PSYCHOTOMIMETICS, CLINICAL AND THEORETICAL CONSIDERATIONS: HARMINE. WIN-2299 AND NALLINEl

HARRY H. PENNES, M. D.,2 PHILADELPHIA, PA., AND PAUL H. HOCH, M. D.,s NBW YORK CITY

This report describes the clinical effects ent days. Each was given in salt form of 3 psychotomimetics in mental patients. but for brevity will be referred to as the The results will be related to nosologicaland base. certain biological aspects of the "model psy- choses" in general. The agents are (I) har- RESULTS mine, an present in plant prepara- GENERAL tions ingested by some South American tribest r ) ; (2) Win-2299, a synthetic Since the new manifestations under the cholinolytic(2) and (3) N-allylnormorphine were not present in the pre-admin- (N alline), a synthetic antagonist istration period, they were clearly distin- (3,4, 5). guishable from the patients' baseline symp- toms. At low dosage, each drug produced slight drowsiness, either with or without MATERIAL AND METHODS other symptoms. With medium or high Single dosages of the drugs were given dosage, the reactions qualitatively resembled to 32 voluntary, physically normal mental those in a former series of similar subjects patients, at the New York State Psychiatric who received or LSD (6, 7, 8). Institute; 29 were in the 18-35 year age Thus, diffuse alterations usually occurred range; 19 were males and 13 females. in many realms-autonomic, motor, per- Twenty-two were schizophrenics of the ceptual, emotional, intellectual, and be- pseudoneurotic and other nondeteriorated havioral. Unlike mescaline or LSD (cf. types, with only the primary symptoms of Discussion for dosages), the present drugs the disorder. Five additional schizophrenics regularly elicited some degree of clouding of had auditory hallucinations or delusions be- consciousness in addition to the preceding fore the drugs. The remaining 5 subjects changes. The characteristic reaction at had severe psychoneuroses or recurrent de- medium or high dosage was a semidelirioid pressions. No patient had clouding of con- or confusional state with intermittent drow- sciousness. Each drug was given about 9: 00 siness or sleep. The confusional periods a.m., after a light breakfast and a 48-hour were cyclic. Their intensity and time of medication-free period. Examination by the occurrence correlated only partly with drow- authors and nurses were made for the re- siness or sleep. Major symptoms were mainder of the day in a shaded private room impairment of contact, attention, grasp, re- and also in the succeeding 72 hours. No sponsiveness, and concentration, with gen- patients were informed of the probable ef- eral "dreamy" or twilight quality. Full de- fects of the procedures. Most subjects lirioid reactions occurred in 2 subjects at showed excellent cooperation in reporting the highest dosages of 2 drugs (Win-2299, drug effects. In most cases, each patient re- Nalline). Most subjects had intermittent ceived one drug of the 3 tested, but some amnesia during the reaction itself but were received different doses of harmine on differ- able to provide adequate descriptions of the major events. A spotty defect in recall was 1Read at the t rzth annual meeting of The Ameri- usually present in the 7z-hour follow-up can Psychiatric Association, Chicago, Ill., April 30- period. May 4,1956. 2 Director of Clinical Research, Eastern Pennsyl- Visual hallucinations (cf. Discussion for vania Psychiatric Institute, Philadelphia, Pa. alternative terminology) occurred at medium s Commissioner of Mental Hygiene, New York or high dosage with all 3 drugs. Subjects State. were easily roused after the onset of drowsi- The actual study was performed at the New York Psychiatric Institute, New York, Department of ness or sleep and reported some of the hal- Experimental Psychiatry. lucinations that had occurred in the "dream- 887 888 CONSIDERATIONS OF PSYCHOTOMIMETICS [Apr. ing" state. In all cases, the hallucinations noted here, after ingestion of an aqueous occurred only with eyes closed and disap- solution of yahe (Banisteria caapi, a source peared promptly when the eyes were opened. of harmine). Visual hallucinations might Hallucinations other than visual were infre- have occurred in the present study with quent. Perceptual distortions of body and higher oral doses, the maximum oral amount environment were moderately frequent. (960.0 mgm.) being 4.8-6-4 times greater Neurological changes included varying de- than the intravenous threshold hallucinogenic grees