TOXICOLOGY
AND
APPLIED
PHARMACOLOGY
42 45-54
Lysergic Acid Diethylamide Haloperidol, Diazepam,
(1977)
Antagonism by Chlorpromazine, and Pentobarbital in the Rabbit
PAULCONSROE,BYRONJONES,ANDPARTHENAMARTIN Department
of Phannacoiog?:
alld
Received
Toxicologv,
January
College of Pharmacy, Arizona 85721
I.?, 1977;
accepted
April
University
of Arizona.
Tucson.
25, 1977
Lysergic Acid Diethylamide Antagonism by Chlorpromazine. Haloperidol. Diazepam, and Pentobarbital in the Rabbit. CONSROE, P.. JONES, B., AND MARTIN. P. (1977). Toxicol. Appl. Pharmacol. 42. 45-54. The single and interactive iv effects of lysergic acid diethylamide (LSD, 50 &kg) given 20 min preceding or following chlorpromazine (CPZ, 1 and 2 mg/kg), haloperidol (HPD. 1 and 2 mg/kg), diazepam (Diaz, I and 2 mg/kg), or pentobarbital (Pb, 5 and 10 mg/kg) were assessed on electroencephalographic (EEG) cortical voltage output (CVO), behavior, and body temperature in unrestrained rabbits. Depending on dose and administration order, each drug partially antagonized the decrease of CVO and (except for CPZ) the increase in standing duration and frozen-like postures caused by LSD. LSD-induced hyperthermia was partially antagonized by CPZ and Diaz, not altered by Pb, and augmented by HPD. Novel stereotypy emerged from the interaction of LSD with HPD, Diaz, or Pb. Additionally, three of five rabbits given LSD died shortly after HPD administration. These data indicate that LSD is partially but not completely antagonized by these drugs, and the nature of the interaction with LSD depends on dose and order of LSDclrug administration.
While there is ample evidence that lysergic acid diethylamide (LSD) may induce serious psychic and somatic distortions includin? prolonged psychotic behavior (Schwarz, 1968; Smart and Bateman, 1967), life-threatening coma, and hyperthermia (Klock et al., 1975), there is a great deal of controversy concerning the clinical specificity and efficacy of pharmacological “antidotes” of LSD toxicity (Wyatt et al., 1976). In general, neuroleptic and sedative/hypnotic drugs are commonly purported to act as antagonists to the effects of LSD. One report has indicated that LSD-induced “flashbacks” were ameliorated after administration of the potent neuroleptic, haloperidol (Moskowitz, 1971). However, findings of neuroleptic drug antagonism of acute LSD psychopathology by chlorpromazine (Bowers, 1972; Isbell and Logan, 1957; Schwarz ef al., 1955) contrast with reports that chlorpromazine (CPZ) is not an effective antagonist (Hatrick and Dewhurst, 1970; Levy, 1971; Muller, 1972; Schwarz, 1968; Shick and Smith, 1970) and may even exacerbate the hallucinogen-induced toxicity (Shick and Smith, 1970; Silverman, 1971). Moreover, some authors (Isbell and Logan, 1957; Taylor et al., 1970) have suggestedthat CPZ’s ameliorative effect on LSD-induced toxicity may be due to a nonselective sedative effect and not due to a specific antipsychotic property. Although controlled clinical studies are lacking, many authors (Levy, 1971: Rappolt, 1971; Shick and Smith, 1970; Taylor et al., 1970) have advocated the useof various sedative/hypnotic drugs (i.e., chlordiazepoxide, diazepam, Copyright 0 1917 by Academic Press. Inc. All rights of reproductmn in any form reserved. Printed in Great Britain
45 ISSN CO4 I-OOXX
46
CONSROE,
JONES,
AND
MARTIN
and the short-acting barbiturates) as treatments for acute LSD-induced psychopathology. While studies in laboratory animals indicate that CPZ and various psychoactive drugs are incomplete antagonists of LSD (Wyatt et al., 1976), there are no reports of corresponding interactive effects of LSD and other neuroleptic or sedative/hypnotic agents that are commonly purported to be antagonists of the hallucinogen. Thus, the present study was undertaken to compare the interaction of LSD with two neuroleptics (CPZ and haloperidol) and two sedative/hypnotics (diazepam and pentobarbital) in the rabbit. In our design, we employed a quantitative electroencephalographic (EEG), behavioral, and body temperature paradigm that we previously found sensitive in ascertaining the effects of potential drug antagonists to &tetrahydrocannabinol, the major psychoactive ingredient of marijuana (Consroe et al., 1975a, 1976). METHODS Subjects New Zealand White rabbits weighing between 3.0 and 4.1 kg were used in the present investigation. All animals were housed in individual cages in a room maintained at constant temperature (25 &- 2’C) and under controlled lighting (12-hr light-dark). The rabbits were allowed access to food and water ad libitum, except during testing. Drugs LSD tartrate, CPZ hydrochloride, haloperidol (HPD), and pentobarbital sodium (Pb) were dissolved in 0.85% NaCl solution. Diazepam (Diaz) was dissolved in a vehicle consisting of 40% propylene glycol, 10% ethyl alcohol, and 50% saline. All drug dosages were calculated as the active base; drugs and vehicles (saline or Diaz vehicle) were injected via a jugular vein catheter and in the volume of 0.1 ml/kg body weight. Doses of LSD (50 pg/kg), CPZ (1 and 2 mg/kg), HPD (1 and 2 mg/kg), Pb (5 and 10 mg/kg), and Diaz (1 and 2 mg/kg) employed in the present study were chosen from pilot studies that indicated that these doses (given singly) produced characteristic EEG, behavioral, and/or body temperature patterns without signs of behavioral toxicity or anesthesia. Electrode Implantation
and Surgical Procedures
As described in detail previously (Consroe et al., 1975a, b), cortical EEG recording electrodes (stainless steel screws) and jugular catheters were implanted in rabbits anesthetized with Pb (10 mg/kg, iv) following pretreatment with CPZ (25 mg/kg, im). Testing Apparatus Unrestrained rabbits were tested in a sound attenuated chamber equipped with a oneway view window for behavioral observation. A shielded EEG cable connected the rabbit (with affixed Amphenol connector) to a Grass Model 7B recorder (Consroe et al., 1975a,b). Dependent Variables Measured EEG. The BEG activity occurring between the left motor and right parietal cortical leads was quantified with a voltage integrator (Grass Model 7PlOB) which yields a
DRUG
ANTAGONISM
OF
LSD
47
