Biological activity of the tetrahydrocannabinols

Journal of Ethnopharmacology, 2 (1980) 197 - 231

197

© Elsevier Sequoia S.A., Lausanne - Printed in the Netherlands

Review Article BIOLOGICAL ACTIVITY OF THE TETRAHYDROCANNABINOLS*

J. J. KETTENES-VAN DEN BOSCH and C. A. SALEMINK

Department of Organic Chemistry of Natural Products. Organic Chemical Laboratory. State University of Utrecht, Utrecht (The Netherlands) J. VAN NOORDWIJK

National Institute ofPublic Health. BiltholJen (The Netherlands) I. KHAN Division of Mental Health, The World Health Organization. Headquarters, Geneva (Switzerland) . (Received March 7.1979; in final form October 15, 1979)

CONTENTS lfu~~~

p.

1.1 Historical background . . . . . . . . . . . . . . . . , 198 1.2 The objective of this review 198 1.3 Literature sources . . . . . . . . . . . . . . . . . . . 199 1.4 Acknowledgements 199 2 Chemistry 2.1 Tetrahydrocannabinol isomers 200 2.2 Occurrence and synthesis 202 3 Biological activity 3.1 Biological activity in animals 205 3.1.1 (-)-trans-A 6 -Tetrahydrocannabinol. 205 3 .1.1.1 Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 3.1.1.2 Behaviour " 205 3.1.1.3 Sleep, pain, temperature regulation 206 3.1.1.4 Conditioned learning 207 3.1.1.5 EEG 208 3.1.1.6 Distribution in the organism 209 3.1.1.7 Interaction with neurotransmitters and enzymes 210 3.1.1.8 futeractions with miscellaneous drugs 212 3.1.1.9 Teratogenicity 212 3.1.1.10 Therapeutic potential ~ 212 3.1.2 {+ ).trans-A6·Tetrahydrocannabinol 214 , .. 214 3.1.3 {± )-cis-A 6.Tetrahydrocannabinol 3.1.4 (+)-trans-A1-Tetrahydrocannabinol 214 3.1.5 (±)-cis.A 1.TetrahYdrocannabinol , 215 3.1.6 (± )-oCl 3.Tetrahydrocannabinol. 215 3.1.7 Other isomers , 215 *This paper was prepared for the discussion at the Expert Committee Meeting on Drug Dependence, in Geneva, Swiherland. 26th September· 1st October, 1977.

198

4 5 6 7 8 9

page 3.2 Biological activity in humans 215 3.2.1 (-)-trans-~6-Tetrahydrocannabinol. 215 3.2.2 (± )-A 3 -Tetrahydrocannabinol. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216 3.2.3 Other isomers 216 Therapeutic potential of (-)-trans-~l-tetrahydrocannabinola nd cannabis 216 Dependence liability and development of tolerance in primates . . . . . . . . . . . . . 219 Summary 220 Conclusions 221 References 222 List of abbreviations 230

Figure 1. Scheme 1. Scheme II.

Tetrahydrocannabinol isomers 201 Synthetic routes to tetrahydrocannabinols, starting from olivetol 203 Conversion of cannabidiol, cis-tetrahydrocannabinol, and cannabichromene into iso-tetrahydrocannabinols 204

1. Introduction 1.1 Historical background

Cannabis preparations have been used for many centuries as psychotomimetic drugs and as folk medicines. The chemical and pharmacological research on Cannabis sativa L. started about 1940. Initially, pharmacological testing was done with crude Cannabis preparations. With the structure elucidation of (-)-trans-~l-tetrahydrocannabinoland other cannabinoids, pharmacological testing was increasingly carried out with single components. (-)-trans-~l-Tetrahydrocannabinoland its (-)-trans-~6-isomer were recognized to be the main psychoactive components of Cannabis. Recently evidence has been found that other components, although not psychotropically active themselves, may modify the activity of (-)-trans-A1-tetrahydrocannabinol and (-)-trans-~6-tetrahydrocannabinol. The consumption of Cannabis preparations has increased tremendously in the Western world during the last decades. Therefore, it was felt that international regulations had to be established regarding the use and trade of Cannabis.

1.2 The objective of this review

The objective of this paper is to review the available knowledge on the biological activity of the isomers of (-)-trans-A1-tetrahydrocannabinol. Their chemistry will not be dealt with in detail since that subject has been adequately covered by others [2 • 4]. The biological activity of Cannabis prepar-

199

ations, e.g. marihuana and hashish, will not be reviewed. (-).tran8·.61.Tetra~ hydrocannabinol is generally accepted to be the main active principle of Cannabis. A wealth of information on pre-clinical as well as clinical testing of this compound is reported in the literature. The literature on the biological activity of (-)-trans-.6 1 -tetrahydrocannabinol is not incorporated here; only its therapeutic potential, its dependence liability, and the development of tolerance to its effects will be discussed briefly.

1.3 Literature sources In preparing the present report the following literature sources have been searched: '-Marihuana: An Annotated Bibliography, C. W. Waller, J. J. Johnsson, J. Buelke, and C. E. Turner, Macmillan Information, Macmillan Publishing Co. Inc. New York, 1976; covers the scientific literature on Cannabis from 1964 through 1974; -the files of the Department of Organic Chemistry of Natural Products, Organic Chemical Laboratory, State University Utrecht, Croesestraat 79, Utrecht, The Netherlands; -the files of the Division of Mental Health, World Health Organization (WHO), 1211 Geneva 27, Switzerland; -the files of the United Nations Narcotics Laboratory, 1211 Geneva 10, Switzerland; --a computer search carried out by C. E. Turner (dated February 28, 1977) covering the literature published in 1975 and 1976 (entries: isomers of tetrahydrocannabinol, biological functions); --a computer search by WHO Medline Center, 1211 Geneva 27, Switzerland, (dated March 2, 1977) covering 1975 and 1976 (entries: tetrahydrocannabinol, pharmacodynamics, metabolism, therapeutic use, toxicity, adverse effects, poisoning, activity in blood and urine).

1.4 Acknowledgements

We gratefully acknowledge the financial support of the Dutch Ministry of Health and Environmental Hygienics. We wish to express our sincere thanks to Dr. R. J. Samsom for his interest; to Prof. Dr. P. G. Waser and Dr. A. Ganz (University of Zurich) for critical remarks; to Mr. W. S. Alexander (Hockessin, Delaware, U.S.A.) for correcting errors in the English text; to Dr. O. J. Braenden (Geneva) and to Dr. C. E. Turner (University of Mississip~ pi) and his colleagues for their help in obtaining part of the literature.

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2. Chemistry

2.1 Tetrahydrocannabinol isomers The structure and stereochemistry of (-)-trans-.t..1-tetrahydrocannabinol*, the naturally occurring active principle of Cannabis sativa, are shown in fonnula I. The empirical formula is CZIHao02' Structural elements are the olivetol moiety (C l1 H 16 0 Z) and the monoterpene moiety (C lO H 16 ). In the literature two systems of numbering are used for the cannabinoids: the terpene numbering system (formula I) and the benzopyran numbering system (fonnula II). The terpene numbering system is more convenient since it can also be used for those cannabinoids in which the pyran ring is absent (as, for instance, in cannabidiol); it will be used throughout this review. Compounds can be considered to be isomers of (-)-trans-.t.. 1 ·THC if -their empirical formula is CZIHao02; ·--they contain the olivetol moiety III (in which the pentyl side-chain Can be branched and/or mono-unsaturated); -they possess a system of three nuclei, of which one is an aromatic ring, one a pyran ring, and one a cyclohexane ring. The isomers of (-)·trans-.t.. 1 -THC can be categorized in several classes (illustrated in Fig. 1): (1) isomers differing from I in the position of the double bond in ring A and in the stereochemistry at positions 1, 3 and 4; (2) the iso-tetrahydrocannabinols, differing from the tetrahydrocannabinols in the way the pyran ring is formed; (3) isomers in which the aromatic hydroxy and pentyl groups are interchanged or present in different positions; N

5"

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*THC will be used as an abbreviation for tetrahydrocannabinol in this review.

