The ocular effects of cannabinoids

Gen. Pharmac., Vol. 11, pp. 419 to 423 © Pergamon Press Ltd 1980. Printed in Great Britain

0306-3623 80 0901-0419S02.1X) 0

MINIREVIEW THE O C U L A R EFFECTS OF C A N N A B I N O I D S AMOS D. KORCZYN From the Maurice and Gabriella Goldschleger Eye Institute and the Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel (Received 28 January 1980)

Abstraet--l. The various effects of delta-9 tetrahydrocannabinol (THC) in the eye are described, with a special emphasis on the ocular hypotensive action which is potentially useful in glaucoma. 2. Critical analysis of the published reports reveals that the mechanism of action of THC is basically unknown. 3. Although several studies indicate that the sympathetic system is involved in the ocular hypotensive action, the details are not understood. 4. It is still debatable whether the THC effect in glaucoma is mainly central or principally due to a direct effect on the eye. This question must be answered in order to proceed logically to a better understanding of the mechanism involved and to the possible synthesis of THC derivatives which reduce intraocular pressure but do not have other actions. INTRODUCTION

The pharmacological armamentarium against glaucoma is diverse. Drugs consist of muscarinic agonists, cholinesterase inhibitors, carbonic anhydrase inhibitors, adrenergic agents as well as adrenergic blockers. A major limitation of all is that they combat not the basic process of the disease (which is still debatable) but one of its manifestations, namely ocular hypertension. Even so, there is interest in new drugs which can lower intraocular pressure (lOP). This is so because the available agents--while being unquestionably efficacious--have their limitations. In a significant number of patients, surgery is necessary, and glaucoma remains the second most common cause of blindness in advanced countries. With the establishment in the 1960's and early 1970's of marihuana as a major drug of abuse, interest developed in its side effects. Ocular symptoms, such as dryness of the eyes and "red eyes" are common, and this led to a systematic investigation. During such a screening, Hepler & Frank (1971) discovered that marihuana smoking induced ocular hypotension. This finding immediately aroused speculation among physicians and in the lay press as to a potential therapeutic effect in glaucoma. Several research workers have joined the field, and the isolation of delta-9tetrahydrocannabinol (THC) as the active component by Mechoulam et al. (Mechoulam & Gaoni, 1965; Mechoulam, 1970) gave additional impetus to the work. During the past decade significant progress was made. The original observations of Hepler & Frank (19711 were confirmed, and attempts to characterize the mechanism of action were made. The present paper discusses the ocular pharmacology of marihuana with special emphasis on the hypotensive action.

equivalent amounts of THC reduces IOP in humans. The fall appears to be proportional to the initial lOP, being quantitatively larger in patients with glaucoma. The mean fall averages about 30% of the baseline pressure. It starts after a latent period of 1 hr or more and continues for 4 or 5 hr. (West & Lockhart, 1978; Shapiro, 1974; Cooler & Gregg, 1976; Purnell & Gregg, 1975; Paton & Pertwee, 19731. The latent period is somewhat longer after oral administration as compared to intravenous injection, but it is longer than one hour even when THC is applied topically to the eye (Hepler et al., 1976; Lockhart, West & Lowe, 1977; West & Lockhart, 19781. This contrasts with the much shorter latency of epinephrine (Garner, et al., 19591 but is comparable to that of pilocarpine (Fenton & Schwartz, 19631.

E F F E C T S O F C A N N A B I N O I D S ON INTRAOCULAR PRESSURE

(a) Humans Smoking marihuana cigarettes or administration of 419

(b) Experimental animals A lowering effect of lOP was demonstrated in the normal rabbit (Green & Pederson, 1973',~Green et al., 1977; Green & Bowman, 1976; Hepler et al., 1976; Dren, 19761 as well as in animals in which ocular hypertension was produced by means of ~-chymotrypsin injections into the eyeball (Mechoulam et al., 19761. These studies have established that the rabbit is similar to the human regarding its sensitivity to THC and the latent period and duration of action. Most of the conclusions concerning the mechanism of action were also derived from studies in the rabbit. THE MECHANISM OF OCULAR HYPOTENSIVE ACTION