cumulative measurement of the area under successive positive and negative EEG waves. The resulting series of integrator resets, each representing 70 ,uV, is directly proportional to the EEG energy content (electrogenesis) or voltage output (Goldstein and Beck, 1965). Comparative evaluation of the quantified cortical EEG is based upon the fact that a high reset frequency (high voltage output) is equivalent to the descriptive term cortical synchronization or deactivation (high voltage, slow wave activity) and a low reset frequency represents cortical EEG desynchronization or activation (low voltage, fast wave activity). Behavior. Patterned after the procedure of Consroe et al. (1975a,b), the frequency and duration of the following behaviors were measured by an experimenter-operated digital event recorder; behaviors and respective interobserver reliability values (Pearson’s r) were: standing (r = 0.89); sprawling (r = 0.99); activity, i.e., locomotion, grooming, and environmental exploration (r = 0.92); and stereotypy, i.e., three or more successive repetitions of abnormal movements like head bobbing, circling, or paw extensions (r = 0.97). Temperature. Body temperature was measured with a Tele-Thermometer (Yellow Springs Instruments, Model 44). The thermistor probe was inserted 3 cm into the rectum. Procedure and Testing Sequence After 10 days of recovery from surgery, the rabbits were adapted to the testing apparatus (Consroe et al., 1975a). Four separate experiments (LSD-CPZ, LSD-HPD, LSD-Pb, and LSD-Diaz) were conducted with six rabbits used in the LSD-CPZ experiment and five rabbits used in each of the other three experiments. The procedure was identical for all four experiments and consisted of the following treatment conditions: 1. Control. Vehicle (saline or propylene glycol/ethanol/saline) was given at Time 0 followed 20 min later by vehicle. 2. LSD and vehicle. LSD (50 pug/kg) was given at Time 0 followed 20 min later by the appropriate vehicle. 3. Vehicle andputative antagonist. Saline was given at Time 0 followed 20 min later by CPZ (1 or 2 mg/kg), HPD (1 or 2 mg/kg), Pb (5 or 10 mg/kg), or Diaz (1 or 2 w/k). 4. LSD and putative antagonist. LSD (50 ,&kg) was given at Time 0 followed 20 mm later by CPZ (1 or 2 mg/kg), HPD (1 or 2 mg/kg), Pb (5 or 10 mg/kg), or Diaz (1 or 2 mg/kg). 5. Putative antagonist and LSD. CPZ (1 mg/kg), HPD (1 mg/kg), Pb (5 mg/kg), or Diaz (1 mg/kg) was given at Time 0 followed 20 min later by LSD (50 pg/kg). Within each treatment condition, drugs or vehicles were given in the order indicated above and simultaneous observations of EEG and behavior were made for eight 4-min time samples, i.e., O-4,5-9, 10-14, 15-19, 20-24,25-29, 3&34, and 35-39 min. In all conditions body temperature was recorded at the conclusion of each 40 min test session. The sequence of treatment conditions was counterbalanced, and a rest period of 7 days was maintained between treatment conditions for each animal. Since two doses of the putative antagonist were tested in treatment conditions No. 3 and No. 4 above, each animal was thus tested once a week for a total of 7 weeks.
48
CONSROE, JONES, AND MARTIN
Data Analysis The results of each of the four experiments were evaluated by an analysis of variance for a repeated measures experiment. Comparisons between means of treatment conditions were made with the Duncan’s New Multiple Range Test (Winer, 1971). In order to accurately compare the drug interactions with single drug effects or vehicle control, only meansderived from time samples20-24 to 35-39 min are illustrated. RESULTS
As illustrated in Table 1, compared to control, LSD (50 pug/kg) given singly (i.e., LSD and saline condition) produced a consistent decrease (p < 0.05) in cortical EEG TABLE
1
EFFECT OF DRUGS AND VEHICLE,GIVEN SINGLY, ON STANDING AND ACTIVITY BEHAVIOR, EEG CORTICAL VOLTAGE OUTPUT (CVO), AND RECTAL BODY TEMPERATURES Treatment Vehicle and vehicle control LSD(50 pg/kg) and vehicle Vehicle and CPZ (1 mg/kg) Vehicle and CPZ (2 mg/kg) Vehicle and vehicle control LSD (50 pgfkg) and vehicle Vehicle and HPD (1 mg/kg) Vehicle and HPD (2 mg/kg) Vehicle and vehicle control LSD (50 pug/kg)and vehicle Vehicle and Diaz (1 mg/kg) Vehicle and Diaz (2 mg/kg) Vehicle and vehicle control LSD (50 pg/kg) and vehicle Vehicle and Pb (5 mg/kg) Vehicle and Pb (10 mg/kg)
Stand (%) 6.5 15.8 6.1 4.3 7.1 17.8 9.3 4.0 12.0 19.6 3.8 0.1 12.0 19.5 1.9 1.5
+_ 2.2 + 2.3b + 2.0 + 1.7 * 1.9 k 2.9b i 4.1 + 2.4 k 3.8 & 3.0b + 2.4b & O.lb k 3.8 + 3.0b + 1.7b * l.Ob
Activity (%) 20.3 11.7 21.6 11.1 6.5 17.4 7.1 3.6 4.5 3.0 0.6 2.1 4.0 2.7 1.0 0.1
+ * k * + & * k + k + + k + * +
6.2 5.3 5.6 3.5 2.4 6.2b 0.5 1.6 1.9 0.8 OAb 1.0 1.8 0.8 0.46 O.Ob
cvo 105.4 51.7 108.3 104.0 92.0 47.5 105.6 54.2 47.8 27.5 75.5 92.6 47.8 27.5 73.1 79.1
+ 19.1 + 5.46 + 15.0 + 11.4 + 12.8 +_ 4.46 + 21.8 + 10.9b f 7.6 i 2.4b 2 6.9b + 14.9b 2 7.6 2 2.3b 2 9.9b f 13.3b
Temperature 39.5 40.8 39.4 39.2 39.5 40.9 40.3 40.1 39.8 41.1 40.1 39.8 39.8 42.1 40.1 39.7
+ k + + 2 i * + + + + + * 2 + &
0 2.4b 0.1 0.1 0 0.26 0.3 0.3 0.3 o.4b 0.3 0.2 0.3 0.4b 0.2 0.3
0 Data presented for drug vehicles, lysergic acid diethylamide (LSD), chlorpromazine (CPZ). haloperidol (HPD), diazepam (Diaz), and pentobarbital (Pb) are the means and standard errors from time samples 20-24 to 35-39 min; the first drug or vehicle of a pair was given at Time 0 and the second drug or vehicle was given at 20 mm. Durations of standing and activity were measured in seconds but data are presented as percentages of time to facilitate comparisons of treatments. CVO is presented as the number of integrator resets and temperature is in degrees Celsius. b Significantly different (n < 0.05) from respective vehicle control.
voltage output and an increase (p < 0.05) in body temperature. Concommitantly, LSD administration resulted in a reliable increase (p < 0.05) in duration of standing that was characterized qualitatively by unusual frozen-like postures. LSD produced little overall change in activity except in one treatment condition where activity (17.4%) was significantly increased (p < 0.05) above that of control (6.5%). No other significant behavioral changes from control were observed with the LSD and vehicle treatments. Given singly (ie., with only vehicle pretreatment), CPZ and HPD at both doses had little effect on standing, activity, and body temperature. CVO was not changed by either
DRUG
ANTAGONISM
OF
49
LSD
dose of CPZ, but decreased (p < 0.05) following the higher dose of HPD. Alternatively, Diaz and Pb reliably depressed standing (p < 0.05) and elicited cortical high voltage synchronization resulting in reliable increases in integrator resets (p < 0.05, each drug). A reliable decrease (p < 0.05) in activity was produced by both doses of Pb, but only by
120 CORTICAL CORTICAL
T-
-* STAND
VOLTAGE
VOLTAGE
OUTPUT
OUTPUl
T
1 1
T
-*
-*
I L! *
STAND
T
42
CPZ-2
TEMPERATURE
SALwe
“PD.