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H

...•

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L

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H.

OH

(1)

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H~OH C6Hn'tl (3)

C~.H D

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201

(2)

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104

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o

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(9)

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(s)

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0

104 .....

104

% :. .' H

H"

C6H"

0

D

0104

CIHll

(10)

Fig. 1. Tetl:ahYdrocannabinol isomeI'll. (Numbers between bl'llckets refer to categories 1 . 10 on pages 200 . 201; dotted lines indicate in which positions the double bond can be present.)

(4) iso-tetrahydrocannabinols in which aromatic hydroxy and pentyl groups are interchanged or present in different positions; (5) isomers in which the methyl group in ring A is present in another position; (6) iso-tetrahydrocannabinols in which the methyl group in ring A is present in another position; (7) isomers in which ring A is saturated, but where the aromatic ring carries a pentenyl side chain; (8) iso-tetrahydrocannabinols in which ring A is saturated but where the aromatic ring carries a pentyl group; (9) isomers in which the pentyl side chain is branched; (10) iso-tetrahydrocannabinols with a branched pentyl side chain. This list is by no means exhaustive. Many other isomers can be visualized; for example, ring A aromatic and ring C mono-unsaturated, rings A, B, and C fused in linear instead of angular fashion, etc. At the present time only few isomers from categories 1 ·6 are known and very little is known about their biological activity. Isomers with a branched or unsaturated penty! group have not been prepared as yet. Recent-

202

ly, some unsaturated analogs have been prepared which show interesting properties [1] . 2.2 Occurrence and synthesis

Of all the isomers listed above, only (-)-trans-,.:l1.THC [136] and (-)trans-A 6 -THC [137] occur naturally in Cannabis sativa. Their chemistry has been reviewed by Mechoulam [2], by Neumeyer and Shagoury [3], and by Wall [4] . The latter author covers, in particular, labeled cannabinoids. Race· mic LiS-THe (IV) was the first isomer to be synthesized, by the group of Adams [5] in the U.S.A. and by the group Todd [6] in England. At the time of these syntheses the exact position of the double bond in the terpene ring was not known. Stereoselective syntheses for the naturally occurring THC isomers were developed much later. In Scheme I the major synthetic routes are shown. Li 8·iso-THC (V) can be obtained from cannabidiol (VI). By acid treatment A8-iBo-THC is converted into Li4 (8)·iso-THC (VII). The latter product can also be obtained from AI-cis-THC (VIII) and from cannabichromene (IX) (see Scheme II) [14] . It should be noted that total syntheses have only been carried out for ~1_, AB ., ,.:l4_, and,.:l6-THC. Other isomers were obtained either as by-products in these syntheses, or they were prepared from £1.1_, AB_, Li 4 _, and ,.:l6-THC. Specific isomers can probably be obtained by careful selection of starting materials and/or reaction conditions. Other routes to Li l . and ,.:l6-THC are: (1) ring closure of cannabidiol with acidic catalysts; depending on reo action conditions either Li1 • or .1 6-THC can be obtained [8, 15,138] ; (2) decarboxylation of the corresponding" (naturally occumng) acids; the acids are not stable and decarboxylate smoothly; their esters are stable; (3) decarboxylation of cannabidiolic acids, followed by ring closure of the cannabidiols to tetrahydrocannabinols (or the reverse procedure). Cannabidiol, its acids and esters and the tetrahydrocannabinol acids and esters do not have psychotropic activity themselves. However, they are potential tetrahydrocannabinol precursors. During smoking, decarboxylation of the acids occurs readily. The conversion of cannabidiol to tetrahydrocannabinol proceeds less readily, but a small amount of tetrahydrocannabinol is formed from cannabidiol during smoking, especially when mixed with (slightly acidic) tobacco [2b, 16, 130,131].

3. Biological activity Before going into detail concerning the biological activity of the tetrahydrocannabinol isomers it may be of interest to mention some structureactivity correlations which were proposed by Mechoulam et al. [17,18] :

203

u,,","

----19-)- -

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6' - THC

K ·Ier/.. AmI C,H (12)

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H~H 0 0

~

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(-). t.~' - THC

C,Hn.n (II

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OH

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C.Hn,n

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OH

OH

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OH

~

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(131

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0

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C.Hn-n

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0

~

o

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( 5,7)

r\ C.Hn,n

C.H1l'n

COOEt

?H

~

o

0

C.Hn-n

u o

0

C,H11'n

1 6 - THe

Scheme 1. Synthetic routes to tetrahydrocannabinols, starting from olivetol (numbers between brackets refer to the literature references),

204

~

/~O ~?H

~

~

1IROH,2)PTS

•

OH

La >-..

OH

E

~

H0",H ?OHH

1IROH/lizSO,

O ~ • JlIII

~"S

OH

~

~~

(]-~

~ OH

I

:JZ:

M.OH/PTS

~ (y--~

PTS

~

Scheme II. Conversion of cannabidiol (VI), cis-!::J.l.tetrahydrocannabinol (VIII), and cannabichromene (IX), into iso-tetrahydrocannabinols [14]. --the tricyclic ring system is a requirement for marihuana activity; the pyran ring does not, by itself, confer activity; -the activity changes with the length of the alkyl side chain; branching also changes the activity, especially when in the a position* to the aromatic ring; -iunher alkyl substitution in the aromatic ring reduces the activity, in particular when the substituent is introduced in the 6' position (probably resulting in distortion of the pyran ring); -replacement of a hydrogen on the aromatic ring with -COOH, -COOR, -COR, -OCOCH s reduces or eliminates the activity; -a free or potentially free hydroxyl group in the 3' position seems to be essential for activity; (-)·trans-il1·THC methyl ether is inactive; ill·THC acetate is active although far less than (-).trans-!::J.I-THC itself; --the stereochemistry in the terpene moiety is very important (+ or -, 3,4-cis or 3,4-trans). Mechoulam and his co-workers used the rhesus monkey to test their compounds. The structure-activity correlations may be slightly different when compounds are tested in other animals or in humans. *The Q: position is carbon atom 1" in formula I.

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3.1 Biological activity in animals 3.1.1 (-)-trans-tl 6 -Tetrahydrocannabinol With the exception of (-)-trans-Ll1-THC, most pre-clinical testing has been done with this naturally occurring isomer. Its biological activity is qualitatively similar to that of (-)-trans-Ll1-THC, although quantitatively it may be different. 3.1.1.1 Toxicity A considerable difference exists between the pharmacologically active and the lethal dose. In mice the acute oral (p.o.) LD 50 is approximately 1500 mg/kg, and the intraperitoneal (Lp.) LD 50 is 1200 mg/kg. Death is due to respiratory arrest [19]. In another study the oral LD 50 is reported to be greater than 2000 mg/kg, the intraperitoneal 210 mg/kg, and the intravenous 31 mg/kg [20]. In rats the same authors found LD 50 values of greater than 2000 mg/kg (p.o.), 560 mg/kg (i.p.) and 97 mg/kg (Lv.). Thompson et al. [21] found a difference in LD 50 for male and female rats (respectively, 1980 and 860 mg/kg orally). Since in the tests mentioned above the sex of the test animals was not specified, the differences in LD 50 may be due to different numbers of males and females, or differences in the period of observation. In dogs the lethal dose has been reported to be greater than 3000 mg/kg [21] . 3.1.1.2 Behaviour Behavioural changes are very similar to those caused by (-)-trans-t.. 1• THC. In rabbits 8 mg/kg Lv. caused restlessness, and increased motor activity and awareness [19] . After 0.5 - 4 mg/kg Lv., periods of agitation were reo ported [22, 23] ,during which the animals were ataxic and showed hyperpnea, mydriasis, exophthalmos, and an almost complete absence of corneal reflex. These periods of agitation alternated with periods of depression, during which the animals assumed an abnormal posture: front limbs spread, head on the floor. No convulsions appeared. In mice, 3 . 32 mg/kg Lp. depressed motor activity [24 - 26] ; the effect is potentiated by tacrine (10 mg/kg) [24]. At 20 mg/kg Lp., ptosis, a cataleptoid state and piloerection were observed [27]. Exploratory behaviour was blocked [28] . Mice made aggressive by isolation, were less aggressive during a 30 - 35-daytreatment with 10 - 50 mg/kg daily [29,30]. Aggressiveness returned to control levels when the treatment was stopped. In Chinese hamsters, aggressive by nature, the same effect was observed [29]. In rats, 5 and 10 mg/kg Lp. produced hypoactivity, abnormal stance, and hyperreactivity to noise and movement [31, 32] . Doses above 2 mg/kg Lp. caused vocalization [32] . A dose of 100 mg/kg administered Lp. to female rats caused excitement initially, followed by depression. After 1 hour the animals lay prostrate in their cage and were very depressed but started squeaking and became very agitated when disturbed; after 7 -10 hours the animals were still hyperexcitable [33] . In open field, behaviour, ambulation, and defecation were dependent on the length of the acclimatization period

