expected and this has actually been observed. 9 The absence of any significant blood pressure reducing effect has permitted the use of meprobamate in headaches of hypertensive origin. Of further interest to the psychiatrist has been the report of a reduction
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of post-electroshock headaches by the use of meprobamate one hour prior to treatment. 13 Whether this is a direct result of some reduction in anxiety preliminary to treatnlent or whether this is due to the musclerelaxing effects of the drug has not been clearly explained. Insolllnia
Insomnia in one form or another is perhaps one of the commonest COlnplaints met by the physician irrespective of his type of practice. This may occur either as an inability to fall asleep upon retiring, or the awakening after a brief period of perhaps one to two hours of sleep and then finding it impossible to return to sleep. In both of these situations, meprobamate has shown considerable effectiveness. 5 , 7,10,11,12 If it is taken during the day, the patient will often be sufficiently relaxed that normal sleep will ensue vvithout medication. On the other hand, if this is not sufficient, then the addition of one or t\VO tablets taken 15 minutes before retiring will solve the problem of the patient who finds it difficult ~o fall asleep. By the same token, a similar dose taken upon awakening during the early morning hours will bring a return of sleep \vithout producing any drowsiness the following day. Presumably meprobamate acts by relieving tension and anxiety, since electroencephalographic studies do not show the characteristic pattern of a barbiturate type of sleep. Patients tend to report a fairly restful sleep without the morning depression and sluggishness seen following barbiturates. In addition, there is apt to be very little dreaming although this seems to be more dependent upon the individual's personality pattern and the degree of anxiety under which he is living at the time. In the severe agitated depressions, however, meprobamate has proved ineffective both as a sleep-inducing preparation and as a euphoriant.
The Psychoses 'I'he author's experience with the use of meprobamate in the psychoses, manic-depressive and schizophrenic, while it may have been somewhat limited (under 100 cases), nevertheless is sufficient to indicate that meprobamate has limited value here. Pennington,14 hovvever, in a study of the effects of various ataraxics on the psychoses, reported favorable results with very large doses in a hospital setting. Such large doses (12 to 25 tablets daily) would not be warranted or even feasible in ordinary private practice where a patient may be under observation only once or twice a week, and the expense to the patient would be a deterrent. The use of meprobamate in ambulatory schizophrenics was somewhat more encouraging, and since this type of patient is more apt to be seen in everyday practice a trial on meprobamate 111ay be \vorthwhile.
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Alcoholislll and Drug Addiction
All of the ataraxics and tranquilizers have been utilized at one time or another both in the treatment of the acute phases of alcoholism and drug addiction as well as in combating the withdrawal symptoms and after-effects of the drying-out period. Meprobalnate has been reported of only slight value in the acute phases of alcoholism and drug addiction. However, it has been observed of very definite value in relieving alcoholic jitters, restlessness, apprehension, guilt feelings and sleeplessness. l"'himann and Gauthier 15 and others 4, 7 all conclude in their respective studies that meprobamate ful£111s the function of an ideal relaxant in the subacute withdrawal stages of alcoholism. It helps the patient remain off alcohol following the withdrawal and aids him to adjust better to the stress and emotional tension of work and family afterwards. ~Finally, the absence of autonomic effects and the absence of increasing depression for patients who are already depressed, as well as the lack of habituation all together increase the value of meprobamate in the follow-up treatment of alcoholisIll. In all of the studies thus far reported, the sIllall number of eases involving the use of meprobalnate in drug addiction makes it impossible to evaluate adequately its efficacy in this condition. It is apparent that considerably more work will have to be done with drug addicts treated with meprobamate before a more positive opinion can be rendered. Psychosolllatic Conditions