I
“PD.2
BLSD
FIG. 1. Mean frequency of integrator resets (cortical EEG voltage output), mean percentage of time standing, and mean body temperature following vehicle control, lysergic acid diethylamide [LSD (50 ,&kg) and saline], and the interaction of LSD (50 &kg) with chlorpromazine (CPZ, 1 or 2 mg/kg) or haloperidol (HPD, 1 or 2 mg/kg). Vertical lines represent standard errors of the mean. An asterisk denotes a significant difference (p < 0.05) from the LSD and saline condition. For illustration purposes, data points for control and LSD and saline conditions represent the mean of the four studies.
the lower dose of Diaz. As with the neuroleptics, Diaz and Pb produced no reliable effect on body temperature compared to the controls. Figure 1 shows the interactive effects of LSD and the neuroleptics, CPZ and HPD. CPZ effectively antagonized the LSD-induced decrease of cortical EEG voltage output in all interaction conditions. Compared to LSD alone, reliable increases (p < 0.05) in EEG voltage were observed with the LSD and CPZ (1 mg/kg), LSD and CPZ (2
50
CONSROE,
JONES,
AND
MARTIN
mg/kg), and CPZ (1 mg/kg) and LSD treatment orders. In contrast, CPZ failed to reverse the LSD increase in duration of standing. Additionally, CPZ (1 mg/kg), given before but not after LSD, prevented LSD-induced hyperthermia 0, < 0.05). Also, HPD reliably (p < 0.05) antagonized the decrease of EEG voltage output caused by LSD, but m cl0 >: :z y (I 80 F
100 CORTICAL
VOLTAGE
CORTICAL
OUTPUT
VOLTAGE
OUTPUl
80
TEMPERATURE
42
TEMPERATURE
FIG. 2. Mean frequency of integrator resets (cortical EEG voltage output), mean percentage of time standing, and mean body temperature following vehicle control, lysergic acid diethylamide [LSD (50 &kg) and saline], and the interaction of LSD (50 #g/kg) with pentobarbital (Pb, 5 or 10 mg/kg) or Diazepam (Diaz, 1 or 2 mg/kg). Vertical lines represent standard errors of the mean. An asterisk denotes a significant difference 0, < 0.05) from the LSD and saline condition. For illustration purposes, data points for control and LSD and saline conditions represent the mean of the four studies.
only when the neuroleptic was given prior to the hallucinogen, i.e., in the HPD (1 mg/kg) and LSD condition. The larger dose of HPD (2 mg/kg) significantly (I, < 0.05) reversed the LSD increase in standing and augmented (p < 0.05) the hyperthermia produced by the hallucinogen. Figure 2 illustrates the effects of Pb and Diaz on the actions of LSD. Pb (5 or 10 mg/kg), given after LSD, significantly (p < 0.05) antagonized the decrease in cortical
DRUG
ANTAGONISM
OF
LSD
51
EEG voltage output and the increase in standing elicited by the latter drug. Premeditation with Pb [Pb (5 mg/kg) and LSD condition] had no reliable effect on LSD-induced changes in EEG or standing. Additionally, under all treatment conditions, Pb failed to reliably alter the increase in body temperature produced by LSD. In all interactions between LSD and Diaz, Diaz reliably (p < 0.05) reversed the decrease of EEG voltage output and the increase of standing behavior produced by LSD. Further, Diaz, in two treatment conditions [i.e., LSD and Diaz (2 mg/kg); Diaz (1 mg/kg) and LSD], reversed and protected against LSD-induced hyperthermia 0, < 0.05). In addition to the above findings, the interaction between LSD and HPD [LSD and HPD (1 mg/kg); HPD (1 mg/kg) and LSD conditions], Pb [Pb (5 mg/kg) and LSD treatment], and Diaz [Diaz (1 mg/kg) and LSD condition] yielded a striking stereotyped behavior consisting mainly of circling and successive paw extensions that lasted for about 1 to 2 min. Surprisingly, HPD administration following LSD pretreatment proved to be lethal in three of the five original rabbits in the LSD-HPD experiments (substitute rabbits were used to keep n constant). One animal died following the LSD and HPD (1 mg/kg) condition, and two LSD-pretreated rabbits died following treatment with the 2-mg/kg HPD dose. These animals died within 40 min following HPD treatment from apparent respiratory arrest. Gross necropsies of the animals revealed a large amount of blood in the abdomen but were otherwise unremarkable. No other deaths, either during or following any of the treatment conditions, were observed.
DISCUSSION
The design of the present study provided a simplemeansof investigating interactions between LSD and four putative LSD-drug antagonists on a variety of dependent measures and under conditions of varying doses and treatment orders. Under the conditions of our paradigm, LSD produced reliable changes in rabbit cortical EEG, body temperature, and posture. This EEG activation by LSD is an observation consistent with those of others for rabbits (Long0 and Bovet, 1964; Schweigerdt et al., 1966) and humans (Gastaut et al., 1953; Pfeiffer et al., 1968; Schwartz et al., 1955). Similarly, the pyrogenic property of LSD in rabbits has been explored extensively by Horita and his colleagues(Horita and Dille, 1954; Horita and Gogerty, 1958; Horita and Hill, 1972). Additionally, there is clinical evidencefor a hyperthermic effect of LSD in humans (Friedman and Hirsch, 1971; Klock et al., 1975). Since EEG activation and hyperthermia are sensitive measuresof LSD in both rabbits and humans, these appear to have the best potential as experimental indicants of antagonismor potentiation of the effects of LSD by other agents. Our results demonstrated that CPZ, Diaz, and Pb can indeed reverse the EEG effects of 50 pug/kgof LSD. While HPD at both doseswas ineffective at reversing LSD, it was effective at a dose of 1 mg/kg in preventing LSD cortical activation. The finding that CPZ reverses LSD-induced cortical voltage diminution is congruent with similar findings in human subjects (Schwartz et al., 1955). While similar dosesof HPD, Diaz. and Pb alone have been shown to produce synchronization of cortical EEG in the rabbit (Bon&to et al., 1975; Consroe and White, 1972; Longo, 1962), no other studieshave tested thesedrugs in combination with LSD.
52
CONSROE,
JONES,
AND
MARTIN
Of the four putative antagonists tested, only Diaz evinced a reliable trend toward reversing (at 2 m&/kg) and preventing (at 1 mg/kg) the pyrogenic effect of LSD. None of the other agents counteracted the existent LSD-dependent hyperthermia, although CPZ at a dose of 1 mg/kg did act as prophylaxis against the pyrogenic effect. Roszell and Horita (1975) reported that neuroleptic pretreatment (thioridazine at either 5 or 10 mg/kg, iv) attenuated the LSD (100 pug/kg)-induced hyperthermia in rabbits. We found a similar protection with CPZ. However, we failed to replicate the finding of Roszell and Horita (1975) of HPD protection against the hyperthermic effect of LSD. In an older study in rabbits, Jacob and Lafille (1964) found that simultaneous iv administration of CPZ (0.3-10 mg/kg) and LSD (10 pg/kg) attenuated the hyperthermic effect of the latter. However, similar administration of HPD (3-10 mg/kg) and LSD produced equivocal results. Thus, the order of LSD-neuroleptic treatment appears to be an important factor in assessing interactions between the two drug types. The brief episodes of stereotypy observed in the LSD-HPD, LSD-Pb, and LSDDiaz treatment conditions were the only overt signs of behavioral distress we observed. We consider the incidence of stereotypy indicative of synergism between LSD and HPD, Pb, or Diaz because when any of these agents at the doses specified were given alone, no such behavior was observed. One of the most salient of our observations was the lethality of the LSD-HPD combination. Both drugs appear to have a low margin of safety in rabbits. Horita and Hill (1972) demonstrated lethal hyperthermia at doses of LSD between 300 and 400 ,&kg, iv, and Jacob and Lafille (1964) reported lethality in rabbits in excess of 30% with HPD at 10 mg/kg, iv. We are currently conducting investigations to test the reliability and character of the lethal combination of LSD and HPD. In conclusion, our findings confirm and extend the findings of others (e.g., Wyatt et al., 1976) that CPZ, as well as HPD, Diaz, and Pb, are incomplete antagonistsof LSD. Moreover, the effects observed in the rabbit are highly dependent on the dose and order of drug administration which reinforces the importance of defining pharmacological variables in studiesof LSD-drug interactions.