206

prior to the experiment. With long-term acclimatization an increase in emotionality was noticed [34]. A biphasic toxicity pattern emerged in a chronic experiment (119 days, 50 " 500 mg/kg) [35]. During the first week the animals were depressed (inactivity, slow movement, bradypnea, hypothermia, weight loss). Death occurred during this depressed period. Gradually the animals became stimulated, hyperactive and aggressive, and hypothermia and weight loss ceased, although body weight remained below that of the control group throughout the experinlental period; no tolerance was developed for the stimulatory effect. In cats, injection of 1 ·8 mg/kg Lp. resulted in ataxia, prostration (at high dose), defecation, emesis, and hypersensitivity to auditory stimuli. The EEG pattern was not characteristic of a psychotomimetic or a paranoidpsychosis-eliciting drug [36] . Intraperitoneal injection of doses up to 6 mg/kg caused diminished spontaneous mobility; the cats crouched in a corner and fell asleep. A slight ataxia was noticed during the recovery period [22]. Dogs vocalized and vomited upon administration of 65.6 - 3000 mg/kg p.o. [21] . The animals were depressed, and showed signs of anaesthesia, tremors, muscle spasms, and clonic-tonic convulsions, but recovered within 24 hours. At 1 mg/kg Lv. [27] severe motor disturbances were observed. The animals were easily frightened, had a diminished level of awareness, and responded sluggishly to acoustic and photic stimuli; after 20 minutes they were in a stuporous state lasting 30 - 50 minutes, with short intermittent periods of alertness. Similar but less severe changes (in some animals) were observed with lower doses (0.25.0.50 mg/kg Lv.). Initial hyperactivity followed by depression was reported for rhesus monkeys (doses of 131.3 - 2000 mg/kg by gastric intubation) [21J. The monkeys were initially hyperreactive to auditory and tactile stimuli and aggressive; later they became inactive and lethargic, and assumed a "thinker" position. After 0.5 mg/kg Lv., monkeys became drowsy, and showed inter· mittent head.drops and ptosis; after 15 minutes motor activity ceased, they assumed a crouched position, and had a blank gaze [27]. The effects were particularly striking in naturally aggressive animals. The behavioural changes could be reversed by injection (after half an hour) of 0.5 mg/kg (±)-amphetamine. In gerbils, digging activity was suppressed (only after Lp. administration), spontaneous mobility decreased, and a typical cataleptoid state was observed, which could be reversed to hyperexcitability by sensori~ stimuli [27]. 3.1.1.3 Sleep, pain, temperature regulation

In anaesthetized rats, a biphasic effect on blood pressure was observed after Lv. injection of 0.1- 3 mg/kg: a transient pressor phase of short duration (maximal! minute after injection) was followed by a sustained decrease in mean arterial blood pressure [37J . Heart rate also decreased, the effect being maximal 5 ·10 minutes after injection. The effects were dose-related. Higher doses (> 10 mg/kg i.p.) caused hypothermia, for which tolerance developed

207

after some days [38,39] ; however, hypothermia reappeared after a drug-free period (10 days). In male rats, 2 mg/kg decreased the heart rate, whereas a decrease in rectal temperature was observed after a dose of 5 mg/kg (dose range tested 0.1 -10 mg/kg Lp.) [140]. Hyperthermia has been reported in a study with water-deprived rats (5.6 - 31.6 mg/kg Lp.) [40] . The hyperthermia probably arises when rats work in a relatively warm chamber. In female rats with adrenal regeneration hypertension, the blood pressure was significantly reduced during a two-week period of daily Lp. administration of 3 mg/kg. Thymus weight decreased and the liver was enlarged r41] . Mice also showed a dose-related hypothennia [42, 43] . With 1 - 3 mg/kg Lp., ethanol-induced sleeping time was prolonged 2 - 4 times in rats; with 5·7 mg/kg the sleeping time was prolonged 4 -10 times [44] . On repeated administration partial tolerance developed for this effect. No change could be detected in blood or brain ethanol levels, or in the metabolic rates. Therefore, the cause for the prolonged sleeping time remains uncertain, but may be due to action on the central nervous system. Hexo~ barbital sleeping time was also prolonged; the effect became less pronounced when ~6.THC treatment was continued for 10 days [39]. Paradoxical and slow-wave sleep decreased in rats and mongrel cats (5 and 10 mg/kg Lp.); periods of wakefulness increased [45] . In sleep-deprived rats the paradoxical sleep rebound was blocked. In the acute experiment, sleep patterns returned to normal on the first recovery day. On chronic administration tolerance developed. Withdrawal symptoms were not noticed. In mice, the analgesic effect of 20 mg/kg Lp. is reported to be equivalent to that of 10 mg of morphine sulphate per kg given subcutaneously [19]. ED oo values using the hot-plate test are 5 mg/kg (p.o.) [46], 8.8 mg/kg (s.c.) [47] , and 10 mg/kg (i.p.) [25] ; in the tail-flick test 24% of the test animals failed to react at a dose of 10 mg/kg Lp.[25] . In rats, 5 mg/kg Lp. increased the tail·flick latency; tolerance for this effect developed rapidly [140]. In rabbits, intravenous injection of 0.3 mg/kg caused a drop in arterial blood pressure, bradycardia, and prolonged the hypotensive response to scia· tic nerve stimulation; 1.2 mg/kg produced prolonged hypotension and bradycardia, and blocked the carotid vasopressor reflex [48] . 3.1.1.4 Conditioned learning Food and water intake have been studied in rats. In a conditioned taste-aversion experiment, water intake decreased significantly at 1, 5, and 10mg/kg Lp. [31]. In a differential reinforcement of low rates of responding (DRL) test, water-deprived rats did not respond for long periods of time (5.6, and 10 mg/kg Lp.); 18 - 32 mg/kg Lp. practically eliminated the response. On the lower dose, response slowly returned to control levels in the course of a 30-day experiment [40] . After chronic treatment with the higher doses, the response rate was either higher or the same as the control rate. Dose-related decrease in water intake was reported in water-deprived rats (2.5,5, and 10 mg/kg i.p.); food intake was also less than normal, resulting in reduced body

