Comparative Action of Various Drugs on the Mescaline-Induced State

CHAPTER 16 _

Studies on Mescaline. IX: Comparative Action of Various Drugs on the Mescaline-Induced State

By HERMAN C. B. DENBER, M.D.

HLORPROMAZINE, reserpine and sodium succinate have been reported as Cbeing capable of blocking the symptoms of the mescaline-induced state. Chlorpromazine is more potent in this regard than reserpine, and opinions on sodium succinate are divided.l" A simple clinical screening method would be useful to study the activity of new psychopharmacologic agents. Present pharmacologic tests used to select drugs for clinical trials in psychiatry are in need of revision, since many are based on psychophysio- logic events (conditioned avoidance response) that seem somewhat remote from clinical psychiatry. A clinical state induced by the same drug, resembling the human endogenous psychosis, could offer a means for comparative testing. Some relevant clinical data might be deduced from the blocking effect of a compound upon mescaline. The evidence for a relationship between the mescaline-induced state and the human psychosis has been reviewed else- where/ for there is reason to assume that the former is the analog of the latter.

MATERIALS AND METHODS

Sixty recently admitted male and female patients without overt psychotic symptoms were studied (TABLE 1). They were selected at random from the admission services and the hospital's research ward. Previous medication, if any, was stopped at least 48 hours before the test. Breakfast was omitted on the morning of the study. Electroencephalograms were run concomitantly in 23 patients. One-half gram of mescaline sulfate dissolved in 20 m!. of distilled water was injected intravenously within five minutes. Pulse and blood pressure were recorded. The patients were then observed by the investigator and nurse from 45 to 60 minutes. The proposed blocking agent was injected intramuscularly at this point.

From the Research Division, Manhattan State Hospital, Ward's Island, New York, N. Y. The author acknowledges with gratitude the assistance of Miss Dorothy I. Kauff- man, R.N., during the course of this study. 203 204 BIOLOGICAL PSYCHIATRY

TABLE 1 Drug Patients Studied Chlorpromazine 25 Promazine 7 Promethazine 3 Triflupromazine 5 Prochlorperazine 8 Thiopropazate 6 Diethazine 6

Each of 25 patients was given a single injection of 50 mg. of chlorpromazine. Five patients (eight trials) received a single injection of either 20 mg., 40 mg. or 60 mg. of trifiupromazine. Seven patients received 100 mg. of promazine. Three patients had 50 mg. of promethazine. Eight patients received 20 mg. of proch lor- perazine. Six patients received 250 mg. of diethazine. The blocking effect of chlorpromazine was determined at the end of one hour; this was taken as a standard. The action of the remaining agents was noted at the end of 15 minutes, although the patients were observed for longer periods. Attention was directed specifically to observable psychological and motor symptoms, i.e., abnormal ideation (delusions, hallucinations, ideas of depersonalization, irrelevant and incoherent thought, flight of ideas), anxiety, tremor, hostility, aggres- sivity, restlessness and bodily movement (overt or symbolic). A drug showed complete blocking if the various symptoms of the mescaline-induced state were abruptly halted. Decreased psychological and/or motor activity in varying degrees was considered a partial block. The patient was rated as unchanged if the mescaline clinical pattern persisted. The patient's state was rated worse when either psychological and/or motor symptoms increased. These criteria and evalua- tions were based on clinical observations. No quantification or rating scales were used.

TABLE 2.-Results with 60 Patients

Complete Moderate Block Block Unchanged Worse Chlorpromazine 24 0 0 1 Trifiupromazine 5 0 0 o Promazine 0 0 7 o Promethazine 0 0 3 o Prochlorperazine 2 1 4 1 Thiopropazate 1 1 4 o Diethazine 0 0 1 5

RESULTS

Chlorpromazine and triflupromazine were most potent in their ability to block the mescaline-induced state (TABLE 2). The effective dose of chlorpromazine was 50 mg. intramuscularly. Although 100 mg. was also tried, no appreciable difference was discerned. As early as two minutes after the injection of chlorpromazine and within 10 to 15 minutes, there