of subjective vertigo, light-headedness, amount (150.0-200.0 mgm.). The amounts subjective and objective ataxia, and sluggish of harmine taken orally under field condi- speech. Like mescaline and LSD, these tions and in Cardenas' study are unknown, drugs produce a variable degree of intensifi- precluding comparison with the present cation of different types of baseline symp- study. Further analysis of the hallucinogenic toms. Harmine also occasionally produced activity of harmine is complicated by nu- a shallow euphoria. Nalline often produced merous botanical and chemical considera- relaxation of rather marked degree. After tionsf r, 10, II, 14). a few initial hours of peak intensity, reac- Additional reactions to harmine which tions usually subsided gradually between the occurred frequently were: nausea and vomit- fourth to eighth hours, often with fluctua- ing; slow, coarse, spontaneous tremor of the tions in degree before complete remission. extremities of an "extrapyramidal" appear- No subject reported effects after 24 hours ance; humming and buzzing noises (no except for minor, nonspecific "hangover" voices); "waviness" of the environment; feelings. "sinking" sensations of the body; subjective sense of body vibration; and subject numb- INDIVIDUAL DRUGS ness, accompanied by objective evidence of reduced sensitivity to light touch and pin- Hannine.-Turner, Merlis, and Carl have prick. These reactions, plus all the preced- recently pointed out that the alleged hallu- ing, occurred in almost every patient with cinogenic activity of pure harmine is a com- the intravenous route; and (except for hal- plicated issue on the basis of the previous lucinations) some occurred with oral dosages literature on crude plant extracts (9). The higher than the threshold of 300.0-400.0 threshold hallucinogenic dose of the pure mgm. The reactions were generally more drug in the present study ranged from 150.0- intense by the former route. 200.0 mgm. intravenously. 'With this route, Win-2299.-The mental effects of Win- S of II subjects reported visual hallucina- 2299 in man have apparently not been de- tions of varying degrees of complexity and scribed previously. The 2 subjects receiving organization. Bradycardia and hypotension 2.0 mgm. had the sedative effect. One of occurred with all doses of intravenous har- these subjects in addition became "hyper- mine despite a 20- to 30-minute injection sensitive" to light and sound, and spots on time, thereby limiting maximum dosage to the wall moved and changed form. At the 300.0 mgm. Average maximum changes 6.0 mgm. level, all 4 subjects had severe were a pulse rate of 18 beats per minute and mescaline- or LSD-like reactions plus a con- systolic blood pressure fall of 16 mm. mer- cury. Injection in one subject was termi- fusional state of moderate degree. These nated at 210.0 mgm. because pulse rate mescaline-like effects included bizarre per- dropped from 82 to 48 per minute and blood ceptual distortions of soma and environment, pressure from 118/78 to 88/60. Recovery unreality feelings, and synesthesias in one occurred in about 30 minutes. The drug was case. The single subject at 10.0 mgm. had not hallucinogenic by the oral or subcuta- a full delirioid episode with complete loss of neous routes. However, ingestion of crude contact, disorientation for time, place, and plant extracts by natives does produce visual person, and responses to complex, organized hallucinations according to field observa- visual and auditory hallucinations. This re- tionsf ro, II, 12). In an experimental study action occurred in brief but cyclic episodes; by Cardenas ( 13), normal subjects also re- partial contact and lucidity were restored ported visual hallucinations and other effects after persistent comments and questions. 1957] HARRY H. PENNES AND PAUL H. HOCH 889

