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Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
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Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
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Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
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Page 49
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
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Page 50
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
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Page 51
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
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Page 52
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
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Page 53
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
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Page 54
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
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Page 55
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 56
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 57
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 58
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 59
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 60
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 61
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 62
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 63
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 64
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 65
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
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Page 66
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
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Page 67
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 68
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
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Page 69
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 70
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 71
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 72
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
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Page 73
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
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Page 74
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
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Page 75
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
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Page 76
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
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Page 77
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 78
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 79
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 80
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 81
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 82
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 83
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 84
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 85
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 86
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 87
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 88
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 89
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 90
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 91
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 92
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 93
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 94
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 95
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 96
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 97
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 98
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
×
Page 99
Suggested Citation:"3. Psychochemicals." National Research Council. 1984. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. Washington, DC: The National Academies Press. doi: 10.17226/9136.
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Page 100

Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

3 PSYCHOCHEMICALS BACKGROUND Military interest in paychochemicals stems from the late 1940~. L. Wilson Green of the Chemical Corps Technical Com~nd at Edgewood proposed that modern military use of paychochemicale might permit the conquerls~g of an enemy without the need for weapons of mass des- truction. Such use, he suggested, might reduce the wholesale killing, hen misery, and property destruction normally experienced in warfare. He proposed a search for a stable chemical with the capacity to produce mental abnor~alitles of military importance; 61 chemicals were suggested as a starting point for this search.1 Over the next few decades. scientists at Ed~ewood encased in — .~ toxicologic and clinical e~raluatlons of the biologic effects of a wide variety of chemicals that could alter the state of mind or mood, largely by affecting the brain. Among those tested on h''m-n volus~- teers were LSD, a hallucinogen; BZ (3-quinuclidinyl benzilate) and related anticholinergic compounds; phencyclidlue, an anesthetic with marked disorienting after-effecta; and dibenzopyra=, CNS depres- sants with powerful capacity to produce orthostatlc hypotension. LSD and the anticholinergice were the subjects of earlier exten- sive evaluations.2~3 This chapter is concerned only with phency~ clidine and dimethylheptylpyran (dibenzopyran) and its isomers. Table 3-l li8t8 the Compounds tested, approximate embers of sub- jects, routes of admini Stratton, and dosages. REFERENCES i. Taylor, J.R., and Johnson, W.N. Research Report Concerning the Use of Volunteers in Chemical Agent Research. DAIG-IN 21-75. Department of the Army, Office of the Inspector General and Auditor General, Washlogton, D.C. 1976. 2. McFarling, D.A., Project Director. LSD Follow~Up Study Report. U.S. Army Medical Department. U.S. Army Health Services Con - A rue . 1980. —47—

3. National Research Council. Committee on 'rosicologg.. Possible Los~g-Term Health Effects of Short-Term Exposure to Chemical A8ente. Vol~e I. Anticholinesterases and Antlcholinerglcs. Washington, D.C.: National Academy Presse 1982. 87 p., Appendices. VOLUNTEER SCREENING, SELECTION, AND CLASSIFICATION In the clinical charts at Edgewood, severe adverse psychologic reactions to SNA or to the ca~abinoide appeared less common than one might expect from experience in civilian laboratories. If these findings were valid, they might be accounted for by subject selection procedures and special characteristics of the experimental milieu. Studies of workers of tern find that workers are hew thier than the general population. This "healthy~worker effect" is generally ascribed to the fact that the working populat ion is in better overall health than the general population, which includes the very alck, the elderly, and the hypersusceptib'e. The selection of volunteers for testing at Edgewood moat likely introduced a "healthy-test-sub ject effect" into the study. In fact, those Bet ected for exposure to the test chew cals were healthier than those used as controls or used in nond rug tests of equipment. The control groups consisted of those who were rejected for drug testing and thus possibly less healthy. Because the exposed subjects were healthier at the start than the nonexposed sub] ects, comparisons bet- ween these two groups may well yield results that understate the rel- ative risk to the esposed subjects. For the study of neurologic pro- cesses and paychologic functioning, subtle effects in the exposed subjects would not be readily evident in a comparison of them with the less healthy, nonesposed subjects. In addition, there was a great deal of preselection, in that all the subjects were soldiera--healthy enough and functioning well enough to meet the criteria for entry into the Army. A detailed set of guidelines, most completely spelled out in a document dated August I2, 196B, described a standard operas ing procedure in the clinical research department (Appendix A, part 2) for forming the exposure group. Multiple criteria were used in the paychologic screening of volunteers. A "yes" answer on any of various items in the medical history without explanations based on further examination by a medi- cal officer would routinely be cause for rejection. When General Test (GT) scores were in the very low range (below 90 or BO), the volunteer was rejected. Minnesota Multiphasic Personality Inventory (MMPI) prof iles were used as approximate guidelines or rules of thumb, rather than to pro- —48—

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vice firm cutof f points. In general, any prospective sub ject who had five or more clinical scales on the MMPI above 65 units was not included in the experiments. A volunteer with high L and K scales was considered Dutiable for the experiments only after careful review of family history and of other indication of possible paycho- logic problems. Any sub ject with high PI), PA, and SC Scales (pays chotici~m) was rejected, as was a subject with high ED, ME, and MA patte`-.ls (sociopathic deviation), particularly if there was a history of "acting out." Careful review of the overall clinical picture, history, etc., took place if the HS, D, HY, PT, and SI patterns ~ neuroticism) were high. Apparently, exceptions were made--for example, if an ambitious college graduate had high ED and MA scales, but no history of acting out. In doubtful cases, corroborating e~ri- dence from the family history was reviewed. Particular attention was paid to the family and developmental histories of prospective volun- teers, especially a history of trouble in school, contact with a pay- chiatrist for anything other than routine acreeDlug, fighting in association with drinking, and overt expreselons of hostility. Screeni ng of the histories and MMPI profiles took place before arrival at Edgewood. After arrival, volunteers were interviewed by of ricers in the Psychopharmacology Branch. On the basis of further testing (Sentence Completion and Picture Frustration teSts), physi- cal examination, and interview, sub Sects were classif fed on a four- point scale. Those rated A were considered suitable for paychochem- ical test ing; tho &e rated B were suitable f or low~dose paychochemi- cals only; those rated C were not suitable for paychochemicala; those rated D were suitable for equipment testing only. The main criteria for an A or B rating were absence of evidence of psychologic prob- leme, absence of a tendency to somaticize or act out intrapsychic tension, good ego strength, flexibi] ity, maturity, good sense of identity, normal ~PI, and fami] y history. Sub jects who seemed to be particularly at ease when handling anxiety and hostile or aggressive impulses were rated A+--suitable for psychochemical tests considered to be of greater than usual stress. Those rated B were similar to the A group, but had had occasional experiences that suggested less control or minor personality disturbances. Arty subject who showed a tendency toward psychosomatic reaction or aggressive acting out, who appeared to be dull or nonverbal, or who had obvious neurotic traits, immaturity, or rigidity was not included in any psychochemical exper- iments. The criteria described in the standard operas ing procedure appear deco be those used either consciously or deliberately in many civilian laboratories that conduct research with psychoactive drugs with normal volunteers. It appears that the subjects actually given pay- chochemicals in these experiments were selected from an optimal pool of mentally and physically hea lthy persons . —50—

Apparently, the precise configuration and staffing of the re- search unit changed over the years during which these experiments occurred. Facilities for the subjects included a controlled environ- ment with padded rooms ~ to protect sub jects from harm from hypoten sign) and an ad jacent communal area. During the f irat hours of the experiment, each subject was in his own padded area with a padded stool. Each subject had a nurse or aid in the room during his pro- gress. Later, the sub jects were an owed access to dayroom facili- ties, where they played cards . When further along in recovery, they could play table tennis. Throughout the entire recovery process, they could be observed through a window. The notes, comments, and data in ache charts reflected what must have been a supportive and well-staffed research unit. The only neg- atl~re comments from subjects in the charts had to do with the quality or preparation of the food . Many posit ive comments ref. lect ing care- ful attic ion, support, and, in general, informed part icipation in the experiments occurred throughout the charts over the years. Retropecti~re chart reviews always involve guessing and specular ion. A best guess is that a supportive atmosphere and careully screened aDd well-informed (with respect to experimental procedures, goals, pitfalls, etc.) subjects were important in determining how well these volunteer sub] ects tolerated the experiments. It is difficult to generalize about the experimental design used in studies of multiple drugs and spanning 10 yr or more. Some gener- alizations are relevant in assessing the quality of data, pattern of effects, and possible consequences. In the usual sequence of exper- iments, the effects of Jow doses were investigated first in a few volunteers, particularly when the route of administration was being changed or when a compound that had been studied previously only in animals ~ such as the car nAbinoide) was being studied. These, depend- ing on the pattern and duration of effects, a small to moderate-sized group of subjects were tested with a few doses in what appeared to be a safe but pharmacological ly active range. Later studies followed up on interesting or possibly worrisome side effects, such as borderline changes in hepatic or renal function. Particularly in later studies based on earlier observations, interventions were made with assumed antidotes or antagonista; for example, drugs that increased blood pressure were given in conjunction with or after dimethy~heptylpyran to investigate the intriguing and important posture' hypotension. The protocols appeared to be flexible and generally conserva- tive, with variatlone often following up preliminary observations. A critical and skeptical reviewer, in retrospect, might say that there was too great emphasis on browsing and that the changes in protocol, with seal 1 groups tested under any single protocol, precluded defini- tive conclusions. These e~cperimer~ts were anal ogous to the Phase 1 clinical trials in human beings now conducted with therapeutic drugs, —51—

in which esa~nati~ of amass groups, attention to borderline bio- chc~ical abnormalities, revision of protocols, and attention to hunches about mechanisms of drug action, 608e, etc., are appropriate research strategies. Placebo controls were not used and were probably not appropriate, glared the goals of the research. One must remember that when these studies began, in the early 1960s, psychopharmacology, particularly opting research strategy and design as we know them today, was truly in its infancy. Not until the mid-1960e was there a general consen- sus in a mlaimally acceptable design for studying paychochemlcals, aM ever now there may be disagreement. lithe experimental design used in the experiments at Edgewood compares favorably with the phaneaco- logic research at other research centers. In the Edgewood studies, SNA was administered intravenously, orally, aM by inhalation. Intravenous doses of 0.l mg/kg given to 10 volunteers produced onset of physiologic and paychologic effects within 3-5 min of indec- Lion that peaked about 10 min to 1 h after injection. Most of the symptoms were no~measurable 5-6 h later. As in all studies with SNA, individual variation was great. For example, of the 10 volunteers given intravenous SNA, four became withdrawn and drowsy and answered when spoken to, but otherwise were silent. The effects on proprio- ception were manifested by limb numbness, vertigo, ataxia, and a feeling of detachment. Various degrees of amnesia regarding the events after the first hour after injection were common. Nausea was common, but considered to be less than expected by the investigators, possibly because the subjects were nonambulatory. Increases in systolic and diastolic blood pressure of up to 20 or 30 mm He occurred soon after injection and lasted for 2-3 h. It was judged by subjects and observers alike that SNA would impair performance in a mili tary f ield situation. After oral doses of up to 30 mg (0.48 mg/kg), similar signs and symptoms appeared in a single test subject. At 30 ma, approximately the first plane of stage three anesthesia was produced. The one sub- ject used was unreeponsive to sensory stimuli, although corneal reflexes were intact. Blood pressure was slightly increased. An hour after the drug administration, he was responsive to stimuli, but still groggy; a h later, he had recovered almost totally, but was Emetic regarding the events of the hours after the drug was adminis- tered. Two volunteers given a combination of SNA (20 ma) arid alcohol had intense "manic" reactions, with much agitation and restleasnes~. Perceptual and cognitive effects lasted 4 d ire one and 2 ~ in the other. At lower oral doses (5 and. 10 mg), volunteers described their subs ective feelings as similar to those of alcohol intoxication. Skin temperature and heart rate increased slightly. Vertigo, atasla, —52—

wea]~Ue88, and nausea were mild and not sufficient to interfere with treadmill exercises that were part of the experiment. Subjects appeared Slow to think and Slow to make declaiona and reported a sub- jective slowing don of time. The subjective effects peaked at about 2-4 h after oral administration and, after the 10-mg dose, were still present to a slight degree at 13-14 h. After the 5-mg dose, effects were generally milder, and subjective symptoms were gone in about h. Perceptual motor functioning, as Judged by Purdue pegboard and Minnesota rate manipulation tests, was definitely impaired after the 10-mg oral dose, markedly impaired after 15 ma, and nearly abeen~c after 5 ma. REVIEW OF AVAIIABLE INFORMATION ON PHENCYCLIDINE CHEMISTRY Phencyc' idine (Sernyl, SNA)--~-~-pheny~cyclohe~yI)plperidine, C17H2,N (molecular weight, 243.38~--1s an ar~ricyclohe~ylamine. It is used as the hydrochloride, C~7H2sN HC] (molecular weight, 279.84), which is crystalilne with a melting point of 214-218°C. Its hydrobromide salt is also crystalline with a melting point of 214-218°C. The hydrochloride is soluble in water, methanol, etha- nol, aniline, and methylene chloride, and the base is almost insol- uble ln water and soluble in toluene, methanol, ethyl acetate, kero- aene, and methylene chloride. The base (SNB) is crystalline with a melting point of 46-46.5°C. The chemical structures of SNA, ketamine, and SHB are show in Figure 3-1. 9~'NHCH3 a Onto ~~e (it) FIGURE 3-1 Structure of ketauine, SILA, aDd SNB. _ _ T; hydrochionde (SNA) ~- at SNA Was originally synthesized and developed as an anesthetic agent for human use by Parke, Davis and Co. under the name SernyI.~3~~5 Itch human use was soon abalones, because it some- times produced postoperative thought disturbances and agitation. It is currently used, under the name Sernylan, as an immobilizing agent in veterinary medicine. In pharmaceutically pure fore, SNA is a white powder that d1~- 8Olve8 readily ire water. When distributed illicitly, phencycildine, —53—