------_._._--_._---- STUDIES ON MESCALINE. IX 205 was a sharp decrease in tension, anxiety, restlessness and agitation. The patients would stop twisting and turning in bed or rushing about the room. Hyperpnea decreased and breathing returned to normal. The intense emotional reaction began to diminish and the motor restlessness subsided. The ideational symptoms then began to disappear. At .the end of a half-hour, the patients would lie quietly in bed. All signs and symptoms due to mescaline had disappeared after one hour. The patients would say, "I guess it's all over now.I'm back in this world again." Three hours afterwards, lethargy, drowsiness and sleep were frequently seen. Some would sleep for several hours. Occasionally some tension with anxiety was observed at the three hour point, and the patients would ask, "What hap- pened?" There were no abnormal ideational symptoms at this time. Triflupromazine showed similar results with an effective dose of 40 to 60 mg. I.M. Promazine and promethazine had no activity. Both drugs produced a state of sedation (much more pronounced with the former). Although promazine was capable of inducing drowsiness with consequent decrease of the emotional and motor components, the effects disappeared after 20 to 60 minutes and the whole mescaline state was reactivated. The ideational symptoms were unaffected at any time. Many patients required intramuscular chlorpromazine to finally block the mescaline effect. Prochlorperazine and thiopropazate were only moderately effective. There was a longer time lag before the mescaline symptoms could be brought under complete control. This sometimes took as much as one hour. The pupils had not always returned to their pre-mescaline state at that time. Even where the symptoms of abnormal ideation had disappeared, the patients were still tense, anxious and restless three to four hours afterwards. These two compounds showed very little sedative properties. Thiopropazate blocked mescaline in one case, but two hours later there was a recrudescence of all symptoms. Diethazine clearly aggravated the mescaline state in five of six patients. This was evidenced by increase in both emotional and ideational components, marked hyperpnea, increased tremor, restlessness and motor agitation. There was a delayed response in one of these cases with a violent reaction 46 minutes after the injection of diethazine. There was no change in one patient. Electroencephalographic changes paralleled the clinical state. Alpha waves began to reappear as early as two minutes with chlorpromazine. When the blocking agent was only relatively effective (prochlorperazine), the muscle tension artefact of the mescaline state remained in the electroencephalographic tracing. P"

206 BIOLOGICAL PSYCHIATRY

CASE REpORT

H. K., 33 years old, dementia praecox, paranoid. 9: 41 a.m. injection of mescaline begun, 0.5 grams. 9: 48 end. "The injection has caused a tightness. Maybe it is a prolonged injection. It's tightness-as if I've been stunned deeply. As if I had a wound on my hand." 9: 58-"1 have thoughts of utter hopelessness and futility. I'm going to waste away intermittently and one day I'll die." 10.05-"i'm a man consumed and burned up and yet I am pure.I attribute it to demonic and satanic forces." 10:27-250 mg. of diethazine I.M. 10:40-"1 feel strange. You've deadened my powers even more. I feel dazed." 10:44-"1 think you've put dope into me and affected what I say. I feel these injections have blacked out my mind.The devil has gotten into psychiatry." 2: 00 p.m.-The patient is still completely con- fused. The mescaline state is unchanged.

