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APPENDIX J ANTICHOLINBRGIC DRUGS AND THE BEG by Hax Fink, Moo. Thla review examines the effects of anticholinergic compounds on the human central nervous ayate~, in relation to their eilltery testing. Such compounds were tester in volunteers to define their role as incapacitating agents for allitary use. The question presented is whether, as tested, the chemicals are likely to produce adverse health effect a or delayed acquelae in the teat subjects, or whether it is possible even to predict that likelihood This review focuses on the data derived from electroencephalography. The data i no lute pro tocola of military experiments teclaasifiet for this review? reports published in the acientlilc literature on animals ant man, and my own atutiea. Between 1956 ant 1966, experimenta were undertaken in my laboratories In New York ant St. Louis to define the effects of anticholinergic drugs on brain function and behavior. We sought to tetersine whether any of the substances had peraIatent behavioral effects that could be useful in treating the severely mentally ill (1-7). Atropine and scopolamine (hyoscine) are prototypic anticholinergic compounds. Their effects are principally antimuscari nic. Compounds usually classified with these pro totypea are those used in the treatment of parkinconis~r-auch as procyclidine (Kematrin), benstropine mesylate (Cogentin), ant trihexyphenidyl (Artane)--and such ~etlcinala as glycopyrrolate (Robinol) ant methantheline (Banthlne). Such experimental anticholinergic compounds as Ditran, JB-329, JB-336, ant WIN 2299 are included in the same class. In some studies, particularly BEG atudioa in patients, the trlcyclic antidepresasats imipramine and amitriptyline have been shown to have atropine-like propertlea. Electroencephalography developed from atutiea published in 1929. In the early aeudiea, changes were assessed by vlanal inspection of ink~written recorte. These have since been replaced by electronic and, lately, digital computer methota of quantitative analysis. These methota provide excellent aseesa~ente of mician1 changes in brain function in man. Unfortunately, the allitarg reports are limited to lnspectlon. LITERATURE REVIEW m e effects of anticholinergic drugs on brain function have been studied extensively. CNS effects in man are definer principally on the basis of self-reports, observer evaluations, *Department of Psychiatry and Behavioral Sciences, School of Medicine, State Univerafty of New York at Stony Brook, Long 1BlaQd, New York Ill 94. J 1

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neuropsychologic Bests, and physiologic measures. O' these, the EEG, especially in its present quantitative form, is a sensitive index of changes in CNS activity, with particular relevance to human performance and states of vigilance (8,9). Anticholine Tic drugs have well defined effects on the EEG, accompanied by measurable behavioral effects. In most drug studies, EEG patterns correlate well with behavioral changes. Studies of atropine in animals, however, elicited reports that their EEG showed increased amplitudes and lowering of frequencies at times when the animals were apparently restless. Animals examined in halters often exhibited running movements, but their EEG patterns were similar to those seen in deep sleep (10). The apparent purposeful movements associated with "aleep-like" EEG records let some observers to define an "EEG-behavioral dissociation" with anticholinergic drugs (1, 11-15). In studisa of pay choactive substances in man' we and others found a close relationship between the changes in EEG patterns and the behavioral effects of drug administration (8). The difference in observations between animals and man led to a symposium in 1966 that summarizer the data available to that time (1). The symposium participants concluded that the apparent "dissociation" in EEG and behavior with antlcholinergic drugs was limited tO observations in animals and was an artefact of the gross nature of the measures used in animal trlala, rarely, the inability tO assess changes in cognition, vigilance, moot, and affect (which are principal targets of anticholine Tic drugs). Anticholinergic drugs have a characteristic dose-relatet effect on brain function, and particularly on the resting, alert scalp-recorded EEG (3,4,6,7,16-27). Low doses, such as 1-2 mg of atropine, are sufficient to induce milt tension, irritability, and anxiety. The subjects are aware of changes in their perception and mood, and they make errors on cognitive tests. At these times, the EEG patterns exhibit an increase in high frequencioa and decreases in the mean alpha frequency and in the amplitude of the dominant (alpha) frequencies. These effects may be accompanied by a decrease in heart rate and some minimal effects on salivation and skin conductance (28, 29). With higher doses, such as 10-30 ma, or repeated administrations, the subjects become delirious, showing restlessness, impairment of motor and sensory functions, cognitive defects, illusory sensations, and thought disorder, including hallucinations and delusions. Heart rate is increased, and the peripheral effects of dry mouth and skin, decreased urination, and difficulty in near vision are prominent. The EEG shows an increase in slow waves, a decrease in mean frequency, a decrease in the percent time and amplitudes of alpha activity, and an increase in the high frequencies, wh.ich can be seen to be "riding" on the slow wave e. There is a direct association between the amount of EEG fast waves with behavioral restlessness and the amount of EEG slow waves with stupor and cognitive defects. At "toxic" doses, patients are in stupor or coma, with rapid heart rate and lowered blood pressure. The EEG demonstrates persistent high-voltage slow waves, with a minimum of alpha and high frequencies e J 2