often called PCP, is highly variable in appearance ( powder or tablets in many colors or as liquid), contains many impurities, is often adulterated, and quite often is misrepresented as another drug, such as ~arl~uana constituents, mescaline, pailocybin, lysergic acid diethylamide (LSD ), or even amphet~mi ne or cocaine . lithe compost cested at Edgewood was pure phencyclidine provided by a pharmaceutical manufacturer and should not be confused with the substance 80~6 0D the street as PCP. The structure of SNA was modified by replacement of its pheny1, cyclohesyl, and piperidine rings and by introduction of subetltuents onto those rings. Replacement of the phenyl ring with a thienyl rlag increased central activity, but bulkier aromatic rings were inac- tive.39 Replacement of the piperidine ring by NHCH3 and some substitutions in ache other rings led to the development of ketamine, an ef fective dissociative anesthetic agent . ABSORPTION, FATE, AND ELIMINATION Two recent reviewa3~22 contain considerable information on the absorption, distribution, metabolism, and excretion of phencyclidine. Absorp tion Early studies in experimental animal 8 and hen subjects46 established that SNA is well absorbed when administered by inhala- tion, percutaneously, irltraocularly, orally, intramuscularly, tntra- venoualy, and intraperi toneally . Dogs esposed to aerosols generated from a 15% aqueous solution of SNA developed prostration, hypersali- vation, and exophthalmos; approximately 50Z of ache dogs had tremors and convulsions. SNA and SNB were dissolved in a number of vehicles, and these preparations were applied to the skin of rabbits. Ataxia confirmed the percutaneous penetration of the drug. This clinical sign also occurred after art alcoholic solution of the base or the salt was instl-~led in the eye n of rabbits. A human volunteer given SNA orally at 0.48 mg/kg reached plane ~ of stage 3 anesthesia ~ h after admir~istratlon. Intravenous admiMstratlon of SNA at 0.01 mg/kg is 10 male volunteers resulted in onset of mental and physical effects within 3-4 min. Nineteen men were given aerosolized SNA in methylene chloride solution. At an exposure as low as 250 ma. min/m3, one sub ject developed visual disturbances and light- headednese in 7 min and perioral and distal paresthesias within 10 min. Inadvertent exposures by inhalation have been reported-. Aniline en al.4 found SNB.in the blood of a 65~ old woman who occupied a secor~d-floor apar~cment directly above a clandestine labo- ratory making SNB by an open-vat process. Pitts et al.52 reported —54—

intoxication in two chemists, employed in a law enforcement labora- tory, who hamiled confiscated samples of SNA. Absorption through the placenta has been shown in mice and rabbite50 and is likely to occur in htonana.30 In the mouse, SNA concentration was 10 times higher in fetal tissue than in maternal blood. Furthermore, SNB appeared rapidly in the milk, reaching con- centrations 10 ti - s those in maternal plasma. Fetal SNA concentra- tions in the rabbit peaked 12 h after parenteral administration to the dam. A neonatal infant whose mother had used SNA during preg- nancy manifested abnormal behavior consistent with effects often seen with this drug. However, blood SNB concentrations were not measured in either child or mother. Aniline and Pitts studied three women who used SNA during pregnancy;3 blood and urine SNB concentrations were determined. Concentrations in cord blood were 2-3 times higher than those in the mother in all cases. Distribution In Spragu - Dawley rats given SNA at 50 mg/kg intraperitoneally, concentrations in adipose tissue 1 h after injection were 13 times higher than those in brain and more than 20 times higher than those in blood. 34 Thus, SNB is highly lipophi ~ c in its distribution; indeed, SNB remained in fat at approximately 10 Agog 48 h after injection--that is equivalent to the highest blood concentration attained (3 h after injection). Brain and blood concentrations were virtually parallel. In one case of an SNB-related death in a human subjects the brain:blood ratio of SNB concentration was 6:l, and the liver:blood ratio was 2:~. In a second case in which it was established that the deceased had smoked SNB, concentrat ion rat ios were as follows: liver:blood, 46:~; lung: brood, 2:~; and kidney: blood, I:~. In a third case, in which latravenous use of SUB was documented, the liver:blood and bile:blood ratios were 4:1 and ~ :l, respectively. A knee synovlAl fluid:plama ratio of 9:l was found in a living subject who had inhaled ("anorted") SNB. Receptor sites specific for binding SNB have been found in rat brain aM other organe.66 The greatest specific birthing was found in the cerbral cortex and the corpus striatum. Bindlug was less in the thalaeus arid hippocampus and least in the medulla oblongata, pons, olfactory bulb, hypothalamus, and cerebellum; none was f ound in the spinal cord. Specific binding ~s also found in heart, liver, lung, and kidney. Distribution studies of ~ 3H]SNB in selected brain regione68 revealed concentrations from 10.4 Prolog in cerebellum to 16.4 nmol/g in anterior cingulate cortex. Another study37 showed that radio- activity from administration of [3H]SNA was distributed almost —55—

every over ~ aJor anatomic areas of the brain; only the hypothal- asme had a high concentration. Most of the radioactivity was associ- ated with the soluble cell fraction, and very little was detected in nuclear and mltochondrial fractions. Chronic adminlatratlon of SNA altered the distribution of ~ 3H] SNB and its metabolizes in the cen- tral nervous system; radioactivity in the cortex was 7-31% ie88 than that in the whole brain. Other areas, particularly the hypothalamus, had a higher concentration relative to that in whole brain. A recent report44 indicated that 30 min after intravenous or oral adminis- tration of [3H]SNA to mice the highest concentration was in the stomach. The nest highest concentrations were in fat (by the intra- venous route) aM in liver an intestine (oral route) aM the lowest in brain and plasma (either route). Metabolism A proposed scheme of the metabolism of SNB in man was reported by ~ r Jasinski _ al.~' After mice became tolerant to SNB, hepatic microsomal cytochrome P~450, cytochrame b5, nicotinamide adenine dinucleotide phosphatase, and NADPH-cytochrome c reductase activities were increased and thus presumably involved in SN8 metabollam.49 These findings confirmed previous observations that chronic SNB administration to the mouse increased liver Microsoft hydrosylation of aniline, pentobarbital, and hexobarbital and the N-demethylation of aminopyrine and ethyl- morphine.32 4-PhenyI-4-piperidinocyclohesanol ( PPC), one of the major metabolizes of SNB, can exist in cis and bans isomers. Both isomers were found to be biologically active in the mouse, producing atria and seizure activity (the latter at high doses). The bans isomer was only slightly more active than the cis isomer.li The presence of an additional me~cabolite in the urine of human subjects ualug SNB has recently been confirmed ;~6 the metabolite had been found in rat an rabbit liver and in dog urine. This metabolite was identified as 5-~-phen~ricyclohesylamlao~valeric acid. In man, PPC is highly conjugated as the glucuro - de and is excrete] fairly in that form.35 Details of the biotransformation of SNB have been ester y re~rlewed.40 Eli mi nation ~ Phar~acokinet ice - It was recognized many years ago tha~c SNB had a prolonged action,46 A huff volunteer given SNB orally at 0.48 mg/kg was not responsive deco stimuli until 4 h after testament, at which time he was stuporous, aM his anes an legs refined in any position in which they were placed. full recovery required about 7 h. In Sprague- Dawley rata, half-lives of SN8 were approximately ~ h in blood, 2 h —56—

in brain, and 3~4 h in adipose tissue.34 Plan half-lives of 2.4 h (monkey) and 2.9 h (dog) have been reported. 69 The half-life in human varies considerably from subject to subject. Acidification of urine results in a markedly decreased half-~;ife.24 Some indication of the slow eliotinatioct of SNB is found in an lnveatigation of coro- nerst cases of persons who died of accidental causes; the highest concentratione of SNB in brain and other organs were noted 7-10 d ricer single high doses of the drug. In brains of S]JB-tolerant mice, the fife was much shorter than that in control an~ale.49 SN11 me~cabolites revalued in the liver of mice up to 14 d Add in the lung up to 21 d.44 Measurable concentrations of She persisted In a hear subject for at least 6 ma after the last known exposure.52 All available ir~for~tion indicates that the phar~acoklnetice of SNB are highly dose-re~ated. The recently reported findings of Cook et al.~9 on the biodis- position of phencyclidine after oral or intravenous administration of trace amounts of radiolabeled o~aterlal are presented in Table 3-2. Quantitatively similar dispoaltional kinetics in the dog were recently published;71 again, there was a wide variability in half- life, as well as a very small renal clearance. These results indicate that, in addition to effectiveness by inhalation and parenteral administration, SNA is wen absorbed in man when administered orally. The drug is 60~701 bound to plasma pro- teins, the Solve of distribution is high (approximately 500 L in an SO~kg man), clearance is largely a result of metabolic processes, the half-life is quite variable from one person to another, and the drug and its metabolites are excreted principally in the urine, regardless of whether it is given orally or in~cravenously. ANIMAL TOXICOLOGY Several animal species (mouse, goat, cat, dog, guinea pig, rab- bit, and rat) were given graded doses of SNA intravenously to deter- mine its LDso an its median effective dose (EDso) for several gross manifestatione--ataxia, salivation, prostration, and convul- sions. Table 3 - 3 lists the LD,os and EDsos for these effects. It shade that in various species the LD,os ranged from ll.7 to 17.9 mg/l~g, and the pharmacologic dose ranged from 50 to SO ug/kg; thus, the margin of safety of this compo~md was high. Atasla, Privation, and prostra~cion occurred wi~chin I-5 min. arid convulsions developed within l-40 mire. Death usually occurred in less than 15 min in the guinea pig, rabbit, and cat; in I-3 h in the mouse; and in 5 min to 24 h in the dog. At 3-5 mg/kg intravenously, SNA caused a decrease in blood pressure, a decrease in heart rate, and mluor cardiac irreg- ularities in cats. It also algM ficantly depressed respiration, but —57—

TABLE 3-2 Biodisposition of Phencyclidine in Mana Disposition of trace amount of phencyclidine: . Oral bioavailability Plasma concentrations ~ ~ h af ter i-mg intravenous dose) Plasma binding Volume of distribution Total clearance Renal clearance Apparent terminal half-life Renal excretion ( 10-d collection) Fecal excretion (10-d collection) 72 + 8% 10 pmol/ml 68-69% f' . 2 _ 0.3 L/kg 380 + 80 ml/min 33 + 8 ml/min 17.6 h ( 7-50 h) 73 + 4: 5 + 1Z LIetabolites of phencyclidine in urine (97: of tgLal 3FI 1ahe Phencyclidine ( SNB) 1-Phenylcyclohexylamine (PCA) 16: trace 1- ( 1-Phenylcyclohexyl )-4-hydroxypiperidine (PCHP) 7t 4-Pheny] -4-piperidinocyclohexanol ~ PPC) 4-( 4' -Hydroxypiperidino )-4-phenylcyclohexanol (dihydroxy metabo1ite) 5-(l-Pheny~cycl ohexylamino~valeric acid Unidentified polar metabolites a Data f rom Cook et al. lg —58— 18% 3: 15% 38%

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had no neuromuscular b~ocklog effect; that indicates that Inca respir- atory depressant effect is riot central.46~62 Death from SNA intosicatlon appears to involve both cardlovas- cular and respiratory systema.46, SNA increases the effects of pentobarbital on both respiration ah heart rate. The depressant effects of SNA on the myocardium and on the Purkinje system are anta- gonized effectl~rely by epinephrine, but not by Metrazol (pentylene- tetrazol) and caffeine. Artiflcial respiration restored cardiac sta- bility and regularity. It was suggested that SNA interferes with oxygen utilization in animals. The circulatory and respiratory responses to SNA were considered to be mediated through the medulla obl ongata. 46, 6 2 The primary~action of SNA is on the brain.3 In low doses, it produces tranqullizat ion in the pigeon, cat, dog, guinea pig, and monkey. In high doses. it ~ ~ , causes repetitive conwisions. The inha- lation toxicity of SNA alla its base (SNIP) given as aerosols was stud- ied in mice. The LCtso for SNA was 22,000 mg~min/m3. Mice and possibly dogs were more susceptible than other species to the lethal effects of aerosols of SNA. The LCtsos for rats and guinea pigs were in Eocene of 115,000 mg~min/m3.46 Recent data of Davis et al. show that bonitrll e (PCC), increases the toxicity of SNA. 2i v ~ a pre sursor in Lathe sis of SNA. PiPeridinocYclohesanecar- Early studies (1957) by Parke, Davis in monkeys showed no evi- dence of tolerance or persistent toxic effects in monkeys after repeated parent eral administration at 1.25 or 5 mg/kg once a day, 5 d/wk, for 43 doses. No persistent toxic signs were seen in dogs after intramuscular injections at ~ mg/kg. Hematologic and biochemical values in the animals remained normal. More recent studies .8, 9, i2 at dosages that Droduce behavioral changes, have shown that chronic intr~acular or intraperitoneal administration of SNA results in development of tolerance to several test situations in several animal species. Tolerance to roughly 2-4 times as much SNA as initially given was evident in the behavioral effects of SNA in these species. Tolerance to SNA was also observed in intramuscular SNA self-admir~istrat ion Studies in the monkey . the development of tolerance, such pharmacologic f actors as dose pe r injection, injection frequency, and duration of chronic exposure were considered to play a more important role than behavioral factors (e. g., reinforcement lose) .9 In - Rhesus monkeys on chronic SNA in~cramuscular ad~ministration ha~re also been show to develop dependence. In experiments in which rhesus monkeys were given unlimited access to SNA, ani male self —60—

administered ao~o~mts sufficient to maintain continuous gross latoxi- cation for period.e of 50 ~ or loriger. Unlike other hallucinogens, SNA is anally self-adminlatered by monkeys. Abrupt discontinuation after long-term intoxication produced withdrawal symptoms that could be reversed by further SNA administration. The spectrum of symptoms varied somewhat among the anio~ale. Four hours after drug ad-1nistra- tion was stopped, SNA intoxication decreased and animals started eat- ing and became lese atasic. At B-12 h, they became markedly hyped responsive with a distinctive oculomotor hyperactivity that was dif- ferent from the nystagmus observed during intoxication. They usually refused preferred food. During the peak hour Talc 12-16 h) of with- drawa1, several of ache following abstinence symptoms were manifested: piloerection, tremor, diarrhea, continuous vocalization, hyperrespon- sivity, oculomotor hyperactivity, priapism, bruxism, and ear and facial twitches. Abdominal contraction, emesis, and convulsions occurred in some and. Food intake decreased by 50: during with- dra~l. The symptoms gradually diminished over the nest 24 h. Plasma concentrations of SNA during self-administration ranged from 105 to 208 ng/mi. The large margin of safety for this compound when given intra- venou~ly, intragastrically, intraperltoneally, and subcutaneously is decreased when the compound ts given in the aerosolized form. Toler- ance and dependence have been obeer~red after chronic admi nistration. NEUROPHARMACOLOGY The neurochemical effects of phencyclidine in animals have been well reviewed.3,22~45~5~53 A weary of these reviews and of some recent papers is presented below. At behavlora~y effective intraperitoneal doses (10 mg/kg), SNA has been reported to increase serotonin ~ 5-MT) concentrations in rat brain. 60 5-Hydroxyindoleacetic acid concentrations are first decreased and then increased. It has beer claimed that SNA 'causes a decrease followed by a compensatory increase in 5-HT turnover. How ever, these studies have been criticized on experimental grounds,36 and later studies showed that SNA produces a decrease. in 5-HT.58 No effects on aromatic amino acid decarbosylase and monoamine oxi- dase, wo enzymes 1~,ro1ved in 5-HT formation and destruction, were obeer~red SNA has been shown to reduce the concentration of the 5-HT precursor tryptophan. The uptake of 5-HT into rat brain prepara- tions is vitro and into the brain stem in viva is somewhat inhibited. There also seems to be a strain difference in response to SNA.6\ In general, acute administration of SNA does not seem consistently to cause marked changes in brain serotonin content or turnover. —61—

