Medical Marijuana & Glaucoma

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1. What research has been done and what is known about the possible medical uses of marijuana?   Marijuana is not generally accepted as a safe and effective treatment for glaucoma. The American Academy of Ophthalmology (1992) stated: "There is evidence that marijuana (or its components), taken orally or by inhalation can lower intraocular pressure. However, there are no conclusive studies to date to indicate that marijuana (or its components) can safely and effectively lower intraocular pressure enough to prevent optic nerve damage. . . . The dose of marijuana necessary to produce a clinically relevant effect in the short term appears to produce an unacceptable level of undesirable side effects such as euphoria, systemic hypotension, and/or dry eye and conjunctival hyperemia in the majority of glaucoma patients in whom the drug has been carefully studied. No data have been published on studies of long-term ocular and systemic effects of the use of marijuana by glaucoma patients.

". . . Because the possibility exists that marijuana (or its components) may be useful in treating glaucoma, the American Academy on Ophthalmology Committee on Drugs believes that a long term clinical study, designed to test the safety and efficacy of marijuana in the prevention of progressive optic nerve damage and consequent visual field loss, appears appropriate."

The National Eye Institute (1997) has recently stated much the same thing. "Studies in the early 1970s showed that marijuana, when smoked, lowers intraocular pressure in people with normal pressure and those with glaucoma. . . . However, none of those studies demonstrated that marijuana--or any of its components--could safely and effectively lower intraocular pressure any more than a variety of drugs then on the market. . . . [and] some potentially serious side effects were noted. . . . Research to date has not investigated whether marijuana use offers any advantages over currently available glaucoma treatments or if it is useful when used in combination with standard therapies. . . . [t]he National Eye Institute stands ready to evaluate any well-designed studies for treatment of eye diseases, including those involving marijuana for treatment of glaucoma."

The initial observation that smoked marijuana lowered intraocular pressure (IOP) in humans in acute experiments was made by Hepler and Frank in 1971. Hepler and Petrus (1976) later reported in greater detail that 4 percent (tetrahydrocannabinol (THC)) marijuana cigarettes lowered the IOP about 27 percent more than did a placebo at 30 minutes in normal volunteers, and that 20 mg of oral THC lowered the IOP about 17 percent more than placebo at 30 minutes. They also reported that smoked marijuana lowered IOP much more dramatically in patients with poorly controlled glaucoma, with 10 of 12 responding, and presented graphs showing the timecourse. One patient demonstrated a reduction from 40 mm Hg to 10 mm Hg in one eye and from 35 mm Hg to 15 mm Hg in the other. Since patients with severe glaucoma did not discontinue their current therapy (pilocarpine - 4 percent, epinephrine - 2 percent, or oral acetazolamide) Hepler and Petrus concluded that smoked marijuana or oral THC were additive to the then-known classes of therapeutic agents, and presumably worked by an independent mechanism (Hepler and Petrus 1976). In these short-term studies, lasting up to 4 hours, 2 cigarettes were as effective as 20 cigarettes, and intoxication occurred. Others confirmed that the marijuana could have a significant adjunctive effect in glaucoma patients, with Cuendet and colleagues reporting that 12/16 eyes of 10 patients had a reduction of 15 percent or more (Cuendet et al. 1976).

Flom and colleagues (1975) concluded that in normal volunteers in acute studies the lowering of IOP was proportional to the "high," and that experienced users who did not experience a "high" did not have a lowering of IOP. Merritt and colleagues (1980) studied the blood pressure (BP) and IOP of 18 glaucoma patients in short-term studies, which compared smoking a single 2 percent THC cigarette versus a placebo cigarette of the same smell and taste and concluded that the IOP was reduced by 4 mm Hg at 30 minutes and by 6 mm Hg at 90 minutes (in patients with either open-angle or synechial angle-closure glaucoma), returning to baseline by 4 hours with THC, while there was no change with the placebo, but that the pulse rose from 82 beats per minute (bpm) to 123 bpm at 15 minutes, and the systolic BP fell 11 mm Hg and diastolic BP fell 5 mm Hg, suggesting that reduced perfusion of the ciliary body accounted for the reduction in IOP and that the adverse systemic effects, including postural hypotension, would limit the potential usefulness of marijuana. Indeed, Merritt concluded in an editorial in the Journal of the National Medical Association (1982) that "Systemic delta-9 THC therapies invariably produce a decreased perfusion pressure to the eye. This decreased perfusion to an already damaged optic nerve may not be of long-term benefit to glaucoma victims." However, there are several anecdotal reports that, on continued use, tolerance develops to the undesirable cardiovascular and mood effects of marijuana, while tolerance does not develop to the beneficial effects on IOP in patients with glaucoma (Palmberg 1997).

Efforts to avoid systemic effects of THC in glaucoma treatment led to studies of topical preparations, such as 1 percent THC in peanut oil. However, no effect of the preparation on IOP was found by Jay and Green (1983).