208

weight [49,50]. The weight loss was more pronounced in (-)-trans-t,6-THCtreated animals than in animals receiving the (-)-trans-t,l-isomer. During chronic administration food intake increased, but water consumption and body weight remained below control levels. In pigeons the pecking response was reduced by (-).trans-~6-THC [51,52]. Above the threshold dose pecking stopped abruptly. A rapid tolerance developed. After two weeks pigeons were toleran~ to doses up to 180 mg/kg Lm. Such doses would have been lethal or severely toxic at the start of the experiment. In a discriminative learning task, rats could discriminate between placebo and (-)-trans-t,6-THC. The t,1_ and t,6-isomers were interchangeable. No transfer was noticed from the tetrahydrocannabinols to other drugs, such as pentobarbital, chlorpromazine, atropine or morphine [531. However, some transfer from (-)-trans-t, 6 -THC to ethanol and pentobarbital has been reported [54, 80] . The acquisition rate of THC discrimination by rats trained in a T-shaped water maze was proportional to the dose administered (0.75 - 5.0 mg/kg i.p.), acquisition being faster with higher doses [55]. Performance decreased with an increasing interval between injection and testing, and when rats were tested with doses lower than the training d9ses. Results in a conditioned avoidance test suggest state-dependent learning [56] . Neither a-methyl-p-tyrosine (a tyrosine hydroxylase inhibitor) nor p-chlorophenylalanine (a tryptophan hydroxylase inhibitor) changed the tetrahydrocannabinol discrimination [55, 64] . This suggests that tetrahydrocannabinol discrimination is not dependent on a lowered content of brain catecholamines and/or serotonin. Asymmetric dissociation (training without drug, testing after drug administration) was observed in a conditioned avoidance response (CAR) experiment with rats (15 mg/kg ip.) [57]. Initial differences observed between rats injected before and after test sessions !lad disappeared when animals were retested after 15 drug-free days. Squirrel monkeys increased their rate of lever pressing in a CAR after 2,4, and 8 mg/kg (±).irans-t. 6 -THC Lp. Rhesus monkeys stopped responding in a delayed matching task after 4 mg/kg Lp. Their behaviour was disrupted for about three days [58] .

3.1.1.5 EEG The EEG has been recorded in several animal species. In cats, the arousal threshold for the reticular formation was raised to the same extent by 2 and 20 mg/kg (-).trans-t. 6 -THC Lv. Cortical and reticular activity were markedly altered. The observed pattern of decreasing frequency and increasing voltage may be indicative of a depressed state. The onset of the effects is faster for (-)-trans-A 6 -THC than for the (-)-trans-6 1 .isomer [59]. A dose of 6 mg/kg Lp. produced moderate synchronization in the EEG, which was easily interrupted by external stimuli [22] . In rabbits, 8 mg/kg Lv. accentuated the ~-rhythm in the cortical region, and lowered the arousal response threshold [19] . Changes were observed in

209

the hippocampal region (0.01-1 mg/kg Lv.), though overt behaviour appeared to be normal [60] . Doses of 0.5 - 4 mg/kg Lv. produced a generalized reduction in the voltage of the EEG waves, and a disappearance of the 0 -waves of the hippocampus [22, 23]. After 15 - 20 minutes spike and wave complexes were noticed, isolated at low doses, almost continuous at higher doses. During periods of behavioural immobility the spike and wave pattern was more frequent in the EEG tracing. In rats, similar changes were observed. The amplitude of early responses progressively increased in squirrel monkeys treated with cumulative doses of 0.25 - 2 mg/kg Lv. The higher doses also increased the amplitude of the late responses, followed by repetitive synchronous activity [61,62] . Changes in negative waves were more pronounced than were those in positive waves. The spiking observed in the electrocorticogram can progress to a spike and wave pattern that is very characteristic for tetrahydrocannabinols and is never seen with other classes of drUgs which modify central nervous system activity, for example barbiturates.

3.1.1.6 Distribution in the organism When tritium-labeled (-)-trans-~6-THC was injected intravenously in rats, after 20 minutes most of the label was found in the liver. In rat brain the highest concentration was found in the particulate matter and in nerve endings [63]. Binding was strongest in brain microsomes and in liver and kidney mitochondria. Fifteen minutes after intravenous injection of 5 mg/kg in rat brains, levels of (-)-trans-A 6-THC, (-)-trans-A I-THe and 7-0H-A6-THC were approximately the same. The tetrahydrocannabinols were rapidly metabolized, in contrast to the 7-hydroxy compound which remained virtually unchanged [64] . The initial rate of metabolism was lower for A6 -THC than for A1-THC. Rat liver lysosomes, incubated in vitro with up to 0.3 mg/ml (-)-trans-A 6 -THC or its (-)-trans-A1-isomer, showed an increase in membrane bursts. The level of radiolabeled A1-THC was found to be substantially higher in rat liver lysosomes in vivo than in other subcellular fractions after intravenous injection (A 6 -THC was not tested in the in vivo experiment). After 30 days of administration no biochemical evidence could be obtained of liver damage in vivo. The increased fragility of the lysosomal membranes indicates a potential impairment of membrane permeability [65]. Spectral interactions between (-)-trans-A 6 - and (-)-trans-Ll1.THC and rat liver microsomes indicated the formation of an enzyme substrate complex with cytochrome P·450. 7-Hydroxy-~6-THC did not produce these changes, suggesting that this metabolite is not oxidized by cytochrome P-450 [66] . Thirty minutes after intravenous injection of 50 mg/kg 14C·labeled (-)-trans-A1-THC or (-)-trans-A 6 -THC in monkeys (Callitrix jacchus), the highest activity was measured in bile, liver and the adrenal gland [67]. Investigation of metabolites showed that the metabolism of (-)-tranS-A 6 -THC was initially slower than that of the AI-isomer, which may account for the lower activity reported by some authors. Six hours after injection, 80 • 90% of the activity had been excreted except from kidney and bile.

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In mice (male 11 mg/kg, pregnant females 5 mg/kg, Lv.) extensive activity was found in the liver, lung, kidney, myocardium and the adrenal cortex. The low activity found in the central nervous system and and foetuses shows the effectiveness of blood-to-brain and placental barriers. A pronounced retention of activity was found in the liver, bone marrow and spleen [68] . The vehicle used influenced the distribution rate.

3.1.1.7 Interaction with neurotransmitters and enzymes In whole rat brain (after 5 mg/kg (-)-trans-A 6 -THC Lv.) acetylcholine was markedly depleted, probably due to a slower release from its storage sites. The synthesis was not affected, since the choline acetyltransferase concentration remained unchanged [69]. (-)-trans-A1-THC, which also reduces acetylcholine release from cat cortex [141] and inhibits acetylcholine biosynthesis in hypothalamic and striatal slices [142], has been shown to inhibit selectively the turnover rate of acetylcholine in rat hippocampus (0.2 mg/kg Lv.), by GABAergic mediation. It has been suggested that this may contribute to the psychotomimetic activity of (-)-trans-A1-THC [143, 144] . The cyclic AMP level was significantly increased in midbrain after 10 mg/kg Lv.; at the same time the activity of adenylate cyclase and cyclic nucleotide phosphodiesterase decreased [70] . In the cerebellum and the medulla the AMP level decreased slightly. An intraperitoneal injection of 30 mg/kg increased the [3H] noradrenaline and [3H] dopamine level in rat brain after an intravenous injection of [3H] tyrosine, the accumulation of [3H] noradrenaline being much more pronounced [71] . The disappearance rate of [3H] noradrenaline was markedly accelerated, that of [3H] dopamine slightly, but not to a statistically significant degree. The results suggest that the cannabinols (DMHP and A~-THC were also tested) mainly increase the intraneuronal dopamine metabolism. In in vitro cultures of rat forebrain, A6 -THC increased the binding of [3H] reserpine to a crude mitochondrial fraction (reserpine did not change the binding of THCs), the highest binding being found in fractions containing nerve endings. The increased [3H] reserpine binding did not parallel the sub· cellular distribution of the THCs and seems to be rather specific for the cannabinoid class of drugs. In view of the ability of A6 -THC to retard some pharmacological effects of reserpine, the increased binding is unexpected. The retarding may be due, however, to a shift from specific to non-specific sites [72] . The synaptosomal uptake of [3H] serotonin in excised rat forebrain in vitro was inhibited for 50% at a concentration of 22.4 11M (-)-trans-A 6 -THC (29.3 11M for the A1 -isomer) [73] . Interactions with neurotransmitters in smooth muscle preparations have been investigated. The response to motor nerve stimulation of a phrenic nerve-diaphragm preparation (rat) was not inhibited [74] (at a concentration of 25 ng/ml). In rat jejunum, concentrations of (0.025 to 0.2) X 10- 6 M showed a weak, non-competitive inhibition of the cholinergic agent furtre-