(a) Central vs peripheral site of action Parenteral administration of THC, e.g. by smoking, produces in the human lOP falls which start simultaneously with the subjective mental effects. Purnell & Gregg (19751 who have examined two subjects, noted that in one of them the hypotensive action outlasted the subjective "high" by about 90 min, and concluded that the decrease of lOP is not mediated through a central action of the drug. However, a central site of

420

AMOS D. KORCZYN

action through which THC lowers IOP has been suggested repeatedly (Perez-Reyes et al., 1976: Flom et al., 1975). The demonstration that local application of THC to the eye is also effective in lowering IOP could have seemingly refuted the claim for a central site of action. Unfortunately the situation is not as clear. Dren (19761 has shown that in rabbits topical ocular application of THC reduces IOP. However, systemic absorption could not be ruled out in this study. Dren used 0.1'~, solution of THC. Presuming that he applied 2 drops to each eye and that the rabbits weighed 2 kg, (this data is not given), the animals could absorb as much as 0.2 mg/kg, a dose which has significant effect in rabbits or in humans when given orally or i.v. (Smith & Kulp, 1976; Hepler & Petrus, 1976; Cooler & Gregg, 1976). The critical test, treating topically one eye and recording pressure changes bilaterally, was apparently not performed by Dren (1976). Green & Bowman (1976) who have subjected rabbits to this test, claim that "about 60-90 min after the drug has been applied topically to one eye, a decrease in IOP is noted in the contralateral eye. The IOP fall follows a similar time course although quantitatively less pronounced than seen in the treated eye". These workers do not supply quantitative results and it is not clear whether the differences between the two eyes are significant. In any case, the demonstration of hypotension in the non-treated eye makes it likely that at least part of the fall is caused by THC absorbed systemically and reaching the CNS or the fellow eye. The latency of the response was similar in both eyes, which would not have been expected if THC would have to be transported from one eye to the other, but is reasonable if a central effect of THC reduces the pressure bilaterally. Thus, the site where THC acts to lower IOP has yet to be definitely established. It is noteworthy that agents having a depressant effect on the central nervous system frequently reduce IOP (Kornblueth, et al., 1959; Magora & Collins 1961). For pentobarbitone sodium the mechanism is probably a decrease of aqueous humor formation (Cevario & Macri, 1974). (b) Effect on the eye IOP is governed by the amount of fluid (aqueous humor) in the ocular chambers. A fall of IOP could result either from a decrease in fluid production or from an increase in outflow facility (or both). Green & Pederson (1973), working with rabbits' eyes in vitro, demonstrated that THC decreases fluid production to about one fourth of normal. The concentrations of THC which were found effective were in the micromolar range, which is the expected concentration in the eye following systemic administration of effective doses in vivo (but direct information on the ocular concentrations are not available). It would be interesting to know if the same depression of humor production would be observed when the in vitro studies are performed after systemic administration of THC in vivo. The decrease in fluid production could result either from a direct influence on the secretory mechanism or from vascular effects leading secondarily to changes in humor production. Carbonic anhydrase inhibitors and epinephrine are examples of drugs acting by these

two mechanisms, respectively. The effect of THC on carbonic anhydrase is unknown. Sympathomimetic effect is possible, and is apparently supported by other adrenergic effects of THC, e.g. tachycardia (Beaconsfield et al., 1972; Malit et al., 1975). The relationship of THC-induced ocular hypotension to the sympathetic system will be discussed below. In the rabbit eye, THC not only diminishes humor formation; it also increases the outflow facility (C,o,). This increase is at least partly due to elevated pseudofacility (Green & Bowman, 1976), not unlike the effect of adrenergic stimulants. (c) Systemic hypotension Another possible explanation is that the ocular hypotensive effect of THC reflects the systemic blood pressure fall produced by the drug (Malit et al., 1975), which in turn reduces passive hydrostatic pressure across the ciliary body-posterior chamber interface. Some support for this view comes from an observation that subjects who respond to THC with marked blood pressure falls also experience exaggerated ocular hypotension (Cooler, 1976). However, this relationship is to be expected if both manifestations are dose-dependent, as they indeed seem to be. In general, the systemic hypotension is small and cannot account for the drop in IOP. (d) Non-specific membrane action THC is thought to possess non-specific membrane effects (Green & Bowman, 1976). Local anesthetic drugs are known to reduce IOP (Carel et al., 1979) but the magnitude of the effect is small, and cannot account for the changes observed with THC. (e) Interaction with prostaglandins