The major uses for meprobamate have already been discussed. However, there have been reported cases in fields somewhat related to psychiatry wherein meprobamate has likewise been of some value. IJerhaps here, too, the action of this medicament in relieving anxiety and tension has been the major contribution. l-'he gastric distress unrelated to ulcer or organic disease, menstrual stress 14 in women who experience tension prior to and during the menstrual flow, neurodermatitis where the emotional aspects are particularly annoying, idiopathic anogenital pruritus,16 allergic reaction, behavior disorders in children and petit mal epilepsy 17 constitute this group. In epilepsy, favorable results \vere reported in the idiopathic petit mal type, but the drug has been of little or no actual value in grand mal epilepsy. When it was effeetive in petit mal, the absence of toxicity increased its value over trimethadione whenever it could be used satisfactorily. l\feprobamate has also been reported of value in cases where 11luscle spasm is a factor. This would be in keeping with its properties as a striated muscle relaxant. Hence, it ,vould be worth a trial in such conditions as ,vryneck, torsion spasm, cerebral palsy, especially where athetosis is a Inajor disturbance, and perhaps in the Inuscle spaSln of acute poliomyelitis. My own experience in these conditions has been somewhat
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limited so I cannot evaluate these results critically but report them for general information and for further investigation. HABITUATION; WITHDRAWAL SYMPTOMS
As with most medications, especially sedative relaxants, the problem of habituation is of utmost concern. The desire, particularly of a dependent person, to rely upon some medication to solve all of his problems, or to shut himself off from the rest of the world in a state of complete sleep or dreamy tranquility, is what has made narcotics, alcohol and barbiturates so popular. With these preparations, habituation and addiction take place readily and unfortunately all too frequently. Thus far, there has been little evidence of actual habituation to meprobamate. Among the men who have used it extensively during the past three years, no real tolerance has been observed, although on occasion some individuals will be reluctant to discontinue its use. The vast majority of patients, perhaps 75 to 85 per cent in my own experience and that of others, will discontinue using meprobamate as they begin to feel better. The remaining 15 to 25 per cent will discontinue gradually at the physician's suggestion. This is especially true at the onset when he outlines to the patient that the primary goal of the therapy is to help him reach a point where he feels well and requires no further medication. My own observations have further shown that in a few instances, approximately 1 per cent, a strong dependence upon meprobamate will take place with a definite reluctance to give up the drug. This usually occurs in extremely dependent, emotionally immature persons who will grasp upon any means to maintain themselves free of their inner tension. These patients will usually require considerable psychotherapy pointing out this dependency before they will forego the use of the medicine. Once, however, they gain this understanding and much of their anxiety has been dispelled, they are only too happy to stop the use of it (even if only for the financial saving). Generally, this has been the experience of other investigators in this field as well. In all of the literature thus far released that has come to my attention, only one case of possible u'ithdrawal symptoms has been reported. This was reported by Lemere 18 and involved a patient taking 16 tablets daily for one month. This patient had one convulsive seizure ten hours after he had abruptly discontinued the use of the drug. He then had no further difficulty. It is not at all unusual to observe some reaction where very large doses of a depressant are taken and then stopped abruptly. The abrupt withdrawal of Dilantin Sodium in epileptics, for instance, may precipitate seizures. Similar reactions have been reported after sudden withdrawal of alcohol and barbiturates. This suggests that a physiological dependence may develop in some people. On the other hand, Pennington,t4 who used doses as large as 12 tablets of meprobamate twice daily, noted no such untoward effect. Again, this may have