Similarly, the effects of SNA on the cat echolamine (norepineph- rine, epinephrine, dopamlne) systems have been widely studied, but the results are far from clear. SNA has been reported to increase rat brain t~rroslne59 aM to decrease rat brain noreoineDhrine (NE) and to increase dopamlne (DA) slightly.60 ~___, _ _ . Alvin cOtlflict irlg results are available. ~~ Apparently, changes in these biogenic Mines depend strongly on the brain region studied and the dose used. Changes in turnover rates of various catecholamlnes have been claimed, but methodologic difficulties prevent firm conclusions, 36 an later studies found no effects on NE turnover. The uptake of NE and DA into rat cortical preparations is markedly inhibited in vltro57 and in ~rivo29 by SNA; interestingly, SNA 1e 100 times more potent than ketamine in this respect. In vitro, SNA is a compet- itive inhibitor of striatal DA uptake and hypothalamic lIE uptake in rata. 29 Tyrosine hydroxylase is inhibited and the catecholamine metabolite homovanillic acid is decreased after acute SNA administra- tion; the latter ef feet is lost durlog chronic treatment . Adenylate cyclase and phosphodiesterase activities are decreased.55 Howe ever, most effects appear to involve DA. SNA increases the accumula- tion of 3~ethosyLyramine, and that indicates that the synaptic con- centrations of DA are increased. SNA also has been shown to affect the release and uptake of DA from brain slices in vitro.5 SNA decreases DA receptors in the brain. Behavioral studies have indi- rectly implicated the ir`,rolvement of the DA system.27 1h general, effects on NE and epinephrine neurons appear smaller than those or DA neurons. It might be concluded that one of the main actions of SNA is on the DA system.47 This might lead one to be concerned about the possibility that a parkinsonian syndrome will develop in later lif e; however, that see" unlikely. The ef fects of SNA on the acetylcholine (ACh) system have been less well studied.36 It has been claimed to raise rat brain ACh content slightly and transiently when given intravenoualy;47 how ever, other studies reported no effects on rat brain ACh content con- centrations when it was given tntraperitoneally.23 SNA does not release brain ACh. It has been shown to increase the activity of acety~cholinesterase in whole brain and to decrease choline acetyl- transferase (CAT) activity in the cerebellum56 while stimulating CAT in the hippocampus.53 The effects on CAT disappear during chronic ~creatmerlt. SNA has been shown to interact with muscarinic, nicotinic, and opiate receptors . 64 It inhibits the potassium- st imulated release of ACh from slices of the striates, but not from the hippocampus. Some evidence suggests that this inhibition of ACh release is mediated via DA. At the neuromuscular junction, SNA blocks neuromuscular transmission, prolongs the action potential, and potent fates muscle twitch. —62—

SMA does not affect the concentrations of histamine and glutamic acid, but it decreases the activity of glutamic acid decarbosylase a ~ reduces the concentrations of gA~-aminobutyric acid (GABA) in rat brain.25 GABA release is inhibited by acute administration, but not by chronic treatment.25 SNA increases serum creatinine phosphokinase content in stressed rats. Recently, SNA was found to decrease methionine-enkepha~ n content in the medulla oblongata and midbrain in the mouse, whereas other areas r-~alned unaffected.48 SNA seems to block K+ conductance speciflcally.l It also affects ion movements and has been show to be a potent blocker of both the Kin channel (ECso, 2.6 ~M) and the Na+ channel (ECso, 9.2 EM) .~63 In weary, SNA administered acutely has potent pharmacologic and toxic properties and thus must have pronounced effects on biochemical events in the brain. These actions are thought to occur predomi- ~antly at the synaptic Petrel. SNA seems to affect a number of neuro- transmitters, biochemlcals, and enzymes in the brain. Most evidence points to an action on the dopamine and acety~choline systems. These changes acount for observed abnorma~cies in behavior and ableness. In addition, SNA blocks excitable membrane chapels associated with impluse conduction, an do other compounds that induce reversible circmoral and distal paresthesias. However, neurochemical changes seem to revert to normal after the drug leaves the animal. Unfortunate fly, results of SNA studies are often inconclusive or even contradictory, ache nature of the exact actions of SNA on chemical characteristics of the braless is still poorly underatood. Some of the reasons for the conflicting results might be the use of acute ve . chronic administration, the use of dif ferent doses, the use of diverse ant mat strains and species, and the selection of specific brain areas. In addition, the -results of in vitro experiments cannot be easily extrapolated to the in vitro situation, because the high concentrations necessary to produce in vitro effects are not accumu- lated by the brain is living organisms. However, the main objection to extrapolating these data to man might well be that all studies use healthy, undisturbed rats, whereas, as is well known, SNA produces its most serious effects in people who are emotionally labile, have had psychiatric problems, or are polydrug users. SNA, an arytcyclohesylamine, belongs to a class of drugs known as dissociative anesthetics. Under the proper conditions of dosage and administration, it can act as a central nervous System (CNS) stimu- lant, a ENS depressant, a hallucinogen, an analgesic, or combinations of these.~4 Related ary~cyc:tohesyin-ines Share some of SNA's phar- macologic actions. The drug was originally developed as a general anesthetic agent, but it proved unsuitable for human use, because deliria often occurred as patients were emerging from anestheala. -63-

SNA had advantages as a surgical anesthetic, however: it can produce anesthesia with marked analgesia in the presence of normal pharyugeal and laryngeal reflexes, and it stimulates, rather than depresses, the respiratory and cardiovascular systems. It has therefore been useful in veterinary surgery, although recentig. its desirability as a drug of abuse has led to termination of its use bar most veterinarians. Ketamine, a phencycl1dine analogue with briefer duration of action, is currently in wide use as a surgical anesthetic.79 The pharmacology of SNA and related components has been reviewed recently.22~51 Early in the study of SNA, it was learned that its overt actions varied enormously from species to species--thus, it produced stimulation ire rats, convulsions irk dogs, and tranquility in rhesus monkeys. SNA has multiple effects on several neural systems, but evidence is increasing that at least some of its effects are mediated aria interaction with a specific brain receptor. Nero laboratories65~72 have independently identified SNA binding sites in rat brain mom branes. These bleeding Sites show specificity and saturability. Other drugs with affinity for these binding sites have behavioral effects similar to those of SNA, and their binding affinity corre- lates well with behavioral potency. The distribution of the binding sites is simi lar to that of the sigma subcategory of opioid recep- tors, aM other sigma agonists have substantial affinity for SNA binding sites . Several laboratories have recently been searching f or an eMogenous ligand for the binding sites/receptora; however, no positive findings have been published. Although these dearer opments how great promise for understanding the actions of SNA, further work is needed to clarify its comples actions. The pharmacologic aspects of SNA that make it desirable as a drug of abuse are unclear.4i The effects depend on dosage, but usually include sedation (light-headedness, atria, and slurred speech), cog- nitive distortions (disorganized thoughts, feelings of sensory isola- tion, a sense of unreality, and lose of ability to distinguish self from aurroundir~ge), and perceptual disorders (visual and auditory hallucinations and numbcesa). Many users become appropriately frightened or angry. Delusions of persecution may occur, arid violent behavior may be directed at oneself or at another person or an ob ject. At higher doses, SNA's effects may progress from severe agi- tation through stupor to coma and death. Autonomic effects are striking. SNA produces tachycardia, hypertension, hypersalivation, sweating, and fever. lathe acute ef fects persist for 4-6 h. 20 Ha' ~ ucinogenlc drugs like LSD are not reinforcing in animals, in that they will not self-administer these drugs. SNA, however, is self-administered in large quantities by monkeys equipped with intra- venous catheters when access is unlimited. Tolerance of the acute —64—

effects of SNA was shown to develop in monkeys and has been clinl- cally reported in ~an. ~ ter SNA is self-admlulatered by monkeys for 20-30 d, abrupt ceseatlon produces physical and behavioral elgna of withdrawal.7, 4 Thus, there is evidence of both tolerance of and physical dependence on SNA, but it is not clear that persistent daily use produces dependence in human subjects. SNA produces an acute psychosis with some similarity to that seen in schizophrenic disordere.35 In some users, this achizophre~ alike psychosis persists for weeks after the ingestion of the drug.2 In come cases, a patient's first psychotic episode has been precipitated by SNA and "e been followed" by long-term schizophrenic symptoms without additional SNA. However, results of predrug examinations of these patients were not available. SNA heat been given experimentally to known achizophre~ce, who were forms to be very senalti.'re to the induction of long-1 asking psychotic symptoms bar the drug. It is not known whether single doses of SNA can produce long-lasting pag~chotic behavior in normal persons or whether this can occur only in persons with pre-esisting mental disorders.42 Chronic c users of large doses of the street drug PCP containing SNA have been reported to undergo personality changes, cognitive impairment, ami Slurred speech for 6-12 mo after stopping the drug. Clinical repose have included the presence of chronic anxiety, depression, anti schizophrenic disorders in former long-term SNA users. Agaln, these reports were based on users examined after their experience filth the drug, and we have no knowledge of their predrug condition. GENETIC AND REPRODUCTIVE EFFECTS Mutagenicity Information on the mutagenic potential of SNA is almost com- pletely lacking. A single abstract reported the cytogenetic effect of chronic use of the drug over 2-3 yr by one mate and four females 18-26 yr old. The most frequent route of administration was inhala- tion of spoke from a blend of SNA and marlduana. ~- ~ No chromosomal abnormalities were found in this limited investigation.28 A cytogenetic study was performed on a group of drug-using par- ents of children with limb-reduction defects or of livaborn triploid infants. SNA as contained in the street drug used was implicated. An lacrease in ploidy was observed that decreased in time when suc- cessive peripheral lymphocyte samples were taken. The published abstract contained no specific data.67 -65-

Given the lack of critical studies of this chemical, no conclu- sion can be made as deco its mutagenic activity. To determine the mutagenic potential of SNA, a battery of available in ~ ro an in vitro studies should be performed, including cytogenetic Studies in cultured mama cell lines and in Alto bone sparrow cells from rodents. In vitro microbial assays with and without activation should be undertaken, to determine whether this chemical causes gene mutations. In vitro and in vitro repair studies would also be infor- mati~re. Additional studies, including ache dominant-lethal assay and body-fluid analysis in rodents and in Kilo a" in bistro abduct forma- Lion, could be undertaken. These studies, with cell tra~foro4tion studies in m~lian cell lines, would also indicate the probability of carclooge~c ef facts . Teratogenic-Reproductive Ef facts Walker and Selg67 reported two ciu8ter8 of agates, limb- reduction defects and liveborn triploid infants born to parents involved in the drug culture. Retro spective investigation suggested that the mothers had ingested street drugs controlling SNA during the early first tri - ster of pregnancy. Acute placental transfer of [3H]SNA was studied in pregnsat rabbits and mice; the chemical readily crossed the placental barrier. In mice, peak concentrations were found 2 h after administration, and fetal concentration was 10 times as high as that in maternal tissue. lactating mice, the chemical was found in breast mink at a concen- tration 10 times that found in plasma.50 Jordan et al.38 reported significant embers of gross anom- a~ies--1ncludi~ dysplasia of ache extremities, microgDathia, cranial dyplasia, and cleft palate--after SNA was given intraperitoneally to rats on days 6-15 of gestation. Sum Err No definitive studies have been conducted in human or experi- mental animals to determine reproductive or genetic effects of $NA. Anecdotal studies (e.g., that of Golden _ al. ,30 who, in a case report of an infant whose mother used SNA, speculated that SNA was related to abnormal behavior and development of dysmorphology and spastic quadriparesis in the infant) and ache limited investigations reported here indicate that this chemical may be teratogenic. If 5NA is shown to be teratoge~4c, further studies would have to be conduc- ted to determine whether the teratogenic effect has a genetic basis. —66—

DUPED AND LOIlG-TERM EFFECTS . . SNA, in its brief use as a dissociative anesthetic in human, produced an excessive number of cases of emergent delirium and post- operati~re beha~rloral disruption. It was eventually withdrawn from medical practice and from veterinary practice in most states. Since the mid-1960s, as PCP, a street drug of unknown purity, it has been a drug of abuse an has been used as an adulterant in other street drugs sold as cocaine , tetrahydrocannabinol ~ THC), and a variety of hallucinogens. Its illicit use and associated mortality rose sharply during 1975-1981. During the last 3 ye, mention of PCP abuse and related mortality has decreased, according to the Date system quarterly reports (Drug Abuse Warning Network, NIDA, Rock~i11e, Md., 1982~. It must be recalled that most PCP conemere never come to the attention of health-care personnel. Information about long-term effects of SNA is derived from two sources: its administration as an anesthetic and its chronic use as a street drug. As to the latter, it must be noted that PCP rarely occurs in a pure form and commonly is abused with other subetances, such as THC and cocaine. Data on drug abusers do not permit the construction of a dose- response curve. However, blood and urine concentrations of SNA after emergency hospitalization may permit some extrapolation to the quan- tities consumed.24 Some 30 phenc yclidine-1ike Compounds are known to produce paycho- physica' effects resembling those of SNA. Of these, ketamlne (Ketalar, Keta ject), a chlorophenyl methylaminocycl ohexanone, is cur- rently used fairly widely as a dissociative anesthetic in humans. Therefore, its use can provide clinical information about undesired effects of single doses of the phencyclidine series. ~ number of possible long-term or delayed effects of SNA can be listed on the basis of esperles~ce witch adverse reactions in drug abusers and ire anesthesiology patients. · Possible psychotic reactions. · Organic brain damage as a residuum of status epilep~cicus or cerebral hemorrhage secondary to acute hypertension resulting from the toxic effects of SNA use.~° · Residual cerebral or other tram in connection with the intoxicated state. —67—

