ORIGINAL CONTRIBUTION

Phencyclidine Deaths R. Stanley Burns, MD Steven E. Lerner, MS San Francisco, California

The potential for a pharmacologic "overdose" and the cause of death associated with phencyclidine abuse is discussed. Nineteen deaths associated exclusively with phencyclidine intoxication have been documented. In 13 cases the immediate cause of death was asphyxia by drowning or trauma with lower levels of phencyclidine present suggesting behavioral toxicity. In two cases, the presence of phencyclidine in high concentrations constituted the only finding, and the probable cause of death was primary respiratory depression accompanied by seizure activity. A secondary drug effect or concurrent disease process may have contributed to the death of the remaining four individuals. Burns RS, Lerner SE: Phencyclidine deaths. JACEP 7:135-141, April, 1978. phencyc/idine, death; drug abuse, phencyclidine.

INTRODUCTION Phencyclidine hydrochloride (sernyl), discovered i n the mid-1950s 1 is a white, stable solid with a m e l t i n g point of 234 to 236 C. 2 It is a weak base t h a t is readily soluble in water 2 and highly lipid soluble at physiological pH. 3 A n i m a l studies of phencyclidine as a surgical anesthetic i n monkeys reveal a low cellular toxicity, high potency without respiratory or cardiovascular depression. 4 The drug was first tested on h u m a n s i n 1957.4, 5 Doses of 0.25 mg/kg given i n t r a v e n o u s l y produced a n e s t h e s i a sufficient for minor a n d major surgery. 4 Because the drug produced postanesthetic confusion and d e l i r i u m of prolonged duration in some cases, clinical investigations were discontinued. 1,~ Phencyclidine is now m a n u f a c t u r e d u n d e r the trade n a m e S e r y n l a n as a n a n a l g e s i c for m o n k e y s and other primates, and appears i n the classification with b a r b i t u r a t e s and lysergide in the Comprehensive Drug Abuse P r e v e n t i o n Act of 1970. 7 Forensic p a t h o l o g i s t s have b e e n i n d i s a g r e e m e n t on w h e t h e r a pharmacological "overdose" and death could result from abuse of street purchased m a t e r i a l c o n t a i n i n g phencyclidine. To address this question a retrospective study of deaths associated with phencyclidine use was conducted.

CASE REPORTS N i n e t e e n deaths associated exclusively with phencyclidine intoxication are k n o w n to have occurred in two counties i n California from J u l y 1970 to J u n e 1 9 7 6 : 1 3 white m e n and six white women, r a n g i n g in age from 15 to 33 years, r e p r e s e n t i n g a m e a n age of 22 years. F o u r t e e n deaths have been documented i n the 21/2 year period since J a n u a r y 1974. In 13 cases, the immediate cause of death was asphyxia by drowning or t r a u m a . Six persons were found dead of no a p p a r e n t cause. Twelve deaths were judged to be accidental. There were five suicidal and two homicidal deaths. Six individuals were k n o w n to be r e g u l a r or chronic phencyclidine users. A clear past history of use of other drugs was present in five cases (Table 1), illustrated by the following case histories: From Steven E. Lerner, MS, R. Stanley Burns, MD, Ronald L. Linder, EdD and Associates, San Francisco, California, and California School of Professional Psychology, Berkeley, California. Address for reprints: Steven E. Lerner, MS, R. Stanley Burns, MD, Ronald L. Linder, EdD and Associates, 350 Parnassus Avenue, Suite 304-A, San Francisco, California 94117.

7"4 (Apr) 1978

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He had been involved w i t h d r u g s and t a l k e d about ~'getting it all over." He was found h a n g i n g by an electrical cord from a b e a m in the garage. Toxicologic e x a m i n a t i o n r e v e a l e d the isolated presence of phencyclidine.

Table 1 PATIENT CHARACTERISTICS OF 19 PHENCYCLIDINE RELATED DEATHS 1970-1976 Intent Accidental Suicide Homocide Asphyxia/ drowning n=11

8

Gunshot wound/head n=2 Unknown n=6

4

2

1

1

1

Route PO Snorting Smoking Unknown

1

3

MATERIALS AND METHODS Reports of d e a t h s for the period 1970 to 1976 w h e r e p h e n c y c l i d i n e was found on toxicological screening were provided by the coroners' offices of A l a m e d a and Orange counties of California. I n v e s t i g a t i o n of the circumstances s u r r o u n d i n g these deaths was carried out by the coroner's office. All autopsies were performed by the coroner or his deputies.

7

2

Deaths of Unknown Cause Case Numbers 1 and 2. A 27year-old man, clad in a white sheet, was observed w a n d e r i n g in the hallw a y of his a p a r t m e n t building. He was going door to door s t a t i n g t h a t he was J e s u s C h r i s t and was hungry. H i s 2 3 - y e a r - o l d w i f e g e s t u r e d to others by pointing to h e r head t h a t he was confused. She r e t u r n e d h i m to t h e i r a p a r t m e n t . Two days l a t e r t h e y were b o t h found dead l y i n g across one a n o t h e r on top of the bed. They w e r e k n o w n to h a v e b e e n e x p e r i m e n t i n g w i t h the d r u g "THC." Ten white capsules found in t h e i r room c o n t a i n e d p h e n c y c l i d i n e . The isol a t e d presence of phencyclidine was confirmed on toxicologic e x a m i n a t i o n of body fluids a n d t i s s u e s in b o t h individuals. Deaths Due to Asphyxia by Drowning or Trauma