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been due to gradual withdrawal although she did not say explicitly. Certainly with the average dosages (four to eight tablets daily), even sudden discontinuance of medication showed no untoward effect. Lemere further stated in his most recent report that true addiction, in the full sense of the word, did not occur since there was no build-up of tolerance wherein increasingly larger amounts are required to produce the same effect. He did, however, believe that some patients experience slight withdrawal symptoms in the form of nervousness and jitters. He further stated that, "Thus far, the benefits of meprobamate far outweigh the problems produced by the relatively infrequent abuse of this drug." OVERDOSAGE
Overdosage, accidental or deliberate (suicidal), thus far has not been much of a problem because of the low toxicity of meprobamate. Selling has reported one patient taking 50 tablets within a 24 hour period, and a second one who took an even larger amount. Both became quite somnolent and a slowing of pulse rate was noted. However, both were easily roused by a combination of black coffee and forced physical activity (walking around). A 10 to 12 hour period of sleep followed at which time they awoke without apparent after-affects. Other reports14 , 17 of deliberate overdosage have been similar. Within the realms of my own experience, I had two patients who had ingested between 20 to 30 tablets at one time, but in each instance gastric lavage within an hour mitigated much of the effect, so that these patients suffered nothing more than an increased period of drowsiness for a six to eight hour period and had no further after-effect. Thus, it is reasonable to conclude that stimulants in the form of caffeine and perhaps Metrazol, as well as physical activity, would counteract the effects of overdosage. MEPROBAMATE IN COMBINATION
Mention has already been made of the occasional combination of the amphetamines with meprobamate where depression has been a major feature along with the anxiety. A 5 mg. tablet of dextro-amphetamine or metamphetamine taken along with meprobamate in the morning and afternoon doses has helped to dispel the depression and permit the patient to deal more effectively with his anxiety. A second preparation which has been found effective in combination with meprobamate is chlorpromazine. In unusually severe anxiety states in which tremendous restlessness and agitation are prominent and hospitalization is not desired and could possibly be avoided, this combination has proved effective, whereas each preparation alone has failed to produce the desired results. Two tablets of meprobamate and two 25 mg. tablets of chlorpromazine, taken together four or five times a day, have enabled the patient to be carried in this fashion until the symptoms have subsided. Then the medication is reduced first to one tablet of each,
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four tinles a day, and further gradual reductions are made over a peri()d of three to six weeks with complete recovery and discontinuanee~~Fall Inedication. SIDE REACTIONS AND TOXICITY
Drou'siness is the principal, and almost the only, side effect.I, 5,7,10,11.,19 This ,vas complained of by approximately 50 per cent of the patients in my o\vn experience. However, this effect subsided rapidly after the first few days of treatment. As a rule, it was not even considered neeessary to reduce the dosage as this effect subsided spontaneously. Here, too, individual variations would enter into the picture and, on rare occasions, amphetamine was added. In other instances, as already mentioned, amphetamine was added to alleviate symptoms of depression. An allergic reaction may occur after the first or second tablet is taken and is apt to be characterized by urticaria with either a macular type of eruption or the raised eruption of giant hives with intense itching. }1'ever, angioneurotic edema, fainting and bronchial spasms were other forms of allergy noted. On the whole, allergic reactions were observed in about 1 per cent of the patients treated. Treatment for the allergic reactions consisted first in stopping the medication, then the use of antihistamines every four hours and of epinephrine and even hydrocortisone where this seemed necessary. In every instance of an allergic reaction, once the drug was discontinued recovery followed promptly either with or without the use of the other preparations, and no further untoward effects were observed either objectively or subjectively or were reported by the patient. Laboratory studies thus far have failed to reveal any evidence of unfavorable effects on the blood, kidneys or liver. No evidence of anemia, leukopenia, albuminuria, glycosuria or other alterations of the blood or urine have been reported even after use of the medication daily for a year or longer. SUMMARY AND CONCLUSIONS
