EFFECT OF EPINR--PHRINE ON THE LSD REACTION @lany of the effects of LSD. In animals and man suggest a state of hyperactivity of the adrenergic autonomic nervous system. Rothlin has postulated that LSD creates a central hyperactive autonomic state. Dille and his coworkers at the University of Washin ton found that phenoxybenzamine 2 blocked LSD-induced hyperthermia and behavioral changes in animals. The same group found that administration of LSD two hours after reserpine resulted I.n marked augmentation of the LSD hyperthermi'a, whereas administration of LSD ten hours after reserp;-ne resulted In little hyperthermia. Since reserpine is-knoern to cause a discharge of serotonin and 2norepinephrine in the brain, the change two hours after reserpine might b e correlated with a discharge of epinephrine and norepinephrine., whereas at ten hours these substances would be depleted in the tissues. in recent experfirents we were unable to show any diminution in the Intensity of the mental sy@p*@oms i2nduced by LSD f---c, prc,rea,6- r,ent of human subjects with various doses of phenoxybenza,-@iine.. This result did not favor the adrenergic h othes is. It %.as: yp therefore, thought,desirable to determine the effect of epinephrine on,the LSD-reaction sin(@e an accentuation o-L' the effect of LSD would favor -the adrem rgic hypothesis. MF-TI.K)DS. Subjects. Nine former-addict Negro males who were serving sentences for violation of the narcotic laws served as subjects In these.expetiments. Their ages varied between 21 and 38 yea rs. All had been abstinent from morphine for several months.. All had experienced the effects of LSD a2nd were familiar with the mental changes produced by that drug. Drugs. LSD was given orally'as the tartrate in solution. The drug was administered at 8 a.m. to Atients in the fasting p state. Epinephrine hydrochloride was administered subcutaneously at 10 a.ra. in doses of 0-4 to 0.6 -ag./70 kg. Tnese amoui-its had been2 shown to induce typical-cardiovascular effects In the experiments involving phenoxybenzamine. The following combinations were studied, using a randomized balanced Latin-square design: LSD plus epinephrine placebo; LSD placebo plus epinephrine 0.4 mg./70 kg.; LSD placebo plus 0.6 mg. epinephrine/70 kg.; 1 mcg./kg. LSD plus O.-4 mg. epinephrine per kg.- and,8 1 mcg./kg. LSD plus 0.6 mg./70 kg. of epinephrine. A,double-placebo combination was not Included, since the- important comparisons were those wit.@i L$D plus epinephrine p@lacebo@and LS!) plus'epinephrine. ..Observations. Pupillary diameters resting Systolic blood pressure.,.and threshold for kneejerks were measured as previously described. These determinations were made every -hour on the hour from 7 a.m. to p.m. An additional measure- ment was obtained at .10:10 a.'m., ten minutes after subcutaneous administration of epinephrine and e inephrine placebo.- This 2 p timing coincides with the height of the epinephrine-effect as determined in przvious experiments. The ,aodi-.Lication of the Jarvik-Abramson questionnaire was administered to the patients every hour on the half-hour from 7:30 a.m. to 3:30 P-m-s except questionnaire was administered at 10:20 a.m., after epinephrine rather thanaat 10:30 a.m. The c2linical grades of the reactions were assigned by our usual system. Analysis. The critical measures were those obtained at 10:00 a.:m.'(pre-epinephrinel and at 10:10 a.m. (height of epinephrine effectl plus questionnaires at 9:30 a.m. and 'LO:20 am. These values were taburated and averaged. acco Since. the 2 Results are sho-wn in tfie -.ipanying table. differ nces between LSD placebo and LSD plus epinephrine i,.,ere quite small and obviously:.7ionsignifican't.., statistical calculations were not made.,.The 'igures do not in di.cate eit-L-,.er Inhibition or accentuation of the LSD reaction by epinep.0,irine. ell Discussion. Like the 4xperiment with phenoxybenzamine, the restlts.do not favor., but also do not disprove, the adrenergid hypothesis of the LSD reaction. In this connection, ---it is important to remember that epinephrine is known to have effects on the central nervous system (changes in the activity of the reticular activating system), so that the lack of effect 7 is probably not Attributable to difficulty in penetration of the blood brain barrier by epinephrine. EFFECT OF EPINEPl-UtINE 611 TI-11--l LSD REACT10N 1,-,I@SURE AND TIME T r@,tlt EA @,l Questions Questions Questions Grade 2 Pulse Pulse Blood Blood Pupils Pupils Knee- linee- Rate Rate Pressure Pressure Total 9: 30 A-%] 10: 10 pji 10 AM 10.,10 AM I 10 AM 10:10 AM 10 AM D Diacebo )ineplirin l.'2 0 2 117 4.7 4.8 1.3 rg./70 kg- 70 74 ZD 1.0 mcg./kg. lus@.epinephrine 2.2 2 6.6 6.7 2.3 2.6' 1'7 1 7 67 @'.4 Big./70 kg- 80 84 122 126 1.0 mcg./kg. 11 12 .1.6 Ius epinephrine 1.6 .69 66 117 124 6.2 .6.2' @.9 1.33 @lacebo- Dlacebo plus I)Lncphrine 0 6 mg./70 kg- 72 77 119 118 4-9 4.7 1#0 1.3 0 bLi 1.0 mcg./kg. epinephrine 1 60 2.2 2 123 127 7.0 7.0 2.7 2@6 15 ll[ kg- 78 85 Figures are averages on 9 subjec'ts.