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thonium [20]. The contractions induced by noradrenaline in isolated vas deferens were potentiated by 10-7 _10- 8 M (not dose-related) [75]. (-).trans.~6-THC is a very weak inhibitor of acetylcholine- and histamine-induced contractions in isolated guinea-pig ileum; the inhibitory action is slow in onset [20]. Gascon and Peres noted a biphasic effect on acetylcholine-induced contractions: at 10-6 M a strong inhibition, at 10-7 M a potentiation occurred [75]. The inhibitory effect of atropine on both acetylcholine and angiotensin was antagonized by ,::\6-THC. The twitch response produced by electric field stimulation was inhibited (ED 50 25 - 50 ng/ml) [74, 76]; the effect is antagonized by eserine. In rats (100 mg/kg Lp. in females) no change in concentration and turnover of brain amines could be detected. Brain and blood tyrosine levels and the GABA level in brain were slightly reduced [33] . Littleton and McLean [77, 78] compared dopamine turnover in brains of rats kept under normal and under high-stress environmental conditions. Under high-stress conditions 10 mg/kg i.p. reduced striatal dopamine turnover, without affecting other monoamines. After injection of 10 and 30 mg/kg (-).trans-6. 6.THC i.p. in rats, an increased turnover of brain amines has been observed. The increases were less marked upon repeated administration [79, 80], indicating a rapid development of tolerance. Intraperitoneal injection of 30 mg/kg in rats lowered the concentration of cholesterol esters in the adrenals with a concomitant rise in corticosterone concentration in plasma. Acetylcholine at 10 tlg/kg provoked an elevation in corticosterone level of the same magnitude, but the effect subsided more quickly. The increase in plasma corticosterone level was found to be dosedependent. No changes were observed in hypophysectomized rats. The ascorbic acid content of the adrenals decreased, and free fatty acid level in the plasma increased. Blood glucose concentrations were unchanged. In rabbits, plasma cortisol levels and free fatty acid levels remained unchanged. Acetylcholine (10 ,ug/kg), however, elicited a marked rise in cortisol concentration as well as in free fatty acids. The data suggest that the release of acetylcholine is stimulated, probably by involvement of the hypothalamus [81] . In rat liver microsomes, (-)-trans-6. 6 -THC (25 - 100 tlM) inhibited testosterone hydroxylation in vitro [145]. In rat lung and brain, monoamine oxidase activity was not changed after administration of 1 or 14 mg/kg i.p. The decrease in monoamine oxidase activity that was observed after treatment of the animals for two weeks, could be attributed to the vehicle and was not caused by (-)-trans-6. 1 ·THC or (-)-trans-~6-THC [146]. In mice and rats, (-).trans-6.6 -THC caused dose-dependent stimulation of tyrosine aminotransferase activity (0 - 200 mg/kg Lp.). In mice,. the steroid-mediated induction of tyrosine aminotransferase activity was inhibited, but not the glucagon-mediated induction. In rats, no effect was observed on the tryptophan-mediated induction [147]. Morphological changes were observed in nuclear membrane bound ribosomes in 3-day-old rats treated with 10 mg/kg [82]. The effect is doserelated, rapid and reversible.

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3.1.1.8 Interaction~ with miscellaneous drugs The half-life of elimination of 14C-labeled pentobarbital was not affected by 20 mg/kg (-)-trans.~6.THC Lp. in rats, but the rate of biotransformation may be decreased. Blood levels of pentobarbital were elevated after oral administration of pentobarbital, but unchanged after intravenous injection. Urinary excretion of pentobarbital and metabolites thereof was significantly decreased during the first few hours after administration [83] . The approach latencies to a water tube in water-deprived mice treated with (-)-trans-~6-THC (1 mg/kg Lp.) were shortened by tacrine, not by damphetamine [84]. Pentobarbital anaesthesia was prolonged in mice by 10 mg/kg Lp. [85]. Doses higher than 0.1 mg/kg potentiated the pressor effect of 0.002 mg/kg Lv. epinephrine and norepinephrine in anaesthetized dogs. Respiration became irregular, and at doses higher than 0.3 mg/kg the mean arterial blood pressure was lowered [25]. In anaesthetized rats respiratory rate, systemic blood pressure, and pulse rate were reduced. The bradycardia and hypotension were less pronounced when animals were premedicated with atropine sulphate or propanolol. Atropine sulphate did not antagonize the effect of THCs on respiratory rate [86] . 3.1.1.9 Teratogenicity No teratogenicity could be detected in the offspring of primiparous rats after fifteen injections of 20 or 40 mg{kg s.c., before conception on alternate days and daily (20 days) during the gestation period. The only effect noticed was bruising around the head and shoulders in neonates. These symptoms disappeared after several days. No abnormalities were seen in the F 2 and Fa generations. There were indications, however, of an adverse effect on fertility [87] . 3.1.1.10 Therapeutic potential The therapeutic potential of (-)-trans-,t,6-THC has been studied, although less extensively than that of (-)-trans-A1-THC.

Morphine abstinence. Five mg/kg i.p. reduced abstinence scores induced by naloxone hydrochloride in highly morphine-dependent rats [881. Spontaneous rotation was a side-effect observed on THC administration to morphine-dependent rats. Haloperidol potentiated the effect of THCs in reducing abstinence scores. Bhargava [89] investigated withdrawal symptoms in morphine-dependent mice. The dose of naloxone hydrochloride required to precipitate withdrawal symptoms in 50% of the animals was increased two-fold by 2.5 and 5 mg/kg, and four-fold by 10 mg/kg i.p. (-)-trans-A 6 THC. Defecation and rearing behaviour, additional signs of morphine abstinence, were also inhibited. (-).trans-A1-THC was more effective (three-fold and six-fold increase in ED 50 , respectively). In vitro experiments showed that A6 -THC competitively inhibits demethylation of aminophenazone but not of