Case N u m b e r 12. A 33-year-old man, who lived a nomadic life style, was known to be a h e a v y user ofphenc y c l i d i n e . He w a s on a l o n g r u n , s n o r t i n g and shooting "rocket fuel" several t i m e s a day. He had become

unhappy, disillusioned and depressed. He was found by r o o m m a t e s moaning and had vomited on the rug. After being read a verse about life in the hereafter, he asked someone to t a k e off his clothes and said, ~'Thank you, Mama. T h a n k you, Mama." He left the a p a r t m e n t and was found d e a d in the s w i m m i n g pool t e n m i n u t e s later. There were no signs of s i g n i f i c a n t head or neck t r a u m a a n d toxicologic e x a m i n a t i o n r e v e a l e d the p r e s e n c e of phencyclidine. Case N u m b e r 13. A 27-year-old woman, k n o w n to have used phenc y c l i d i n e r e g u l a r l y for four y e a r s , smoked one h a l f of a "crystal joint" while p u t t i n g on h e r s w i m m i n g suit. She t h e n dove into the b a c k y a r d pool as h e r fiance was s u i t i n g up. She was found a few m i n u t e s l a t e r at the bottom of the pool and pronounced dead at the scene. There was no evidence of head or neck t r a u m a , and toxicologic studies were positive for phencyclidine only. Case N u m b e r 18. A 15-year-old boy, reported to be "out of hand," was seen e a r l i e r in the m o n t h for bizarre b e h a v i o r at a local m e d i c a l center.

Toxicologic Examination Findings Body fluids and tissues submitted for toxicologic e x a m i n a t i o n included blood, urine, bile, liver tissue and the stomach contents. Two indep e n d e n t l a b o r a t o r i e s of forensic toxi c o l o g y w i t h d i f f e r e n t m e t h o d s of analysis performed these studies (vida infra). Cases were excluded if other agents were p r e s e n t in detectable levels in a d d i t i o n to p h e n c y clidine or if there was a history of recent use of lysergic acid d i e t h y l a m i d e (LSD) or m a r i j u a n a t h a t could not be d e t e r m i n e d chemically. Toxicologic studies in 16 cases were p e r f o r m e d by the I n s t i t u t e of Forensic Sciences, O a k l a n d , California. U r i n e l e v e l s of p h e n c y c l i d i n e w e r e d e t e r m i n e d by g a s l i q u i d c h r o m a t o g r a p h y . D e t e r m i n a t i o n s of phencyclidine in blood, bile a n d tissue specimens were performed by gas liquid c h e m a t o g r a p h y after separation of i n t e r f e r i n g m a t e r i a l s by a back-extraction technique. Q u a n t i t a tion was performed by comparison of peak heights or p e a k a r e a s of stand a r d and u n k n o w n samples. A n a l y s i s of q u a l i t y control s a m p l e s y i e l d e d

Table 2 RESULTS OF TOXICOLOGIC EXAMINATION IN DEATHS OF UNKNOWN CAUSE

Case

Blood (pg/ml)

Urine (pg/ml)

Liver (pg/ml)

1 2 3 5 6 8

2.3 0.5 0.3 1.8 4.0 5.0

5.1 100.0 38.0 330.0 21.5 119.8

8.0 6.0 0.9

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50.0 36.0

Bile (pg/ml)

Brain (pg/ml)

0.1

34.5

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Lung (pg/ml)

0.4

Kidney (pg/ml)

Gastric Contents (rag or rag/100 ml)

0.1

6.3 mg total 9.6 mg/100ml 70.0 mg total

47.0

6.5 mg total 185.4 mg total

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coefficients of v a r i a t i o n of 8.4%. Body fluids and tissues were screened for the presence of toxic metals a n d other common volatile, acidic, n e u t r a l and basic drugs. In the Toxicology L a b o r a t o r y , Office of the CorVner, Orange County, California, blood, urine, stomach contents a n d t i s s u e s from three cases were screened by one or more techn i q u e s i n c l u d i n g u l t r a v i o l e t spectroscopy, i n f r a - r e d s p e c t r o s c o p y , gas-liquid chromatography and t h i n layer chromatography. A n a l y s i s for phencyclidine and other basic drugs was by g a s - l i q u i d c h r o m a t o g r a p h y e m p l o y i n g a f l a m e i o n i z a t i o n detector. The bile and urine when available was screened for morphine and other a m p h o e n t e r i c c o m p o u n d s by thin-layer chromatography. Q u a n t i t a t i v e studies of phencyclidine in blood and u r i n e were carried out in 16 and 11 cases, respectively (Table 2 and Table 3). These values have been grouped by cause of death. This study is based on review by the a u t h o r s of the history, autopsy findings and toxicology results in 19 deaths associated with phencyclidine abuse.

Table 3 RESULTS OF TOXICOLOGIC EXAMINATION IN DEATHS OF KNOWN CAUSE

Case

Blood (pg/ml)

Urine (,gg/ml)

4 7 9 10 11 12 13 14 15 16 17 18 19

not found 0.36 trace 1.0 trace 0.6 1.06 0.55 0.74 1.20 0.20 0.10 0.15

0.5 0.6 present

2.3 10.6 2.4

DISCUSSION

Table 4 PATHOLOGIC FINDINGS ON EXAMINATION OF LUNGS

Pathologic Findings The autopsy findings in 13 cases were consistent with the k n o w n immediate cause of death by drowning or t r a u m a . In the six phencyclidine related deaths of u n k n o w n cause, p u l m o n a r y congestion and other pathologic changes were found on e x a m i n a t i o n of the lungs (Table 4). Acute posterior lobar p n e u m o n i a or b r o n c h o p n e u m o n i a was p r e s e n t in t h r e e cases. In one, gross p u l m o n a r y edema was found, and in another, aspiration of the gastric contents. N u m e r o u s macrophages were present in the alveoli in two cases. There were no needle marks indicating an intravenous route of a d m i n i s t r a t i o n or the possible complications thereof in these six cases. Viral hepatitis, septic abscesses, b a c t e r i a l e n d o c a r d i t i s , f o r e i g n body g r a n u l o m a s or necrotizing" angitis were not in evidence in these cases. In a single case, the r i g h t kidney had b e e n s u r g i c a l l y r e m o v e d . No other evidence of pre-existing or active disease was found. A s i m i l a r f i n d i n g of n u m e r o u s alveolar macrophages i n five cases of known cause of death was associated with the presence of refractile material in the l u n g s or occasional foreign body g i a n t cells in two cases.

