Marihuana-derived material: biochemical studies of the ocular responses.

Some biochemical factors of the iris-ciliary body of the rabbit have been examined for effects induced by water-soluble marihuana-derived material (MDM). Adenylate cyclase activity and sensitivity to beta-adrenergic agonists were unchanged, as measured 4 hours after MDM administration in vivo. Magnesium-dependent and anion-sensitive, but not sodium-potassium, ATPase activities were inhibited 6 hours after MDM administration in vivo, although they were unaffected by in vitro incubation. Topical administration of a potent substance P antagonist had no effect on the time course or magnitude of intravenous MDM-induced ocular effects in rabbit. Intravenously administered sugars antagonized the effects of MDM on intraocular pressure. A variety of drugs which display a range of biochemical effects varying from beta-adrenergic receptor agonism, to alteration of glycoprotein residues were employed. None of the agents employed, ranging from cAMP modifiers to protein synthesis blockers, had any effect on the MDM-induced response. It is apparent that the mechanism underlying the ocular hypotensive effect of MDM does not reside in mediation through adenylate cyclase, ATPase or substance P, but rather through a mechanism mediated by terminal sugar moieties on the molecule. The data suggest that modification of the surface membrane glycoprotein residues on the ciliary epithelium can induce marked alterations in aqueous humor flow rate.

Intraocular pressure following systemic administration of cannabinoids.

Various cannabinoids have been tested for activity compared to delta 9-THC in reducing intraocular pressure after intravenous administration in rabbits at 0.1 mg or 1 mg/animal. Comparison of l-delta 9-, delta 8-, 11-OH-delta 9- and 11-OH- delta 8-THC indicates that minor configurational changes have only a small influence on activity with regard to induction of a fall in intraocular pressure, although 11-OH-delta 8-THC has increased activity. 8 alpha-OH-, 8 alpha-diOH- and 8 beta-diOH-delta 9-THC have little or no activity but 8 beta-OH-delta 9-THC is as active as delta 9-THC indicating that the hydroxyl group in the beta-position does not influence activity. Modification of the C5H11 alkyl side chain (3'-OH-delta 9-THC) reduced activity to 20% relative to delta 9-THC. Cannabidiol (CBD), cannabichromene, cannabigerol and olivetol had no activity, but 10-OH-CBD had some activity at 2 mg/animal. Cannabinol (CBN) had about half the activity of delta 9-THC and activity was reduced further with 1'-OH-CBN, indicating that side chain modification reduced activity. Neither delta 9-THC, nor cannabigerol, had any effect on intraocular pressure or total outflow facility in the rhesus monkey, suggesting species differences in ocular responses to cannabinoids. Further studies on modification of these compounds is warranted in order to further delineate the structure-activity relationships.

Water soluble marihuana-derived material: pharmacological actions in rabbit and primate.

Further studies have been made with water soluble marihuana-derived material (MDM). Neither adrenergic, cholinergic, aldosterone, dopamine or serotonin antagonism affected the fall in intraocular pressure induced by MDM. Partial blockade was obtained with galactose, glucose, or mannose, but not arabinose, when the latter were given at intravenous concentrations of 1 gm/animal and MDM was given at 25 micrograms animal, suggesting that these sugars may be involved at the active site of the MDM glycoproteins. Dexamethasone was without effect on either intravenous or intravitreal MDM indicating that the MDM effect is not a non-specific response to a protein. A similar plant glycoprotein, larch arabinogalactan, at 200 micrograms/animal was without effect on intraocular pressure. Aqueous humor flow rate was increased 3 hours after MDM administration, a period corresponding to the intraocular pressure increase caused by MDM, and fell to 20% of control values when the fall in intraocular pressure occurred. Blood flow through the iris was increased at both one and six hours after intravenous MDM injection indicating a vasodilation which could contribute to the initial increase in intraocular pressure. Intravitreal injection of MDM in rabbit and rhesus monkey caused a fall in intraocular pressure only after a 24 hour delay: the unilateral response indicated that systemic metabolism was not required for activity and the delay was likely caused by the diffusion time to the ciliary processes from the mid-vitreal injection site. The changes in beta-receptors, adenylate cyclase and carbonic anhydrase in the ciliary processes are minimal indicating a possible vascular mechanism of action of MDM.

Ocular and systemic responses to water soluble material derived from Cannabis sativa (marihuana).

A water soluble material, isolated from Cannabis sativa, has been tested in albino and pigmented rabbits and rhesus monkeys for both ocular and systemic effects. Intravenous administration produced a dose-related fall in intraocular pressure in both albino and pigmented rabbits with concentrations as low as 0.005 mg/animal being effective, but no response was found in monkeys. High concentrations (0.2 to 1 mg/animal) induced a hypertensive phase in intraocular pressure prior to the ocular hypotension; higher concentrations (2 or 5 mg/animal) also induced antidiuresis and general relaxation. Tachyphylaxis was found to repeated daily injections. Alpha and beta-adrenergic antagonists caused some reduction of the hypertensive phase but had no effect on the hypotensive phase. Superior cervical ganglionectomy did not influence the time course of the intraocular pressure response. Indomethacin inhibited the hypertensive intraocular pressure phase but was ineffective against the hypotensive phase. Systemic blood pressure was unchanged following intravenous administration of 0.2 mg material/animal. Aqueous tumor protein concentration was increased at both 1 and 6 hours after intravenous administration, becoming greater at the later time. Aqueous humor turnover rate was substantially reduced reaching a minimum 8.75 hours after administration. Topical administration was ineffective in eyes when the epithelium was removed in rabbits with and without pretreatment with aspirin. Neither gastric nor suppository administration of large quantities (10 mg or greater) of material had any influence on intraocular pressure.