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morphine in rat liver microsomes. In this system cannabidiol proved to be a much stronger inhibitor of drug metabolism than the THCa [90]. Anti-convulsant activity. (-)-trans-,66-THC has been suggested to have anti-convulsant or anti-epileptic properties. Rats, susceptible to audiogenic seizures were protected against audiogenic (ED 50 4.7 mg/kg Lv.) and maximal electroshock (ED 50 2.6 mg/kg i.v., 72 mg/kg Lp.) convulsions. In pentetrazolinduced seizures, protection was only obtained against maximal seizures, not against minimal seizures and lethality. The ratio between the effective and the neurotoxic dose (TDf)() 1.85 mg/kg Lv., 4.3 mg/kg Lp.) was unfavourable, however [91, 92] . Mice were protected to some extent against pentetrazol.induced convulsions. At a dose of 50 mg/kg, 80% of the animals were protected and mortality due to convulsions was reduced to zero [93]. Animals Were not protect.ed against maximal electroshock-induced convulsions in doses of 25 • 100 mg/kg [93, 94]. The protection provided by phenobarbital against chemoshock seizures (5 mg: 50%) was enhanced to 100% by 25 mg/kg (-).trans-,61.THC and to 90% by 25 mg/kg (-).tranS-,66-THC. In amygdaloid-kindled cats, seizures could only be suppressed in the initial stages and not when partially or fully developed [95]. In Senegalese baboons, intraperitoneal injections of (-)-trans-,66-THC failed to affect myoclonic response to photic stimulation. "However, there was a dose-related anti-epileptic effect upon established kindled convulsions provoked by electrical stimulation of the amygdala; this inhibition was due to suppression of propagation of the induced after-discharge to distant cerebral structures [96]. In rabbits, intracerebral administration of (-)-trans-,66.THC in the right hippocampus elicited epileptiform discharges in remote areas of the brain [97]. Since intracerebral administration causes a very high concentration at a specific site, it is difficult to correlate these effects with those that may be obtained in intact animals. In a strain of rabbim which were susceptible to convulsions due to autosomal recessive mutation, (-)-trans-,61- and (-)trans.,66-THC induced convulsions in all animals tested. Tolerance may develop for the effect [98] . Tonic immobility was studied in chickens. This immobility may be related to psychopathological states in humans. Results indicated a potentiation of fear (prolonged duration of immobility) [99]. Cytostatic activity. The antitumor effect of (-)-trans-,66·THC has been investigated in cell cultures. [3H] Thymidine uptake in Lewis lung carcinoma cultures was inhibited (EDf)() 2.99 /lM). In vivo primary tumor growth was inhibited and survival time increased in mice. Leukemia L 1210 and bone marrow cells showed similar in vitro effects, although the ED 60 values were slightly different. L 1210 was not inhibited in vivo, which has been attributed to the short doubling time of this virus resulting in rapid development of tolerance. (-)-trans-.6. 1 -THC is more promising as a therapeutic agent against

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Lewis lung carcinoma: it was much more toxic to Lewis lung cultures than to bone marrow cultures [100 - 1021. Concentrations of 0.02 - 0.06 mg per 100 ml inhibited the regeneration of the planarian worm (Dugesia tigrina). Although not toxic per se, serotonin enhanced the toxicity of (-)·tran8-~6-THCwhen both substances were added in low concentrations [104]. Ophthalmic effects. Mechoulam et al. [103] reported that administration of a 0.001% solution of (-)-trans-A 6 -THC in the conjunctival sac of rabbit eyes in which stable glaucoma had been induced, lowered the intra-. ocular pressure to the same extent as a pilocarpine solution of the same concentration.

3.1.2 (+).trans.~6 -Tetrahydrocannabinol No analgesic activity (hot-plate test) was reported when (+)·trans-~6­ THO (50 mg/kg) was injected subcutaneously in mice [47]. Racemic trans~6-THC (6 mg/kg Lp.) failed to produce behavioural changes or changes in the EEG in rabbits [22]. Only some reduction of the corneal reflex was noted. This may be attributable, however, to the (-)-isomer present in the racemate. In rats the racemate produced the same EEG and behavioural changes as the (-)-isomer, but twice as much of the racemate was required. This indicates that the (+ )-isomer is inactive in rats [22J . Mechoulam et al. reported the (+)-isomer to be inactive in the monkey test at a dose of 1.0 mg/kg [17] and not to reduce intraocular pressure in rabbits with stable glaucoma when topically applied in a 0.01% solution (the (-)-isomer is active in a 0.001% solution) [103] .

3.1.3 (±)-cis-A 6-Tetrahydrocannabinol This compound showed no CNS activity in mice in doses up to 25 mg/kg Lv. [106]. 3.1.4 (+ )-trans-~I-Tetrahydrocannabinol The (+)-isomer of A1-THC was reported to be inactive in the monkey test in a dose of 0.5 and 1.0 mg/kg Lv. [17]. The immobility indices of mice were determined after intravenous injection. The (+)-isomer was approximately 13 times less potent than the (-)-isomer. Immobility increased with increasing dose. The activity may be attributed to contamination of the (+)-isomer with about 3% of the (-)isomer. The mean total brain concentrations of the two isomers did not differ significantly; the concentration of (+)-7-0H-~1·THC (putative) was 1.8 times higher, however, than that of the (-)-isomer. The results suggest that the (+)-isomer is essentially inactive and that the lack of effect is not due to differences in distribution or metabolism [105].

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.1.1.5 (±)-cis-fl1-Tetrahydrocannabinol This isomer is inactive in the monkey test after intravenous injection of 1.5 mg/kg [17]. In mice the approximate LD 60 was reported to be 50 mg/kg Lv., the median effective dose for the popcorn effect and ataxia was 10 mg/kg Lv.; 100 mg/kg was not sufficient to produce analgesia in the hot-plate test. Spontaneous motor activity was reduced 25% by a dose of 100 mg(kg Lp. The compound was characterized as being a weak depressant ~1011. At 100 mg/kg Lp. it was inactive in protecting mice against pentetrazol-mduced seizures [107].

3.1.6 (±)_fl 3 -Tetrahydrocannabinol In the monkey test, racemic fl3-THC was active in doses of 1 mg/kg (Lv.) and higher. Twenty mg/kg produced severe stupor and ataxia, full ptosis, immo bility and a "thinker" position lasting for at least three hours, during which animals did not react to external stimuli [17]. Hardman et al. [108] reported that 6 3 -THC caused a CNS depression similar to (-)-trans-fll-THC although it was less potent. Orally, in rats, it had one-fourth the potency of AI-THC. In dogs, its potency was reported to be one-fifth of that observed in rats. The duration of the effect was dose-dependent [109]. The ED 50 in the Gayer test was reported to be 0.3 mg/kg. It was nonlethal in mice in an intravenous dose of 200 mg/kg. In rats 60 mg/kg (s.c.) had the same analgesic effect as 7.5 mg/kg pethidine hydrochloride [110] . The (+)-isomer had only 38% of the potency of the racemic compound in the dog ataxia test; the (-)-isomer was 1.66 times as potent. The (+). isomer was inactive in the Gayer test in doses of 6 - 8 mg/kg [111, 112]. Carlini et al. [113] found absence of corneal reflex in rabbits at a dose of 4.6 mg/kg, an ED 50 for reduction of spontaneous motor activity of 54.9 mg/kg Lp., for catatonia 162 mg/kg Lp., and for isolation-induced aggressiveness in mice 3.84 mg/kg. 3.1. 7 Other isomers (-)-3,4-trans-A 5 -THC is inactive in the monkey test in doses up to 10

mg/kg, although it has the endocyclic double bond and the natural configuration at Ca-C 4 [9) . Racemic Ll. 1 (7).THC is also inactive in the monkey test [17].

3.2 Biological activity in humans 3.2.1 (-)-trans-fl6-Tetrahydrocannabinol The spectrum of clinical effects in human beings is similar to that of (-)-trans-fl1-THC. When administered orally its potency is approximately 75% of that of the fll-isomer [114, 115]. In the recumbent position a slight increase in pulse rate and conjunctival injection were noted. Performance on psychometric lists was not changed, despite a substantial subjective "high" (dose 20 and 40 mg). After intravenous administration (1 - 9 mg) the same symptoms became apparent. With increasing doses the time of peak effect

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was delayed. The potency ratio with intravenous administration was esti· mated to be the same as for oral administration. The results are questionable, however, since a limited number of subjects was available. Karniol and Carlini [116] administered smoke to human volunteers via a spirometer (5 - 20 mg mixed with 500 mg of placebo were burned); pulse rate increased, time estimation was disturbed (70% of the subjects estimated 1 minute below 55 seconds). Subjects rated their "high" qualitatively similar to a "high" produced by Al-THC, but about half as potent. Agurell et al. noticed an increase in heart rate and a decrease in performance both in critical flicker fusion rate and in reaction time in subjects who smoked 8.3 mg in an ordinary pipe. Plasma levels down to 0.3 ng/ml could be measured. Immediately after smoking, plasma levels were high, after half an hour the level declined to 10 - 20 ng/ml. High plasma levels could not be correlated with maximal impairment of performance [117]. In an experiment with students, de Souza et al. [118] studied the tonal preference after oral administration of 5 - 40 mg. A reproducible change was found to occur, with a preference for higher frequency tones (placebo: preference for 400 Hz; drug: preference for 750 and 5000 Hz). The frequency discrimination was not affected. Blood incubated with (-)-trans-A 6 -THC showed a decreased mitotic index. The decrease was concentration-dependent. No visible damage or structural rearrangements could be detected [119]. Decreased mitotic activity was also reported by Stenchever et al. [120], at a concentration of 200 }J.g. No difference with controls could be detected in breaks, gaps, aneuploidy, isochromatid and chromatid lesions. The lack of change may be due, how· ever, to the short exposure times (4 hours). 3.2.2 (±)-A 3 -Tetrahydrocannabinol

When smoked, this isomer ~hows a pattern of effects similar to that of Al-THC. Its potency is estimated to be 15 - 30% of the potency of Al·THC [114] . 3.2.3 Other isomers

No other isomers have been tested in humans.