Some prostaglandins induce elevation of IOP (Beitch & Eakins, 1969). The notion that prostaglandins regulate the IOP under normal conditions or in glaucoma is tenuous, but some work was done on the interaction of THC with prostaglandin-induced IOP rise. It was found that THC does not interfere with the IOP elevation following administration of prostaglandin E2. However, the ocular hypertensive response to arachidonic acid (which is presumably metabolized to prostaglandins) is antagonized by THC (Green & Podos, 1974). This finding is probably not relevant to the mechanism of action of THC in glaucoma. Aspirin and indomethacin, drugs which inhibit prostaglandin synthesis, do not reduce IOP (Podos et al., 1973). Thus, interference with prostaglandin synthesis or action does not seem to underlie the ocular hypotensive action of THC. (f) Adrenergic system As mentioned above, THC-induced ocular hypotension results from a combination of depressed aqueous humor production and increased outflow facility (C,o,). Green & Kim (1976a, 1976b) have demonstrated that the changes in Cto, can be prevented by pretreatment with an alpha adrenergic blocker, phenoxybenzamine, whereas propranolol is ineffective. On the other hand, the IOP fall induced by THC in the rabbit could be reduced to about 500/o by either phenoxybenzamine or propranolol (Green & Kim, 1976a). Phentolamine also inhibited the fall,

The ocular effects of cannabinoids but to a lesser degree than phenoxybenzamine whereas sotalol, another beta blocker, was more effective than propranolol and in fact abolished the fall altogether (Green & Kim, 1976a). These results were interpreted to mean that THC-induced ocular hypotension has two components, alpha-adrenergic mediated, increasing C,o,, and beta-adrenergic mediated, causing a decrease in humor formation. Some reservations must be taken to these conclusions. The measurement of l O P in rabbits is notoriously difficult and baseline values vary rega~-dless of treatment. Anesthesia limits (but does not abolish) the "spontaneous" fluctuations, but introduces other complications because of the effects of general anesthetics on IOP (Magora & Collins, 1961) and the results may differ qualitatively from those obtained in the awake animal (Langham, 1965; Langham et al., 1973). The adrenergic blockers, and particularly the alpha antagonists, produce severe systemic cardiovascular changes which affect l O P secondarily. It is also unclear why sotalol should be more effective than propranolol. Finally, Green et al., (Green & Kim, 1976a) present their results as percentage of change of baseline lOP, and do not give absolute values. Unfortunately they also do not always give statistical tests to evaluate the significance of their results (e.g., Green & Kim, 1976a). In any case the results of these studies indicate that the sympathetic system is involved in THC mode of action. In order to localize the site of action, Green et al., compared the THC effect in normal and sympathetically denervated eyes (Green & Kim, 1976b; Green, et al., 1976). Interpretation of the results is again complicated because the lOP fall following drugs is expressed as percentage of baseline levels, disregarding the fall of IOP which usually follows the decrease of sympathetic tone. It was found that chronic sympathetic denervation reduced lhe fall from 25~o to 8~o (Green et al., 1977), whereas following sympathetic decentralization (preganglionic denervation) THC had an effect about midway between the normal and ganglionectomized eye (Green et al., 1977). The effect of hexamethonium, a ganglion blocker, was similar to that of sympathetic denervation (Green & Kim, 1976b) although the effect is pharmacologically decentralization. The conclusions of Green et al., are that THC acts partly centrally and partly locally in the eye. Because both effects are abolished by adrenergic blockade, Green et al., assume that both the direct ocular action and the central effect involve the sympathetic system. From here on the phrasing of their conclusions is somewhat blurred. The l O P reduction by THC is smaller in denervated eyes than in decentralized ones, from which Green et al. conclude that THC may act as an indirect sympathomimetic (although they do not use this term). Following denervation all catecholamine stores should be depleted and it is unclear how the residual effect originates. THC could have some direct effects on adrenergic receptors, and Green et al., may imply such a mechanism when they mention an alpha and a beta adrenergic effect of THC. However, if this were the case, then following surgical denervation, supersensitivity should develop (Korczyn, 1975a; Korczyn " 1975b). A lesser degree of supersensitivity should develop after decentralization (Korczyn, & Shavit,