7:4 (Ap r) 1978

phencyclidine concentrations in five c a s e s r a n g e d from 0.6 to 5 mg/100 g m t i s s u e . L i v e r to blood r a t i o s ranged from 3 to 12.5. The complete toxicologic findings i n this group of c a s e s are listed (Table 2). More e x t e n s i v e q u a n t i t a t i v e s t u d i e s of t i s s u e d i s t r i b u t i o n were carried out in two cases (Table 2). R e l a t i v e l y h i g h c o n c e n t r a t i o n s of p h e n c y c l i d i n e were found i n l u n g a n d b r a i n t i s s u e . The b l o o d / b r a i n ratio in case 3 was 0.33. Adipose tissue was not sampled. Phencyclidine was present in the victims' gastric contents in five of the six deaths of u n k n o w n cause, indicating an oral route of a d m i n i s t r a t i o n . Values ranged from a concentration of 63 pg/ml to a total recovery of 185.4 mg of phencyclidine. In three cases, bile was sampled and biliary excretion of this drug was demonstrated. U r i n a r y pH was not measured, alt h o u g h p h e n c y c l i d i n e e x c r e t i o n is k n o w n to be pH-dependent.

Case

Condition

1

Congestion, bronchopneumonia, aspiration of gastric contents 2 Congestion, broncbopneumonia, microscopic edema 3 Congestion, acute posterior lobe pneumonia 5 Congestion 6 Congestion, numerousaIveolaf macrophages 8 Congestion, gross pulmonary edema, alveolar macrophages

Toxicologic Findings Blood concentrations of phencyclidine in t e n deaths due to asphyxia by drowning or t r a u m a ranged from 0.10 to 1.2 pg/ml, w i t h a m e a n of 0.60 pg/ml. U r i n e levels of 0.5 to 10.6. IJg/ml were measured in five of these cases. In six cases where the cause of death was u n k n o w n , blood concent r a t i o n s r a n g e d f r o m 0.3 to 5.0 p g/ml, with a m e a n of 2.9 gg/ml. The levels of phencyclidine in u r i n e ranged from 5.1 to 330 pg/ml. Liver

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P h e n c y c l i d i n e , a n d its b e t t e r k n o w n derivative k e t a m i n e , belong t6 the a r y l c y c l o a k y l a m i n e g r o u p ~ and have a similar spectrum of activity. 1° A d m i n i s t e r e d to a n i m a l s in increasing doses, these drugs produce excitation, ataxia, catalepsy, general anesthesia and convulsions. Their characteristic s y m p a t h o m i m e t i c effect appears to be due to central nervous system s t i m u l a t i o n 2 The degree of c e n t r a l n e r v o u s system s t i m u l a t i o n a n d depression and the anesthetic potency vary with t h e species2,11,12 B a s e d on behavioral criteria, phencyclidine and k e t a m i n e act p r i m a r i l y as c e n t r a l nervous system depressants in both humans and monkeys. Immediate e x c i t a t i o n does not u s u a l l y occur, whereas surgical anesthesia is more readily induced in h u m a n s t h a n in other species. 2,9,13 K e t a m i n e is less potent, has a shorter d u r a t i o n of action, and produces convulsions less frequently2,~4,15 Electro physiologic ally, phencyclidine and k e t a m i n e induce a cont i n u u m of s u b c o r t i c a l a n d cortical electroencephalogram (EEG) changes in a n i m a l s associated with catatonia or i m m o b i l i t y a n d c o n s i s t e n t w i t h central nervous system stimulation. In a n i m a l s and epileptic h u m a n subj e c t s w i t h i m p l a n t e d d e p t h electrodes, limbic and temporal electrical seizure a c t i v i t y has been observed following k e t a m i n e a d m i n i s t r a t i o n . The electrical seizure activity is not always manifested by convulsive be-