Prolonged Psychotic Reactions A achizophre~form psychosis can follow administration of single or multiple, U8Uall, high, doses of Shy. Glen and Young reported on nine patients seen oared a 13-mo period at an Army hospital with SNA psychosis within a week of multiple esposures.2 Despite anti- paychotic treatment, three had not recovered from the residue of their psychosis 30, 60, and 90 ~ later. Erard et al.25at43 believe that the paychoale is a specie form of an acute schizophrenic episode activated by the drug in come sus- ceptible persons. Luisada estimated that 1-5X of the population may be susceptible (I`uisada, P.V. persona communication). Atthough the Army volunteers were psychologically screened, preachizop~en~c test subjects may have been included. As noted, the psychotic reactions associated with SNA typically occur immediately or soon after con- sumption of the drug. If serious mental consequences were not observed during the immediate followup period or during the later Army tour of duty, it seeme unlikely that a delayed SNA psychosis occurred. That a low dose was administered only once or a very few times in the Army research does not completely rule out the possibility that a Alterable subject might have developed a delayed psychotic reation. The dose given by mouth in Edgewood experiments was up to 5 m~-a modest amount, but one that shoed produce Some symptoms of intosica- tion in most noneoleran~c aubJecta.t Other subjects inhaled unknot amounts in aerosol form. Table 3-4 lists the clinical effects of various doses of SNA. Doses of 250 me as`d more have been ingested by chronic users after the development of tolerance. In comparison, 5-10 me intravenously can result in delirium, 20 mg in coma, aDd 50 mg in condo. Organic Brain Damage Case reports lndlcate that chronic organ) c brain impairment has resulted fros' frequent, latensive SNA use.3~26 Carlin et al.~° studied 12 chronic users, a like number of polydrug users who did not use SNA, and a group of non~rug-usis~g controls. All the drug users had been abstinent for at least 3 wk. The are rage length of abetl- nence of the SNA group was 27 mot Six in the SNA group, flue in the polydrug group, a'K1 none in the control group showed mild neuro- psychologic impairment. The most frequent effects were difficulties in abstracting aM impairment of complex psychomotor skids. In the amounts given to the experimental sub jects at Edgewood, i is highly unlikely that ma jor chronic organic brain syndrome deve- loped, inasmuch as no status eplleptlcus or cerebral hemorrhage —68—

TABLE 3-4 Clinical Ef fects of Various Oral Doses of SNAa Do se, mg Ef fee to . 5-10 10-20 50 100 Atasia, nystagmus, mood changes, hallucinations, vomiting, analgesia, paresthesias; onset, 1-2 h; duration, 4-8 h Stupor, eyes open, random movements, resting horizontal or vertical nystagmus, hyperreflexia, hypertension; onset, 0.5-1 h; duration, B-24 h Deep coma, chills, nystagmus ~ eyes open or closed, hypertension, labored breathing, seizures; duration, up to 4 d Lethal; 3-10 d of respiratory depression, hypertensive crisis, cerebral bleeding, loss of deep tendon reflexes, decreased reread and liver function l a Data from Hollister; Vehicle unknown occurred after drug administration. However, the development of more subtle neuropaychologic impairment, such as difficulties in cognitive func tiering and the impairment of complex psychomotor skills, cannot be ruled out, because these were not evaluated. Residual tram ire Connection with the Intoxicated State The behavioral toxicity that can accompany SNA intoxication can lead to head and other injuries and perhaps leave permanent residue. Such injury would occur during intoxication or delrium and would have been recorded in the Edgewood sub jects ' charts. No such incidents were recorded. Food and Drug Administration Reports of Adverse Reactions Only two reports are available on neuropaychiatric complications reported by anesthesiologists to the Food and Drug Administration in connection with SNA. One involved conwisions, and the other, —69—

psychosis. In addition to SNA, ketamine produced untoward reactions. It is clear that psychosis, hallucination, and convulsions are the most frequent immediate complications. These FDA reports did not include the doses of SNA or the dura- tion of the adverse reactions. Ketamine doses ranged from 80 to 575 me intravenously or intramuscularly in the cases with postoperative adverse reactions. Neither the~FDA (for proprietary reasons) nor Parke, Davis and Co. provided any other information about SNA despite requests. Summary The target organs that may be involved in prolonged or delayed effects of SNA exposure are the brain and cardiovascular system. At high doses taken over a prolonged period, the effects on the brain are immediate and transitory, but occasionally a prolonged psychotic state is recorded. Neuropaycholologic effects include psychosis, a paranoid state, convulsions, and depression. Irreversible effects, such as organic mental disorders, might be encountered after frequent consumption. A prolonged or irreversible effect might be geese when a schizophrenic process is precipitated af ter exposure to SNA. The cardiovascular effects of acutely administered high doses inch ude hypertension and tachycardia. These are transient and do not leave permanent residue, except after a cerebral hemorrhage. At the dosages used at Edgewood, it is not expected or likely that any long-term or delayed effects have occurred or will occur, because immediate prolonged mental or cardiovascular ef fects did not take place within a week of drug administration. However, no follow- up clinical data are available to confirm this. Therefore, the de~re- lopment of more subt ~ e neuropsychologic impairment, such as dif f icul- ties in cognitive functioning and impairment of complex psychomotor skills, cannot be ruled out, as these were not evaluated immediately af ter administration of the test drug arid cannot now be evaluated in the framework of this Study. Results from the questio ~ aire now being analyzed may shed light on some of these matters. EFFECT S ON VOLIJNTEELS The following summary of acute effects in humans is based prima- rily on a review of the charts in the clinical files at Edgewood. Like many clinical records, these vary greatly in extent of detail, ranging from sketchy and incomplete notes or one-line summaries to records that could serve as models for research documents. Indepen- dent chart reviews by NRC scientists provided some cross-checks on —70—

the completeness of data. In addition, technical reports prepared at the time of the experiments provided summary data on the SNA esperimenta. The SNA research going on throughout the world at about the time of the Edgewood studies is relevant to this study. lathe experiments at Edgewood were not unusual and did not involve extraordinary doses (see Table 3-1) or Special populations of volunteers, compared with experiments in the laboratories and clinics of scientists and clini- cal researchers throughout the world. When the Army began experiments at Edgewood with SNA in the late 1950s, a fair amount was already known about it, because of the clin- teal Sculler sponsored by Parke, Davis. Reports pub' ished between 1958 and 1972 described the effects of SNA given to more than 1,500 people. Most were surgical and obstetrical patients given large, generally anesthetic doses ranging from ~ to 70 me intravenously. A substantial renumber of children received SNA, sometimes repeatedly, for anesthesia during burn-dressing changes or tonsillectomies. Over 200 psychiatric patients, including over 100 schizophrenics, were given doses averaging about 6 me (3-18 ma) intravenously, orally, or intramuacularly. Over 100 normal volunteer research subjects repre- senting a variety of student populations were given average doses of ~ mg intravenously or orally. Multiple doses were given to psychi- atric patients to facilitate therapeutic sessions. Repeated doses were given chronically to paychlatric patients for periods of 4-6 wk. Of seven subjects who underwent a water loading test, those treated with SNA at 0.1 mg/kg before a saline infusion showed evi- dence of inhibition of a~.tidiuretic hormone secretion. Another group of sub] ec to were tested on the treadmill at high temperature (100°F) before and af ter receiving oral doses of 5 and 10 me of SNA. SNA at these doses did not significantly add to the _. induced heart-rate changes, metabolic rate, evaporative heat losses, or tolerance times and in general did not interact greatly with the temperature 8tre88. The only studies done at Edgewood that were not similar to those done in many civilian settings involved the administration of SNA by inhalation. SNA was dispersed in a methylene dichloride solution and delivered to the subjects as an aerosol in a small inhalation cham- ber. Nineteen volunteers were exposed to SNA and nine others to SNB for periods of 0.5-3 min. The concentration varied, but averaged 100 mg min/~3, to produce a retained dose of approximately 100 ug/kg. At 25-62 ~g/kg, subjects had feelings of unreality--dream- like states with perceptual size changes. Both horizontal and verti- cal nystagmus developed. Affect and mood changed and were variable, rarefying from euphoria to sullen withdrawal. Some subjects were talk- ative and uninhibited, others passive and withdrawn. At 100 ~g/kg, —71—

the aforementioned symptoms became more intense and were accompanied by visual disturbance, blurred vision, ataxia, limb paresthesias, and memory impairment. Sub jects rapidl y became noncommunicative. At approximately 100-~80 ,,g/kg, analgesia, nausea, and vomiting devel- oped rapidly. Four subjects were given the largest dose ~ 225 ug/kg ); collapse and prostration occurred in three and incapacitation in the fourth, and convulsions did not occur. They recovered over the next few hours. In these aerosol studies, dose was measured in milligrams of a 2- to 5-pm aerosol per minute per cubic meter. It was estimated that the anesthetic dose was about 20-50 me min/m3. Exposures were 250-~8 mg/m3 for the most part over 3-4 min. with Ct's of 249- 2,955 mg min/m3. In the se experiment a, as in most of the o~chers at Edgewood, rou- tine biochemical tests were used to screen for unexpected hepatic or renal toxicity. No clinically significant abnormal! ties were noted in the records. In wary, the Edgewood studies of SNA demonstrated a dose- dependent effect on a number of systems. Blood pressure increased, respiratory minute volume increased, and heart rate increased with no evidence of arrhythmia. At moderate doses, reflex activity was not impaired. An outstanding effect of the drug was amnesia, which was one of the properties that first attracted investigators' attention to it. Excitation and arouse, occurred in some sub jects and seda- tion, depression, and withdrawal in others at the same dose range--a well-known variability in response to SNA. Body boundaries were altered, feelings of estrangement and loneliness occurred in some, and an alcoholic-like euphoria occurred in others. Thought was gen- erally disorganized, with an inability to maintain set. Some sub- ; ects appeared catatonic and reported dream-like experiences at the highest doses. Performance in tasks that involved sequential and organized thinking was impaired. Perceptual discriminat ions were altered. Psychomotor retardation was evident, with distractibility and slowing in task performance. No subjects became overly asser- tive, hostile, or unmanageable . In general, the signs and symptoms were relatively short-lived, disappearlag at 6-8 h, although at the highest doses in occasional subjects symptoms persisted for 24 or 48 h, or even longer. The variation in response observed from the beginning of SNA research in civilian studies was evident in the Edgewood studies. REFERENCES . . . . 1. Albuquerque, E.X., Aguayo, L.G., Warnick, J.E., Ickowicz, R.K., and Blaustein, M. P. I,nteractions of phencyclidine with ion charmers of nerve arid muscle: behavioral implicat ions. Fed. Proc ., Fed . Am. Soc . Exp . Biol . 4 2 : 2584-2589 , 198.] . —7 2—

Allen, R.M., and Young, S.J. Phencyclidine-induced psychosis. Am. J . Psychiatry 135 :1081-1084 , 19 7%. Aniline, 0., and Pitts, F.N., Jr. Phencyclidine (PCP): A review and perspectives. Crit. Rev. Toxicol. 10 :145-177, 1982. Aniline , 0 ., Pitts , F. .N., Jr., Allen, R. E., and Burgoyne, R. Incidental intoxication with phencyclidine. J. Clin. Psychiatry 41: 393-394, 1930. 5. Ary, T.E., ad Komiskey, H.L. Phencyc~ idine: Inhibitlon of synaptosomal uptake and release of previously accumulated 3H- catecholamines. Pharmacologlat 21: 241, abet . no . 506, 1979. 6. Bailey, D . N., Shaw, R. F., and Cuba , J . J. Phencyclidine abuse : Plasma levels and clinical findings irk casual users and in phen- cyclidine-related deaths . J. Anal . Toxicol . 2: 233-237, 1978. / ~ Balater, R.L., and Chair, L.D. The behavioral effects of phen- cyclidine in animals. In Petersen, R. C., and Stiliman, R. C., editors. Phencyc~idine (PCP) Abuse: Art Appraisal. National Institute on Drug Abuse, Rockville, Md. NIDA Research Monograph 21, 19 7B, p . 5 3-6 5. 8. Ba~ster, R.L., and Chait, L.D. The behavioral pharmacology of phencyclidir~e. Clin. Toxicol. 9: 513-528, 1976. 9. Balster, R.L., and Woo1,rerton, W.L. Tolerance and dependence to phencyclidine . In Domino , E. F ., ed. PCP ~ Phencyclidine): Historical and Current Perspective s . Ann Arbor, MI .: NPP Books. 1981. p. 293-306. 10. Carlin, A. S., Grant, I., Adams, K.M., arid Reed, R. Is phen- cyclidine (PCP) abuse associated with organic mental impairment? Am. J. Drug Alcohol Abuse 6:273-281, 1979. 11. Carroll, F.I., Brine, G.A., Boldt, K.G., Cone, ~.J., Yousef- ne dad, D., Vaupel, D.B., and Buchwald, W.F. Phencyclidine metabolism: Resolution, structure, and biological activity of the isomers- of the hydroxy metabolize, 4-phenyl-4-~1- piperldinyI)- cyclohexanol. J. Med. Chem. 24:1047-1051, 1981. 12. Chait , L . D ., and Balat er, R. L . The ef fee ts of acute and chronic phencyclidine on schedule-coD;trolled behavior in the squirrel morlkey. J. Pharmacol. Exp. Ther. 204: 77-87, 1978. 13 . Chen, G . Pharmacology of l-( phenylcyclohexyl) piperidine-HC1 . Fed. Proc., Fed. Am. Soc. Fop. Biol. 17 : 358, abet . no . 1410 , 1958. —73—

