13 Llay 1959 ELYZAOCLAVINR- (43-Y). Elymo@-lavine (V'-A-22) is a material isolated from a cultured saprophytic fungus by the Research Laboratories of Tal,,eda Pharmaceu'6ical Industries in,-Japan. It is related to agro- cla-,rine (V-A-18) and @o d@lhydroagroclavin2e, both of vinich have sedative and hypnot-ic effects in man,,-although they are primarily expitant in animals. All these drugs are related to the ergot group. 'In elymoclavine the acid amide group of LSD has been replaced with a hydrogen and a C"20H group. .Accord'ing to Yu! and Takeo (1) agroclanrine and elymocla-vinc cause a syndrome 0"'L' "cen+-ral sympathetic excitatio-,i" in mice, rabbits, cats and dogs manifested by mydriasis, tachypnea, convulsions, hyperactivity, etc; whereas dihydroagroclavine, dihydroergokryptine, etc., cause sedation. r-.Iymoclavine and agroclavine had analeptic effects in reserpine sedated mice. Because of discr epancy In the effects of agrocla vin-e (in 0 animals, excitation and in man, sedation) a preliminary study of elymoclavine was thought to be of Interest. The study was designed to determine the effective dose range in ria,-i, and to determine if LSD-like (psychosomirietic) effects were induced. Paoe METHODS Sub.iects. Nontolerant former opi.ate addicts who were serving sentences for violating the Federal narcotic laws volunteered for these experiments. All were healthy males between 21 and 40 years.of age who presented no evidence of any of the major psychoses on mental status examinations. All had experienced the e.tfects of LSD-25,in previous experiments. C-eneral Conditions. The experiments were conducted in a special ward. Pa.tients entered this ward on the night before experiments were conducted,, and were observed hourly by specially.trained attendants. Between observations the patients were free to remain in their own rooms, to slee p or to socialize 2 wi'6h other pati-ents in a comnon day room. 'Dru2s. Elymoclavine was given orally in solution at 8 a.m. The taste was,ma:s.ked with cherry syrup. In preliminary experiments', the dose of elymoclavine was cautiously elevated from 1 Tncg/kg to 7.5 mcg/kg. No psycho- somi,netic effects were observed, and with the larger doses patients began to reoort9 headaches and'drowsiness. Accordingly Pa@;s more formal 'experiments were carried out in which 12 patients received on two separate occasions 10 and 15 mcg/kg of V-A-22. In addition, 5 patients'received PO mcg/kg'and 4 received 2r' mcg/kg. Observations. The fo-Ilowing observations were ma,,Ie at hourly inter2vals twice before,,and eight times after adminis- tration of V-A-22: pi@pillary size, sys-tolic blood pressure, and threshold for eliciting the kneejerk. In addition patients completed a questionnaire houriyl with the help of an aide, and short meii",6al status examinations were made at appro-riate intervals. The methods of making the observat'.1o.,is and analyzing 2 the data were described by Isbell et al (2,3). For comt)arative purdoses, data on 9 other subjects who received a placebo and 1.0 mcg,/Ag of LSD in other experiments are included. RESULTS The combined data are presented in Table I which shows that3 as compared with LSa, elymoclavine had relatively minor effects on pupillary diamet9er, threshold for kneejerk, and blood pressure (except at-the 25 mcg/kg level). The table also shows the lack of any psychosomimetic effect, even w;-th 25 mcg/kg. Positive responses on the questionnaire after ely-loclavine were usually to such Items as: "I feel sleet)y," 'IT am iiauseated et--* P a V-A-22 dido however, induce symptoms differing from those of LSD. The most commonly reported symptoms were sleepiness and relaxation.(Table 2). DISCLJSSION Like agroclavine and Lilr@ 23194, elymoclavine had sedative effect, rather than ps7,ychosomimetic effects in man. Whet4her such sedation could-be exploite.d therapeutically remains to be determined. In further work, the sleed-inducing properties of elymoclavine should be compared with those of a barbiturate. .-3 -,z Page REFERENCES 1. YUI2 T. and TAHEO, Y.: Neuropharmacological studies on a new series of ergot alkaloids. Elymoclavine as. a potent analeptic on reseroind sedati'on. Japaaese J. Pharmacol., :L: 157-161 (March) 10/58. 2 2. ISBF-LL -L H. ,' B,z ILL E .%-R* Eoj FRASAR., H. Fe, WIKLF.Rs A,,, and LOGX4,,.C,@ R.: Studies on lysergic acid diethylamide. 1. Effects in former morphine addicts and development of toleran--e during chronic intoxication. A.M.A. Arch. Neurol. Psyc2hiat., 761. 468-L78 (Nov.) 1956. 3. ISBtz-LL., H.., LOOauN.. C. R., and MI14E.R, E. J.: Studies on lysergic acid diethylamide (LSD-25). 111. Attempts to attenuate the L.SD-reaction in man by pretreatment with neuro- hu,moral blocking agents. A..V,.A. Arch. Neurol. Psychiat., 8i: 20-27 (Jan.) 1959.. Table 1. Comparison of the Effects of Elymoclavine (V-A-22) with those of LSD-25. DRUCI AND DOSE @mcqz g)'_ t.ii---A,,tJRE Placeb2ol LSD-251 ELY.MOCLAVINE 1.0' 1 0 20 Ptipillary Size o.2 I.I@ +10.2 1.2 0.4 1.3 1.2 1.3 + 3.0 2.2 1.92 2.5 13tood Pressure +15.6 13.5 61@. 8 10.9 +25 t 11 +43 Ih- +24 t 12 +91t.5 8.7 Threshold for liiieejerk +20.7 11 -50.9 31 7.6 8 1.25 -16.7 9 +10 9 I'ctal positive i-i,r,ponses on (@liestionn,-.Ire 0.1 0.3 57,- 23.2 5 +- lo3 7.3 .1 09 5.2 3.2 6.5 3.9 Clinical 2 Grade 0 0 2.2 0.4 0 + 0 0 0 0 0 0 i 0 1. Figures are means i standard errors of observations on 9 subjects In the case of placebo and I mcg/kg of LSD; 12 subjects in case of 8 10 and 15 mcg/kg of V-A-22; 5 subjects In case of 20 mcg/itg of V-A-22; and 4 subjects in case of 25 mcg/kg of V-A-22. Pa-e Table 24' Incidence-of Certain Symptoms after Elymoclavine. DOSE (mcg/kq) -0 2 ..I 15 2,0 Number of Subects 7 12 IP Sleepiness 9 9 3 2 Relaxed 7 8 3 2 F,eadache 2 4 2 0 Nausea 3 2 2 Dizziness 0 0 1 0 Feel t'dii'ferentlt 7 2 2