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h a v i o r or reflected i n the conventional surface EEG. 16,17 Profound behavioral effects are seen in several species following phencyclidine a d m i n i s t r a t i o n 2 s In the m o n k e y , r e i n f o r c i n g properties have been d e m o n s t r a t e d by the initia t i o n a n d m a i n t e n a n c e of l e v e r pressing for a reward of injections of p h e n c y e l i d i n e . T h e a n i m a l selfa d m i n i s t e r s the d r u g i n a m o u n t s producing a state r e s e m b l i n g general anesthesia (RL Balster, verbal comm u n i c a t i o n , J u n e , 1975)2 s I n hum a n s , p h e n c y c l i d i n e h a s psychot o m i m e t i c p r o p e r t i e s . The psychosis p r o d u c e d i n n o r m a l v o l u n teers is difficult to d i s t i n g u i s h from schizophrenia, Zg,26 reproducing more of the p r i m a r y symptoms t h a n other drug models.i, 19 E x t r e m e exacerbation of existing psychoses following the a d m i n i s t r a t i o n of phencyclidine to chronic schizophrenic p a t i e n t s has been reported29, 2° Phencyclidine is active orally as well as p a r e n t e r a l l y in h u m a n s 2 , 2 , ~9 In several studies i n v o l v i n g n o r m a l subjects, c o m p a r a b l e s u b a n e s t h e t i c doses of p h e n c y c l i d i n e , 0.1 m g / k g g i v e n i n t r a v e n o u s l y over 2 to 12 minutes, (or 7.5 mg orally) produced slowed t h i n k i n g , d e c r e a s e d concentration, and increased reaction t i m e . " l , 22 A l t h o u g h s u b j e c t s were able to c o m m u n i c a t e a d e q u a t e l y , 2z sensory functions were generally impaired,2z, e3-2a a n d t h e i r g a i t was ataxic.2Z, 23 Some p a t i e n t s exhibited catatonia and repeated vomiting. With intravenous administration over five minutes, the onset was imm e d i a t e with p r o m i n e n t s y m p t o m s lasting one to two hours. 24 Following oral a d m i n i s t r a t i o n , subjects have reported changes in their physical or psychological state w i t h i n 45 minu t e s w i t h m a x i m u m effects at 90 minutes. 2~ In a similar study of five obsessional patients, given 5 to 10 mg phencyclidine orally, an onset of 30 to 60 m i n u t e s with a d u r a t i o n of one to three hours was r e p o r t e d Y G i v e n i n t r a v e n o u s l y in a n e s thetic doses of 0.25 mg/kg (a total dose of 17.5 mg) over 35 m i n u t e s , phencyclidine increases the m i n u t e volume, rate and depth of respirations of low order. 4 A m e a n i n c r e a s e in m i n u t e volume of 1140 cc was measured in seven n o r m a l patients. Their t i d a l volume a n d r e s p i r a t o r y r a t e s increased a m e a n of 15.3 cc and 2.57 cc respectively. A consistent and significant m e a n increase of 26 m m Hg in systolic and 19 m m Hg in diastolic p r e s s u r e w a s o b s e r v e d . T h e pulse rate change was less consis-

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tent, increasing in three subjects and d e c r e a s i n g in t h r e e . 4 S u r g i c a l patients given 20 mg of phencyclidine i n t r a v e n o u s l y , following premedication with pethidine hydrochloride and atropine, became u n r e s p o n s i v e to pain aider a few m i n u t e s , and most p a t i e n t s were completely unresponsive for periods up to 90 m i n u t e s w i t h o u t r e s p i r a t o r y depression. In the initial clinical trials, doses of 1.0 mg/kg i n t r a v e n o u s l y produced clinically observed seizure activity. 4 In the monkey, 1 mg/kg of phencyclidine g i v e n i n t r a v e n o u s l y produced 40 m i n u t e s of anesthesia. A dose of 4.0 mg/kg resulted in tonicclonic seizures in all a n i m a l s tested. Serious r e s p i r a t o r y depression was seen at 14 mg/kg, and death caused by respiratory failure followed doses of 15 mg/kg or greater. A therapeutic r a t i o n C m i n i m a l l e t h a l dose/anest h e t i c t h r e s h o l d dose") of 26 h a s been reported.l°, I1 In various a n i m a l species, phencyclidine has a relatively short duration of action. 2 In the monkey, for example, it is r a p i d l y m e t a b o l i z e d and excreted in the urine as conjugated di- and mono-hydroxyl metabolites.2S, 29 After s i n g l e i n t r a v e n o u s doses, 60% of the radioisotope labels were recovered in the u r i n e w i t h i n 12 hours, and approximately 75% by e i g h t days. 2s In m a n , the r e l a t i v e concentrations of mono-hydroxyl met a b o l i t e a n d the p a r e n t c o m p o u n d phencyclidine recovered in urine after acid hydrolysis and assayed by gas liquid chromatography were 68% and 32%, r e s p e c t i v e l y . No d i - h y d r o x y l metabolite was evident. 2s S u b s e q u e n t l y , two m o n o - h y droxyl m e t a b o l i t e s were d e t e c t e d in u r i n e from patients acutely intoxicated with phencyclidine, after enzymatic hydrolysis. 3° There is no evidence that these two compounds possess cataleptic anesthetic activity. 31 T i s s u e d i s t r i b u t i o n s t u d i e s in a n i m a l s demonstrate relatively high and p e r s i s t e n t c o n c e n t r a t i o n s in adipose and b r a i n tissue with lower a n d r a p i d l y f a l l i n g blood concentrations.3, 3° These results are consist e n t with the drug's pKa of 8.5 and lipid p a r t i t i o n coefficient a t physiological pH. 3e The h a l f life in rat blood after i n t r a p e r i t o n e a l injection is approximately 3~t2 hours. ~ The drug c o n c e n t r a t i o n h a l f life i n t h e dog following i n t r a v e n o u s a d m i n i s t r a t i o n is approximately one hour. 3°

Street Pharmacology P h e n c y c l i d i n e is sold on the West Coast as Crystal, Angel Dust,