14 . Chen, G .M ., Ensor , C . R., Russell , D., and Bohner , B . The phar- macology of 1-~1-phenylcyclohe~yl) piperidine-HCl. J. Pharmacol. Exp. Ther. 127: 241-250, 1959. Chen, G. M., and Weston, J.K. The analgesic and anesthetic ef feet of 1-( I-pheny~cyclohe~yl) plperidine-HC1 on the monkey. Anesth. Analg. 39 :132-137, 1960. 16 . Cohen, L. S ., Gosenfeld , L., Wilkins , J., Kammerer, R. C., and Tachiki, K. Demonstratlon of an amino acid metabolite of phen- cyclidine. N. Engl. J. Med. 306 :1427-142B, 1982. 17. Cohen, M.L., Chan, S.L., Bhargava, H.N., and Tremor, A.J. Inhibition of mammalian brain acetylcholinesterase by ketamine. Biochem. Pharmacol. 23:1647-1652, 1974. 18. Cohen, S. Angel dust. J. Am. Med. Assoc. 238: 515-516, 1977. 19. Cook, C.E., Perez-Reyes, M., Jeffcoat, A.R., and Brine, 1).R. Phencyclidine disposition in h~ns after amall doses of radio- labeled drug. Fed. Proc. Fed. Am. Soc. Exp. Biol. 42: 2566-2569, 1983. 20. Davies , B. M., ar~d Beech, H.R. The ef feet of 1-arylcyclohe~yl- amine ~ sernyl ~ on twelve normal volunteers . J. Ment. Sci . 106: 912-924, 1960. 21. Davi s , W. M., Borne , R. F ., Hacke t t , R. B ., and Wat ers , I . W. Piperidinocyclohexanecarbonitrile (PCC): Acute toxicity alone and potentiation of the lethality of phencyclider~e (PCP). Fed. Proc., Fed. Am. Soc. E:cp. Biol., 38 :435, abst. no. 1095, 1979. Domino, E. F., ed. PCP (Phencyclidine): Hi~torical add Current Perspectives. Ann Arbor, MI.: NPP Books, 1981. 537 p. 23. Domino. E.F., and Wilson, A.E. Psychotropic drug influences on brain acetyIcholine utilization. Paychopharmacologia 25: 291-29B, 1972. 24. Done, A.K. ,. Aronow, R., and Miceli, J.N. The pharmacokinetics of phencyclidine in overdosage and its treatment . In: Petersen, R. C., and Stillman, R. C., editors. Phencyclidine ~ PCP) Abuse . An Appraisal. National Institute on Drug Abuse, Rock~rille, Md. NIDA Research Monograph 21, 1978, p. 210-217. 25. Dye, D.J., and Taberner, P.V. The effects of some newer anaes- thetice on the in vitro activity of glutamate decarboxylase and GABA tranaminase in crude brain extracts and on the le~rele of amino acids in vivo. J. Neurochem. 24: 997-1001, 1975. —74—

25a. Erard, R., Luisada, P. V. and Peele , R. The PCP psychosis : pro- longed into~lcation or drug-precipitated functional illness? J. Psychedelic Drugs 12: 235-251, 1980. Fa''m~ n, M . A., and Fatima n, B . J . Chronic phencyclidine ~ PCP ~ abuse : A psychiatric perspective. In Domino, E. F., ed. PCP (phencyclidine): Historical and Current Perspectives, Ann Arbor, MI .: NPP Books . 1981. p . 419-436 . 27. Finnegan, K.T., Kanner, M.I., and Meltzer, H.Y. Phencyclidine- induced rotational behavior in rats with nigrostriatal lesions and its modulation by dopaminergic and cholinergic agents. Pharmcol. Biochem. Behav. 5: 651-660, 1976. 28. Foin, A., and Fisher, K.M . Cytogenetic ef fects of the popular drug PCP. Genetics 77: S22, 1974. 29 . Carey , R . E., and Heath , R . G . The ef f ec ts of phencyclidine on the uptake of 3H-catecholamines by rat striatal and hypo- thalamic synaptosomes. Life Sci. 18:1105-1110, 1976. 30. Golden, N.L., Sokol, R.J., and Rubin, I.L. Angel dust: Possible effects on the fetus. Pediatrics 65:18-20, 1980. 31. Hitzemann, R.J., Loh, H.H., and Domino, E. F. Effect of phen- cyclidine on the accumulation of 14C-catecholamines formed from 14C-tyrosine . Arch. Int . Pharmacodyn. Ther. 202: 252-25B, 197 3. 32. Ho, I.K., Onoda, K., and Flint, B.A. Effect of chronic adminis- tration of phencyclidine on hepatic mixed-function o~cidases in the mouse . Biochem. Pharmacol. 30: 545-547, 1981. 33. Hollister, L.E., ed. Phencyclidine (PCP) use: Current prob- lems. Ink. Drug Therapy Newsl. 14:17-20, 1979. 34. James , S . H., asked Schnoll, S . H. Phencyclidine : Tissue distribu- tion ire the rat. Clin. Toxicol. 9: 573-582, 1976. 35 . Jasinaki , D. R., Shannon , H . E ., Cone , E . J ., Vaupel , D. B ., Risner , M.E., McQuinn, R.L., Su, T-P., and Pickworth, W. B. Inter- disciplinary studies on phencyclidine. Ire Domino, E. F., ed. PCP (Phencyclidine): Historical and Current Perspectives. Arson Arbor , MI .: NPP Books . 19 81. p . 331-400 . 36. Johnson, K. M. Neurochemical pharmacology of phencyclidine . In Petersen, R.C., and Stiliman, R.C., editors. Phencyclidine (PCP) Abuse: An Appraisal. National Institute on Drug Abuse, Rockville, Md. NIDA Research Monograph 21, 197S, p. 44-52. —75—

37. Johnson, K.M., arid Balater, R. L. Acute and chronic phencycli- d~e administration: Relationships between biodispo6itional- factors and behavioral ef facts. Subat. Alcohol Actions/Misuse 2: 131-142, 1981. 38. Jordan, R.L., Young, T.R., and Harry, G.J. Teratology of phen- cyclidine in rats: Preliminary studies . Teratology 17: 40A, Abst ., 19 78. 39. Kal i r, A. Structure activity relationships of phencyclidine derivatives . In Domino, E. F., ea., PCP ~ Phencyclidine): Historical and Current Perspectives . Ann Arbor, MI .: NPP Books. 1981. p. 31-46. 40. Kammerer, R.C., and Cho, A.K. The biotransformation of phen- cyclidine. In Domino, E.F., ed. PCP (Phencyclidine) : Historical and Current Perspectives. Ann Arbor, MI.: NPP Books. 1981. p. 177-189. Lerner, S.E., and Burns, R.S. Phencyclidine use among youth: History, epidemiology, and acute and chronic intoxication. In Petersen, R. C ., and Stillman, R. C., editors. Phencyclidine (PCP) Abuse: An Appraisal. National Institute on Drug Abuse, Rockville, Md. NIDA Research Monograph 21, 197B, p. 66-118. 42. Luby, E.D., Cohen, B.D., Rosenbaum, G., Gottlieb, J.S., and Kelly, R. Study of a new schizophrenomimetic drug--sernyl. AMA Arch. Neural . Psychiatry 81: 36 3-369, 1959 . Luisada, P. V. The phencyclidine psychosis: Phenomenology and treatment. In Petersen, R. C., and Stillman, R. C., editors. Phencyclidine (PCP) Abuse: An Appraisal. National Institute on Drug Abuse, Rockville, Md. NIDA Research Monograph 21, 1978. p. 241-253. 44. Mart in, B.R. Long-term disposition of phencyclidine in mice . Drug Metab. Dispos. 10 :189-193, 1982. 45. Martin, B.R., Chairman. Symposium: Pharmacokinetics and mech- ani em of action of phencyclidine . Fed . Pro c . Fed . Am. Sac . Exp . Biol. 42: 2559-2589, 1983. 46. McNamara , B. P., Kimura , K. K., and Wiles , J. H. Summary Report on Project New Year: Section III. U.S. Army Chemical Corps Research and Development Command. U. S. Army Chemical Warfare Laboratories. Army Chemical Center, Md. CWL Special Publication 4-17. 1960. p. 25-62. —76—

1 47. Meltzer, H.Y., Sturgeon, R.D., Simono~ric, M., and, Fessler, R.G. Phencyclidir~e as an indirect dopamine agonist. In Domino, E. F ., ed. PCP ~ Phencyclidine): Historical and Current Perapec- tives. Ann Abor, MI.: NPP Books. 1981. p. 207-242. 48 . Nabeshima , T ., Hiramatsu , M., Amano , M., Furukawa , H., and KameyamA, T. Phencyclidine-induced decrease of methionine- eakephalin levels in mouse brain. Eur. J. Pharmacol. 86: 271-273, 1982. 49. Nambeshlma , T., Sivam, S .P ., Tai, C.Y., and Ho , I. K. Develop- ment of dispositional tolerance to phencyclidine by osmotic minipump in the mouse. J. Pharmacol. Methods 7: 239-253, 1982. 50. Nicholas , J.M., Lipshitz , J., and Schreiber, E. C. Phencycli- dine: Its transfer across the placenta as well as into breast milk. Am. J. Obstet . Gynecol. 143 :143-146, 1982. Petersen, R. C., and Stillm~n, R. C., editors. Phencyclidine (PCP) Abuse: An Appraisal. National Institute on Drug Abuse, Rockville, Md. NIDA Research Monograph 21, 1978. 313 p. 5 2 . Pit ts , F . N ., Jr., Allen, R . E ., Aniline , O ., and Yago , L. S . Occupational intoxiciation and long-te`-~ persistence of phen- cyclidine (PCP) in law enforcement persounel. Clin. Toxicol. 18: 1015-10 20, 19 81. 53. Pradhan, S .N. Phencyclidine ~ PCP): Basic and Clinical Aspects. Consultant' s Report to be published. (in press), 1983. 54. Slif er , B . L., Woolverton, W. L ., and Balster, R. L. Behavioral dependence in Rhesus monkeys with chronic phencyclidine adminis- tration. In Harris, L.S., editor. Problems of Drug Dependence, 1981. National Institute on Drug Abuse, Rockville, Md. NIDA Research Morlograph 41, 1982. p. 184-189. S 5 . Smi th, R . C ., Leelavathi , D . E., Hau , L., Ho , B . ~ ., Tansey , W., Taylor, D ., and Biggs , C. Acute versus chronic administration of phencyclidine: Ef fects on beha~rior and brain biochemistry. Ir~ Domino , E . F ., ed . PCP ~ Phencyclidine ): Historical and Curren~c Perspectives. Ann Arbor, MI.: NPP Books. 1981. p. 243-291. 56. Stringer, J.L., and Guyenet, P.G. Effec~c of phencyclidines on hippocampal pyramidal cells. Brain Res. 252:343-352, 1982. 57. Taube, H.D., Montel, H., Hau, G., and Starke, K. Phencyclidine and ketamine: Comparison with the effect of cocaine on the nor- adrenergic neurones of the rat brain cortex. Naunyn-Schmiede- bergs Arch. Pharmacol . 291: 47-54, 1975. —77—

58. Tonge , S . R., and Leonard , B . E . Partial antagonism of the behavioural and neurochemical ef fects of phencyclidine by drugs affecting monoamine metabolism. Psychopharmacologia 24: 516-520, 19 72. 59. Tonge, S .R. and Leonard, B. E. The ef feet of some hallucinogenic drugs on the amino acid precursors of brain monoamines. Life Sci. 9 :1327-1335, 1970. 60. Tonge, S .R. and Leonard, B. E. The ef fects on some hallucino- genic drugs upon the metabolism of 5-hydroxy-tryptamine in the brain. Life Sci. 8, Part 1: 805-814, 1969. 61. Tonge, S .R. and Leonard, B . E. Variation in hydroxytryptamine metabolism in the rat: Ef fects of the neurochemical response to phencyclidine. J. Pharm. Phar~acol. 23: 711-712, 1971. 62. tum-Suden, C. Metker, L.W., and Witls, J.H. Report on the cir- culatory and respiratory ef fects of SNA. U. S . Army Chemical Corps Research and Development Command. Chemical Research and Development ~boratories. Army Chemical Center, Md. Technical Report CRDLR 3022. 19 60. 16 p . 63. Vincent, J.P., Bidard, J.N., Lazdu~ki, M., Romey, G., Tourneur,Y. and Vignon, J. Identification and properties of phencyclidine-binding sites in ner~rous tissues. Fed. Proc. Fed. Am. Soc. Exp. Biol. 42: 2570-2573, 1983. 64. Vincent , J. P., Cavey, D., Kamenka , J,~., Geneste , P., and Lazdunski, M. Ir~teraction of phencyclidine with the muscarinic and opiate receptors in the central ner~rous system. Brair~ Res. 152: 176-182, 1978. 6 5. Vinc ent , J. P ., Kartalovski , B ., Ger~e st e , P ., Kamenka , J . M., and Lazdunski, ~I. Interaction of phencyclidine ~ "angel dust" ~ with a specif ic receptor in rat brain membrar~es. Proc. Natl. Acad . Sci. USA 76 :4678~4682, 1979. 66. Vincent , J. P., Vignon, J., Kartalo~rski , B., and Lazdunski , M. Receptor sites for phencyclidine in mammalian brair1 and peri- pheral organs. In Domino , E. F., ed. PCP (Phertcyclidine): Historical and Current Perspectives . Ann Arbor, MI .: NPP Booka. 1981. p. 83-103. 67. Wallcer, F.A., and Seig, J.~. Phencyclidine and envirorlmental teratogen. Mutation Res. 21:348-349, abst. no. 8, 1973. 68. Weinstein, H., Masyani , S ., Glick, S .D., and Meibach, R. C. Integrated studies on the biochemical, beha~rioral and molecular pharmacology of phencyclidine--A progress report. In Domino, —78—

E.F., ed. PCP (Phencyclidine): Historical and Current Perspectives. Ann Arbor, MI.: NPP Books. 1981. p. 131-175. 69. Wilson, A.E., and Domino, E.F. Plasma phencyclidine pharmaco- kinetice in dog and monkey using a gas chromatography selected ion monitoring assay. Biomed. Mass Spectrom. 5:112-116, 1978. 70. Winters, W.D. Epilepsy or anesthesia with ketamine . Anesthesiology 36:309-312, 1972. 71. Woodworth, J.R., Owens, S.M., and Mayersohn, M. Phencyclidine ~ PCP) disposition kinetics in dogs: Preliminary observations . Res. Commun. Subst. Abuse 4: 49-5B, 1983. 72. Zukin, S.R., and Zukin, R.S. Specific t3H] phencyclidine binding in rat central nervous 33y~t~m. Proc. NatI. Acad. Sci. USA 16: 5372-5376, 1979. REVIEW OF AVAILABLE INFORMATION ON DIBENZOPYRANS: DIbIETHYLHEP'IYLPYRAN AND RELATED COMPOUNDS CHEMISTRY The structure of the active principle of the cannabis pi ant ~ Cannabis saliva), A-9-tetrahydrocannabinol, or THC ~ Figure 3-2), was elucidated in the mid-1960s, 11, 22 ~ 42 However, Adams and Baker2 and 'Todd and co~orkeral2 in 1940 independently syDthe- sized a 06a, lea congener that dif fered from the natural material by the position of the cyclic double bond. A series of homologues of that congener was prepared in which the alkyl side chain on the aro- matic ring was varied, and the compounds were tested for their capa- city to produce ataxia in dogs .3 ~ 5 The most active compound was dimethylheptylpyran ~ D~P), the 1, 2-dimethylheptyl analogue (EA 1476) . Table 3-5 shows the relative potencies of several natural and synthetic d ibenzopyrans . 3 ~ 5 TABLE 3-5 Relative Potencies of Several Dibenzopyrans4 Potency (Capacity to Compound Produce Atagia in Dogs) Synthetic C5H11 Acetate (natural THC acetate) Natural THC by hydrolysis of acetate Natural THE from cannabidiol (Dl1HP) -79- 512 1.00 (standard) 14.6 7~8 7.3