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In epileptic patients, stable Intramuscular a/ministrations of atropine at up to 2 mg/kg (30) and 1.2 me of intravenous hyoacine (24) elicited epileptic spike EEG activity. The changes were transient, and the records ant behavior of the patients returned to normal within 24 h. EEG and behavioral effects may be modifier by the concurrent administration of other drug e. ~us, atropine (or Ditran) and chlorpromazine resulted in behavioral stupor that was very deep (sllowlng surgery without pain reaponaea), accoelpaniet by persistent EEG high-voltage slow warren and decreases in fast waves. When Dltran ant yoh$mblne or Ditran and ioIipraoline were given together, restlessness increased, as tit the ratio of fast waves to slow waves in the EEG. When patience who e~ibltet a toxic delirium to Ditran or atroplne were given tetrahydroaminacrin (THA), the stupor wee relieved ant the EEG shower decreases in both the low ant high frequencies (1, 7 ~ 31) ~ After acute administration of various compounds, the time for recovery varies with lose--at low tones, the peak effects on parenteral administration are seen in 0.5 h and last for up to 6 h; at high doses, the effects persist for up to 24 h; at toxic doses, there is a return to baseline values the second day after administration. Followup EEG data are limited, the principal data being reports of atropine toxicity. The few statements about EEGs sugggest that the effects are gone within a few days of the last exposure (32-37~. In studies of imipramine, some patients developed an acute psychotic reaction. These patients were identified as being young and as exhibiting a "schizophrenic" syndrome--an observation that led to administration of imiprsmine as a test of "schizophrenia' (2, 38) . Although no long-term EEG study of anticholinergic drugs is available, one study of cholinesterase inhibitors may be cited. Duf fy en al. (39) reported persistent quantitative differences in EEG patterns between worker e exposed to the organophosphate compound sarin and a control group of workers in the same plant not so exposed . MII`ITARY DATA The principal military data on EEG studies are in the Dries provided in Case Report Summaries - Anticholinergics, and an addendum provided in a letter by Dr. Frank Marsull! of October 8, 1981. This latter Mary included all the useful EEG records cited in the formal protocols of the military studies. No EEG records were found of subjects receiving atropine, scopolamine, EA 3443, or EA 3167. Of the available records, five were relater to BE, two to EA 3SBO, and one to EA 3834. The reports stated that the pretreatment records were within normal limits and the postexposure records, taken at Parlous times, were also within normal limits. The records were assessed visually. The reports did not state the conditions of testing, nor in it clear how long after exposure the testing was done. These records were customary for the time and reflected nonspecific effects that are similar to those reported for many CNS active compounds. The reports dld provide neuropsychologic-test J 3

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data, however, which indicate that the effects of exposures to the antlcholinergic substances on the military volunteers were transient, revertlag to baseline values within a few hour a or, in a few teats repeated at longer intervals, within a few weeks (40-49. In other studies of the relationship between the changes induced in EEG and in neuropaychologic teats by CNS-active drugs, there wee a parallel in the oases and duration of the effects in the different measures. Argulog by analogy, we would anticipate airily reversions to nonfat for the EEG changes in these volunteere. Conclusions In the experiments in which patient a and normal volunteers were exposed to single or multiple doses of anticholinergic drugs, a consistent pattern of EEG ant behavioral change has been described. In moat volunteer studies, dosea have been low, exposures usually single, and effects transient. There is no evidence of persistence of behavioral or EEG effects in these experimental trials (50). In patients who have been given heroic doses of atropine and scopolamine (up to 250 ma) and in whom the doses have often been repeated three timea a week for up no 4 ma, there have been few signs of persistent toxicity. The patients have been subjected to periods of coma lasting up to a day. Death has been reported in only one luatance. In many patlenta, the peralatent effects have been considered salutary--l.e.; the patients have been conaidered improved in mental state and discharged to the community' -In the remainder, they have been reported to be no worse than before treatment. Conaiderlag the many hundred a of patlenta 90 created and the continuation of this form of therapy in patients in eastern Europe today, it is unlikely that there is a behavioral syndrome of toxicity. Focusing exclusively on the anticholinergic properties of the drugs examined in military volunteers, considering the low doses used and the minimal exposures, ant aware that heroic doses of ant! cholinergic drug e (inexplicably) fail to stimulate a defined toxic syndrome, we deduce that the sidle exposures of toses of anticholinergic drugs used in the volunteers were insufficient to stimulate a persistent toxic syndrome. The data available are sufficient to conclude that, as tested, the chemicals are not likely to produce adverse health effects. For a more definitive conclusion, a prospective study or a study similar to that re port et by Duffy et al. (39) in parkinaonta~ patients or Intuatrial workers exposes to anticholinerglcs la re quired . J 4