Most subjects had a moderate degree of tal changes which are the criteria of psycho- mydriasis; blood pressure and pulse rate tomimetic action. For example, clinical changes were insignificant. differentiation may be made between a con- Nalline.-The results with NaIline in the fusional-hallucinatory state and a simple, main confirmed previous observations of progressive depression of level of conscious- others in different types of subjects, includ- ness elicited by narcotics and other agents. ing normals (3, 4, 5). Past and present High dosage alone would therefore not pre- findings included varying degrees of relaxa- clude the classification of the present or tion or euphoria, anxiety and dysphoria, other drugs as psychotomimetic in a selec- miosis, nausea, drowsiness and sleep, thought tive or specific sense. Transient cerebral disturbances, feelings of heaviness or light- anoxia could have resulted from the hypo- ness of limbs, and visual hallucinations. In tension and bradycardia with intravenous the present series, visual hallucinations oc- harmine or a respiratory depressant action curred in the single subject receiving 10.0 of Nalline, which has been reported at dos- mgm., in 7 of 8 at 20.0 mgm., and in 2 of ages used in this study (3, 5). The florid 3 at 30.0 mgm. In 4 cases (and in 2 with and diffuse reactions elicited by these 2 drugs harmine) the hallucinations were Lilliputian would certainly not appear to be character- in type, a not infrequent feature of acute istic of those in cerebral anoxia. In addition, toxic psychoses in general. So far as can the circulatory effects of harmine usually be judged from the literature, a possible disappeared about 20 minutes after termi- major difference from previous observations nation of injection, whereas the mental re- consisted in the occurrence of frank mesca- actions lasted at least several hours at peak line-like or delirioid reactions. At 20.0 mgm, intensity. 3 subjects had typical diffuse, bizarre per- Harmine, Win-2299, and Nalline funda- ceptual disturbances, severe unreality feel- mentally produced an acute organic reaction ings, and other signs of psychic disorganiza- type, because of the basic mental clouding tion. At 30.0 mgm., a similar reaction and confusional effects. Harmine and N al- occurred including auditory hallucinations line each produced mental clouding together and synesthesias. In another subject at this with systemic toxicity (cf. above) ; on the dose the effect was overtly delirioid, with a other hand LSD and mescaline elicit neither strong resemblance to the Win-2299 toxic clouding or toxicity in major form within a psychosis previously described. The intra- certain dosage range. However, Win-2299 venous route probably accounts in part for did not display this association of the 2 ef- the appearance of these reactions, since pre- fects, since severe mental clouding occurred vious reporters of the mental effects of without obvious systemic toxicity. It is pos- N alline have used the subcutaneous route, sible that confusional aspects may be more usually at dosages of 10.0-15.0 mgm. and prominent for a given agent whose threshold sometimes higher (3, 4, 5)· psychotomimetic dosage is high relative to threshold dosage for any effect. Quantita- DISCUSSION tive data relevant to this proposition are Relatively high doses of harmine by the lacking for any psychotomimetic but are ob- intravenous route were required to produce tainable in principle. It is very probable, the full psychotomimetic effect with visual however, that absolute dosage thresholds for hallucinations. The same was probably true psychotomimetic activity correlate poorly of Nalline. It is conventionally stated that with mental clouding. In ascending order, acute toxic psychoses occur in apparently these dosages are very approximately: LSD normal individuals after high dosages of (oral or intravenous) under 100 micro- various other drugs, for example, grams; Win-2299 (oral) and Nalline (sub- and (I S). There is a dearth of pre- cutaneous or intravenous) 5.0-20.0 mgm.; cise data on the number of such drugs, dos- harmine (intravenous) and mescaline (oral ages required, and regularity of effects. or intravenous) over 100.0 mgm. LSD and However, not all drugs in relatively high mescaline are at opposite extremes of an dosage produce the diffusely abnormal men- enormous absolute dosage range, and produce CONSIDERATIONS OF PSYCHOTOM1METICS [Apr. practcially no clouding whereas the 3 inter- invariable drowsiness (c], Results, Gen- mediate agents elicit frank clouding at near eral) ; disappearance on eye opening is also threshold. consistent with the hypnagogic quality of the There is evidence, however, that LSD and response. According to Ardis and McKellar, mescaline may produce clouding of con- spontaneous visual hypnagogic images in sciousness at dosages well above threshold. normals are usually experienced in the Pennes has previously reported a sedative drowsy state and with eyes closed. These effect of LSD in 26.0% of a series of schizo- authors also found strong resemblances in phrenics (8) . The drug less occasionally