DISCUSSION

The data indicate clearly that chlorpromazine and triflupromazine were most active in blocking the effects of mescaline. The action of proch lor- perazine and thiopropazate was mediocre, and delayed even where effective. The sedative properties of promazine and promethazine were out- standing, while their blocking action was absent. The results would suggest that the clinical effects of promazine may be influenced in part by the marked sedative action. Diethazine was reported previously as producing a state featured by muscular weakness, staggering gait, difficulty in ver- balization and acute panic in five of 13 patients when injected one-half hour before mescaline." The present observations support these findings even though the drug was administered after mescaline. Himwich and collaborators" have speculated that "three carbon phenothiazine derivatives which check reticular activation should be used in clinical trials for new drugs." The blocking action against mescaline in this study was linked to chemical structures where a three carbon side chain between two nitrogen atoms was found with a halogen at the number two position on the phenothiazine nucleus (FIG. 1). The law of the halogens would suggest that triflupromazine is more active than chlorpromazine. Its blocking action against mescaline was equal with regard to dose and time. Increase in pharmacologic potency is not necessarily followed by augmentation of the clinical effect. Certainly, the safety margin is narrowed. While the piperazine side chain compounds require smaller doses, it has not yet been shown that their over-all effectiveness is increased. When the halogen is removed, the antipsychotic component disappears for the most part, leaving a marked sedative action. Fellows and Cook" reported that chlorination of promethazine had little effect upon its conditioned response-blocking activity. The halogen itself does not seem to be the effective antipsychotic factor. There more probably is a spatial arrangement and electronic effect between halogen and side chain that determines this activity. 1 ~~ ~~ a:X)Ol~~ ~~ CC0~~ ~~ O:DCCD a:0~ 0:01 Ul I I I I I i >-l H3C-C-H H-C-H H-C-H H-C-H H-C-H H-C-H G I I I I I ~ ,N, H-~-H H-~-H H-7-H H(_C_H H-C-H Ul CH3 CH N N N o 3 " ", " z eR;cu, OR;OR; eR;eR; ~ is: 1:<:1 tn o I ()I ~ H-C-H H-C-H 52 H I H-C-H ~ oI ~ o-I o H-b-H H Promethazine Promazine Chlorpromazine Triflupromazine Prochlorperazine Thiopropazate

FIGURE 1

""o " F"S

208 BIOLOGICAL PSYCHIATRY

On the other hand, lengthening of the side chain by addition of a piperazine and methyl group (prochlorperazine) or an acetyl-oxy group (thiopropazate) seems to remove the sedative capacity while leaving the antipsychotic effect. While perphenazine was not studied, it could be speculated that its blocking activity would be similar, since its chemical formula lies between both. Theoretically, prochlorperazine and thiopro- paza te should be more active against mescaline than chlorpromazine; actually this was not the case. If these results are extrapolated into clinical studies, phenothiazines containing any of the following alone or in com- bination probably exert their effects differently: 1) three carbon side chain with a halogen at the number two position, 2) three carbon side chain without halogen, 3) three carbon side chain, halogenated number two position with piperazine and additional methyl or other groups. These agents showed a splitting of the sedative and antipsychotic effects with mescaline, the most effective having both qualities. One could wonder, then, if sedation is not a needed component of psychiatric treatment. The potentiating action of diethazine gives some meaning to our previously reported results. The chemical formulas of diethazine and mescaline show similarities in their side chains. LSD has a diethylamide similar to diethazine (FIG. 2). A review of biochemical questions related to the matter of inducing disorders of human behavior led to the implication of a two carbon amine linkage," It was suggested that amine metabolism might play some role in this problem.

H I

t<"\ t<"\ ~ tlr 888

Q H-C-H CCOI • R-C-H H-C-H • I ,N, N ' .. HR CR2 CH2 I, CR} CR} Mescaline Diethazine LSD

FIGURE 2

------.----. STUDIES ON MESCALINE. IX 209 by mescaline in animals. It affects high voltage slow wave activity similarly to mescaline." It could well be that large amounts of two carbon amines overload a system that genetically lacks the capacity effectively and rapidly to deaminate such substances. The results with diethazine add to the information available concerning the implication of a two carbon amine linkage with regard to the problem of disordered states of human behavior. It is uncertain whether the carbon linkage or terminal position of the amine group is more important. The relationship of many anticholinergic compounds to such a structural formula is to be noted. How do these results relate to clinical investigation? Sedation is not usually observed clinically with prochlorperazine or thiopropazate, but has been noted with promazine and promethazine. The post-mescaline tension and anxiety response has its counterpart in prochlorperazine-treated patients who frequently show these symptoms during the early treatment period. Although diethazine has been used extensively in Europe for Par- kinson's disease, it has not been reported as being capable of producing psychotic symptoms in such patients. Could this have some relation to the fact that most potent phenothiazines have the property of inducing marked extrapyramidal symptoms? It is claimed that phenothiazines with piperazine side chains are more potent, implying thereby that the clinical results are better. It is of interest to note that in Ayd's-? large-scale study the im- provement rates for schizophrenic and manic-depressive psychoses were approximately the same for chlorpromazine, triflupromazine, perphenazine, prochlorperazine and thiopropazate. The blocking action, in any case, is not specific in its relationship to clinical activity. Barbiturates are fairly potent but lack antipsychotic properties. It is difficult to predict the clinical potential of a compound based upon its mescaline-blocking action. Where positive, further trials are certainly indicated. A negative result, like all laboratory tests, must be interpreted within the context of the total study.