JACEP

PCP, THC, and C a n n a b i n o l . 33-3~ Appearing on the illicit m a r k e t in 1965, it continues to be available in powder, tablet and leaf m i x t u r e forms. 33 Most street preparations c o n t a i n the hydrochloride salt, although the free base has been observed. 36 The crystalline or g r a n u l a r powder form is found most frequently as Crystal or Angel Dust, which usually c o n t a i n s 50% to 100% p h e n c y c l i dine. 38 Sold u n d e r a variety of other names, the purity drops to a range of 10% to 30%. 33 Most tablets contain approximately 5 rag, r a n g i n g from 1 to 6 mg. 33 Leaf m i x t u r e s have been found to c o n t a i n b e t w e e n 0.24% to 7.9% phencyclidine, a v e r a g i n g 1 mg phencyclidine/150 mg l e a v e s Y Phencyclidine is t a k e n orally, by i n h a l a t i o n , insufflation, a n d rarely by the i n t r a v e n o u s route. Powder forms are g e n e r a l l y s p r i n k l e d on p a r s l e y , m i n t , o r e g a n o , or o t h e r leaves, and smoked in the form of a cigarette. A c c o r d i n g to o u r s t u d i e s a n d others,33, 37 the estimated a m o u n t of p h e n c y c l i d i n e u s e d per episode, smoking, is 1.5 to 3.5 rag, a n d the a m o u n t per dose in powders a n d tablets averages between 2 to 6 rag. V a r i o u s p a t t e r n s of p h e n c y clidine use have emerged. Although the occasional, o r , r e c r e a t i o n a l , use p a t t e r n is seen, its d e v e l o p m e n t is mediated by an i n i t i a l experience of u n e x p e c t e d a n d u n p l e a s a n t effects.3a, 3~ In a r e a s where the drug has been c o n t i n u o u s l y available, it has gained a preferred drug status with small cluster groups of individuals who use it on a chronic, daily basis for periods of six months to six years.aS,37 C h r o n i c u s e r s c l a i m t h a t the conversion from oral use of tablets and capsules in 1972 to s m o k i n g the powder form on leaves h a s allowed greater success in t i t r a t i n g th6 dose. R e g u l a r u s e r s p u r c h a s e 1 gm a m o u n t s of the crystalline phencyclidine, using about 50 mg to prepare one cigarette and s m o k i n g a n estimated 30 to 75 mg per. episode.3% 3s The o n s e t of subjective effects after s m o k i n g is reported to occur w i t h i n two to five m i n u t e s l a s t i n g four to six hours. A more rapid onset, 30 seconds to one m i n u t e , follows insufflation of the powder form. 37 P s y c h o l o g i c a l d e p e n d e n c e and t o l e r a n c e to the psychic effects of phencyclidine have been reported by chronic users, as well as paranoia, a u d i t o r y h a l l u c i n a t i o n , v i o l e n t behavior, severe depression and anxiety following prolonged periods of

7"4 (Apr) 1978

daily, r e g u l a r use. 38 The confused s t a t e i n d u c e d by typical street doses is characterized by i m m o b i l i t y , or c a t a l e p s y , a n d a " b l a n k s t a r e " in a p a t i e n t who is noncommunicative, followed by disorientation, m o t o r restlessness or excitement, a n d gross a t a x i a of gait, lasting a p p r o x i m a t e l y five hours. In addition, we have noted the presence of m u s c l e r i g i d i t y , a~ We o b t a i n e d m e a s u r e m e n t s of s e r u m levels of 54 to 230 ~g/ml (unpublished data) in six p a t i e n t s in a confused state induced by phencyclidine intoxication. An a d d i t i o n a l case of a y o u t h des c r i b e d as " d r o w s y " w i t h a blood p h e n c y c l i d i n e c o n c e n t r a t i o n of 51 ~g/ml h a s also been reported. 36 In phencyclidine s t u p o r or coma, the eyes m a y r e m a i n open, a l t h o u g h the p a t i e n t is responsive only to deep pain. H y p e r t e n s i o n and t a c h y c a r d i a are present, a n d in all b u t the more massive oral ~'overdose," r e s p i r a t i o n s are n o r m a l . 8~,39 P u r p o s e l e s s movements, facial g r i m a c i n g , a n d muscle r i g i d i t y on s t i m u l a t i o n are common f i n d i n g s . R e p e a t e d e p i s o d e s of v o m i t i n g and increased bronchial secretions frequently occur.35, 39 Massive o r a l overdoses involving up to 1 gm of s t r e e t - p u r c h a s e d mater i a l h a v e r e s u l t e d in p e r i o d s of stupor and coma of several hours to five d a y s in duration.35,37,39, 4° De~.~tayed a n d prolonged h y p o v e n t i l a t i o n and a p n e a m a y result. Such cases are also m a r k e d by s u s t a i n e d hypertension a n d t a c h y c a r d i a a n d g e n e r a l motor s e i z u r e s p r e c e d e d by muscle tremors, myoclonus, opisthotonus, and d e c e r e b r a t e rigidity.~7,39, 4° A child in coma was found to have a blood level of 49 ~g/ml, 3° a n d serum levels of a b o u t 100 to 300 p g / m l were m e a s u r e d in p a t i e n t s described as in coma. 3 Two c o m a t o s e a d u l t s with evidence of mild r e s p i r a t o r y depression h a d p l a s m a concentrations of phencyclidine between 190 and 220 ~g/ml. 41 O n e a d u l t p a t i e n t , w i t h hypoxia, myoclonus a n d clonic seizures associated with coma, who recovered, had a s e r u m concentration of 340 ~g/ml. 42 C o m a w i t h se;cere respiratory depression, a n d a p n e a and repetitive seizures w i t h recovery was associated w i t h a blood level of 530 ~g/ml. S t a t u s e p i l e p t i c u s w i t h cardiopulmonary arrest, followed by coma w i t h o u t r e c o v e r y , w a s assoc i a t e d w i t h a b l o o d l e v e l o f 7 . 0 vg/ml, t3 Nine o t h e r phencyclidine r e l a t e d deaths are r e p o r t e d in the l i t e r a t u r e since 1974 (Table 5). S t a t u s epilepticus, a r e s p i r a t o r y a r r e s t - - and, in one i n s t a n c e , s e i z u r e s - - h y p e r -

7:4 (Apr) 1978

Table 5 DEATHS REPORTED IN THE LITERATURE

Case Age

Sex

Cause Status epilepticus Cardiopulmonary arrest Respiratory arrest

1 2

17

F

3 4 5 6

31-50 Adult 13

M M

7 8

Adult 16

M

9

22

M

Hypertensive crisis, intracerebral hemorrhage Seizures, hyperpyrexia, cardiac arrest Rhabdomyolysis with acute renal failure, followed by aspiration pneumonitis and death, hospital day 50