From a psychiatric standpoint, lneprobamate has proved to be of great benefit in anxiety and tension states, phobias, tension headaches, some psychosomatic disorders, insomnia either alone or as a feature of one of the aforementioned, alcoholism, premenstrual tension, neurodermatitis and behavior disorders. It has been less effective but still somewhat helpful in ambulatory schizophrenics, conversion and obsessive compulsive neuroses, petit mal epilepsy, muscle spasms and neurologic disorders including cerebral palsy. It is both a tranquilizer and muscle relaxant and seems to exert its effect upon the thalamus. Side eff~cts except for drowsiness are infrequent and are easily controlled. Even the latter subsides after the first
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fevv days of treatment. The drug is virtually. free of habituation and addictive properties, and does not have hypotensive or depressive effects. Perhaps the greatest value of llleprobamate lies in its use as an adjunct in psychotherapy. This is equally true -vvhether the psychotherapy is primarily supportive (suggestion, re-education and reassurance), as eornnlonly utilized by the general practitioner, or the deeper interpretive and free association approach of the psychiatrist. REFERENCES 1. Selling, L. S.: Clinieal Study of a New Tranquilizing Drug. J.A.M.A. 157: 15~)4, 1955. 2. Berger, F. M.: Pharmaeologieal Properties of 2-Methyl-2-n-propyl-1,3-propanediol Dicarbamate (Miltown), a New Interneuronal Blocking Agent. J. Pharmacol. & Exper. Therap. 112: 413, 1954. 3. Hendley, C. D., Lynes, T. E. and Berger, F. M.: Effect of 2-Methyl, 2-n-propyl1,3-propanediol Dicarbamate (Miltown) on Central Nervous System. Proc. Soc. Exper. BioI. & Med. 87: 608, 1954. 4. Lemere, F.: New Tranquilizing Drugs. Northwest Med. 54: 1098, 1955. 5. Borrus, J. C.: Study of Effect of Miltown (2-Methyl-2-n-propyl-1, 3-propanediol Dicarbamate) on Psychiatric States. J.A.M.A. 157: 1596, 1955. 6. Berger, F. 1\1.: Anticonvulsant Activity of 2,2-Disubstituted-1,3-propanediols in Electroshock Seizures. Proc. Soc. Exper. BioI. & Med. 78: 277, 1951. 7. Selling, L. S.: A Clinical Study of 1Vliltown, a New Tranquilizing Agent. J. Clin. & Exper. Psychopath. & Quart. Rev. Psychiat. & Neurol. 17: 7, 1~)56. 8. Hendley, C. D., Lynes, T. E. and Berger, F. M.: Effect of 2-Methyl-2-n-propyl1,3-propanediol Dicarbamate (Miltown) on ElectricaJ Activity of the Brain. Fed. Proc. 14: 351, 1955. 9. Berger, F. M.: Meprobamate: Its Pharmacologic Properties and Clinical Uses. Internat. Rec. of Med. & Gen. Pract. Clin. 169: 184, 1956. 10. Lasagna, L.: A Study of Hypnotic Drugs in Chronically Hospitalized Patients. J. Chron. Dis. 3: 122, 1956. 11. Osinski, W. A.: Treatment of Anxiety States with Miltown. Submitted for publication, 1956. 12. Hollister, L. E., Stannard, A. N. and Drake, C. F.: Treatment of Anxious Patients with Drugs. Am. J. M. Se. In press, 1956. 13. ThaI, N.: Premedication for Electroshock Treatment (Effect of Meprobamate in 120 Psychotic Patients). Dis. Nerv. System 17: 3, 1956. 14. Pennington, V. M.: Effects of Six Ataraxics in Neuropsychiatric Patients. Paper read at Academy of Psychosomatic Medicine Meeting, New York City, October 6-8, 1955. 15. Thimann, J. and Gauthier, J. W.: Miltown as a l'ranquilizer in Treatment of Alcohol Addicts. Quart. J. Stud. Alcohol 17: 19, 1956. 16. Sokoloff, O. J.: Use of Meprobamate (Miltown) as an Adjunct in the Treatment of Anogenital Pruritus. Arch. Dermat. & Syph. In press, 1956. 17. Perlstein, M. A.: Use of Meprobamate (Miltown) in Convulsive and Related Disorders. J.A.M.A. 161: 1040, 1956. 18. Lemere, F.: Drug Habituation (Correspondence). J.A.M.A. 160: 1431, 1956. 19. Fabing, H. D.: The Ataractic Drugs: Their Uses and Limitations in Psychiatry. Am. Professional Pharmacist 22: 413, 1956. 184 Livingston Avenue New Brunswick, New Jersey