detail between mescaline visual hallucina- (about 10.0% of cases) produced a con- tions and normal visual hypnagogic imagery fusional state (7). MacDonald and Galvin (18). Previous workers with Nalline have more recently reported a 58.0% incidence of variously used the terms visual hallucina- mental clouding and confusion after LSD in tions, day-dreaming, vivid visual fantasies in 50 subjects. The psychotic subjects in their a dreamy state, or nightmares. series apparently received the drug in dos- The apparent differences between the ages (per kilogram of body weight) up to present drugs and mescaline or LSD may 6.0 micrograms as compared with 1.0-2.0 therefore be quantitative rather than quali- micrograms orally in Pennes' series(16). tative. The conclusion would be that mesca- Mescaline sulfate (400.0-600.0 mgm., intra- line and LSD may also basically produce an venously) often produces slight drowsiness organic reaction type. It is a familiar ob- throughout the entire reaction and occasional servation that the visual hallucinations which confusional states (7) . are so characteristic of the drugs under con- There may be an underlying similarity for sideration are relatively infrequent in all the drugs under discussion in the rela- chronic schizophrenia. These considerations tionship of the visual hallucinogenic response obviously do not preclude various possible to visual restriction and hypnagogic mecha- relationships between psychotomimetics and nisms. First, it will be recalled that visual a possible endogeneous "toxic factor" or hallucinations with the present drugs always metabolic disturbance in the "functional" disappeared when the eyes were opened. psychoses. Hoch and Wikler have recently Wikler noted the same in post-addicts under and independently summarized the other im- mescaline(4). The authors have not noted plications of the drugs and the "model" psy- this effect in frank form with either mesca- choses for experimental psychiatry (19, 20). line or LSD but have occasionally observed The nucleus, alleged to be specific that hallucinations are reported as less dis- for psychotomimetic activityfzr ), is absent tinct and vivid when the eyes are opened. in mescaline, Win-2299, and Nalline. How- Darkening of the room does initiate or in- ever, with the exception of mescaline, the tensify visual hallucinations with eyes open remaining 4 psychotomimetics contain a ter- under mescaline or LSD. If eye closure and tiary nitrogen grouping (2 in LSD). Since reduction of intensity of external light af- these compounds are otherwise grossly dis- fect drug-induced hallucinations by the same similar in molecular configuration (fig. I), mechanism, then the difference with respect the entire structure undoubtedly has to be to this mechanism may therefore be negli- taken into account. Despite this well-known gible between the present drugs and LSD. factor and the very small series of drugs, Such a mechanism may be related to that there are certain indications that the tertiary presumably operative in hallucinations and nitrogen grouping may contribute to psycho- other mental disturbances recently reported tomimetic activity. In brief, some of the evi- as occurring with generalized restriction of dence relates to effects of apparently minor sensory input (17) . changes in the LSD molecule, effects of Secondly, the abnormal visual phenomena quaternization of vVin-2299on its eNS po- with the present drugs are probably best tency(2), and comparison of the actions of categorized as hypnagogic hallucinations or with those of its tertiary amine even more broadly as hypnagogic imagery derivative, bufoteninef zz ). However, in ad- or visions. This term is used because of the dition to mescaline, the literature reports 1957] HARRY H. PENNES AND PAUL H. HOCH

other psychotomimetics without the tertiary nitrogen groupings: marijhuana, which is non-nitrogeneous (9) and 3A,5-trimethoxy- , a mescaline derivative (23) . "';'"'""'Some types of centrally acting drugs other CH30 ~ OCH3 than psychotomimetics also possess the ter- OCH3 tiary nitrogen grouping. Futher analysis of MESCALINE0 these relationships will be presented else- wheref zq.). There is no apparent common neurophar- macological basis for the psychotomimetic action in general and for harmine, Win-2299, and Nalline in particular (2, S, 25). Win-

NH 2299 is qualitatively similar to atropine in animals by virtue of its peripheral cholinoly- H LYSERGIC ACID DIETHYLAMIDE tic and central actions(2). The mechanism