Because DIP contains three asymmetric carbon atoms, it can exist as four diastereoisomeric racemates, each consisting of a (+) and a (-) isomer. These isomers, Synthesized by Aaron and Ferguson1 and isolated as the acetates, have been assigned the designations EA 2233-1 through EA 2233-~; the racemic mixture was designated EA 2233 (Figure 3-2~. ~ mixture of isomers 2 and 4 was designated EA 2233-24. Table 3-6 lists the optical rotations of the isomers . DIP is a colorless or pale yellow viscous oil that readily undergoes autoxidatlon. It is insoluble in water, but soluble in alcohols, benzene, and nonpolar solvents. Because the acetate form ~ EA 2233) retains the atactic potency of the parent compound in dogs and is more stable, it and its stereoisomers were a focus of atten- tion at Edgewood arid were tested on hen volunteers. The DIP used in these tests was procured from Shell Development Corporatlon or made at Edgewood. AnalyLlc information on the test material is not available, but some Edgewood-prepared samples were reported to have a purity of 981. EA 2233 was produced at Edgewood, but no specific analytic information on the material used is available. The eight optical isomers of EA 2233 were synthesized at Edge- wood and analyzed by gas-liquid chromatography. Each of the eight products exhibited three peaks; a primary product in the first peak represents about 85% of the total mixture, a second peak represents about 10-22%, asked a third peak represents 3-5~. The impurities were not identified, but they were not isomers. ABSORPTION. FATE. AND ELIMINATION Absorption Early research on ef fects of UMHP and its acetate ester (1)~P acetate) was conducted in a variety of animals (mice, rats ~ rabbits, cats, dogs, and monkeys ~ with intravenous adminis tration . 44 Rapid onset of such Signs as ataxia, mydriasis, generalized weakness, nys- tagmus, and ptosis was seen with this route. With ore' administra- tion, fatigue, thirst, headache, postural hypotension, temporary blurring or loss of vision, and pronounced psychomotor activity were observed in h''ma~. 44 These results indicate that both drugs are well absorbed when administered orally. Efficacies of the drugs where administered parenterally and orally have been confirmed by addi- t tonal studies in cats, ~ rats and rabbi ts, 32 mice, 29 and man.28~31,35,36,3B,40 —80—

- ~ 1 I=\ ~1 1 ~ - a3~ I A-9-tetrahydrocannabinol 83, AH CHOW ~ ~ GY ~{SH11 CH3 ~ eN3 Congener of I H - [H _ tS~lI ~ H ~ ~ ~ C5N H3 3 - . - 1V a-6a, lOa-Dimethylheptylpyran (DIP) EA 1476 EA 2233, Acetate form of EA 1476 FIGURE 3-2 EA 1476 and EA 2233, derivatives of A-9-tetrahydrocannabinol tested at Edgewood. -81-

TABLE 3-6 1 Optical Rotation of Isomers of DMHP Acetatea I somer 2 3 4 5 6 7 8 +65 -130 +133 -70 +94 -110 +105 -93 a Isomers 1 and 4, 2 and 3, 5 and 8, and 6 and 7 are en ntiomorphic pairs . Dis tribution [BID, deg (MeOH) Tissue concentrations were measured in rats and rabbi to sacri- ficed at selected times after intravenous administration of ~ 14C]DMHP. 32 Radioactivity (from DAMP and its metabolizes) in rats at ~ h after administration was highest in lung and liver. Con- centrations decreased to approximately 10% of initial values in 24 h and gradually diminished during the next 48 h. Radioactivity was lower in brain than in other tissues assayed. Plasma concentrations of [14C]D~P decreased from an initial value of approximately 5,000 d pm/ml to about 50 dpm/ml at 72 h. Disappearance was in two phases; the initial one was attributed to tissue distribution ~ breakpoint, 6 h), and the second to elimination. Rabbit spleen, liver, and lung exhibited their highest radioactivity 3 h af ter in Jection; radio- activity in all tissues diminished with time. In this species, ini tial disappearance from plasma ~ and, presumably, distribut ion to other tissues) was more rapid, and the secondary phase sl ower. The investigators concluded that the tissue distribution of total radio- activity (from both DEEP and its metabolizes) is similar to that of THC. The oc tanol-water part it ion coef ficient was 7, 500, compared with 6, 000 for THC. . . . 3 7 1 · · ~ [3H]D~P was irl`]ecte~ ineravenousty into adult male albino Tuck strain No. 1 nice;2 20 min after administration, the blood:brala concentration ratio was 3.7:1. Braln concentration of the drug, on the basis of radioactivity, was approximately 2.5 picograma/gram (Pg/8) 15 min after injection and about 1.7 pg/g at 90 mini it slowly decreased to nearly 1.2 pg/g af ter 16 h. —82—

In three young men who received 200 fig of a racemic mixture of DEEP containing ~ i4C ~ DEEP, 31 radioac tiv! ty disappeared f rom plasma in a multiphasic manner. The rapid initial disappearance was attributed to uptake and distribution into tissues, and the later disappearance to metabolism and excretion. Me tabolism Cann~binoids may be metabolized to both hydroxy and dihydroxy metabolites . 9 The hydroxylated compounds are not taken up ire the circulation after metabolism by the liver, but are predominantly ex- creted in bile . It is unlikely, but not known, whether the dihy- droxylated compound can be further metabolized or activated to form more reactive compounds. Metabolism of t14C]D~P was studied in vitro with 9000 ~ liver supernatant fractions obtained from rabbits, mice, rats, guinea pigs, or dogs and in vitro in rats and rabbits.32 Incubation for ~ h with the supe' Blatant fractions in the presence of an NADPH-generating sys- tem resulted in metabolism of the following percentages of the total amount of DEEP: rabbi t, 68; mouse, 63; rat, 44; guinea pig, 41; arid dog, 34. Thus, of the species studied, the rabbit preparation was the ma st ac five, and that of the dog the least ac Live . The rabbi t preparation gave rise to three radioactive metabolizes; one of these appeared to be further metabolized to one of the other metabolizes. All seemed to be more polar than the parent drug, according to their behavior ire thin-layer chromatographic systems. Den ~ 14C ~ DAMP was administered intravenously to rats or rab- bits, it appeared that DMHP was hydroxylated and then further oxi- dized to at least one acidic compound, which was recovered from urine. No nonmetabolized DMHP was found in the urine of either species . A similar in vitro system used [3H] ~9-DMHP*; mass spectra of incubat ion extracts were silylated and sub; ected to gas chromato- graphy/mass spectrometry. Strong evidence was accumulated that the major metabolize was 11-hydroxy-D~P. Overall recovery of the metab- olite was only 4. 7%; this low yield was insuf f icient for conf irmatory analyses by other methods, such as nuclear magnetic resonance . The low recovery indicated to the investigators that DMHP and its metabo- lites are much more strongly bound to tissue components than are THE and its metabolites. Sixteen hours after injection of ~3H]D~IP into mice, their brains were extracted. Gas chromatography of the extracts indicated retention times identical with those of synthetic 11-hydroxy-D~P, which accounted for 90% of the radioactivity; two * This DMHP is a - 9 form, ire contrast with the DEEP used at Edgewood and by Lemberger, which was a ~6a, 10a DEEP. —83—

other fractions were noted, which the investigators referred to as "non-extractable material" and " polar metabolize . " Lemberger _ al.30 used gas chromatography/mass spectrometry and reported that the hydroxymethyl metaboli te represents only two minor me tabolites produced by rat liver microsomes; this suggests that with DIP the methyl group at Cell is not active and therefore that the 11-hydroxy DIP would not be a major metabolize. Lemberger have given evidence that the hydroxylation occurs primarily on one of the me thyl groups of the side chain. Elimination Kinetic data on the cannabinoids are limited, but it appears that they are el iminated slowly f ram the body. Reported THC half-lives in human plasma have ranged from 19 to 57 h. Because of their high lipid solubility, cannabinoids and their metabolizes can be seques- tered in fatty tissues, and traces may be detectable for over a week. The pharmacologic significance of these persistent cannabinoids and their metabolites is unknown. 26 Very slow elimination (or at least displacement or metabolism at bioactive sites) was suspected ire early studies of the effects of DIP and DIP acetate on human volunteers, because such signs and symptoms as sluggishness, inability to concentrate, dimness and blur- ring of vision, and orthostatic hypotension occurred up to 48 h after drug administration.44 At high doses of DIP, cats "lay in plastic-like poses for hours or dais against the side of the con- tainer in which they were placed e" DIP in plasma appears to have a half-lif e of 20 h in both rat and rabbit;32 the half-life of total radioactivity ~ [14C]D~P plus C-labeled metabolites) in the slower phase of elimination was ap proximately 24 h. In the rat, 7 07: of the total radioac tivi ty of the intravenous dose was recovered in urine and f eces during 7 2 h; 4% was excreted in urine and 66X was found in feces. A 7-d collection of urine and feces of rabbi ts given ~ 14C ~ DIP resulted in recovery of 87: of the total radioactivity--24: in urine and 63: in feces. In mouse brain,29 the half-life of [3H] 09-D~P appeared to be about 20 h, whereas 11-hydroxy-D~P and the "polar metabolize" seem to have (by extrapolation) half-lives in excess of 48 h. All three values were calculated on the basis of the slower phase of elimination. Studies on human volunteers given DIP intravenously indicated a half-life of the terminal phase Of ~ 14c ~ DMHP elimination of 39 h; 58% of radioactivity was excreted in the feces and 11: in the urine during a 7-d collection period. 31 The investigators concluded that —84—

the plasma disappearance curve in humans obtained ~ th DMHP is sim- ilar to that obtained with THC. In summary, both DEEP and DMHP acetate are well absorbed at ter oral and parenteral administration, have a- relatively long half-life, are extensively metabolized, and are excreted mainly via the feces. ANIMAL 'TOXICOLOGY The ar~imal-toxicity data in this section, taken from several source; ,1B, 20, 35, 36, 40, 44 show that the compounds most studied in animals and h''m~s were DMHP and DMHP acetate (more light- and air- stable than DMHP). Although eight optical isomers of the acetate were tested in humans, no specific toxicology data were found. Route of Administration and Vehicle The intravenous route of administration was usually used for test ing the se compounds in animals . Because they are insoluble in aqueous solvents, they were dissolved in small amounts of alcohol or emulsi.f fed wi th an oil-lecithin mixture or polyethylene glycol . Toxicit~of DMHP DMHP was chosen as the prototype of the various cannabinol test compounds used at Edgewood and was studied more thoroughly than i ts congeners . Acute toxicity studies have been performed in various animals: mice, rats, rabbits, cats, dogs, and macaques. LS,20,35,36,40,44 Lethal doses of DMHP are extremely high, in comparison with the small doses required to produce its pharmacodynamic effects. For instance, the intravenous LDso in mice is 63 mg/kg, whereas the minimal effective dose in 50% of the art Is (MEDso) is 0.075 mg/kg, for a safety factor of 840. The dose required to produce tranquilization in the unanesthetized dog is 0.05 mg/kg, and the minimal lethal dose is 10 mg/kg by the same route. The margin of safety in the dog is about 200. By comparison, the margin of safety of reserpine is 5. O. The ma jor signs of toxicity are acacia, analgesia, mydriasis (less prominent in monkeys at lower doses), and profound central ner- vous system (CNS ~ depression lasting from several hours to several days, depending on dose. At higher doses, the CNS depression may be preceded by CNS st imulation and convulsions . Marked hypothermia at an intravenous dose of 1 mg/kg, hypotension, and respiratory depres- sion are ocher significant effects of this compound. DAMP produces a —85—

marked decrease in mean arterial pressure in the anesthetized dog. This effect occurs slowly at small doses, but the latent period is considerably shortened at large doses . Ill the monkey, the minimal ef fictive intravenous dose to produce ptosis and to decrease activity was 0.0316 mg/kg, whereas the minimal lethal dose was 10 mg/kg by the same route, for a safety factor of about 300. Death after intravenous administration of DMHP in dogs is pre- ceded by ventricular f ibrillat ion, which may be secondary to hypo- thermia. However, there are no fatalities if the animals' rectal temperature is kept from falling. Studies of the interaction of DRIP with other drugs were per- formed with dogs. If such compounds as cocaine, caffeine, d-ampheta- ~ine, and nalorphine are used to antagonize the CNS depression pro- duced by DMHP, they also can produce a marked increase in toxicity an detach. Death occurred during the depressed state that followed the st imulation induced by these agents . Subchronic toxicity was studied in rats and dogs by administering DMHP intravenously over a period of a month. 18 DMHP at 0. I, 1.0, and 10 mg/kg-d was given intravenously to male albino rats ( 10 per dosage) for 20 daily injections over a 4~k period. No effects were seen at O . 1 ~ng/kg. However, rats at both 1. 0 and 10 mg/kg-d showed the following ef fec ts: gross signs of toxicity, decreased body weight gain, decreased liver and kidney weights, and decreased ratios of liver and kidney weights to body weight. In addition, the high- dosage group showed decreased food consumption and histologic lesions of the lungs. Histologic examination revealed of mild to severe pneumonitis, fatty metamorphosis of the liver, arrest of spermato- genesis, and cellular alterations of the ovaries among all dogs. No hematologic changes occurred at any dosage . In dogs, repeated intra- venous doses at 0.1 and 1.0 mg/kg-d were given to mongrel dogs (three per dosage) for 10 daily injections during a 2-wk period. Transient signs of ef feet at 0.] mg/kg~ consisted of moderate hyperpnea and a slight decrease in activity, which were noted after each injection. Similar signs of toxicity were seen at 1 mg/kg-d, and these generally persisted throughout the course of the study. Terminal body weights were significantly lower in all high-dosage dogs, and significant changes in ratios of organ weights to body weight occurred among both groups. Although hematuria had been observed in earlier studies ire mice and cats, it was not observed in these long-term studies . Studies with dogs and monkeys have shown that tolerance to the toxic effects of DbIHP develops.20,35,36,40,44 —86—