ACKNOWLEDGMENTS This research was supported
by Grant No. DA 01448 from the National
Institute on Drug
Abuse (NIDA) of the Alcohol, Drug Abuse, and Mental Health Administration. The authors thank Dr. Monique Braude of NIDA for the generous supply of LSD and for her encouragement. We also acknowledge the generous supplies of CPZ (Thorazine; Smith Kline & French Laboratories, Philadelphia, Pennsylvania), HPD (Haldol; McNeil Laboratories, Fort Washington, Pennsylvania), Diaz (Valium; Hoffmann-La Roche, Inc., Nutley, New Jersey). and Pb (Nembutal; Abbott Laboratories. North Chicago, Illinois) used in these studies.
REFERENCES BONFITTO, M., DELLA BELLA, D., AND SANTINI, V. (1975).Study of the action of somecentrally acting drugs on the EEG and on a conditioned avoidance reflex in the rabbit. Arch. Znt. Pharmacodyn. Thu. 217, 131-139. BOWERS, M. B. (1972). Acute psychosis induced by psychotomimetic drug abuse. I. Clinical findings. Arch. Gem Psychiat. 27, 437-440.
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P., AND WHITE, R. (1972). Effects of haloperidol and chlorpromazine on central adrenergic and cholinergic mechanisms in rabbits. Arch. Int. Pharmacodyn. Ther. 198, 6775. CONSROE, P. F., JONES, B. C., AND CHIN, L. (1975a). A9-Tetrahydrocannabinol, EEG and behavior: The importance of adaptation to the testing milieu. Pharmacol. Biochem. Behal). 3, 173-177. CONSROE, P., JONES, B., AND AKINS, F. (1975b). A9-Tetrahydrocannabinol-methamphetamine interaction in the rabbit. Neuropharmacology 14, 371-383. CONSROE, P., JONES, B., AND LAIRD, H. (1976). Interactions of A9-tetrahydrocannabinol with other pharmacological agents. Ann. N. Y. Acad. Sci. 281. 198-211. FRIEDMAN, S. A., AND HIRSCH. S. E. (1971). Extreme hyperthermia after LSD ingestion. J. Amer. Med. Ass. 217, 1549-1550. GASTAUT, H.. FERRER, S., AND CASTELL. C. (1953). Action du L.S.D. 25 sur les fonctions psychiques et l’Clectroenc&phalogramme. Con$n. Neurol. (Base0 13, 102-120. GOLDSTEIN, L., AND BECK, R. A. (1965). Amplitude analysis of the electroencephalogram: Review of the information obtained with the integrative method. Int. Rev. Neurobiol. 8. 265312. HATRICK, J. A., AND DEWHURST. K. (1970). Delayed psychosis due to LSD. Lancer 2, 742. HORITA, A.. AND DILLE, J. M. (1954). Pyretogenic effect of lysergic acid diethylamide. Science 120,11~111. HORITA, A., AND GOGERTY, J. H. (1958). The pyretogenic effect of 5-hydroxytryptophan and its comparison with that of LSD. J. Pharmacol. Exp. Ther. 122, 195-200. HORITA. A.. AND HILL, H. F. (1972). Hallucinogens. amphetamines and temperature. In The Pharmacology of Thermoregulation Symposium, San Francisco. pp. 417-43 I. Karger, Basel. ISBELL. H., AND LOGAN, C. R. (1957). Studies on the diethylamide of lysergic acid (LSD-25) II. Effects of chlorpromazine, azacyclonol and reserpine on the intensity of the LSD-reaction. A.M.A. Arch. Neural. Psychiat. 77, 350-358. JACOB, J., AND LAFILLE, C. (1964). Antagonistes de I-action hyperthermisante du lysergamide chez le lapin. Proc. 2nd Int. Pharmacol. Meeting 2. 249-261. KLOCK. J. C., BOERNER. U.. AND BECKER. C. E. (1975). Coma, hyperthermia and bleeding associated with massive LSD overdose: A report of eight cases. Clk. Toxicol. 8, 19 I-203. LEVY, R. M. ( I97 1). Diazepam for L.S.D. intoxication. Lancet 1, 1297. LONGO. V. (I 962). Electroencephalographic Atlas for Pharmacological Research. Elsevier, New York. LONGO, V. G.. AND BOVET, D. (1964). A neuropharmacological investigation on hallucinogenic drugs: Laboratory results versus clinical trials. Acta Neurochir. 12, 2 15-229. MOSKOWITZ, D. (1971). Use of haloperidol to reduce LSD flashbacks. Milit. Med. 136, 754156. MULLER, D. J. (1972). ECT in LSD psychosis: A report of three cases. Amer. J. Ps-vchiat. 128, 35 l--352. PFEIFFER, C., GOLDSTEIN, L., AND MURPHREE. H. (1968). Effects of parenteral administration of haloperidol and chlorpromazine in man. 1. Normal subjects: Quantitative EEG and subjective responses. J. Clin. Pharmacol. 8. 79-88. RAPPOLT. R. (1971). Practical treatment of drug abuse. Sem. Drug Treat. 1, 207-223. ROSZELL. D.. AND HORITA, A. (1975). The effects of haloperidol and thioridazine on apomorphine- and LSD-induced hyperthermia in the rabbit. J. Psych&. Res. 12, 117-123. SCHWARZ, C. J. (1968). The complications of LSD: A review of the literature. J. Nerzl. Ment. Dis. 146, 174-186. SCHWA=, B., BICKFORD, R., AND ROME, H. (1955). Reversibility of induced psychosis with chlorpromazine. Proc. Staff Meet, Mavo Clin. 30,407-4 17. SCHWEIGERDT, A. K., STEWART. A. H., AND HIMWICH, H. E. (1966). An electrographic study of d-lysergic acid diethylamide and nine congeners. J. Pharmacol. Exp. Ther. 151, 353-359. SHICK. J., AND SMITH, D. (1970). Analysis of the LSD flashback. J. Psyehedel. Drugs 3, 13- 19. SILVERMAN, .I. (1971). Research with psychedelics: Some biopsychological concepts and possible clinical applications. Arch. Gen. Psychiat. 23. 498-5 10. CONSROE,
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SMART, R. G., AND BATEMAN, K. C. (1967). Unfavourable reaction to LSD: A review and analysis of the available case reports. Canad. Med. Ass.J. 96, 1214- 122 1. TAYLOR, R. L., MAURER, J. I., AND TINKLENBERG, J. R. (1970). Management of “bad trips” in an evolving drug scene. J. Amer. Med. Ass. 213,422-425. WINER, B. J. (197 1). Statistical Principlesin ExperimentalDesign,2nd ed. McGraw-Hill, New York. WYA~, R. J., CANNON, E. H., STOFF, D. M., AND GILLIN, J. C. (1976). Interactions of hallucinogens at the clinical level. Ann. N. Y. Acad. Sci. 281,456-486.