~ /C2"5 of production of abnormal mental effects Q0 2 2 - - CH -CH - N 'C H HeL may be similar for both drugs, Win-2299 ap- I "'5 2 S WIN·2299 parently having a lower threshold dosage. s 2· OlETHYlAMINOETHYL CYCLOP[NTvL (2 THI[NYl) GLYCOLATE HYDROCHLORIDE According to recent speculations, some psy- chotomimetics may produce their effects as antagonists of cerebral serotonin (26, 27). The mental effects of oral LSD and intra- venous harmine (both and peripheral antiserotonins) differ in many respects (Re- ~ HeL sults, General and Harmine). The difference in route of administration is not a factor in OH CH o view of the finding of Hoch that oral and N - ALLYLNORMC1\PHINE Het. intravenous LSD have the same qualitative Structures of Some Psychotomimetics. effects(28). However, differencesin relative FIG. I.-Harmine was supplied in 2 forms: as the dosage levels may contribute to the apparent base isolated from Banisteria caapi (1) and as the dissimilarities between the 2 drugs. synthetically-prepared HCI·2H20. The following dosages refer to hydrochloride form in each case. Harmine: oral, II patients, 20.0-960.0 mgm.; sub- SUMMARY cutaneous, 6 subjects, 40.0-70.0 mgm.; and intra- Harmine, Win-2299, and Nalline in single venous, II patients, 100.0-300.0 mgm. vVin-2299 tablets: 7 patients, 2.0-IO.O mgm. Nalline: intra- dosage produce many new mental effects in venous, 12 subjects, 10.0-30.0 mgrn. Intravenous schizophrenics grossly similar to those elic- harmine and Nalline were injected over a 20-30 ited by mescaline and LSD. Many of the minute period. same effects are reported in normals after Mescaline and lysergic acid diethylamide (LSD) harmine and Nalline (other workers). Un- were not given in this study. LSD and harmine contain the indole nucleus whereas the remainder do like mescaline and LSD at usual dosage not. The tertiary nitrogen grouping is present in levels, the present psychotomimetics regu- LSD (both in aliphatic chain and cyclic constit- larly produce drowsiness and sleep along uent), harmine (non-indole member), Win-2299 with the aberrant mental effects. The re- (aliphatic side chain), and Nalline (linking allyl side chain with ring member). Cf. Discussion. sultant state is partly that of "hypnagogic" Both forms of harmine were supplied as the dry visual hallucinations or imagery. The results compound by Dr. K. K. Chen, Eli Lilly Labora- with increased dosage suggest that the basic tories, Indianapolis, Indiana. For parenteral admin- istration, solutions in pyrogen-free distilled water, Allylnormorphine HCI = Nalline HCl; ampoules of 20 cms.," were used several hours after autoclaving. distilled, pyrogen-free water containing sodium bi- Win-2299 was supplied by Sterling-Winthrop Re- sulfate, 0.2% and sodium citrate, dihydrate I.5'%. search Institute, Rensselaer, N. Y., as the racemic For intravenous administration, ampoule contents mixture of the hydrochloride salt. Nalline was sup- were diluted up to 20.0 ems." with pyrogen-free dis- plied by Merck and Co., Rahway, New Jersey, N- tilled water. CONSIDERATIONS OF PSYCHOTOMIMETICS [Apr. effect of these agents is to produce an acute II. Iberico, C. C. Bol. mus, Hist. Nat., 5: 313, toxic reaction type. The difference between 1941. 12. Schultes, R E. Natural History, 64: 120, them and mescaline or LSD with respect to 1955· clouding of consciousness and certain aspects 13. Cardenas, G. F.Estudio Sabre el Principio of the hallucinogenic response may be quan- Activo del Yage. Thesis, Universidad Nacional, titative rather than qualitative.The indole Facultuaa de Medicina y Ciencias Naturales, nucleus is not necessary in the structure of Bogota, 1923. 14. Albarracin, L. Contribuci6n al estudio de 105 psychotomimetics since Win-2299 and Nal- Alcaloides de Yage, Thesis, Bogota, 1925. line are non-indoles. The tertiary nitrogen 15. Goodman, L., and Gilman, A. Pharmacologi- grouping may contribute to certain aspects cal Basis of Therapeutics. ad Ed. New York: of psychotomimetic action. MacMillan, 1955. 16. MacDonald, J. M., and Galvin, J. A. V. Am. ]. Psychiat., II2: 970, 1956. BIBLIOGRAPHY 17. Bexton, W. H., Heron, W., and Scott, T. H. Canad. J. Psychol., 8: 70, 1954. 1. Chen, A. L., and Chen, K. K. Quart. J. 18. Ardis, ]. A., and McKellar, P. J. Ment. Sci., Pharm. Pharmacol., 12: 30, 1939. 102: 22, 1956. 2. Luduena, F. P., and Lands, A. M. J. Pharm. 19. Hoch, P. H. Am. J. 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