4. Therapeutic potential of (-)-trans-Al-tetrahydrocannabinol and cannabis The therapeutic potential of marihuana and (-)-trans-Al-THC has recently been outlined in the proceedings of a conference held at Asilomar (November, 1976) [121], and in a monograph on the pharmacology of marihuana [122]. Subjects covered are: ophthalmic effects, pulmonary and preanaesthetic effects, effects on mental functioning, tumor problems, anticonvulsant activity, and synthetic cannabinoid·like compounds. A concise review will be given here.

217 Ophthalmic effects. (-)-trans·A1-THC reduces the intraocular pressure in animals and humans when taken orally odntravenously; in animals it is also active when topically applied. Smoking marihuana is also effective. (-)trans-A 6 -THC has similar effects. Application in glaucoma patients has been suggested [121] . In rabbits, CBD, CBN and the THC metabolites 7-0H-~6-THC, 7·0H,el1·THC, 6cx- and 6~-OH-AI-THC also lowered the intraocular pressure; CBD and CBN were inactive in humans. When topically applied in rabbits, mineral oil was a more effective vehicle than sesame oil [148] . Pulmonary effects. Inhalation of an aerosol spray of (-)·trans-,ell-THC results in bronchodilatation, without the adverse effects noticed when marihuana is smoked or taken orally (fewer cardiac and CNS effects) [121]. However, aerosolized (-)-trans-,el1-THC has been demonstrated to have a local irritating effect on the airways [149]. Bronchospasm can be reversed in asthmatic patients by smoking marihuana [121] . Oral administration of (-)-trans-A I-THC has little therapeutic value since its bronchodilatory action is mild and inconsistent, and one asthmatic patient developed severe bronchoconstriction after oral administration of (-).trans-AI-THC [150] . Healthy young men can tolerate excessive doses of (-+trans-,11-THC without significant change in breathing and circulation, and CNS control of these vital systems (the subjects became very frightened, however). The general effect is an increase in sympathomimetic stimulation and parasympathetic inhibition of cardiovascular control pathways [121, 151]. Cytostatic activity. (-)-trans.,ell-THC has a higher toxicity for Lewis lung tumor cells than for bone marrow cells (in contrast to (-)-trans-,el6-THC which is equally toxic for both) [121]. In Syrian hamsters, 10 - 1000 mg/kg (s.c.) (-)-trans-,elI.THC did not induce chromosomal damage in bone marrow cells, but the mitotic index decreased [152]. In human cells (HeLa S3), (-)-trans-,elI.THC (5 - 40 11M) depressed the proliferative activity of exponentially growing cells and decreased the apparent syntl"~-js of DNA, RNA and proteins. The effects were dose-dependent [153] . In vivo, mice infected with Lewis lung tumor survive longer, when treated with these THC isomers. In vivo growth of leukaemia L 1210 is not inhibited, however. In patients with advanced cancer, (-)-trans-Li1.THC seems to act as a mild tranquillizer and euphoriant. Patients tend to maintain weight. It may have a beneficial effect on symptoms such as depression, pain, nausea, and vomiting [121]. Reports on the anti-emetic effect are contradictory. In dogs (-)-trans-,ell-THC did not antagonize the emetic agent apomorphine [154] . In humans, (-)-trans-,ell-THC seems to be effective as an anti-emetic only when the next dose is administered before the psychotropic activity caused by the previous dose wears off. The most apparent side-effects, limiting its use, are psychotropic activity, somnolence, dizziness, dissociation, visual distortions, and hallucinations.

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Analgesic effects. Analgesic properties have been mentioned. Results of experiments in humans are contradictory. In humans, increased sensitivity to electrically produced, painful stimulation has been found, which was attributed to the experimental set-up. In cancer patients oral (-)-trans-~l-THC may exert an' analgesic effect. An ti-alcohoI drug. It is often said that smoking marihuana reduces the use of alcohol, and it has been suggested that it can be used in treatment of alcoholism. Marihuana itself or (-)-trans-~l-THCseems to be ineffective, but the combination with disulfiram, a common anti-alcohol drug, might be more promising. However, it has recently been reported that (-)-tranS-.6. 1 -THC increases the alcohol level in blood after taking social doses of both drugs simultaneously, and has an adverse effect on performance (standing steadiness, manual dexterity, perceptual speed, and Vienna Determination Apparatus). The same doses of either alcohol or THC did not cause a decrease in performance [123]. In ethanol-dependent mice, (-)-trans-.6. 1 -THC increased the severity of handling-induced convulsions, but it suppressed the enhanced responsiveness to electric foot shock [155] . Anti-convulsant activity. Computer analysis of EEGs showed that inhalation of cannabis smoke decreases the total energy output in the EEG signal. .Epileptics , suffering from petit mal, show an increase in energy output. (-)trans-~l-THC, (-)-trans-~6-THC,and marihuana have been suggested to be anti-convulsants. Although in some animal experiments seizures could be inhibited by these drugs [121, 156 - 158], in other experiments epileptic symptoms could be induced or were potentiated [121, 159, 160]. The therapeutic usefulness is therefore questionable. Anti·depressant activity. (-)-trans-.6. 1-THC has been suggested to be an anti-depressant and to be helpful in solving psychological problems. Its value as an anti-depressant is questionable since in several experiments increased fear has been observed. The question of using Cannabis products to solve psychological problems remains open to debate. It is very possible that, in order to be effective, continuous use is required. Anti-fertility drug. In ovariectomized rhesus monkeys, (-)-trans-.6. 1. THC caused a reversible depression in luteinizing hormone and folliclestimulating hormone levels [161, 162]. In rats administered (-)-tran8-~1­ THC, serum levels of luteinizing hormone and prolactin were reduced [124, 125] ; the oestrous cycle was disturbed after treatment with Cannabis extract [126]. In adult human males, integrated plasma testosterone and luteinizing hormone levels were within normal limits [163]. Cannabis extract antagonized estradiol in increasing the monoamine oxidase activity of prepubertal rats (estradiol decreases monoamine oxidase activity) [127, 128] . Therefore, it has been suggested that (-)-trans-fl.l-THC may have an adverse effect on fertility. However, Braude et al. [129] did not find any effect on