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28. Antrews, P.A., Miller, R.D. and Gordon, A.S. 1955: Evaluation of atropinization by various routes in Havana. Chemical Corps Medical Laborat vies Contract Report #59. 29. Wechsler, R. ant Koakoff, Y.D. 1955: Effect on humane of moderate doses of atropice. Chem. Corps Hed. Labs. Contract #54. 30. Zsadanyi, 0. ant Molnar, C. 1972: Electroencephalographic analysis of atropine coma. Acta Physiol. Acad. Sci. Hugger. 41: 63-72. 31. Gershon, S. ant Angriat, B. 1973: Effects of alterations of cholinergic function on behavior. In: Cole, J., Freedman, A. and Friedhoff, A. (Eds. ): Psychopathology and Psychopharmacology. Baltimore, Johns Hopkins Press, 15-36. 32. Forrer, G.R. 1950: Atropine toxicity in the treatment of schizophrenia. J. Mich. State Het. Soc . 49: IB4-~85. 33. Forrer, G.R. 1956: Symposium on atropine toxicity therapy. History and future research. J. nerv. sent Dis. 124:256-259. 34. Goldner, R.D. 1956: Symposium on atropine toxicity therapy. Experience of use in private practice, J. nerv. ment Dis. 124:276-280. 35. Goldner, R.D. 1967: Scopolamine sleep treatment in private practice. Int . J. Nieuropsychiat . 3: 234-247. 36. Schwarz, H. 1956: Symposium on atropine toxicity therapy. Statistical evaluation. J. nerv. meet. Dis. 124: 281-286. 37. Wada, T., Horigome, S. and Sakurada, T. 1960: Clinical experience of the so-called "atropine toxicity therapy" ~ Forrer) . Tohoku J. Exp. Hed. ?2: 398-404. 38. Pollack, M., Klein, D.~., Willner, A., 81umberg, A. and Fink H. 1965: Imipramine-induced behavioral disorganization in achizophrecic patients: Physiological and psychological correlations. Rec Adv. Biol. Paychiat. 7: 53-61. 39. Duffy, Fin., Burchfiel, J.L., Bartela, P.El., Gaon, M. ant Sim V.~. 1979: Long-term effects of an organophosphate upon the human electro-encephalogram. Toxicol. Applied. Phamacol. 47 :161-176. 40. Ketchum, J.S. 1963: The human assessment of BZ. CRDL Techn. Memo. 20-29. 41. Aghajanian, G.K., Kitzes, D.L., Harper, D.G. and Bottlglierl, N.G. 1965: EA 3580A. Estimate of minimal effective dose in man. CRDL Techn. Memo. 2-12. 42. Crowell, E.B. EA 3580A: 1965: Estimate of incapacitating Dose in Man. CRDL Techn. Hemo. 2-20. J 7

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43. Hart, J.J. ant Balter, L. 1966: A atuty of posalble realdual effects of EA 3443 ant EA 3580 on cogultive abilityO EATR 4044. 44. Hayes, A.~. CAR 301,060: 1967. tose in man. EATM 114-12. 45. Sidell, F.~., Karger, S. 9 Slmons, Compound 302,668: ~ Estimate of mintmal effecti~re C.J. and Weimer, J.T. 1970: Aeroso1 ad~inistration to man. EATR 4395. 46. Sidell$ FeRe, 1972: Retchuo', J.S., Mselcts, J.E. and Rysor, K.P. Compount 302,196: Intramnacular ado~inistratlon in man. EATR 4634. 47. Sitell, FeRe and Braun, B.G. EA 3834A: 1972: Effecta In man after a single oral dose. EA" AS97. 48. Ketchum, J*S., Kitzes, D. and Copeland, H. Effects in man. EATR 4713. EA 3167: 1973: 49. Ketchum, J. S., Sitell, FoRe . Crowell, E.B., AghaJanlan, G.K. ant Hayes, A. Ho Acropine, acopolaotine ant Di ban: Comparati~re phaneacology ant antagoniats ln man. PaychopharoIacologia 28: 124-145, 1973 b. 50. Klapper, A.J., McCarroll, J.E. and McColloch, M. 1972: Long tero~ followup of medical volunteers. Edgewood Arasnal Techulcal Report #4611, 1972. J 8