Year Reported

Toxicologic Findings

1974 Kessler et a143 1974 Kessler et a143

2.5 (IJg/ml)B* 7.0 (IJg/ml) B

1974 Liden et a144 Present 1974 Kazyak 5.0 (pg/ml) B 1975 Baselt et al4e 3.0 (IJg/ml) B 1975 Eastman et a146 Present B 1976 Lin et aP° 2.7 (pg/ml) B 1976 Fauman et a146 Present 1976 Dandavino et a147

Present

*whole blood concentration

p y r e x i a a n d cardiac a r r e s t were the reported drug-induced causes of d e a t h in t h r e e cases. 42-t~ R e p o r t e d medical complications resulting in two deaths were h y p e r t e n s i v e crisis w i t h i n t r a c e r e b r a l h e m o r r h a g e . In one case, e a r l y r h a b d o m y o l y s i s w i t h acute r e n a l failure followed by aspir a t i o n p n e u m o n i t i s on hospital day 50 resulted in death. 46,47 Blood concentrations of phencyclidine in five cases r a n g e d from 2.5 to 70 pg/ml.3°,42, 44,4s S t a t u s epilepticus was associated with a blood level of 7.0 pg/ml. 43 In the cases reviewed retrospectively here, d e a t h occurred in association w i t h phencyclidine intoxication in 19 i n d i v i d u a l s . In 12 cases, the i m m e d i a t e cause of d e a t h was asp h y x i a by d r o w n i n g or t r a u m a with lower levels of phencyclidine present on t o x i c o l o g i c a l e x a m i n a t i o n . Circ u m s t a n t i a l evidence s u g g e s t s t h a t d e a t h w a s s e c o n d a r y to t h e beh a v i o r a l toxicity of phencyclidine. In one case, coma r e s u l t e d in d e a t h by d r o w n i n g in a shower. In p e r s o n s found dead w i t h no a p p a r e n t cause, phencyclidine was p r e s e n t in blood a n d body tissues. A secondary drug effect or c o n c u r r e n t disease process m a y have c a u s e d or c o n t r i b u t e d to the d e a t h of four individuals. In two cases, however, the presence of phen-

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cyclidine in high concentrations cons t i t u t e d the only positive finding. It s e e m s r e a s o n a b l e to conclude t h a t these d e a t h s were due to the p r i m a r y p h a r m a c o l o g i c e f f e c t s of p h e n c y clidine. Eight deaths resulted from drowni n g in a s w i m m i n g pool. P h e n c y c l i d i n e u s e r s often r e p o r t swimm i n g while intoxicated because t h e y experience an u n u s u a l but p l e a s a n t sensation. Sensory disturbances, a t a x i a a n d muscle r i g i d i t y which follow the use of typical "street" doses of phencyclidine m a y seriously interfere w i t h a person's ability to swim, drive, climb at heights, flee from a fire or sense e m i n e n t danger. Suicide by self-induced gunshot wound or h a n g i n g accounted for the deaths of t h r e e persons. They had all been characterized as moody or depressed and one was a known chronic phencyclidine user. In one additional case, t h r e a t e n i n g b e h a v i o r r e s u l t e d in p r o v o k e d h o m i c i d e . D e p r e s s i o n and violent behavior are frequently associated w i t h a confusional state in a c u t e p h e n c y c l i d i n e i n t o x i c a t i o n . 4° Violent, aggressive and t h r e a t e n i n g b e h a v i o r characterize the p e r s i s t e n t psychosis seen in some i n d i v i d u a l s following phencyclidine use. 2° Severe depression w i t h r e p e a t e d suicide att e m p t s h a s followed chronic, d a i l y

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use of phencyclidine.37 The massive o r a l ' % v e r d o s e " is s e e n m o s t freq u e n t l y in the chronic user who is in possession of large a m o u n t s of phencyclidine and ingests it in a suicide attempt. 49 A wide r a n g e of blood concentrations of phencyclidine was present w i t h some o v e r l a p p i n g of cause of d e a t h due to b e h a v i o r a l t o x i c i t y , medical complications, or the pharmacologic effects of p h e n c y c l i d i n e . This suggests rapidly c h a n g i n g blood levels and variations in the route of a d m i n i s t r a t i o n , dose, a n d e l a p s e d time. Differences in the a m o u n t absorbed, metabolized a n d excreted can be predicted. A n i m a l studies reveal high rates of m e t a b o l i s m a n d e x c r e t i o n w i t h rapidly falling blood concentrations and a relatively short d u r a t i o n of action. The studies c o r r e l a t i n g blood levels and clinical state are incomplete. Cases are reported where phencyclidine rapidly disappeared from the blood and was not detecta b l e at 0.5 ~g/ml l e v e l s by gas c h r o m a t o g r a p h y despite the persistence of a comatose state for several hours thereafter. 3 A prolonged period of coma lasting several days followed by a long period of f l u c t u a t i n g confusion and d e l i r i u m has been seen clinically after large oral "overdoses" of p h e n c y c l i d i n e , a~ S t u d i e s of the se: q u e n t i a l c o n c e n t r a t i o n s of phencyclidine in blood have not been carried out in these cases. C u r r e n t l y , no a v a i l a b l e d a t a exist on the relationship of dose to blood level, or the pharmacokinetic constants for a d m i n i s t r a t i o n of phencyclidine by inhalation, insufflation or orally. Some i n f o r m a t i o n is a v a i l a b l e from limited toxicologic studies35,4°,4~ i n c l i n i c a l cases of a c u t e p h e n c y clidine intoxication. These results m a y be c o m p a r e d w i t h t h o s e obtained in phencyclidine related deaths. Serum and blood levels of phencyclidine of .05 to .23 pg/ml have been associated with a state of confused drowsiness 3°,a° in chronic users. In nine deaths secondary to the b e h a v i o r a l effects of phencyclidine, blood c o n c e n t r a t i o n s r a n g e d from 0.10 to 1.0 pg/ml. One of two individuals with a level of 1.0 pg/ml was a k n o w n chronic user who died by drowning w i t h i n m i n u t e s of s m o k i n g p h e n c y c l i d i n e . I n a l l o t h e r cases levels were less t h a n 0.75 pg/ml. Our patients (unpublished data, March, 1975) and those of others al have b e e n r e p o r t e d to be i n coma