Animal studies have yielded conflicting results about the mechanism of action of THC on the IOP. The studies by Green in rabbits suggested central effects mediated through the adrenergic nervous system (Green 1979), but the studies of Colasanti (1990) in cats indicated no effect of either sympathetic or parasympathetic denervation on the action of THC. She also found that THC has no effect on aqueous production in anesthetized cats, but rather increased aqueous outflow facility threefold.

The mechanism in humans has never been investigated by modern means, including fluorophotometry, coupled with the older method of tonography, which could yield clear information about the mechanism of action, whether on inflow, conventional outflow, or uveo-scleral outflow. In addition, it would now be possible to test the additivity of marijuana to a wide variety of agents now available, including beta-1 and beta-2 agonists and antagonists, alpha-2 agonists, dorzolamide, and latanoprost, to see whether or not THC works by a separate mechanism.

2. What are the major unanswered scientific questions?

Researchers do not know the mechanism of action of cannabis on IOP, given either as smoked marijuana or as oral THC.

Additional studies of long-term marijuana use are needed to determine if there are or are not important adverse pulmonary, central nervous system (CNS), or immune system problems.

It needs to be determined if smoked or eaten marijuana is more effective in lowering IOP on a chronic basis than THC alone, as marijuana advocates maintain on the basis of anecdotal experience, or if pure THC, without the particulates and carcinogens of marijuana smoke, could be inhaled by means other than smoking, or taken orally, with equal long-term effect on IOP.

Researchers do not know if marijuana would be additive to the new, very potent types of eyedrops now available to treat glaucoma, including alpha-2 agonists, dorzolamide and latanoprost (a prostaglandin that increases uveoscleral outflow and, like THC, causes conjunctival hyperemia). If marijuana were not to be additive to one of these agents, marijuana would be obsolete, since these agents have no systemic side effects (other than slightly dry mouth in some patients with apraclonidine and bromonidine), and they have a duration of action of 12 to 24 hours.

What are the diseases or conditions for which marijuana might have potential as a treatment and which merit further study?

Further studies to define the mechanism of action and to determine the efficacy of delta-9-tetrahydrocannabinol and marijuana in the treatment of glaucoma are justified.

In glaucoma, there does not appear to be any obvious reason to use smoked marijuana as a primary " stand alone" investigational therapy, as there are many available agents for treatment, and these topical preparations seem to be potentially ideal. An approach that may be useful is to study smoked marijuana in incomplete responders to standard therapies. The suggested design for clinical studies is to add marijuana, oral THC, or placebo to standard therapy under double-blind conditions. Studies proposed should consider the following measures:

• Establish dose-response and dose-duration relationships for IOP and CNS effects.
  
  
• Relate IOP and blood pressure measurements longitudinally to evaluate potential tolerance development to cardiovascular effects.
  
  
• Evaluate CNS effects longitudinally for tolerance development.

References

American Academy of Ophthalmology. "The Use of Marijuana in the Treatment of Glaucoma." Statement by the Board of Directors of the American Academy of Ophthalmology, PO Box 7424, San Francisco, CA, June 1992.

Colasanti, B.K. Review: Ocular hypotensive effect of marijuana cannabinoids: Correlate of central action or separate phenomenon? J Ocular Pharmacol 6(4):259-269, 1990.

Cuendet, J.F.; Saprio, D.; Calanca, A.; Faggioni, R.; and Ducrey, N. Action of delta-9-tetrahydrocannabinol on ophthalmotonus. Opthalmologica 172:122-127, 1976.

Flom, M.C.; Adams, A.J.; and Jones, R.T. Marijuana smoking and reduced pressure in human eyes: Drug action or epiphenomenon? Invest Ophthalmol 14(1):52-55, 1975.

Green, K. Marihuana in ophthalmology--past, present and future. (Editorial). Ann Ophthalmol 11(2):203-205, 1979.

Hepler, R.S., and Frank, I.R. Marijuana smoking and intraocular pressure. (Letter). JAMA 217:1392, 1971.

Hepler, R.S., and Petrus, R.J. Experiences with administration of marihuana to glaucoma patients. In: Cohen, S., and Stillman, R.C., eds. The Therapeutic Potential of Marihuana. New York: Plenum Medical Books, 1976. pp. 63-75.

Jay, W.M., and Green, K. Multiple-drop study of topically applied 1% delta 9-tetrahydrocannabinol in human eyes. Arch Ophthalmol 101(4):591-593, 1983.

Merritt, J.C. Glaucoma, hypertension, and marijuana. (Editorial). J Natl Med Assn

74(8):715-716, 1982.

Merritt, J.C.; Crawford, W.J.; Alexander, P.C.; Anduze, A.L.; and Gelbart, S.S. Effect of marihuana on intraocular and blood pressure in glaucoma. Ophthalmology 87(3):222-228, 1980.

National Eye Institute. "The Use of Marijuana for Glaucoma." Statement of the National Eye Institute of the National Institutes of Health, February 18, 1997.