421

1976). However, following either preganglionic or postganglionic denervation, the effect of THC is decreased rather than increased. Thus, the evidence is conflicting and to this reviewer the confusion probably reflects a reliance on results which have not been solidly based. While, as mentioned, the sympathetic system seems to be involved in THC-induced l O P fall, the exact mechanism cannot be pinpointed before the question is answered whether the effect is central or peripheral or both. In addition to the points raised above, the following experiment of Green & Kim (1976b) is illustrative of the difficulties. In this study, rabbits who had undergone unilateral cervical sympathectomy were used. THC was applied to one eye. The lOP fell bilaterally, but not to the same degree. The fall was by 25~o in the intact eye and by 7% in the denervated eye. T h i s was the result whether T H C was applied to the normal or to the sympathectomized eye. The most likely explanation to this observation is that the THC was absorbed from the treated eye and reduced lOP indirectly (perhaps through a central action). It should be mentioned that the ocular hypotensive effect of acetazolamide is affected by manipulations of the sympathetic system in a similar way (Macri & Cerario, 1975). Thus, reservations must be made when conclusions are drawn mainly indirectly, e.g. through the use of a ganglion blocker. The evidence for involvment of the sympathetic nervous system in THC-induced ocular hypotension, gains additional interest from the recent findings (Gash et al., 1978) that smoking marihuana increases plasma norepinephrine and epinephrine. It is therefore possible that THC lowers lOP, at least partly through the action of catecholamines transported into the eye via the blood.

TOLERANCE

Although it is usually claimed that there is no tolerance to the ocular hypotensive effect of T H C (Hepler, 1976), this needs confirmation. Green et al., (1977), have shown with some cannabinol derivatives given chronically to rabbits, that the effect on lOP decreases with time (cf. their Fig. 1). Moreover, the results of the same observers show also tachyphylaxis i.e. that 4 hr following a dose of the drug, when the effect is declining, another dose is less effective.

EFFECTS OF THE DERIVATIVES ON IOP

l l-Hydroxy-THC and 8fl-ll-dihydroxy-THC, two major THC metabolites were found to be effective in lowering IOP in rabbits (Green & Bowman, 1976). ll-hydroxy-THC was in fact more potent than THC when given topically or i.v. (this however, may reflect pharmacokinetic rather than pharmacodynamic factors). On the other hand, several compounds were inactive. These include 8ct-hydroxy-THC, 8ct-dihydroxyTHC, 8fl-hydroxy-THC, 8~t-ll-dihydroxy-THC, cannabidiol and 11-hydroxy-AS-THC. Some new synthetic derivatives are interesting. Although most of them mimic the effect of THC, some,