Toxicity of DRIP Acetate ( EA 2233) The same types of toxicity data were gathered on DMHP acetate as on DMHP. i~ In mice, the intravenous LI)so was greater than 25 mg/kg, and the FEDso (median effective dose) was 0.1 mg/kg, for a safety mar- gin greater than 250. In the dog, slight hypertension was seen at 0.1 and 1 mg/kg. In monkeys trained on a visual discrimination test, minimal behavioral effects were seen at O. 316 mg/kg, and moderate to marked effects at 1.0 mg/kg. Repeated intravenous administrations of DAMP acetate at 0.01, 0.1, and 1. 0 mg/kg~ to male albino rats ( 10 per dosage ~ were carried out for 20 daily injections during a 4-wk period. Miosis was observed at the intermediate and high dosages, and lacrimation only at the high dosage . The high-dosage animals exhlbi ted signif icantly lower food consumption, growth rates, liver and kidney weights, and ratios of liver to body weight and significantly higher ratios of adrenal to body weight. No changes attributable to the compound were seen in blood chemical tests or in gross or microscopic pathologic tests. When dogs were treated with DRIP acetate at 0.01 or 0.1 mg/kg-d for 10 daily injections, no significant effect we'; seen at the low dosage. Marked defensive hostility developed at the high dosage-- perhaps a sign of a cumulative effect. At this dosage, there was histologic evidence of glycogeI1 storage in ache liver. MECHANISM OF ACTION The mechanism of ac tion of cannAbinoids is not understood. Gill and Lawrence13 have shown that some active car~n~binoid derivatives produce disordering of artificial lipid membranes, whereas inactive compounds either do not have this action or actually increase men brane ordering, an determined by electron spin resonance. This sug- gests that the cannabinoids resemble anesthetics in their mode of action. Cannabinoids do, however, appear to exhibit selectivity. Thus, DRIP, which is active in animals and produces marked vasomotor changes in humane, does not induce subjective effects ;31 but nabi- lone, which is structurally related to D~P' causes both subjective and vasomotor changes. Burstein and Hunter have suggested that cannabir~oids exhibit specificity in interacting with such enzymes as phospholipase At and cholesterol esterase, which may mediate some of their actions. —87—

NEUROPHARMACOLOGY . Little is known about the pharmacology of DEEP and UNHIP acetate, but the reference compound, THC, has been excessively described both in humane and in an] nals. Many reviews and symposia have discussed marl Juan and the cann~binoids . 6, 10, 19, 26.39 The National Inati- tute on Drug Abuse has reported to the Congress annually on research on marijuana. And the National Research Council34 and the Insti- tute of Medicine23 issued recent reports on marl juana. Thus, we will briefly describe marijuana before commenting on the two com- pounds tested at Edgewood. The pharmacology of THC ire humans has been careful y explored. THC intake at 50 ~:g/kg by smoking produces feelings of giddiness and changes in time sense and the perception of visual and auditory sti- muli. At this dose, sub jects may behave in a "slily" manner. Higher doses ~ over 200 ug/kg orally) may produce nausea, marked visual and auditory distortions, feelings of unreality and depersonalization, and auditory arid visual hallucina~cions. The perceptual changes may be associated with panic reactions. Pulse rate is increased in a dose-related manner; blood pressure decreases, particularly on stand- ing (orthostatic hypotension); and conjunctival injection (reddening) is observed.24 Although some subjects liken marijuana and THC to LSD, the ef feces of these drugs car be clearly dif ferentiated by sub- jects in double-blind comparisons.25 The cannabinoids mad also increase blood pressure ~ particularly diastolic pressure . 5 Hepler and Fra~c21 have shown that smoking marl juana reduces intraocular pressure, and Adams et al.4 demonstrated that this property was shared by THC. This effect is thought to be due to vasoconstriction of the afferer~t blood vessels to the ciliary body, which causes a decrease in perfusion pressure.14 THC also has an antiemetic action. 37 Marl juana and THC also produce bronchodilatation. 41 'The ef fee te of THC and other cannabinoids on psychomotor pert or- mance are not easily summarized. There is clear impairment in mos t psychomotor tasks at high doses . The ma jor conclusions that can be drawn are probably that moderate doses of THC have little effect on at tent ion or on perf ormance of very simple and well-prac ticed tasks . Furthermore, performance of complex tasks and tasks requiring complex processing of information is significantly impaired by THC and other centrally active cannabi noids . Of the specif ic ca~abinoide studied at Edgewood, pharmacologic data are available on DMHP. It was ef fective in producing sedation in animal s at oral doses lower than 0.5 mg/kg. Several doses and routes of administration were studied, up to 1 mg/kg given intra- venously. In rats, sedation occurred without initial stimulation; in dogs and monkeys, hyperactivity was followed by depression and then, at higher doses, by coma. Motor ef fects were dramas ic, in that ani- mals developed spastic ataxia and showed extremely active deep tendon _~_

reflexes. If the animals were handled while sedated by the drug, extensor seizures of ten occurred. In contrast with these results in intact animals, ani~ls sub jected to spinal transection showed mild depression of deep tendon refiexes.17 Autonomic changes were quite prominent in DMHP-treated animals-- hypothermia, mydriasis, hypersalivation, bradycardia, and reduced respiratory rate. Several experimental manipulations were undertaken to determine the mechanism of these autonomic changes. The tentative conclusion was that the drug was acting centrally to reduce sympa- thetic tone. DMHP was also found to have anticonvu1sant properties. Studies conducted in mice showed that it was ~ times as potent as THC. 27 DMHP was found to be 20 times as potent as THC in prolonging hex- obarbital sleep time in mice. The drug produced BEG changes similar to those produced by morphine. In an experiment that tight link some of DMHP' s ef fects to opiate receptors, DMHP-induced sedation, ataxia, and analgesia were ~igaiflcantly reversed by the mixed-opioid antago- nist nalorphine . i6 DAMP appeared to have a wide margin of safety for acute toxic ef fee ts . One investigator calculated the therapeutic ratio for pro- ducing tranquilization in nonanesthetized dogs. ~ 6 The ratio of LD,o to EDDY was 2, 000:1, compared with only 5:1 for reserpine, a clinically approved drug. No long-term ef fects ire arrimale af ter single doses were looked for, and no repeated-dose or chronic- toxicity studies of DMHP were reported. DAMP has more potent and more prolonged hypotensi~re effects than THE, but far fewer psychologic ef fee ts . MUTAGENI CITY, TERATOGENICITY, AND CARCINOGENICITY -Although the literature on cannabinoids is large, no information is available wi th regard to the capacity of DMHP and the eight ace- ~cate isomers to produce mutagenesis, teratogenesis, or carcinogenesis in animals or man. DELAYED AND LONG-TERt1 EFFECTS DMHP and a series of optical isomers of DRIP acetate, studied at Edgewood in humans, produce similar symptoms, but vary greatly in potency. The more potent isomers appear to produce postural hypo- tension and fewer psychologic effects than equivalent doses of THC. However, they all evoke redness of the eyes, dryness of the mouth, a _89_

sense of hunger, tachycardia, and drowsiness . 31 ~ 38 Postural hypo- tension is immediately reversed and blood pressure returned to normal by lying down. Death due to inhalation or ingestion of marl juana has not been reported. Nor are there lasting ill effects from the acute use of marl juana,45 except that the acute or chronic use of marl juana occasional! y precipitates or exacerbates a -schizophrenic state .43 Isomer 2 is the most potent of the DEEP acetate isomers ~ being active at intravenous doses of 0. 5-2. ~ ~g/kg. Postural hypotension was reg- ularly noted, but euphoric responses were infrequent . DMHP has been the no st extensively studied of these analogues .44 At toxic doses roof 50 Vg/kg or more, postural hypotension, tachycardia, hypothermia, and lethargy were noted. Fatigue, thirst, and headaches were associ- ated symptoms. Prolonged or delayed effects of a Oman number of acute doses were not mentioned in the literature. The literature on THC is much more voluminous and may be used in this evaluation, because DMHP and the DIP acetate isomers and THC are related chemically and pharmacologically. This ca~binoid also produces no known long-term or delayed effects, except when admin- istered chronically in large doses . 3 The doses of the dibenzopyrans used at Edgewood were similar to those used by other invest igators . Lemberger e t al .30 used DROP at 200 fig per 70 kg intravenously, for example. The severe postural hypotension that occurs when the drug is taken intravenously, intra- muscularly, or orally is a limiting factor in giving hallucinogenic amounts of DbIHP isomers. Iwo long-term ef fects are theoretical considerations. One is that exposure to the cannabinoids may somehow have caused a chronic or delayed posttraumatic stress disorder. In the dosage and fre- quency used, this is unlikely. The postexperimental effect that was most undesirable was postural hypotension. 'This resulted in dizzi- ness and faintness, from which all subjects recovered. Such a stress is insuf ficient to provoke a delayed or chronic pos~traumatic stress syndrome, rigor is there any evidence that any such syndrome occurred . A second consideration is that exposure to DMHP at Edgewood may have produced a tendency toward abuse of cannabinoids ire later years. This is not possible to assess. The target organs that may be involved in prolonged or delayed effects are the brain and the cardiovascular system. The mental ef feet consists of a transient or reversible psychosis, which may in rare instances result in activation of a schizophrenic process. The cardiovascular effects are postural hypotension and tachycardia. These are tranaltory and leave no permanent residue. —90—

Given the absence of followup information on the effects of DAMP, ache Committee cannot evaluate the possibility that the exposures at Edgewood produced delayed or long-Berm effects. However, information on THE suggests that such effects are unlikely to be associated with the exposures tested. In addition, clinical evaluations immediately after test administration did not indicate any acute effects likely to presage future complications or long-term sequelae. A review of the epidemiologic aspects of DMHP is in Appendix C. EFFECTS ON VOLUNTEERS This review of acute effects on volunteers is based on clinical records at Edgewood. When the cannabinoid studies began at Edgewood in November 195B, much less was known about the pharmacology of DMHP than about the pharmacology of phencyclidine (SNA). The Studies of the DMHP series in humane spared the period from ~ 958 through 196B, wi th concentration in 196 3-1966 . Although they are generally more potent, the DAMP derivatives had ef fects in the normal volunteers at Edgewood that were very similar to those later described over the ~ ast 15 yr by many research labora- tories working with cannabis and THC. After administration of DMHP, there was more orthostatic hypotension than with THC or cannabis and possibly fewer subjective and mood effects. The time course appeared more variable, arid DAMP' ~ ef facts were of ten slower or more erratic in onset, particularly when it was given orally, than were those of THC. DEEP' s ef fects also persisted longer. In some of the earliest studies, beginning about November 195B, racemic mixtures of DAMP were given to approximately 35 volunteers at 0.5-4 mg per 70 kg of body weight. At 0.5 mg per 70 kg, fatigue, drowsiness, mild headache, and occasionally increased thirst deve- loped. At 1 and 2.5 me per 70 kg, postural hypotension was common, and faintness on standing was observed often. Blood pressure in a supine or prone position was normal or slightly increased. Weakness, ataxia, a feeling of giddiness, and general slowing of motor activity were common. At the highest doses, the subjects often showed marked psychomotor retardation, sluggishness, difficulty in concentrating, and blurred vision lasting for as long as 48 h after a single dose. Fewer comments were made about postural hypotension, probably because at this dose volunteers were unwilling or unable to get out of bed. Volunteers given over 2 mg of DMHP were judged to be incapable of performing their regular military duties. The intensity and duration of the hypotension, tachycardia, decrease in oral temperature, visual disturbance, sub jective symptoms of thirst and dry mouth, and decreases in motor performance were generally dose-related, but their intensity varied among subjects . Thus, many of the signs and symp- toms of DMHP intoxication were similar to those reported ire recent —91—

years in many car~nAbia and THE studies of volunteers, except that DMHP was more potent and probably had more effects an the cardiovas- cular system. The most extensive experiments at Edgewood were done in 1963-1966 with DIP acetate. Approximately 100 volunteers were given doses of a DMHP acetate racemic mistune during this period. Oral, intramuscu- lar, and intravenous routes of administration were used. Oral doses ranged from 3 to about 60 ~g/kg. Intravenous doses ranged from 0.5 ~g/kg to (in a few subjects) 5 ~g/kg. Intramuscular doses were between 0.5 and 5 ug/kg. Most sub jects received only one drug expo- sure, and a few had multiple exposures, but rarely more than two. Cardiovascular effects were most vocable. Tachycardia and ortho- static hypotension were seen in some subjects at almost all doses. ECGs occasionally showed such nonspecific changes as inverted ~ waves. ECGs documented the 6- to 10-s lag in heart-rate increase caused by DliHP acetate after standing. Many subjects felt light- headed and faint on standing. As the studies progressed and the relationship between dose and orthostatic hypoter~sion was better appreciated, this ef feet was less likely to occur . In general, oral doses produced changes ire heart rate and blood pressure at 1 or 2 h and peak ef fects at 6-10 h. Ma jor effects on the cardiovascular ~ys- tem disappeared in most subjects after 24 h, but persisted for sev- eral days in a few subjects in whom hypotension and increased heart rate occurred. As is often observed with cannabis, conjunctival blood vessel injection was common. Body temperatures decreased, sometimes by 3-4°F. These changes were generally dose-dependent. Dryness of the mouth and throat, nasal stuffiness, apathy, and nausea were com- mon. and their intensity was dose-related. Psychomotor impairments were measured by such test batteries as the numerical facility, speed of closure, Purdue pegboard, and Strom- berg manual dexterity tests. Anecdotal reports, both by sub jects and by staff, of changes in behavior and mood general y paralleled the other symptoms . lithe spectrum of the ef facts and their intensity i s similar to that corona y reported in the recent literature on canna- bis studies in other volunteer populations. However, UMHP acetate seemed deco elicit more orthostatic hypotension, and cannabis, a greater degree of mental effects. The lack of evidence of severe mental or emotional disturbances, even is volunteers who were observed to experience intense and per- sistent cardiovascular effects, is noteworthy. Although DMHP acetate elicits far greater cardiovascular consequences than other canna- binoids, it appears to induce less severe mental impairment. I t is possib] e that careful screening and a supportive test milieu tend to mi nimize the occurrence of adverse mental ef fects . —92—

