The results of this study, which appeared in the North Carolina Medical Journal in 1953, corroborate and supplement the earlier findings of George Tayleur Stockings, which are found in the preceding chapter. In this instance, the use of py ahexyl, another of the synthetic active principles of marihuana, produced astonishingly favorable results in the symptomatic treatment of one of our major social diseases, alcoholism.

At the time of writing, Dr. Thompson was Professor of Psychiatry, Bowman Gray School of Medicine of Wake Forest College, and Director of Graylyn Hospital; Dr. Proctor was Assistant Professor of Psychiatry at the Bowman Gray School and Assistant Director of Graylyn Hospital, in Winston-Salem, North Carolina.

The use of cannabis, or marihuana as we best know it, and related compounds antedates recorded history. Its earliest use was in Oriental countries, and it was introduced into Western countries about the middle of the nineteenth century. In reading through the literature one would gain the impression that marihuana-like compounds have been used mainly as intoxicants. Actually this group of drugs has been used legitimately for years in the treatment of various bodily complaints and conditions. For example, Dr. Oscar W. Bethea, in his book, Practical Materia Medica and Prescription Writing,' published in 1917, listed several prescriptions using cannabis in some form. He mentioned the use of the drug as a sedative, an anodyne, and a narcotic, and suggested its use in the treatment of headache, neuralgia, and kindred conditions. It is unfortunate that through the recent exposés in the popular press marihuana has gained such a bad name.

A few years ago Professor Roger Adams, at the University of Illinois, developed synthetic substances resembling marihuana to be used in the study of the marihuana problem. One of these has been called pyrahexyl in this country and synhexyl in England. We shall not attempt in this clinical paper to go into the various chemical and pharmacologic aspects of marihuana in any detail. Those who are interested may refer to Professor Adams' report, appearing in the 1941-1942 edition of the Harvey Lectures.2 The first comprehensive study done on pyrahexyl compound was done by Edwin G. Williams and others at the U. S. Public Service Hospital, Lexington, Kentucky.°

Effects

Briefly, marihuana produces in the majority of individuals general impairment of cerebral function, with mild clouding of consciousness. The higher physiologic functions—those mediated by the thalamus and the cortex in their normal interrelationship—are the most easily disturbed by the drug. Most observers agree that its central action far outweighs any peripheral effects. It acts predominantly on the higher functions. It appears to impair the activity in most areas of the cortex, although those functions which are commonly localized in the frontal lobe appear to be the most acutely affected.

The observed physical effects are (1) elevation of the pulse rate in direct proportion to the degree of intoxication by the drug; (2) elevation of the blood pressure, varying with the individual but usually rising in direct proportion to the pulse; (3) injection of the conjunctival blood vessels, varying with the dose; (4) dilatation of the pupils and sluggish reaction to light and accommodation; (5) slight change in the vision for proximity, distance, and color; (6) circumoral tremors, with tremulousness of the protruded tongue and the extremities; (7) dryness of the oral and pharyngeal mucous membranes; (8) increased frequency and decreased amplitude of thoracic respiratory movements; and (9) ataxia with hyperreflexia. Not all of these effects occur in all individuals, but one or more will be present.

The observed psychologic effects are (1) apprehension and anxiety; (2) euphoria; (3) loquaciousness; (4) lowering of inhibitions; (5) hunger and thirst; (6) feeling of being "high"; (7) uncontrollable bursts of laughter or giggles; and (8) drowsiness, languor, lassitude, and a pleasant feeling of fatigue. Clinical tests reveal that marihuana produces no significant changes in basal metabolic rates, blood chemistry, hematologic picture, liver function, kidney function, or electrocardiographic studies. Marihuana delays gastric and intestinal motility somewhat, and produces a definite increase in the frequency of the alpha wave in electroencephalographic recordings, thus indicating increased relaxation.