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w i t h blood p h e n c y c l i d i n e c o n c e n trations of 0.10 to 0.30 pg/ml. Coma with r e s p i r a t o r y depression and/or seizures was associated with blood levels of 0.34 to 0.53 pg/ml.4°,42 In case 16, the i n d i v i d u a l lapsed into coma while in a shower a n d drowned in a few inches of water. The blood concentration was 1.2 pg/ml. A death is reported in the literature due to status epilepticus with a blood level of 7.0 pg/ml.a3, a4 Other reported values w i t h o u t details on the cause of death ranged from 2.5 to 5.0+ pg/ml. I n t h e six d e a t h s of k n o w n cause, blood p h e n c y c l i d i n e concentrations ranged from 0.3 to 5.0 p.g/ml. In cases I and 8, there were significant findings on pathologic exami n a t i o n of aspiration of stomach cont e n t s associated w i t h p n e u m o n i t i s , and p u l m o n a r y edema. Blood phencyclidine levels of 2.3 and 5.0 pg/ml a n d recovery of 6.3 a n d 185.4 mg p h e n c y c l i d i n e in the stomach contents, respectively, indicated large oral doses. W h e t h e r p u l m o n a r y edema represented a hypersensitivity reaction and the role of asphyxia and/ or p n e u m o n i t i s s e c o n d a r y to aspiration in these deaths are u n k n o w n . In cases 2 and 3, with the lowest blood levels of 0.50 a n d 0.30 pg/ml, b r o n c h o p n e u m o n i t i s with microscopic edema, and acute lobar pneumonia were present. To what degree these disease processes were significant in c o n t r i b u t i n g to the individuals death is uncertain. Chronic drug use may predispose one to develop infectious diseases or prolonged hypov e n t i l a t i o n m a y p r o m o t e t h e development of p n e u m o n i a as a terminal event. In cases 5 and 6 there were no findings on complete pathologic examination. The presence of phencyclidine in blood at concentrations of 1.8 a n d 4.0 pg/ml c o n s t i t u t e d the o n l y p o s i t i v e f i n d i n g . D e a t h was probably due to the p r i m a r y pharmacologic effects of phencyclidine. In a n i m a l s lethal doses of phencyclidine induce first tonic-clonic seizures and t h e n r e s p i r a t o r y failure. Repetitive seizures and delayed and prolonged h y p o v e n t i l a t i o n and a p n e a have been observed clinically with m a s s i v e oral overdoses of phencyclidine. Status epilepticus has been reported. The probable cause of death in high dose phencyclidine intoxications is p r i m a r y respiratory depression accompanied by seizure activity. Numerous alveolar macrophages seen on pathologic e x a m i n a t i o n in s e v e n cases, a n d a s s o c i a t e d With

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foreign body giant cells or refractile material in two instances, appear to have resulted from s m o k i n g phency. clidine in leaf m i x t u r e s and insuffla. tion of phencyclidine powder. In one i n d i v i d u a l with a h i s t o r y of intrav e n o u s p h e n c y c l i d i n e use, needle m a r k s were f o u n d . R e p o r t e d intravenous use is rare due to the rapid o n s e t of the d r u g effects a n d the superior control of dosage possible by smoking phencyclidine. Medical complications of the intravenous route were a b s e n t , a n d one would predict infrequent acute allergic reactions. The role of tolerance to the behavioral effects of phencyclidine with chronic use on the toxicity of this drug and the occurrence of injury or death is u n k n o w n . The authors would like to acknowledge the generous cooperation of both the Alameda and Orange County Coroner's Offices.

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11. Chen GM, Weston JK: The analgesic and a n e s t h e t i c effect of 1-(1-phenylcyclohexyl) piperidine HCL on the monkey. Anesth Analg 39:132, 1960. 12. Chert G, Ensor CR, Russell D, et al: The pharmacology of 1-1 (phenylcyclohexyl) piperidine HCL. J Pharmacol Exp Ther 127:241, 1959. 13. Chen G: Evaluation of phencyclidinetype cataleptic activity. Arch Int Pharmacodyn Ther 157:193-201, 1965. 14. Domino EF, Chodoff P, Corssen G: Pharmacologic effects ofCI-581, a new dissociative anesthetic in man. Clin Pharmacol Ther 6:279-291, 1965. 15. Corssen G, Domino EF: Dissociative anesthesia: further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581. Anesth Analg 45:29~40, 1966. 16. Ferrer AT, Breckner VI, Dymond A, et al: Ketamine induced electroconvulsive phenomena in the h u m a n limbic and thalamic regions. Anesthesiology 38:333344, 1972. 17. Winters WD, Ferrer AT, GuzmanFlores C, et al: The cataleptic state induced by ketamine: a review of the neuropharmacology of anesthesia. Neuropharmacology 11:303-315, 1972. 18. Balster RL, Chait LD: The behavioral pharmacology of phencyclidine. Clin Toxicol 9:513-528, 1976. 19. Collins VJ, Gorospe CA, Revenstine EA: Intravenous nonbarbiturate, nonnarcotic analgesics: preliminary studies. 1. cyclohexylamines. Anesth Analg 39:302306, 1960. 20. Luisada P, Reddick C: An epidemic of drug-induced schizophrenia. Presented at the 128 Annual Meeting of the American Psychiatric Association, Anaheim, California, May 5-9, 1975. 21. Luby ED, Cohen BD, Rosenbaum G, et al: Study of a new schizophrenomimetic drug - - sernyl. Arch Nerol 81:363-369, 1959. 22. Rosenbaum G, Cohen BD, Luby ED, et al: Comparison of sernyl with other d~ugs. Arch Gen Psychiatry 1:113-118, 1959. 23. Davies BM: Phencyclidine: its use in psychiatry, in Crocker R, Sandison RA, Walk A (eds): Hallucinogenic Drugs and Their Psychotherapeutic Use, The Proceedings of the Royal Medico-Psychol. As-