AND
APPLIED
PHARMACOLOGY
42 45-54
Lysergic Acid Diethylamide Haloperidol, Diazepam,
(1977)
Antagonism by Chlorpromazine, and Pentobarbital in the Rabbit
PAULCONSROE,BYRONJONES,ANDPARTHENAMARTIN Department
of Phannacoiog?:
alld
Received
Toxicologv,
January
College of Pharmacy, Arizona 85721
I.?, 1977;
accepted
April
University
of Arizona.
Tucson.
25, 1977
Lysergic Acid Diethylamide Antagonism by Chlorpromazine. Haloperidol. Diazepam, and Pentobarbital in the Rabbit. CONSROE, P.. JONES, B., AND MARTIN. P. (1977). Toxicol. Appl. Pharmacol. 42. 45-54. The single and interactive iv effects of lysergic acid diethylamide (LSD, 50 &kg) given 20 min preceding or following chlorpromazine (CPZ, 1 and 2 mg/kg), haloperidol (HPD. 1 and 2 mg/kg), diazepam (Diaz, I and 2 mg/kg), or pentobarbital (Pb, 5 and 10 mg/kg) were assessed on electroencephalographic (EEG) cortical voltage output (CVO), behavior, and body temperature in unrestrained rabbits. Depending on dose and administration order, each drug partially antagonized the decrease of CVO and (except for CPZ) the increase in standing duration and frozen-like postures caused by LSD. LSD-induced hyperthermia was partially antagonized by CPZ and Diaz, not altered by Pb, and augmented by HPD. Novel stereotypy emerged from the interaction of LSD with HPD, Diaz, or Pb. Additionally, three of five rabbits given LSD died shortly after HPD administration. These data indicate that LSD is partially but not completely antagonized by these drugs, and the nature of the interaction with LSD depends on dose and order of LSDclrug administration.
While there is ample evidence that lysergic acid diethylamide (LSD) may induce serious psychic and somatic distortions includin? prolonged psychotic behavior (Schwarz, 1968; Smart and Bateman, 1967), life-threatening coma, and hyperthermia (Klock et al., 1975), there is a great deal of controversy concerning the clinical specificity and efficacy of pharmacological “antidotes” of LSD toxicity (Wyatt et al., 1976). In general, neuroleptic and sedative/hypnotic drugs are commonly purported to act as antagonists to the effects of LSD. One report has indicated that LSD-induced “flashbacks” were ameliorated after administration of the potent neuroleptic, haloperidol (Moskowitz, 1971). However, findings of neuroleptic drug antagonism of acute LSD psychopathology by chlorpromazine (Bowers, 1972; Isbell and Logan, 1957; Schwarz ef al., 1955) contrast with reports that chlorpromazine (CPZ) is not an effective antagonist (Hatrick and Dewhurst, 1970; Levy, 1971; Muller, 1972; Schwarz, 1968; Shick and Smith, 1970) and may even exacerbate the hallucinogen-induced toxicity (Shick and Smith, 1970; Silverman, 1971). Moreover, some authors (Isbell and Logan, 1957; Taylor et al., 1970) have suggestedthat CPZ’s ameliorative effect on LSD-induced toxicity may be due to a nonselective sedative effect and not due to a specific antipsychotic property. Although controlled clinical studies are lacking, many authors (Levy, 1971: Rappolt, 1971; Shick and Smith, 1970; Taylor et al., 1970) have advocated the useof various sedative/hypnotic drugs (i.e., chlordiazepoxide, diazepam, Copyright 0 1917 by Academic Press. Inc. All rights of reproductmn in any form reserved. Printed in Great Britain
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and the short-acting barbiturates) as treatments for acute LSD-induced psychopathology. While studies in laboratory animals indicate that CPZ and various psychoactive drugs are incomplete antagonists of LSD (Wyatt et al., 1976), there are no reports of corresponding interactive effects of LSD and other neuroleptic or sedative/hypnotic agents that are commonly purported to be antagonists of the hallucinogen. Thus, the present study was undertaken to compare the interaction of LSD with two neuroleptics (CPZ and haloperidol) and two sedative/hypnotics (diazepam and pentobarbital) in the rabbit. In our design, we employed a quantitative electroencephalographic (EEG), behavioral, and body temperature paradigm that we previously found sensitive in ascertaining the effects of potential drug antagonists to &tetrahydrocannabinol, the major psychoactive ingredient of marijuana (Consroe et al., 1975a, 1976). METHODS Subjects New Zealand White rabbits weighing between 3.0 and 4.1 kg were used in the present investigation. All animals were housed in individual cages in a room maintained at constant temperature (25 &- 2’C) and under controlled lighting (12-hr light-dark). The rabbits were allowed access to food and water ad libitum, except during testing. Drugs LSD tartrate, CPZ hydrochloride, haloperidol (HPD), and pentobarbital sodium (Pb) were dissolved in 0.85% NaCl solution. Diazepam (Diaz) was dissolved in a vehicle consisting of 40% propylene glycol, 10% ethyl alcohol, and 50% saline. All drug dosages were calculated as the active base; drugs and vehicles (saline or Diaz vehicle) were injected via a jugular vein catheter and in the volume of 0.1 ml/kg body weight. Doses of LSD (50 pg/kg), CPZ (1 and 2 mg/kg), HPD (1 and 2 mg/kg), Pb (5 and 10 mg/kg), and Diaz (1 and 2 mg/kg) employed in the present study were chosen from pilot studies that indicated that these doses (given singly) produced characteristic EEG, behavioral, and/or body temperature patterns without signs of behavioral toxicity or anesthesia. Electrode Implantation
and Surgical Procedures
As described in detail previously (Consroe et al., 1975a, b), cortical EEG recording electrodes (stainless steel screws) and jugular catheters were implanted in rabbits anesthetized with Pb (10 mg/kg, iv) following pretreatment with CPZ (25 mg/kg, im). Testing Apparatus Unrestrained rabbits were tested in a sound attenuated chamber equipped with a oneway view window for behavioral observation. A shielded EEG cable connected the rabbit (with affixed Amphenol connector) to a Grass Model 7B recorder (Consroe et al., 1975a,b). Dependent Variables Measured EEG. The BEG activity occurring between the left motor and right parietal cortical leads was quantified with a voltage integrator (Grass Model 7PlOB) which yields a