422

AMOS D. KORCZYN

like SP-106, seem to have predominantly a peripheral site of action [Green et al., 1977). It is interesting that the latter drug is poorly soluble in oil and therefore would be expected to have limited ability to penetrate the blood-brain barrier. Another compound, Abbott 43981 has only minimal CNS effects. However, both agents reduce IOP, thus strengthening the view that the action is extracerebral. It is of course possible that the ocular hypotensive effect of T H C is central but can still be dissociated from other CNS effects (if different "'receptors" are involved or the areas of action differ). Clearly additional information is needed. Other ocular (ffects in humans 1. Pupils. The original impression of pupillary dilatation in man following marihuana smoke (for review, see Paton & Pertwee 1973), has been refuted by several studies, which have demonstrated that miosis, rather than mydriasis, occurs after T H C (Hepler et al., 1972: Domino et al., 1976). However, the question is not settled yet, because a more recent paper again maintains that mydriasis occurs (Stefanis et al., 1976). Several other investigators claim that smoking marihuana does not affect the pupil (for review, see Paton & Pertwee, 1973). It is noteworthy that in a more recent paper Hepler et al. (1976) claim that the miosis is slight and statistically not significant. It is possible that part of the conflict derives from the conditions under which the studies were performed, e.g. ambient illumination, expectation and dosage. There is no clue as to the mechanism of action and even whether the effect is central or peripheral, and whether tolerance occurs. The relationship of the pupillary changes to sedation or excitation produced by marihuana (Paton & Pertwee, 1973) is unknown. In rabbits, doses of T H C which reduce I O P are said to be without an effect on the pupil (Green & Kim, 1976b), whereas in rats mydriasis occurs (unpublished results). 2. Tear secretion. Tear secretion, measured by the Schirmer test, decreases following marihuana use (Hepler et al., 1976). This leads to a subjective feeling of dryness of the globe (Shapiro, 1974). It is interesting that xerostomia is also a manifestation of smoking cannabis (Paton & Pertwee, 1973). 3. Conjunctiva. Conjunctival vessels are dilated by marihuana smoke, causing redness of the globe (Shapiro, 1974: Smith & Kulp, 1976). It is not clear whether this is an irritant effect of the smoke itself or whether it is a more specific effect, Furthermore, this action contrasts with the effect on ciliary body vessels which is presumed to be constrictor (Green & Kim, 1976a). 4. Photophobia. This is a frequent complaint in marihuana smokers (Shapiro, 1974). The mechanism is obscure. 5. Corneal anesthesia. This is another manifestation of unknown pathogenesis (Walsh & Hoyt, 1969). 6. Lids. The palpebral fissure is narrowed after smoking marihuana. This was interpreted as blepharospasm (Shapiro, 1974), in which case it may be related to the photophobia mentioned above. Alternatively, the narrowing was attributed to swelling of the eyelids (Paton & Pertwee, 1973) or to ptosis (Domino et al., 1976).

CONCLUSIONS The clinical effects of T H C in humans have been well described both regarding the CNS and the eye. However, in neither case is the mechanism involved clear. T H C and some derivatives seem to be promising agents to treat glaucoma, and a concerted effort to understand the underlying process is justified. The first question which should be answered is whether THC-induced ocular hyptotension is due to a central or a peripheral action.

