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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—

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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—

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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—

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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—

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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—

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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—

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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—

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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—

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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—

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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—

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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—

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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—

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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—

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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—

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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—

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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-

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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-

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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_

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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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