In recent years conflicting reports have appeared in the literature concerning the use of marihuana-like drugs in treating the opiate withdrawal syndrome. Allentuck and Bowman found that with the marihuana substitution method of treatment the withdrawal symptoms were ameliorated sooner.4 Yet Hitrimelsbach states that a synthetic marihuana-like drug had no appreciable ameliorative effect on the opiate abstinence syndrome.° The dosage used in both case studies was approximately the same.

More recently, work has been done in England by various investigators. Parker and Wrigley reported a total of 62 patients, indicating psychotics of various types as well as depressive states, in which they recorded subjective improvement in cases of melancholia and neurotic depression. However, when an inert drug was given to a control group, similar results were obtained.°

Material, Method, and Response

Late in 1949 we were able to secure a supply of pyrahexyl for clinical investigation. In the intervening years we have used the drug in 101 cases. Originally, because of the pharmacologic properties of the drug, which usually produce exaltation and feelings of happiness, and because of the reports in the British literature, we used the drug in treating patients with symptoms of depression. Then, because of results reported by Terry from the Livermore Sanitarium in California,7 we began to use pyrahexyl in the treatment and management of acute alcoholic withdrawal symptoms and those associated with the withdrawal of various addicting and habituating drugs.

Depressive States

Our method of treatment for the cases of depression was, briefly, as follows: Three 15 mg. doses of pyrahexyl were administered to the patient the first day of admission. If there was no alleviation of symptoms, the dosage was raised by 15 mg. daily, either until improvement resulted or toxic symptoms appeared. The latter included nausea, "giddiness," disturbance in space and time relationships, and other signs which will be mentioned later. The results obtained showed that the drug, in our opinion, was not of sufficient benefit to warrant continuation of this phase of the study. In 20 cases of neurotic depression, only 4 showed evidence of improvement. In the 6 cases of psychotic depression treated we found no improvement. Because of these disappointing results, the use of pyrahexyl in the treatment of depressive states was abandoned.

Alcoholic and Drug Addiction States

The major part of this report is based on the results obtained in the 70 post-alcoholic states and the following drug withdrawal cases: barbituates 6; morphine 6; Dilaudid 4; Demerol 12; Pantopon 2; and paregoric 1. The most gratifying results were obtained in the 70 post-alcoholic cases. The method of treatment was, in the main, similar to that previously outlined for use in the depressive states.

Most of the patients were admitted to Graylyn in the typical post-alcoholic state. The symptoms presented were tremulousness, restlessness, apprehension, sleeplessness, and anorexia. Their mood was irritable and depressed, and they were unable to sit still. In many instances the patient had eaten little for days prior to admission. Immediately on admission and after a physical examination was done, the patient was given 15 mg. (1 capsule) of pyrahexyl. This dose was repeated twice on the day of admission. Fifteen milligrams 3 times daily was continued for from 3 to 5 days.

In a large percentage of cases the patients showed a favorable response to the medication. From 30 minutes to 2 hours after ingestion of the first capsule the patient became calm, lost his irritability and restlessness, began to feel better, and developed a good appetite. Following the eating of a meal he generally went to sleep for several hours. With the dosage employed, we encountered only a few side reactions. These were usually very mild and confined to generalized dull, aching headaches, minimal ataxia, and dryness of the mucous membranes. During the three to five days of treatment the patients remained mildly euphoric and happy, their appetite remained good, and they slept well. When the medication was stopped, we noted no withdrawal symptoms. Our experience in this respect paralleled that of Allentuck and Bowman,4 who felt that the use of marihuana does not give rise to a biologic or physiologic dependence, and that discontinuance of the drug does not result in withdrawal symptoms.

Results

In the treatment with pyrahexyl of 70 cases of the post-alcoholic syndrome we can report clinical alleviation of the symptoms in 59, or 84.28 per cent. The 11 cases that did not show improvement (or 15.72 per cent) did not differ a great deal clinically from the other 59. By that we mean that the duration of the last alcoholic bout was about the same, and the amount of alcohol consumed was no different from that in some patients who did show improvement. The same applied to age and sex incidence. We have no explanation as to why 59 out of 70 patients showed improvement while 11 did not. Perhaps an individual idiosyncrasy to the drug is the explanation, for it is known that individual reactions to other drugs do occur.