The acute of facts of eight op tical isomers of DEEP acetate giver Singly or in combluseion were assessed in about 125 volunteers. Several of these subjects had participated or were participating con- currently in other DMHP esperimente. The isomers were given intra- muscularly or intravenously. Some of the intravenous injections were given with the isomer diluted in propylene glycol and others with alcohol as the vehicle. Isomers I, 3, 5, 6, 7, and ~ appeared to have 1itt1 e biologic activity (generally at about 0.5-10 ~g/kg) . Apart from nonspecific symptoms, such as pain at the injection site, subjects appeared unaffected subjectively and objectively. In one sense, this series of experiments provides some index of placebo responsi~reness-~inimal. Many subjects commented (as recorded in the charts) that they generally en joyed the experiments, thought we11 of the stat f support, and, in general, had few complaints other than about the food. Isomers 2 and 4 and mixtures thereof had significant biologic activity. Intravenous doses of l-2 me of isomer 2 produced fairly intense tachycardia and orthostatic hypotension in the volunteers, an already described. The postural hypotension was marked, increases in heart rate were present but less intense, and feelings of impaired cognition and concentration and altered mood were present and dose- dependent . The volunt eers seemed able to function reasonably weU-- if they were able to get out of bed and walk around. However, during the first few hours of intoxication, this was virtually impossible in many cases, because of hypotension. Dryness of the mouth, increased thirs t and hunger, mi 1 d sleepiness, in jec ted conjunctival, and wild to severe hypotension are consistent with the effects of cannabis. Some~charts contain comments about such observations as skin pallor on standing. These are understandable in the light of the circum- stances . During the DMHP studies, hepatic function and renal function were assessed. Although occasional borderline-aboorma1 results were noted af ter exposure, these were generally followed up and did not appear to be clinically significant. Some attention was given to EEG and ECG assessments to follow the intensity and duration of any drug- induced changes in cardiovascular and brain functions. In no instances of followup, did the ef fects appear to be particularly specific or clinically significant for acute or long-term toxicity. In awry, DMHP and some of its acetate isomers produced vari- ous degrees of physical incapacitation due largely to the moderate to marked and prolonged orthostatic hypotension. Blood-pre~sure was normal in the supine position. Mental effects of DRIP were much less severe than tho se of THC or cannabi ~ at doses that produced similar degrees of or~chostatlc hypoteasion. Individual dif ferences in inten- si ty of response were coD.siderable: some sub jects showed little or no response at doses that produced intense symptoms in other subjects. —93—

This pattern of variability has been commented on in the extensive civilian literature on cannabinoid research. Duration of effects also varied. With most doses and subjects, the majority of measur- able ef fects disappeared in 24 h, although in a few instances they persisted for 2 or 3 d. DEEP and biologically actl~re isomers of its acetate cause greater and longer-lasting orthostatic hypotension and fewer paychologic ef fee to than THC; otherwise, they are very similar on the measures recorded during these experiments. The potencies of DMHP acetate and DMHP itself seemed relatively similar. The eight isomers of DMHP acetate varied greatly in potency. Those with bi o- logic activity seemed similar to DRIP in their effects. REFERENCES 1. Aaron, H. S., Bra Ferguson, C.P. Synthesis of the eight Stereo isomers of a tetrahydrocannabinol congener. J. Org. Chem. 33: 684-689, 1968. 2. Adams, R., and Baker, B.R. Structure of cannabidiol. VII. A method of synthesis of a tetrabydrocannabinol which possesses maribuana activity. J. Am. Chem. Soc. 62: 2405-240B, 1940. Adams , R., Chen, K. H., and Loewe , S. . Te trabydrocannabinol homo- logs wi th a s-alkyl group in the 3-position. XVI. J . Am. Chem. Soc. 67: 1534-1537, 1945. 4. Adams, A.J., Flom, M.C., and Jones, R.T. Influence of marl juana on intraocular pressure. Am. J. Optom. Arch. Am. Acad. Optom. 49:~80~81 (abet. ), 1972. 5. Adams, R., MacKenzie, S ., Jr., and Loewe, S . Tetrahydrocaurla- binol homologs with doubly branched alkyl groups in the 3-position. XlIIII. J. Am. Chem. Soc. 70: 664-6 6B, 1948. 6. Braude, M. C., and Szara, S., editors . Pharmacology of Marihuana. Volumes ~ arid 2. A Monograph of the National Institute on Drug Abuse. New York: Raven Press. 1976. 865 p. 7. Buratein, S. and Hunter, S.A. The biochemistry of the canna- bluoids. Rev. Pure Appl. Pharmacol. Sci . 2: 155-226, 1981. B. Dagirmanjian, R., and Boyd, E. S. Some pharmacological effects of two tetrahydrocannabinols . J. Pharmacol. Exp . Ther. 135: 25-33, 1962. 9. Domi no, E. F. Neurobiology of phencyclidine--An update. In Petersen, R.C., and Stillborn, R.C., editors. Phencyclidine (PCP) Abuse: An Appraisal. Rockville, Md.: U.S. National Institute on Drug Abuse. NIDA Research Monograph 2l, 1978. p. t8-43. —94—

10. Dombush, R.L., Freedman, A.M., and Fink, M. eds. Chronic Cannabis Use. Ann. N.Y. Acad. Sci. 282 :~-430, 1976. 11. Gaoni , Y., and Mechoulam, R. Isolation, structure, and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc. 86: 1646-1647, 1964. 12. Ghosh, R., Todd, A.R., and Wilkinson, S. Cannabis indica. Part IV. The synthesis of some te trahydrodibenzopyran derivatives . J. Chem. Soc ., Part II : 1121-1125 , 1940. 13. Gill , E .W., and Lawrence , D. K. The physicochemical mode of action of tetrahydrocann~binol on ce] ~ membranes. In Braude, M. C., and Szara, S., edltora. The Pharmacology of Marihuana. New York: Raven Press. 1:147-155, 1976. 14. Green, K., and Bowman, K. Effects of marihuana and derivatives on aqueous humor dyDA~ics in the rabbit. In Braude, M.C., and Szara, S., editors. The Pharmacology of Marihuana. New York: Raven Prese. 2:80~813, 1976. 15. Hardman, H. F., and Hosko, M. J. Autonomic ef fects : An over~riew of the cardiovascular-autonomic actions of cannabis . In Braude, M.C., and Szara, S., editors. The Pharmacology of Marihuana. New York: Raven Press . 1: 231-23B, 1976. 16. Hardman, H. F., Do~no , E. F ., and Seevers , T'I. H. General pharmaco- logical actions of some s~chetic te trahydrocannabinol deriv- atives. Pharmacol. Rev. 23: 295-315, 1971. 17. Hardman, H. F., Domino, E. F., and See~rers , M . H. The Chemistry and Pharmacology of EA 1476. Terminal Report on Cor~tract No. DA 18-108-C~-5663. U. S . Army, Chemical Warfare Laboratories, Army Chemi cal Center, Md. 1959. ~17 ~ p. 18. Hardman, H. F., Domino, E. F., and Seevers , M. H. The Chemis try and Pharmacology of EA 1476 and The Chemistry and Pharmacology of Certain Compounds Af fecting the Central Ner~rous System of Animals and Man. Reports issued under Contract No. DA-l8-108-CHL 5663 between 1956 and 1959. U.S. Department of the Army, Chemical Warfare Laboratories, Aruly Chemical Center, Md. 19. Harris, L.S., Dewey, W.L., and Razdan, R.K. Canuabis: Its chem- istry, pharmacology, and toxicology. Handb. Exp . Pharmakol. 45/II: 371~29, 1977. 20. Hazleton Laboratories, Inc., Falls Church, Va. Reports issued under Con~cract No. DA-~-108-405-CML-826 between 1960 and 1963. U.S. A`=y Chemical Research and Development Laboratories, Army Chemical Center, Md . —95—

21. Hepler , R. S ., and Frank , I . R. Marihuana smoking and intraocular pressure. J. Am. Med. Assoc. 217: 1392, 1971. 22. Highly, R.L., Mosher, W.A., and Hoffmann, F.W. Isolation of trans-~6-tetrahydrocannabinol from marijuana. J. Am. Chem. Soc. 88: IB3 2-183 3, 1966. 23. Institute of Medicine. Mart juana and Health. Washington, D.C.: National Academy Press. 1982. 133 p. 24. Isbell, H., Gorodetzaky, C.W., Jasinaki , D., Claussen, U., Spulak, F., and Korte, F. Effects of (-~69-trans-tetrabydro- cann~ binol in man. Paychopharmacologia 11 :134-133, 1967 . Iabell, H., and Jasi~ki, D.R. A comparison of LSD-25 with (-~-A 9-tra=-tetrahydroca~abinol (THC) and attempted cross toler- ance between LSD arid THC. Psychopharmacologia 14:115-123, 1969. 26. Jones, R.T. Cannabis and health. Ann. Rev. Med. 34: 247-25B, 1983. 27. Karler, R., Cely, W. and Turkanis, S.A. Ar~ticonwlsan~c proper- ties of A9-tetrahydrocannAbinol and other ca~abinoids. Life Sci. 15: 931-947, 1974. 28. Klapper, J.A., McColloch, M.A., and Sidell, F.R. The effect on personality of reactivity to 1, 2 - imethyl-heptyl tetrahydroca~a- binol. Arch. Gen. Psychiatry 26: 483-485, 1972. 29. Lawrence, D.K., Pertwee, R.G., Gill, Eels., and Piper, J.M. Brain levels aM relative potency of the 1,2-dimethy~heptyl analogue of Al-tetrahydrocannabinol in mice. Biochem. Pharmacol. 23: 3017- 3027, 1974. 30. Lemberger, L., McMahon, R., and Archer, R. The role of metabolic conversion on the mechanism of action of cannabi-noids. In Braude, M.C., asps Szara, S., editors. The Pharmacology of Mari- huana. New York: Raven Press. 1:125-132, 1976. 31. Lemberger, L., McHahon, R., Archer, R., Matsumoto , K., and Rowe , H. Pharmacologic effects and physiologic disposition of delta6a, i°adimethyl heptyl tetrahydroca~abinol ~ DMHP) in man. Clin. Pharmacol. Ther. 15: 380-386, 1974. 32. Lemberger, L., McMahon, R.E., Archer, R.A., Matsumoto, K., and Rowe H. The in vitro and in viva metabolism of ^6a,l°adimethyl heptyl tetrahydrocannabinol (DMHP). J. Pharmacol. Exp. Ther. 187:169-175, 1973. -96-

33. Mendelson, J. H., Babor, T. F., K~ehnie , J. C., Rossi , A. M., and Bernstein, J.G., Mel 1 a, N.K., and Greenberg, I. Behavioral and biologic aspects of marl juana use. Ann. N. Y. Acad. Sci . 282: 136- 210, 1976. 34. National Research Council. Committee on Substance Abuse and Hab- itual Behavior. An Analysis of Marijuana Policy. Washington, D.C.: National Academy Press. 1932. 41 p. 35. Neitlich, H.W., and Pleas, J.E. Effect on MAn of Parenteral Administration of A Produc~cion-1 ine Mixture of Isomers 2 and 4, EA 2233 (U). U.S. Army Edgewood Arsenal. Chemical Reserch and Development Laboratories. Edgewood Arsenal, Md. CRDL Technical Memorandum 2-36. 1965. 17 p. 36. Pless, J. E. The Ef fects of Isomer 2 of EA 2233 Administered Intravenously to Hllm~ll Sub jects (U) . Medical Research Labora- tory, Research Laboratories, Edgewood Arsenal, Md. Edgewood Arsenal Technical Memorandum EATM 114-5. 1966. 19 p. 37. Sallan, S.E., Zinberg, N.E., and Fret, E. A~tiemetic effect of 9-tetrahydrocannabinol in patients receiving cancer chemo- ~cherapy. N. Engl. J. Med. 293: 795-797, 1975. 38. Sidell, F.R., Pless, J.E., Neitlich, H., Sussman, P., Copelan, H. W., and Sim,- V. M. Dime thy~heptyl-delta 6a-lOa-tetrahydro- cannabinol: Effects after parenteral administration to man. Proc. Sac. Exp. Biol. Med. 142:867-873, 1973. 39. Singer, A.J., ed. Mart juana: Chemistry, Pharmacology, and Patterns of Social use. Ann. N.Y. Acad. of Sci. 191:~-269, 1971. 40. Sussman, P. Effects of Intravenous Isomer 4, EA 2233 in Man (U). Department of the Army, Edgewood Arsenal, Research Laboratories, Medical Research Laboratory, Edgewood Arsenal, Md. Edgewood Arsenal Technical Memorandum EATM ll4-10. 1967. 19 p. 41. Tashkin, D.P., Shapiro, B.J., and Frank, I.M. Acute pulmonary physiologic effects of smoked marijuana and oral A9-tetrahydro- - cann~binol in healthy young men. N. Engl. J. Med. 289: 336-341 , 1973. 42. Taylor, E.C., Lenard, K., and Shvo, Y. Active constituents of hashish. Synthesis of dl-66-3~4-trans-tetrahydrocann~binol. J. Am. Chem. Soc. B8:367-369, 1966. 43. Treffert, D.A. Marijuana use in Schizophrenia: A clear hazard. Amer. J. Psychiat. 135:1213-1215, 1978. -97-

44. U.S. Army Chemical Research asks Development Laboratories. Edgewood Arsenal, Maryland. Summary Report on EA 1476 and EA 2233 (U). CRDL Special Publication i-44. 1963. 65 p. 45. Witten, B. The Search for Toxic Chemical Agents. Edgewood Arsenal Technical Report EATR 4210. Department of the Army, Research Laboratories, Chemical Research Laboratory, Edgewood Arsenal, Md. 1969. p 149-155. CONCLUSIONS The Committee found the evidence on the long-term health effects of the tested psychoche~ cals to be sparse. The target organs that may be involved in prolonged or delayed ef fects of phencyclidine are the brain and cardiovascular system. Mental or cardioyasc~tar effects were not observed, however, within one week of exposure to the drug at Edgewoocl. One measure of the margin of safety of a drug can be estimated by considering the ratio of the lethal dose to the pharmacologically effective dose (the dose at which some detectable biologic effect occurs). On this basis, the margin of safety is large for acute intravenous, intragastric, intraperitoneal, and subcutaneous adminis- tration of pher~cyclidine ire armada. It is somewhat smaller for inhalation of the aerosolized form. On the basis of the Scientific literature alone, it is not pos- sibie to predict whether any long-term effects would be associated wi th the expo sure s to pher~cyclidine used . However, at the sma t 1 doses arid low frequencies of administration used at Edgewood in a small number of test subjects, it is not likely that any detectable long-term or delayed ef fects have occurred. Acute admi nistrati~ of the dibenzopyrans ( dimethy~heptylpyran and congenera) produced various degrees of physical incapacitation in Edgewood sub] ects, ma inly because of moderate to marked and pro- longed orthostatic hypo~cension. The duration and intensity of effects varied among doses and sub Sects. Despite these variations, there is a large pharmacologic margin of safety in the use of these compo~mds in armada . The d iber~zopyrans produced more pa tent long- lasting orthostatic hypotension and weaker (but otherwise similar) psychologic effects than A-9-tetrahydrocann~binol during the Edge- wood experiments . There is no information on chronic ef fects of d ibenzop yrarm . _98_

Evaluation of the toxicity literature and the Edgewood studies led the Cocci thee to conclude that at the doses and frequencies of administra~cion of phencyclidine and dibenzopyrans used at Edgewood i t is not likely that detec table long-term or delayed ef fee ts have occurred or will occur. Specific information to support this con- clusion is, however, lacking. _99_ -

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