SUMMARY AND CONCLUSIONS 1. Chlorpromazine and triflupromazine were found to be most active in a comparative study of the blocking action of various phenothiazine agents upon mescaline. 2. Prochlorperazine and thiopropazate showed a splitting of the clinical effect, retaining some antipsychotic properties but losing most sedative action. 3. Promazine and promethazine were ineffective. 4. Diethazine potentiated and accentuated the mescaline effect. 5. An aliphatic two carbon amine linkage seems to have some relevance to the problem of disordered states of human behavior. 208 BIOLOGICAL PSYCHIATRY

On the other hand, lengthening of the side chain by addition of a piperazine and methyl group (prochlorperazine) or an acetyl-oxy group (thiopropazate) seems to remove the sedative capacity while leaving the antipsychotic effect. While perphenazine was not studied, it could be speculated that its blocking activity would be similar, since its chemical formula lies between both. Theoretically, prochlorperazine. and thiopropazate should be more active against mescaline than chlorpromazine; actually this was not the case. If these results are extrapolated into clinical studies, phenothiazines containing any of the following alone or in com- bination probably exert their effects differently: 1) three carbon side chain with a halogen at the number two position, 2) three carbon side chain without halogen, 3) three carbon side chain, halogenated number two position with piperazine and additional methyl or other groups. These agents showed a splitting of the sedative and antipsychotic effects with mescaline, the most effective having both qualities. One could wonder, then, if sedation is not a needed component of psychiatric treatment. The potentiating action of diethazine gives some meaning to our previously reported results. The chemical formulas of diethazine and mescaline show similarities in their side chains. LSD has a diethylamide similar to diethazine (FIG. 2). A review of biochemical questions related to the matter of inducing disorders of human behavior led to the implication of a two carbon amine linkage." It was suggested that amine metabolism might play some role in this problem.

H I

t<'\ t<'\ III dr 8 s 8 a.n 0H-C-H , H-O-H, H-O-H I H-O-H I ,N, N ' .• HH OH2 OH2 I, OH3 OH3 Mescaline Diethazine LSD

FIGURE 2

Fink" has reported that "psychotic phenomena were clearly manifested in some subjects" after the intravenous injection of diethazine. Diethazine inhibits amine oxidase." It actually increases the deconditioning induced STUDIES ON MESCALINE. IX 209 by mescaline in animals. It affects high voltage slow wave activity similarly to mescaline." It could weII be that large amounts of two carbon amines overload a system that geneticaIIy lacks the capacity effectively and rapidly to deaminate such substances. The results with diethazine add to .the information available concerning the implication of a two carbon amine linkage with regard to the problem of disordered states of human behavior. It is uncertain whether the carbon linkage or terminal position of the amine group is more important. The relationship of many anticholinergic compounds to such a structural formula is to be noted. How do these results relate to clinical investigation?Sedation is not usually observed clinically with prochlorperazine or thiopropazate, but has been noted with promazine and promethazine. The post-mescaline tension and anxiety response has its counterpart in prochlorperazine-treated patients who frequently show these symptoms during the early treatment period. Although diethazine has been used extensively in Europe for Par- kinson's disease, it has not been reported as being capable of producing psychotic symptoms in such patients. Could this have some relation to the fact that most potent phenothiazines have the property of inducing marked extrapyramidal symptoms? It is claimed that phenothiazines with piperazine side chains are more potent, implying thereby that the clinical results are better.It is of interest to note that in Ayd's-? large-scale study the im- provement rates for schizophrenic and manic-depressive psychoses were approximately the same for chlorpromazine, triflupromazine, perphenazine, prochlorperazine and thiopropazate. The blocking action, in any case, is not specific in its relationship to clinical activity. Barbiturates are fairly potent but lack antipsychotic properties. It is difficult to predict the clinical potential of a compound based upon its mescaline-blocking action. Where positive, further trials are certainly indicated. A negative result, like all laboratory tests, must be interpreted within the context of the total study.