REFERENCES

BEACONSFIELD P., GINSBURG J. & RA1NSBURYR. (1972) Marijuana smoking: cardiovascular effects in man and possible mechanism. New Engl. J. Med. 287, 209-219. BEITCH B. R. & EAKINSK. E. (1969) The effects of prostaglandins on the intraocular pressure of the rabbit. Br. J. Pharmac. 37, 158-167. CAREL R. S.. KORCZYNA. D. & BOYMANR. (1979) Amethocaine and intraocular pressure. Ophthalmic Res. II, 212 215. CEVARIOS. J. 8£ MACRI F. J. 0974) The inhibitory effect of pentobarbital Na on aqueous humor formation. Invest. Opthalmol. 13, 384-386. COOLER P. (1976) Discussion In The Therapeutic Potential of Marihuana (Edited by COHEN S. & STILLMANR. C.) p. 89. Plenum, New York. COOLER P. & GREGG J. M. (1976) The effect of delta 9-tetrahydrocannabinol on intraocular pressure in humans. In The Therapeutic Potential of Marihuana (Edited by COHEN S. & STILLMAN R. C.) pp. 77-94. Plenum. New York. DOMINOE. F., PENNICKP. & PEARLJ. H. (1976) Short term neuropsychopharmacological effects of marihuana smoking in experimental man users. In The Pharmacology of Marihuana (Edited by BRAUDEM. C. & SZARA S.) pp. 393-412. Raven Press, New York. DREN A. T. (1976) Preclinical neuropharmacology of three nitrogen containing heterocyclic benzopyrans derived from the cannabinoid nucleus. In The Therapeutic Potential of Marihuana (Edited by COHENS. • STILLMAN R. C.) pp. 439-455. Plenum, New York. EBERT D. M. & DREN A. T. (1977) lntraocular pressure lowering properties of Abbott-43-981, a cannabinoid derived heterocyclic benzopiran with minimal CNS activities. Pharmacologist 19, 230. FENTON R. H. & SCHWARTZ B. (1963) The effect of 2°o pilocarpine on the normal and glaucomatous eye. I. The time response of pressure. Ire'est. Ophthalmol. 2, 289. FLOM M. C.. ADAMSA. J. & JONESR. T. (1975) Marihuana smoking and reduced pressure in human eyes. Invest. Ophthalmol. 14, 52-55. GARNER L. L., JOHNSTONEW. W., BALUNTINEE. & CARROLL M. E. (1959) Effect of 2°0 epinephrine on the intraocular pressure of the glaucomatous eye. Archs. Ophthalmol. 62, 230-238. GASH A., KARLINER J. S., JANOUSKY D. & LAKE C. R. (1978) Effects of smoking marijuana on left ventricular performance and plasma norepinephrine. Annls. Int. Med. 89, 448-452. GREEN K., BIGGER J. F., KIM K. & BOWMAN K. (1977) Cannabinoid action on the eye as mediated through the central nervous system and local adrenergic activity. "Expl, Eye Res. 24, 189-196. GREEN K. & BOWMANK. (1976) Effect of marihuana and derivates on aqueous humor dynamics in the rabbit. In The Pharmacology of Marihuana (Edited by BRAUDEM. C. & SZARAS.) pp. 803-813. Raven Press, New York.

The ocular effects of cannabinoids GREEN K. & K1M K. (1976a) Interaction of adrenergic antagonists with prostaglandin E2 and tetrahydrocannabinol in the eye. Invest. Ophthalmol. 15, 102-112. GREEN K. & K1i K. (1976b) Mediation of ocular tetrahydrocannabinol effects by adrenergic nervous system. Expl. Eye Res. 23, 443-448. GREEN K., KIM K. & BOWMANK. (1976) Ocular effects of Ag-tetra hydrocannabinol. In The Therapeutic Aspects of Marihuana (Edited by COHEN S. & STILLMAN R. C.) pp. 49-62. Plenum, New York. GREEN K. & PEDERSONJ. E. (1973) Effect of delta 9-tetrahydrocannabinol on aqueous dynamics and ciliary body permeability in the rabbit. Expl. Eye Res. 15, 499-507. GREEN K. & PODOS M. (1974) Antagonism of arachidonic acid induced ocular effects by A~-tetrahydrocannabinol. Invest. Ophthalmol. 13, 422-429. HEPLER R. S. (1976) Discussion. In The Therapeutic Potential of Marihuana. (Edited by COHEN S. & STILLMAN R. C.) p. 92. Plenum, New York. HEPLER R. S. & FRANK 1. M. (1971) Marihunaa smoking and intraocular pressure. J. Am. Med. Assn 217, 1392. HEPLER R. S., FRANK I. M. & UNGERBIDER J. T. (1972) Pupillary constriction after marihuana smoking. Am. J. Ophthalmol. 74, 1185-1190. HEPLER R. S., FRANK I. M. & PETRUS R. (1976) Ocular effects of marihuana smoking, In The Pharmacology of Marihuana. (Edited by BRAUOE M. C. & SZARA S.) pp. 815-824. Raven Press, New York. HEELER R. S. & PETRES R. J. (1976) Experience with administration of marihuana to glaucoma patients. In The Therapeutic Potential of Marihuana (Edited by COHEN S. & STILLMANR. C.) pp. 63-75. Plenum, New York. KORCZVN A. D. (1975a) Denervation supersensitivity in Homer's syndrome. Ophthalmol. 170, 313-319. KORCZYN A. D. (1975b) Adrenergic denervation supersensitivity. Adv. Neural. 9, 113-120. KORCZYN A. D. & SHAVIT S. (1976) Prolongation of response in decentralization supersensitivity. Res. commun. Chem. Path, Pharmac. 15, 405-407. KORNBLUETH W., ALADJEMOEFL,, MAGORA F. & GABaAV A. (1959) Influence of general anesthesia on intraocular pressure in man. AMA Archs.. Ophthalmol. 61, 84-87. LANGHAM M. E. (1965)'The response of the pupil and intraocular pressure of conscious rabbits to adrenergic drugs following unilateral superior cervical gang!ionectomy. Expl. Eye Res. 4, 381-389. LANGHAM M. E., SIMJEEA. & JOSEPHS S. (1973) The alpha and beta adrenergic responses to epinephrine in the rabbit eye. Expl. Eye Res. 15, 75-84. LOCKHART A. B., WEST M. E. & LOWE H. 1. C. (1977) The potential use of Cannabis sativa in ophthalmology. West Indies Med. J. 26, 66-70. MACR~ F. J. & CEVXRIO S. J. (1975) A possible vascular