In the treatment of drug addictions our experience is less extensive but none the less significant. Out of 6 cases of barbiturate addiction, amelioration of symptoms was noted in 4; in 4 cases of Dilaudid addiction we noted alleviation in 3; in 2 cases of Pantopon and one of paregoric addiction all patients reported a smooth withdrawal course, without the usual symptoms noted in such conditions. We were especially pleased with the results obtained in 12 cases of Demerol addiction. With 10 of these patients, or 83 per cent, we were able to withdraw the drug completely in one week's time without having to resort to any other type of medication. Occasionally a patient would report mild apprehension or transient cramplike pains of the lower extremities, but these were infrequent and when they did occur, were mild and transient. The 2 patients who showed no response were long-term users of Demerol who had received treatment on two other occasions by the gradual withdrawal method.

With 6 cases of morphine addiction the results were less satisfying. Only 2 patients reported a course of withdrawal without any markedly unpleasant symptoms with the use of parahexyl. It was necessary in the other 4 patients to use other methods of treatment.

In those cases where results were obtained by the use of pyrahexyl in the treatment of drug withdrawal symptoms, the side symptoms produced were of a mild character. The patients felt physically stronger and showed increased psychomotor activity. They had an increased appetite and such withdrawal symptoms as nausea, diarrhea, and perspiration were diminished or eliminated. The feeling of euphoria produced helped in rehabilitating the physical condition and in facilitating social reorientation. An outstanding result was a subjective feeling of relaxation. The sleep induced by the drug likewise contributed to the general improvement in the patient's health.

Comment

At the time of the first examination the patients with post-alcoholic syndromes were beginning to feel a severe "hangover" and subjectively complained of remorse, agitation, depression, tremulousness, and tension. They all complained of anorexia and some of nausea. The administration of pyrahexyl produced within 30 minutes to 2 hours a marked change in the psychologic and physiologic status of 84 per cent of the patients in our series. With continued administration of adequate doses over a 3 to 5 day period, the patients passed smoothly through their period of alcoholic withdrawal, without marked subjective complaints. From a psychological standpoint, it is our feeling that this result is beneficial in the overall handling of a patient and in establishing rapport. We do not hold with the opinion that alcoholics must be treated harshly and made to "sweat it out" in order to repent of their actions. Our experience with pyrahexyl indicates that alcoholic patients appreciate consideration for their feelings and respond to it by being more cooperative in therapeutic relationships.
In those patients who presented complaints resulting from the withdrawal of various drugs (or medicaments)—namely, barbiturates and opiate derivatives—the picture was similar. We attribute the difference in the results obtained in Demerol addicts from others to the individual addictive properties of the drug itself and the development of less physiologic dependence on the drug as compared to other opiate derivatives.

Illustrative Cases

The results of treatment with pyrahexyl in one patient with drug addiction and in one with alcoholism will be described briefly:

Drug Addiction (Case 1)

A 32-year-old man entered Graylyn Hospital with the chief complaint of morphine addiction for the past one and one-half to two years, and of pain in both ankles of about two years' duration. He was admitted to the hospital for insulin subshock therapy and for the treatment of morphine addiction. He had been taking from Va to 1/2 grain intramuscularly every 4 hours for a long time prior to entry here. On admission he was extremely lethargic, garrulous, and uncooperative, and complained bitterly of pain in his lower extremities, although there were no positive physical findings referable to this area. He did express a strong desire to be free of drug addiction and to return to normal health again. The physical examination was not remarkable in the main. Laboratory findings were within normal limits.