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mating activity or fertility in rats. Therefore, in this respect the usefulness of (-)-trans-t..1-THC also remains questionable. Many experiments conducted so far have been acute experiments. Development of tolerance has not yet been sufficiently investigated but may be as limiting a factor in the therapeutic use as is the psychotropic activity. 5. Dependence liability and development of tolerance in primates Physiological and psychological dependence on (-)-trans-t..1-THC have been observed in rhesus monkeys [132]. Initially the rhesus monkeys were injected with increasing amounts of (-)-trans-~l-THC(0.1 - 0.4 mg/kg in 24 days). After .36 days (12 days the highest dose of 0.4 mg/kg) all six monkeys showed abstinence signs and two of them started self-administration of the drug. Abstinence signs included hyperirritability, increase in aggressiveness, tremors and twitches in the muscles, yawning, photophobia, etc. Prominent effects of (-)-trans-~l-THCsuch as ptosis, quietness, docility, and loss of aggressiveness were observed at the initial administration and when doses were increased. Tolerance to the effects developed rapidly. Reports on humans are contradictory. Perez-Reyes et at. [133] reported that frequent use of marihuana does not alter the response qualitatively or quantitatively to the intravenous injection of (-)-trans-A1-THC. Babor et at. [134] compared heavy and moderate marihuana users in a 31·day study during which subjects could smoke marihuana ad libitum. Daily consumption increased gradually in both groups. No tolerance was observed to increase in. pulse rate and subjective "high" ratings. However, Jones et at. [135] pointed out that conditions for optimal development of tolerance and dependence require continuous neuronal exposure. In their experimental set-up the subjects received (-)-trans-A1.THC or Cannabis every four hours (24 hours a day). Tolerance developed rapidly as concluded from subjective "high" ratings, and drug-induced physiological alterations (salivary flow, heart rate, blood pressure, intraocular pressure). Tolerance did not develop to all effects. Abstinence symptoms were observed when drug administration was stopped abruptly (weight loss, changes in the EEG, increase in salivary flow, fine hand tremor, hyperactivity). We may conclude that humans may become tolerant to (-).trans.A 1• THC, to some of its effects more readily than to others. Dependence and abstinence symptoms may also develop, under conditions of continuous neuronal exposure. Dependence liability and development of tolerance have not been extensively investigated with (--)-trans-~6-THC. Tolerance to many of its effects have been observed in animals (see preceding chapters). In view of the great similarity in effects of (-)-trans-Ll1-THC and (-).trans-Ll 6-THC, one can assume, however, that the dependence liability of the Ll 6 ·isomer is comparable to that of (-)-trans-Ll1-THC. Dependence liability of other THe isomers has not yet been investigated.

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6. Summary (-)-trans-A l-Tetrahydrocannabinol is the main psychoactive constituent of Cannabis sativa. Its activity in animals and humans is well-documented. Although Cannabis has been used since ancient times in folk medicine, the investigations as to therapeutic potential of (-)-trans-Al.THC (as an anticonvulsant, anti·emetic, anti·glaucoma, anti·cancer, and analgesic drug) have started only recently. The results to date have not been convincing. Adverse effects and the possible development of tolerance seem to be the limiting factors. Of the numerous possible isomers of (-)-trans-A 1 -THC (I) only (-)6 trans-A ·THC (X), which occurs naturally as a minor constituent of Cannabis, has been investigated extensively. Its activity is qualitatively similar to that of (-)-trans-t:..l-THC; quantitatively there may be differences. Its therapeutic potential has not been investigated as extensively as has that of its Al-isomer. Its effect on proliferating cell growth is similar to that of (-)-trans-t:..l-THC. However, the selective toxicity to Lewis lung tumor cells exhibited by (-)trans-Al.THC, is lacking. It has been tested as an anti.convulsant, as an anti· glaucoma drug, and as an inhibitor of abstinence symptoms in morphinedependent rats with results similar to those observed with (-)·trans-Al-THC. The non-naturally occurring AS-THC (IV) is also known to possess marihuana activity, although its potency is less than that of the (-)-trans-A l isomer. Hexylpyran (XI; other names: Parahexyl, Synhexyl, and Pyrahexyl) and DMHP (dimethylheptylpyran, XII), which are potent eNS depressants and both of which are controlled under Schedule I of the Convention on Psychotropic Substances, are homologs of AS-THC. (+ )-trans-t:.. 1 .Tetrahydrocannabinol and (+ )-trans-A 6 -tetrahydrocannabinol, optical isomers of I and X, respectively, are reported to be inactive. (+)-cis-A 1 .Tetrahydrocannabinol has been characterized as a weak depressant. (+)-cis-A 6 .Tetrahydrocannabinol showed no CNS activity in mice in intravenous doses up to 25 mg/kg. (-).3.4.trans.11 6 .Tetrahydrocannabinol and (+ )-A 1 (7)-tetrahydrocannabinol have been reported to be inactive in the monkey test. The biological activity of all other isomers is unknown.

0 ~ ..•'HOH

H

=

'1'0

I

0 ~ ..•,HOH

H

.

~ '1'0

x

61

H

J-o~

221

7. Conclusions (1) The literature concerning the biological activity of Cannabis is extensive. The earlier literature contains several examples of emotional involvement and bias on the part of the investigators. In recent times the number of such publications has diminished as the investigators have become more objective. (2) The two main psychotomimetically active components of Cannabis are (-)-trans-Ct. 1 -tetrahydrocannabinol and (-)-trans-Ct. 6_tetrahydrocannabinol. These are the only THC isomers whose biological activity has been thoroughly investigated. Ct. 3 .Tetrahydrocannabinol has been tested in some depth. However, many of the tests with the latter compound have been carried out with the racemic mixture of isomers. The abuse potential of (-)-trans-Ct. 1 .tetrahydrocannabinol and (-)-trans6 Ct. -tetrahydrocannabinol shows wide variation. Tolerance to several of the effects has been observed. The literature only rarely reports withdrawal symptoms; when such symptoms are reported, they occur only after prolonged use of excessive doses. Ct. 3 -Tetrahydrocannabinol has not been tested for its abuse potential. The ~8.tetrahydrocannabinolhomologs, Parahexyl (XI) and DMPH (XII) are more active than A3 -tetrahydrocannabinol itself.. (3) Cannabis has been used as a folk medicine since ancient times. Therapeutic uses of (-)-trans-Ct. 1 .tetrahydrocannabinol and (-)-trans-A 6 tetrahydrocannabinol have been reported recently. Although these com· pounds are effective to some extent, development of tolerance and adverse effects are limiting factors which should be thoroughly investigated before a decision can be made about their therapeutic usefulness. It should be realized that adverse effects of drugs sometimes become evident only after prolonged intake by a large number of individuals over a considerable period of time. The drugs are then already beyond the stage of controlled clinical trials on a limited number of patients. Analogs or - less likely - homologs of tetrahydrocannabinols may be much more effective as therapeutic agents. (4) The literature on Cannabis shows that the results of pharmacological tests reported by one worker, or group, can frequently not be duplicated by others. Some publications are inconsistent in themselves. This may be due to: -the use of ill.defined, or chemically and/or optically insufficiently pure matepals; --too small a number of test animals to obtain a reliable estimate of the mean and the variance of the effects; --the use of different animal species or strains; --the use of different external conditions;

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-different routes of administration, in different vehicles; -differences in protocol (interval, duration, and method of observation). In view of the high cost of pharmacological and clinical testing, standard methods should be agreed upon to test cannabinoids systematically and - as far as possible - unequivocally, for: -dependence liability and tolerance, -psychotomimetic effects, "-effects on physiological functions, -therapeutic potential, and -interaction with other drugs. Pharmacological testing to any extent should only be carried out if the chemical and stereochemical purity of the material has been sufficiently characterized to enable duplication of experiments elsewhere, and if adequate amounts are available.

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9. List of abbreviations

THe DMHP

tetrahydrocannabinol dimethylheptylpyran (formula XII)

231

CBD CBN DRL CAR

CNS GABA AMP MAO EEG LD oo ED 50 Lp. Lv.

Lm. p.o. s.c.

cannabidiol cannabinol differential reinforcement of low rates of responding conditioned avoidance response central nervous system 'Y·aminobutyric acid adenosine 5'.monophosphate;.cyclic AMP is adenosine 3' 5'·mono· phosphate monoamine oxidase electroencephalogram median lethal dose median effective dose intraperitoneal(ly) intravenous(ly) intrarnuscular(ly) oral(ly) subcutaneous(ly)