423

mechanism for the inhibition of aqueous humor formation by ouabain and acetazolamide. Expl. Eye Res. 20, 563-569. MAGORAF. & COLUNS V. J. (196l) The influence of general anesthetic agents on intraocular pressure in man. Archs. Ophthalmol. 66, 81)6-811. MALIT L. A., JOHNSTONET. W., BOURKED. I., KULP R. A., KLEIN V. & SMITH T. C. (1975) Intravenous delta-9tetrahydro-cannabinol. Effects on ventilatory control and cardiovascular dynamics. Anesthesiology 42, 66--673. MECHOULAM R. (1970) Marihuana chemistry. Science 168, I 159-1166.

MECHOULAM R. & GAONI Y. (1965) A total synthesis of delta-9-tetrahydrocannabinol, the active constituent of hashish. J. Am. Chem. Sac. 87, 3273-3275. MECHOULAM R., LANDER N., DIKSTEIN S., CARLINI E. & BLUMENTHAL M. (1976) On the therapeutic possibilities of some cannabinoids. In The Therapeutic Potential of Marihuana (Edited by COHEN S. & STILLMAN R. C.) pp. 35-48. Plenum, New York. PATON W. D. M. & PERTWEE R. G. (1973) The actions of cannabis in man. In Marijuana Chemistry, Pharmacology, Metabolism and Clinical Effects. (Edited by MECHOULAM R.) pp. 287-324. Academic Press, New York. PEREZ-REYESM., WAGNER D., WALL M. E. & DAVISK. H. (1976) Intravenous administration of cannabinoids and intraocular pressure. In The Pharmacology of Marihuana (Edited by BRAUDE M. C. 8I. SZARA S.) pp. 829-832. Raven Press, New York. Pooos S. M., BECKER B. & KASS M. A. (1973) Prostaglandin synthesis, inhibition and intraocular pressure. Invest. Ophthalmol. 12, 426~,33. PURNELL W. D. & GREGG J. M. (1975) Ag-tetrahydrocannabinol, euphoria and intraocular pressure in man. Ann. Ophthalmol. 7, 921-923. SHAPIRO D. (1974) The ocular manifestation of the cannabinols. Ophthalmologia 168, 366-369. SMITH T. C. & KULP R. A. (1976) Respiratory and cardiovascular effects of delta-9-tetrahydrocannabinol alone and in combination with oxymorphone, pentobarbitol and diazepam. In The Therapeutic Potential of Marihuana (Edited by COHEN S. 8(. STILLMAN R. C.) pp. 123-132. Plenum, New York. STEFANISC., BONLONGOURISJ. & LIAKEOSAA. (1976) Clinical and psychopharmacological effects of cannabis in long term users. In The Pharmacology of Marihuana (Edited by BRAUDE M. C. & SZARA S.) pp. 659-672. Raven Press, New York. WALSH F. B. & HOYT W. F. (1969) Clinical Neuro-ophthalmology. Williams & Wilkins, Baltimore MD. WEST M. E. & LOCKHART A. B. (1978) The treatment of glaucoma using a non-psychoactive preparation of cannabis sativa. West Indies Med. J. 27, 16-25.