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cumulative measurement of the area under successive positive and negative EEG waves. The resulting series of integrator resets, each representing 70 ,uV, is directly proportional to the EEG energy content (electrogenesis) or voltage output (Goldstein and Beck, 1965). Comparative evaluation of the quantified cortical EEG is based upon the fact that a high reset frequency (high voltage output) is equivalent to the descriptive term cortical synchronization or deactivation (high voltage, slow wave activity) and a low reset frequency represents cortical EEG desynchronization or activation (low voltage, fast wave activity). Behavior. Patterned after the procedure of Consroe et al. (1975a,b), the frequency and duration of the following behaviors were measured by an experimenter-operated digital event recorder; behaviors and respective interobserver reliability values (Pearson’s r) were: standing (r = 0.89); sprawling (r = 0.99); activity, i.e., locomotion, grooming, and environmental exploration (r = 0.92); and stereotypy, i.e., three or more successive repetitions of abnormal movements like head bobbing, circling, or paw extensions (r = 0.97). Temperature. Body temperature was measured with a Tele-Thermometer (Yellow Springs Instruments, Model 44). The thermistor probe was inserted 3 cm into the rectum. Procedure and Testing Sequence After 10 days of recovery from surgery, the rabbits were adapted to the testing apparatus (Consroe et al., 1975a). Four separate experiments (LSD-CPZ, LSD-HPD, LSD-Pb, and LSD-Diaz) were conducted with six rabbits used in the LSD-CPZ experiment and five rabbits used in each of the other three experiments. The procedure was identical for all four experiments and consisted of the following treatment conditions: 1. Control. Vehicle (saline or propylene glycol/ethanol/saline) was given at Time 0 followed 20 min later by vehicle. 2. LSD and vehicle. LSD (50 pug/kg) was given at Time 0 followed 20 min later by the appropriate vehicle. 3. Vehicle andputative antagonist. Saline was given at Time 0 followed 20 min later by CPZ (1 or 2 mg/kg), HPD (1 or 2 mg/kg), Pb (5 or 10 mg/kg), or Diaz (1 or 2 w/k). 4. LSD and putative antagonist. LSD (50 ,&kg) was given at Time 0 followed 20 mm later by CPZ (1 or 2 mg/kg), HPD (1 or 2 mg/kg), Pb (5 or 10 mg/kg), or Diaz (1 or 2 mg/kg). 5. Putative antagonist and LSD. CPZ (1 mg/kg), HPD (1 mg/kg), Pb (5 mg/kg), or Diaz (1 mg/kg) was given at Time 0 followed 20 min later by LSD (50 pg/kg). Within each treatment condition, drugs or vehicles were given in the order indicated above and simultaneous observations of EEG and behavior were made for eight 4-min time samples, i.e., O-4,5-9, 10-14, 15-19, 20-24,25-29, 3&34, and 35-39 min. In all conditions body temperature was recorded at the conclusion of each 40 min test session. The sequence of treatment conditions was counterbalanced, and a rest period of 7 days was maintained between treatment conditions for each animal. Since two doses of the putative antagonist were tested in treatment conditions No. 3 and No. 4 above, each animal was thus tested once a week for a total of 7 weeks.
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Data Analysis The results of each of the four experiments were evaluated by an analysis of variance for a repeated measures experiment. Comparisons between means of treatment conditions were made with the Duncan’s New Multiple Range Test (Winer, 1971). In order to accurately compare the drug interactions with single drug effects or vehicle control, only meansderived from time samples20-24 to 35-39 min are illustrated. RESULTS
As illustrated in Table 1, compared to control, LSD (50 pug/kg) given singly (i.e., LSD and saline condition) produced a consistent decrease (p < 0.05) in cortical EEG TABLE
1
EFFECT OF DRUGS AND VEHICLE,GIVEN SINGLY, ON STANDING AND ACTIVITY BEHAVIOR, EEG CORTICAL VOLTAGE OUTPUT (CVO), AND RECTAL BODY TEMPERATURES Treatment Vehicle and vehicle control LSD(50 pg/kg) and vehicle Vehicle and CPZ (1 mg/kg) Vehicle and CPZ (2 mg/kg) Vehicle and vehicle control LSD (50 pgfkg) and vehicle Vehicle and HPD (1 mg/kg) Vehicle and HPD (2 mg/kg) Vehicle and vehicle control LSD (50 pug/kg)and vehicle Vehicle and Diaz (1 mg/kg) Vehicle and Diaz (2 mg/kg) Vehicle and vehicle control LSD (50 pg/kg) and vehicle Vehicle and Pb (5 mg/kg) Vehicle and Pb (10 mg/kg)
Stand (%) 6.5 15.8 6.1 4.3 7.1 17.8 9.3 4.0 12.0 19.6 3.8 0.1 12.0 19.5 1.9 1.5
+_ 2.2 + 2.3b + 2.0 + 1.7 * 1.9 k 2.9b i 4.1 + 2.4 k 3.8 & 3.0b + 2.4b & O.lb k 3.8 + 3.0b + 1.7b * l.Ob
Activity (%) 20.3 11.7 21.6 11.1 6.5 17.4 7.1 3.6 4.5 3.0 0.6 2.1 4.0 2.7 1.0 0.1
+ * k * + & * k + k + + k + * +
6.2 5.3 5.6 3.5 2.4 6.2b 0.5 1.6 1.9 0.8 OAb 1.0 1.8 0.8 0.46 O.Ob
cvo 105.4 51.7 108.3 104.0 92.0 47.5 105.6 54.2 47.8 27.5 75.5 92.6 47.8 27.5 73.1 79.1
+ 19.1 + 5.46 + 15.0 + 11.4 + 12.8 +_ 4.46 + 21.8 + 10.9b f 7.6 i 2.4b 2 6.9b + 14.9b 2 7.6 2 2.3b 2 9.9b f 13.3b
Temperature 39.5 40.8 39.4 39.2 39.5 40.9 40.3 40.1 39.8 41.1 40.1 39.8 39.8 42.1 40.1 39.7
+ k + + 2 i * + + + + + * 2 + &
0 2.4b 0.1 0.1 0 0.26 0.3 0.3 0.3 o.4b 0.3 0.2 0.3 0.4b 0.2 0.3
0 Data presented for drug vehicles, lysergic acid diethylamide (LSD), chlorpromazine (CPZ). haloperidol (HPD), diazepam (Diaz), and pentobarbital (Pb) are the means and standard errors from time samples 20-24 to 35-39 min; the first drug or vehicle of a pair was given at Time 0 and the second drug or vehicle was given at 20 mm. Durations of standing and activity were measured in seconds but data are presented as percentages of time to facilitate comparisons of treatments. CVO is presented as the number of integrator resets and temperature is in degrees Celsius. b Significantly different (n < 0.05) from respective vehicle control.
voltage output and an increase (p < 0.05) in body temperature. Concommitantly, LSD administration resulted in a reliable increase (p < 0.05) in duration of standing that was characterized qualitatively by unusual frozen-like postures. LSD produced little overall change in activity except in one treatment condition where activity (17.4%) was significantly increased (p < 0.05) above that of control (6.5%). No other significant behavioral changes from control were observed with the LSD and vehicle treatments. Given singly (ie., with only vehicle pretreatment), CPZ and HPD at both doses had little effect on standing, activity, and body temperature. CVO was not changed by either
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dose of CPZ, but decreased (p < 0.05) following the higher dose of HPD. Alternatively, Diaz and Pb reliably depressed standing (p < 0.05) and elicited cortical high voltage synchronization resulting in reliable increases in integrator resets (p < 0.05, each drug). A reliable decrease (p < 0.05) in activity was produced by both doses of Pb, but only by
120 CORTICAL CORTICAL
T-
-* STAND
VOLTAGE
VOLTAGE
OUTPUT
OUTPUl
T
1 1
T
-*
-*
I L! *
STAND
T
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TEMPERATURE
SALwe
“PD.