210 BIOLOGICAL PSYCHIATRY

REFERENCES 1. Hoch, P. H.: Experimental induction of psychoses. In The Biology of Mental Health and Disease. New York, Hoeber, 1952. 2. Stevenson, 1. and Sanchez, A. J. Jr.: The antidotal action of sodium succinate in the mescaline psychosis. Am. J. Psychiat. 114: 328-332, 1957. 3. Scheuler, F. W.: The effect of succinate on mescaline hallucinations. J. Lab. & Clin. Med. 33: 1297-1303, 1948. 4. Denber, H. C. B.: Drug-induced states resembling naturally occurring psychoses. In Garattini, S. and Ghetti, V., Eds.: Psychotropic Drugs. Amsterdam, El- sevier Publishing Company, 1957. 5. --: Studies on mescaline. VII: The role of anxiety in the mescaline-induced state and its influence on the therapeutic result. J. Nerv. & Ment. Dis. 124: 74-77, 1956. 6. Himwich, H. E., Rinaldi, F. and Willis, D.: An examination of phenothiazine derivatives with comparisons of their effects on the alerting reaction, chemical structure and therapeutic efficacy. J. Nerv. & Ment. Dis. 124: 53-57, 1956. 7. Fellows, E. J. and Cook, L.: The comparative pharmacology of a number of phenothiazine derivatives. In Garattini, S. and Ghetti, V., Eds.: Psychotropic Drugs. Amsterdam, Elsevier Publishing Company, 1957. 8. Fink, M.: Effect of diethazine on EEG and significance for theory of con- vulsive therapy. Presented before the Eastern Association of EEG, New York, Dec. 11, 1957. 9. Rhone-Poulenc-Specia Laboratories, Paris, France: Personal communication. 10. Ayd, F. J., Jr.,: The current status of the tranquilizers. In Masserman, J. H., Ed: Biological Psychiatry.New York, Grune & Stratton. In press.

Discussion by Harold HimwichJ M.D. Dr. Denber has made an excellent study of the effects of various tranquilizers in drug-induced psychotomimetic states produced by the administration of mescaline. Some of his findings are in accordance with those noted in the treatment of psychotic

FIG. l.-Phenothiazine model. patients. One of them is different from what might have been expected. The chemical configuration of the model formula for the phenothiazine derivatives is presented in FIGURE1.Most successful phenothiazines have Y replaced by a three carbon-straight STUDIES ON MESCALINE. IX 211 chain. A chain of greater or shorter length, two or four carbons, for example, does not seem to be equally potent in managing psychotic patients. Furthermore, as X is replaced first by hydrogen, then chlorine, and finally fluorine, the drugs become more potent in their antipsychotic actions. When the side chain is longer and more complicated, where R, + R, form, for example, a piperazine ring, instead of methyl groups, that structure requires a longer time for oxidation. For that reason,· the drug remains in the body for long and a smaller amount of the drug is required to produce a given action. Dr. Denber has made further suggestions from his work, namely that lengthening of the side chain removes sedative capacity while leaving the antipsychotic effect potent. The unexpectd results comes in regard to diethazine or Diparcol. We have already mentioned that a two-carbon chain is usually bereft of antipsychotic action. But Dr. Denber goes still further and finds that in this case the two carbon chain exacerbates the effects of mescaline. Though this applies in the mescaline-induced state, parkinsonian patients on diethazine do not exhibit behavioral abnormalities. This research of Dr. Denber illustrates clearly the many similarities between the drug-induced psychotomimetic state and the disease process with spontaneous psychic disorders. But Dr. Denber also points out that one is not the duplicate of the other. The result with diethazine establishes that point.