Following admission to the hospital he was given pyrahexyl tablets-3 the day of admission, 3 then for the next five days, and 1 on the sixth day. During this period mild euphoria was noted and the patient gradually began to complain less of pai= in his legs, was much easier to manage, and cooperated to a much greater extent. He did notice a sensation of elation and at times felt rather dizzy, but experienced no nausea or vomiting or any other side effects of note. He was not given morphine from the time of entrance. With the administration of pyrahexyl, paraldehyde, and Sodium Amytal, none was deemed necessary. Throughout his 20-day hospitalization period, during which he received insulin subshock therapy, he did very well and was discharged much improved. He volunteered the information that some type of medicine that we were giving him had made him feel better than anything he had ever used and, as mentioned, he did notice euphoria, elation, and some dizziness

Alcoholism (Case 2)

A 37-year-old married businessman was brought to the hospital by his brother for consultation about over-indulgence in alcohol. When he first entered the office, it was obvious that the patient had had a drink or two on the way down to fortify himself for the ordeal. He was tremulous, somewhat thick in speech, perspiring freely, and quite restless.
The brother revealed a history of excellent business ability on the part of the patient but told also about numerous periods of excessive drinking. The patient readily admitted the former but minimized the latter. During his denial of any problems he grew more restless and pale, and frankly asked for a drink. He was told that patients were not treated with bourbon or Scotch, but that we had other methods of treatment. He was given a capsule of pyrahexyl, and the interview continued. In about 20 minutes the patient spontaneously remarked that he felt better. He was asked whether he still felt the need for a drink and his answer was in the negative. Admission to the hospital was arranged without further argument or persuasion.

On the day of admission he received 2 more pyrahexyl capsules. On the following day 2 more were given and then this medication was discontinued. The restlessness and tension had subsided and the patient had joined the group activities.

With the aid of psychologic studies and the efforts of the psychiatric social worker in adjusting family problems, the patient returned to his place in business and in the community, where he has remained sober and efficient for almost a year. In the meantime he has referred another member of his family for treatment of alcoholism.

Conclusions

It is our conclusion that pyrahexyl and related compounds are beneficial in the treatment of withdrawal symptoms from the use of alcohol to a marked degree, and in the treatment of withdrawal symptoms from the use of opiates to a less marked, but still significant degree. We offer for consideration an over-all series of 101 patients in whom pyrahexyl has been used. We have not been able to differentiate, prior to therapy, those patients who would fall into the group successfully -treated from those who would not respond. Perhaps this paper will stimulate some to continue this study with such a view in mind. We offer it as a preliminary report and study.

References

1. Materia Medica and Prescription Writing. Oscar W. Bethea. 2nd Revised Edition. F. A. Davis Company, Publishers, Philadelphia, 1917, p. 114.
2. The Harvey Lectures-1941-1942. Professor Roger Adams. "Marihuana." pp. 168-197.
3. Public Health Service Reports, vol. 61, pp. 1050-1083, No. 29, July, 1946. Williams, E. G., Hinunelsbach, C. K., Wilder, A., Ruble, D. C., and Lloyd, B. J., Jr.: Studies on Marihuana and Pyrahexyl Compound.
4. Allentuck, S., and Bowman, K. M.: The Psychiatric Aspects of Marihuana Addiction, Am. J. Psychiat. 49:248-251 (Sept.) 1952.
5. Himmelsbach, C. K., and Andrews, H. L.: Studies on Modification of the Morphine Abstinence Syndrome by Drugs. J. Pharmacol. & Exper. Therap. 77:17-23 (Jan.) 1943.
6. Parker, C. S., and Wrigley, F.: Synthetic Cannabis Preparations in Psychiatry: Synhexyl. J. Men. Sc. 99:276-279 (Jan.) 1950.
7. Letter from Dr. Terry. Adams, R., Loewe S., Jelineh, C., Wolff, H.: Tetrahydrocannabinol Homologs with Marihuana Activity, J. Am. Chem. Soc. 63:1971- 1976, 1941.
Pond, D. A.: Psychological Effects in Depressive Patients of the Marihuana Homologue Synhexyl, J. Neurol. Neurosurg. 11:271-279 (Nov.) 1948.
Stockings, G. T.: A New Euphoriant for Depressive Mental States, Brit. M. J. 1:918-922 (June 18) 1947.