I
“PD.2
BLSD
FIG. 1. Mean frequency of integrator resets (cortical EEG voltage output), mean percentage of time standing, and mean body temperature following vehicle control, lysergic acid diethylamide [LSD (50 ,&kg) and saline], and the interaction of LSD (50 &kg) with chlorpromazine (CPZ, 1 or 2 mg/kg) or haloperidol (HPD, 1 or 2 mg/kg). Vertical lines represent standard errors of the mean. An asterisk denotes a significant difference (p < 0.05) from the LSD and saline condition. For illustration purposes, data points for control and LSD and saline conditions represent the mean of the four studies.
the lower dose of Diaz. As with the neuroleptics, Diaz and Pb produced no reliable effect on body temperature compared to the controls. Figure 1 shows the interactive effects of LSD and the neuroleptics, CPZ and HPD. CPZ effectively antagonized the LSD-induced decrease of cortical EEG voltage output in all interaction conditions. Compared to LSD alone, reliable increases (p < 0.05) in EEG voltage were observed with the LSD and CPZ (1 mg/kg), LSD and CPZ (2
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mg/kg), and CPZ (1 mg/kg) and LSD treatment orders. In contrast, CPZ failed to reverse the LSD increase in duration of standing. Additionally, CPZ (1 mg/kg), given before but not after LSD, prevented LSD-induced hyperthermia 0, < 0.05). Also, HPD reliably (p < 0.05) antagonized the decrease of EEG voltage output caused by LSD, but m cl0 >: :z y (I 80 F
100 CORTICAL
VOLTAGE
CORTICAL
OUTPUT
VOLTAGE
OUTPUl
80
TEMPERATURE
42
TEMPERATURE
FIG. 2. Mean frequency of integrator resets (cortical EEG voltage output), mean percentage of time standing, and mean body temperature following vehicle control, lysergic acid diethylamide [LSD (50 &kg) and saline], and the interaction of LSD (50 #g/kg) with pentobarbital (Pb, 5 or 10 mg/kg) or Diazepam (Diaz, 1 or 2 mg/kg). Vertical lines represent standard errors of the mean. An asterisk denotes a significant difference 0, < 0.05) from the LSD and saline condition. For illustration purposes, data points for control and LSD and saline conditions represent the mean of the four studies.
only when the neuroleptic was given prior to the hallucinogen, i.e., in the HPD (1 mg/kg) and LSD condition. The larger dose of HPD (2 mg/kg) significantly (I, < 0.05) reversed the LSD increase in standing and augmented (p < 0.05) the hyperthermia produced by the hallucinogen. Figure 2 illustrates the effects of Pb and Diaz on the actions of LSD. Pb (5 or 10 mg/kg), given after LSD, significantly (p < 0.05) antagonized the decrease in cortical
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EEG voltage output and the increase in standing elicited by the latter drug. Premeditation with Pb [Pb (5 mg/kg) and LSD condition] had no reliable effect on LSD-induced changes in EEG or standing. Additionally, under all treatment conditions, Pb failed to reliably alter the increase in body temperature produced by LSD. In all interactions between LSD and Diaz, Diaz reliably (p < 0.05) reversed the decrease of EEG voltage output and the increase of standing behavior produced by LSD. Further, Diaz, in two treatment conditions [i.e., LSD and Diaz (2 mg/kg); Diaz (1 mg/kg) and LSD], reversed and protected against LSD-induced hyperthermia 0, < 0.05). In addition to the above findings, the interaction between LSD and HPD [LSD and HPD (1 mg/kg); HPD (1 mg/kg) and LSD conditions], Pb [Pb (5 mg/kg) and LSD treatment], and Diaz [Diaz (1 mg/kg) and LSD condition] yielded a striking stereotyped behavior consisting mainly of circling and successive paw extensions that lasted for about 1 to 2 min. Surprisingly, HPD administration following LSD pretreatment proved to be lethal in three of the five original rabbits in the LSD-HPD experiments (substitute rabbits were used to keep n constant). One animal died following the LSD and HPD (1 mg/kg) condition, and two LSD-pretreated rabbits died following treatment with the 2-mg/kg HPD dose. These animals died within 40 min following HPD treatment from apparent respiratory arrest. Gross necropsies of the animals revealed a large amount of blood in the abdomen but were otherwise unremarkable. No other deaths, either during or following any of the treatment conditions, were observed.
DISCUSSION
The design of the present study provided a simplemeansof investigating interactions between LSD and four putative LSD-drug antagonists on a variety of dependent measures and under conditions of varying doses and treatment orders. Under the conditions of our paradigm, LSD produced reliable changes in rabbit cortical EEG, body temperature, and posture. This EEG activation by LSD is an observation consistent with those of others for rabbits (Long0 and Bovet, 1964; Schweigerdt et al., 1966) and humans (Gastaut et al., 1953; Pfeiffer et al., 1968; Schwartz et al., 1955). Similarly, the pyrogenic property of LSD in rabbits has been explored extensively by Horita and his colleagues(Horita and Dille, 1954; Horita and Gogerty, 1958; Horita and Hill, 1972). Additionally, there is clinical evidencefor a hyperthermic effect of LSD in humans (Friedman and Hirsch, 1971; Klock et al., 1975). Since EEG activation and hyperthermia are sensitive measuresof LSD in both rabbits and humans, these appear to have the best potential as experimental indicants of antagonismor potentiation of the effects of LSD by other agents. Our results demonstrated that CPZ, Diaz, and Pb can indeed reverse the EEG effects of 50 pug/kgof LSD. While HPD at both doseswas ineffective at reversing LSD, it was effective at a dose of 1 mg/kg in preventing LSD cortical activation. The finding that CPZ reverses LSD-induced cortical voltage diminution is congruent with similar findings in human subjects (Schwartz et al., 1955). While similar dosesof HPD, Diaz. and Pb alone have been shown to produce synchronization of cortical EEG in the rabbit (Bon&to et al., 1975; Consroe and White, 1972; Longo, 1962), no other studieshave tested thesedrugs in combination with LSD.
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Of the four putative antagonists tested, only Diaz evinced a reliable trend toward reversing (at 2 m&/kg) and preventing (at 1 mg/kg) the pyrogenic effect of LSD. None of the other agents counteracted the existent LSD-dependent hyperthermia, although CPZ at a dose of 1 mg/kg did act as prophylaxis against the pyrogenic effect. Roszell and Horita (1975) reported that neuroleptic pretreatment (thioridazine at either 5 or 10 mg/kg, iv) attenuated the LSD (100 pug/kg)-induced hyperthermia in rabbits. We found a similar protection with CPZ. However, we failed to replicate the finding of Roszell and Horita (1975) of HPD protection against the hyperthermic effect of LSD. In an older study in rabbits, Jacob and Lafille (1964) found that simultaneous iv administration of CPZ (0.3-10 mg/kg) and LSD (10 pg/kg) attenuated the hyperthermic effect of the latter. However, similar administration of HPD (3-10 mg/kg) and LSD produced equivocal results. Thus, the order of LSD-neuroleptic treatment appears to be an important factor in assessing interactions between the two drug types. The brief episodes of stereotypy observed in the LSD-HPD, LSD-Pb, and LSDDiaz treatment conditions were the only overt signs of behavioral distress we observed. We consider the incidence of stereotypy indicative of synergism between LSD and HPD, Pb, or Diaz because when any of these agents at the doses specified were given alone, no such behavior was observed. One of the most salient of our observations was the lethality of the LSD-HPD combination. Both drugs appear to have a low margin of safety in rabbits. Horita and Hill (1972) demonstrated lethal hyperthermia at doses of LSD between 300 and 400 ,&kg, iv, and Jacob and Lafille (1964) reported lethality in rabbits in excess of 30% with HPD at 10 mg/kg, iv. We are currently conducting investigations to test the reliability and character of the lethal combination of LSD and HPD. In conclusion, our findings confirm and extend the findings of others (e.g., Wyatt et al., 1976) that CPZ, as well as HPD, Diaz, and Pb, are incomplete antagonistsof LSD. Moreover, the effects observed in the rabbit are highly dependent on the dose and order of drug administration which reinforces the importance of defining pharmacological variables in studiesof LSD-drug interactions.