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sociation in London, F e b r u a r y , 1971, 42-47. 24. Davies BM, Beech HR: The effect of 1-arylcyclohexylamine (sernyl) on twelve normal volunteers. Journal of Mental Science 106"912-924, 1960. 25. Morgenstern FS, Beech HR, Davies BM: An investigation of d r u g induced sensory disturbances. Psychopharmacology 3:193-201, 1962. 26. Beech HR, Davies BM, Morgenstern FS: Preliminary investigations of the effects of sernyl upon cognitive and sensory processes. Journal of Mental Science, May, 1961, pp 509-513. 27. Davies BM: Oral sernyl in obsessive states. Journal of Mental Science, January, 1961, pp 109-114. 28. Ober RE, Gwinn GW, McCarthy DA, et al: M e t a b o l i s m of 1-(1-phenylcyclohexyl) piperdine (sernyl). Federation Proceedings 22 (pt 1): 539, 1963. 29. Glazko AJ: Identification of chloramphenicol metabolites and some factors affecting metabolic disposition. Antimocrob Agents Chemother 1966, American Society for Microbiology, 1967, 660-661. 30. Lin DC, Fentiman AF, Foltz RL, et al: Quantification of phencyclidine in body fluids by gas chromatography, chemical ionization, mass spectrometry and identification of two metabolites. Biomed Mass Spectrom 2:206-214, 1975. 31. McCarthy DA, Potter D: The hydroxy m e t a b o l i t e s of phencyclidine. Pharmacologist 5:265-273, 1963. 32. Done AK, Aronow R, Miceli JN, et al: P h a r m a c o k i n e t i c o b s e r v a t i o n s in the treatment of phencyclidine poisoning, in Rumack BH, Temple AT (eds): Management of the Poisoned Patient, Princeton, Science Press, 1977, pp 79-102. 33. LundbergGD, GuptaRC, Montgomery SH: Phencyclidine: patterns seen in street drug analysis. Clin Toxicol 9:503-511, 1976. 34. Perry DC: PCP revisited. PharmChem Newsletter 4:1-7, 1975. 35. Burns RS, Lerner SE, Corrado R, et al: Phencyclidine-states of acute intoxication and fatalities. West J Med 123:345349, 1975. 36. Shulgin AT, MacLean D: Illicit synthesis of phencyclidine (PCP) and several of its analogs. Clin Toxicol 9:553-560, 1976.

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37. Lerner SE, Burns RS: Youthful phencyclidine (PCP) users, in Friedman A(ed): National Youth Polydrug Study, National Institute of Drug Abuse (to be published). 38. Burns RS, Lerner SE: Street PCP use: clinical studies of acute and chronic intoxication. Newsletter of the California Association of Toxicologists, August 2, 1975, pp 32-59. 39. Burns RS, Lerner SE: Management and treatment for acute phencyclidine intoxication, in Bourne PC(ed): Acute Drug Abuse Emergencies, New York, Academic Press, 1976, pp 297-305. 40. Burns RS, Lerner SE: Perspectives: acute phencyclidine intoxication. Clin Toxicol 9:477-502, 1976. 41. Marshman JA, Ramsay MP, Sellers EM: Quantification of phencyclidine in biological fluids and application to human overdose. Toxicol Appl Pharmacol 35:129-136, 1976. 42. Stockard JJ, Werner SS, Aalbers JA, et al: Electroencephalographic findings in phencyclidine intoxication. Arch Neurol 33:200-203, 1976. 43. Kessler GF, Demers LM, Berlin C, et al: Phencyclidine and fatal status epilepticus. N Engl J Med 291:979, 1974. 44. Liden CB, Lovejoy FH, Costello CE: Phencyclidine. JAMA 234:513-516, 1975. 45. Fauman B, Aldinger G, Fauman M, et al: Psychiatric sequelae of phencyclidine abuse. Clin Toxicol 9:529-538, 1976. 46. Eastman JW, Cohen SN: Hypertensive crisis and death associated with phencyclidine abuse. J A M A 231:12701271, 1975. 47. Dandavino R, Friborg J, Beaudry C, et al: Un cas d'intoxication aigu~ d la phencyclidine avec atteinte musculaire importante et insuffisance renale aigu~. L'Union Medicale Du Canada 104:57-60, 1975. 48. Baselt RC, Wright JA, Cravey RH: Therapeutic and toxic concentrations of more than 100 toxicologically significant drugs in blood, plasma, or serum: a tabulation. Clin Chem 21:44-62, 1975. 49. Burns RS, Lerner SE: Perspectives: acute p h e n c y c l i d i n e i n t o x i c a t i o n (revised). Problems of Drug Dependence 1976, Committee of Problems of Drug Dependence, National Academy of Sciences, 1976, pp 552-574.

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