ACKNOWLEDGMENTS This research was supported
by Grant No. DA 01448 from the National
Institute on Drug
Abuse (NIDA) of the Alcohol, Drug Abuse, and Mental Health Administration. The authors thank Dr. Monique Braude of NIDA for the generous supply of LSD and for her encouragement. We also acknowledge the generous supplies of CPZ (Thorazine; Smith Kline & French Laboratories, Philadelphia, Pennsylvania), HPD (Haldol; McNeil Laboratories, Fort Washington, Pennsylvania), Diaz (Valium; Hoffmann-La Roche, Inc., Nutley, New Jersey). and Pb (Nembutal; Abbott Laboratories. North Chicago, Illinois) used in these studies.
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P., AND WHITE, R. (1972). Effects of haloperidol and chlorpromazine on central adrenergic and cholinergic mechanisms in rabbits. Arch. Int. Pharmacodyn. Ther. 198, 6775. CONSROE, P. F., JONES, B. C., AND CHIN, L. (1975a). A9-Tetrahydrocannabinol, EEG and behavior: The importance of adaptation to the testing milieu. Pharmacol. Biochem. Behal). 3, 173-177. CONSROE, P., JONES, B., AND AKINS, F. (1975b). A9-Tetrahydrocannabinol-methamphetamine interaction in the rabbit. Neuropharmacology 14, 371-383. CONSROE, P., JONES, B., AND LAIRD, H. (1976). Interactions of A9-tetrahydrocannabinol with other pharmacological agents. Ann. N. Y. Acad. Sci. 281. 198-211. FRIEDMAN, S. A., AND HIRSCH. S. E. (1971). Extreme hyperthermia after LSD ingestion. J. Amer. Med. Ass. 217, 1549-1550. GASTAUT, H.. FERRER, S., AND CASTELL. C. (1953). Action du L.S.D. 25 sur les fonctions psychiques et l’Clectroenc&phalogramme. Con$n. Neurol. (Base0 13, 102-120. GOLDSTEIN, L., AND BECK, R. A. (1965). Amplitude analysis of the electroencephalogram: Review of the information obtained with the integrative method. Int. Rev. Neurobiol. 8. 265312. HATRICK, J. A., AND DEWHURST. K. (1970). Delayed psychosis due to LSD. Lancer 2, 742. HORITA, A.. AND DILLE, J. M. (1954). Pyretogenic effect of lysergic acid diethylamide. Science 120,11~111. HORITA, A., AND GOGERTY, J. H. (1958). The pyretogenic effect of 5-hydroxytryptophan and its comparison with that of LSD. J. Pharmacol. Exp. Ther. 122, 195-200. HORITA. A.. AND HILL, H. F. (1972). Hallucinogens. amphetamines and temperature. In The Pharmacology of Thermoregulation Symposium, San Francisco. pp. 417-43 I. Karger, Basel. ISBELL. H., AND LOGAN, C. R. (1957). Studies on the diethylamide of lysergic acid (LSD-25) II. Effects of chlorpromazine, azacyclonol and reserpine on the intensity of the LSD-reaction. A.M.A. Arch. Neural. Psychiat. 77, 350-358. JACOB, J., AND LAFILLE, C. (1964). Antagonistes de I-action hyperthermisante du lysergamide chez le lapin. Proc. 2nd Int. Pharmacol. Meeting 2. 249-261. KLOCK. J. C., BOERNER. U.. AND BECKER. C. E. (1975). Coma, hyperthermia and bleeding associated with massive LSD overdose: A report of eight cases. Clk. Toxicol. 8, 19 I-203. LEVY, R. M. ( I97 1). Diazepam for L.S.D. intoxication. Lancet 1, 1297. LONGO. V. (I 962). Electroencephalographic Atlas for Pharmacological Research. Elsevier, New York. LONGO, V. G.. AND BOVET, D. (1964). A neuropharmacological investigation on hallucinogenic drugs: Laboratory results versus clinical trials. Acta Neurochir. 12, 2 15-229. MOSKOWITZ, D. (1971). Use of haloperidol to reduce LSD flashbacks. Milit. Med. 136, 754156. MULLER, D. J. (1972). ECT in LSD psychosis: A report of three cases. Amer. J. Ps-vchiat. 128, 35 l--352. PFEIFFER, C., GOLDSTEIN, L., AND MURPHREE. H. (1968). Effects of parenteral administration of haloperidol and chlorpromazine in man. 1. Normal subjects: Quantitative EEG and subjective responses. J. Clin. Pharmacol. 8. 79-88. RAPPOLT. R. (1971). Practical treatment of drug abuse. Sem. Drug Treat. 1, 207-223. ROSZELL. D.. AND HORITA, A. (1975). The effects of haloperidol and thioridazine on apomorphine- and LSD-induced hyperthermia in the rabbit. J. Psych&. Res. 12, 117-123. SCHWARZ, C. J. (1968). The complications of LSD: A review of the literature. J. Nerzl. Ment. Dis. 146, 174-186. SCHWA=, B., BICKFORD, R., AND ROME, H. (1955). Reversibility of induced psychosis with chlorpromazine. Proc. Staff Meet, Mavo Clin. 30,407-4 17. SCHWEIGERDT, A. K., STEWART. A. H., AND HIMWICH, H. E. (1966). An electrographic study of d-lysergic acid diethylamide and nine congeners. J. Pharmacol. Exp. Ther. 151, 353-359. SHICK. J., AND SMITH, D. (1970). Analysis of the LSD flashback. J. Psyehedel. Drugs 3, 13- 19. SILVERMAN, .I. (1971). Research with psychedelics: Some biopsychological concepts and possible clinical applications. Arch. Gen. Psychiat. 23. 498-5 10. CONSROE,
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SMART, R. G., AND BATEMAN, K. C. (1967). Unfavourable reaction to LSD: A review and analysis of the available case reports. Canad. Med. Ass.J. 96, 1214- 122 1. TAYLOR, R. L., MAURER, J. I., AND TINKLENBERG, J. R. (1970). Management of “bad trips” in an evolving drug scene. J. Amer. Med. Ass. 213,422-425. WINER, B. J. (197 1). Statistical Principlesin ExperimentalDesign,2nd ed. McGraw-Hill, New York. WYA~, R. J., CANNON, E. H., STOFF, D. M., AND GILLIN, J. C. (1976). Interactions of hallucinogens at the clinical level. Ann. N. Y. Acad. Sci. 281,456-486.
