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Glaucoma refers to a group of eye conditions that lead to damage to the optic nerve. This nerve carries visual information from the eye to the brain.

In most cases, damage to the optic nerve is due to increased pressure in the eye, also known as intraocular pressure (IOP).

GLAUCOMA and cannabis studies completed 

1977 - Study - Effect of delta-9-tetrahydrocannabinol on intraocular pressure in humans.

1979 - Study - Effects of tetrahydrocannabinol on arterial and intraocular hypertension

1980 - Patent - US Patent 4189491 - Tetrahydrocannabinol in a method of treating glaucoma.

1980 - Study - Effect of marihuana on intraocular and blood pressure in glaucoma.

1981 - Study - Delta 9-tetrahydrocannabinol in cancer chemotherapy. Ophthalmologic implications.

1981 - Study ~ Topical delta 9-tetrahydrocannabinol and aqueous dynamics in glaucoma.

1981 - Study ~ Cannabinoids in glaucoma: a primary screening procedure.

1981 - Study ~ Isolation of ocular hypotensive agents from Cannabis sativa.

1982 - Study ~ Glaucoma, hypertension, and marijuana.

1982 - Study ~ Ocular Effects of Topical Administration of {Delta}9-Tetrahydrocannabinol in Man.

1982 - Study ~ Intraocular pressure following systemic administration of cannabinoids.

1983 - Study ~ Multiple-Drop Study of Topically Applied 1% {Delta}9-Tetrahydrocannabinol in Human Eyes.

1984 - Study ~ Intraocular pressure, ocular toxicity and neurotoxicity after administration of delta 9-tetrahydrocannabinol or cannabichromene.

1984 - Study ~ Ocular Hypotension, Ocular Toxicity, and Neurotoxicity in Response to Marihuana Extract and Cannabidiol.

1987 - Study ~ Central Nervous System and Peripheral Mechanisms in Ocular Hypotensive Effect of Cannabinoids.

1990 - Study ~ A comparison of the ocular and central effects of delta 9-tetrahydrocannabinol and cannabigerol.

1998 - Study - Marijuana Smoking vs Cannabinoids for Glaucoma Therapy.

1998 - News ~ Smoking dope restored my sight.

1999 - Study ~ Cannabis and cannabinoids: pharmacology and rationale for clinical use.

2000 - Study ~ Involvement of Cannabinoid Receptors in the Intraocular Pressure-Lowering Effects of WIN55212-2.

2001 - Study - Therapeutic Aspects of Cannabis and Cannabinoids.

2002 - Study ~ Chronic Cannabis Use in the Compassionate Investigational New Drug Program: An Examination of Benefits and Adverse Effects of Legal Clinical Cannabis.

2002 - Study ~ Delta-9-tetrahydrocannabinol (THC) in the treatment of end-stage open-angle glaucoma.

2002 - Study ~ Comparison of the enzymatic stability and intraocular pressure effects of 2-arachidonylglycerol and noladin ether, a novel putative endocannabinoid.

2003 - Study ~ Effect of WIN 55212-2, a Cannabinoid Receptor Agonist, on Aqueous Humor Dynamics in Monkeys.

2004 - Study - Cannabinoids and glaucoma.

2004 - Study - Cannabis Improves Night Vision.

2005 - Study ~ CB2 cannabinoid receptors in trabecular meshwork cells mediate JWH015-induced enhancement of aqueous humor outflow facility.

2005 - Study ~ Finding of endocannabinoids in human eye tissues: implications for glaucoma.

2006 - Study - Effect of Sublingual Application of Cannabinoids on Intraocular Pressure.

2006 - Study ~ Noladin ether acts on trabecular meshwork cannabinoid (CB1) receptors to enhance aqueous humor outflow facility.

2006 - Study ~ R(+)-methanandamide and other cannabinoids induce the expression of cyclooxygenase-2 and matrix metalloproteinases in human nonpigmented ciliary epithelial cells.

2006 - Study ~ Cannabinoids In Medicine: A Review Of Their Therapeutic Potential.

2007 - Study ~ Involvement of the Endocannabinoid System in Retinal Damage after High Intraocular Pressure–Induced Ischemia in Rats.

2007 - Study ~ Additive Effects of Timolol and Cannabinoids on Intraocular Pressure in a Rat Glaucoma Model.

2007 - Study - Dronabinol and retinal hemodynamics in humans.

2007 - Study - Neuroprotective effect of Delta9 tetrahydrocannabinol and cannabidiol

2007 - Study - Neuroprotective and Intraocular Pressure-Lowering Effects of Delta 9 -Tetrahydrocannabinol.

2008 - Study - The role of endocannabinoid system in physiological and pathological processes in the eye.

2008 - Study - Endocannabinoids in the retina: From marijuana to neuroprotection.

2008 - Study - Reduction of Congenital Nystagmus in a Patient after Smoking Cannabis.

2008 - Study ~ N-arachidonylethanolamide-Induced Increase in Aqueous Humor Outflow Facility.

2008 - Study ~ Mediation of Cannabidiol Anti-inflammation in the Retina by Equilibrative Nucleoside Transporter and A2A Adenosine Receptor.

2008 - Study ~ Topical WIN55212-2 Alleviates Intraocular Hypertension in Rats Through a CB1 Receptor-Mediated Mechanism of Action.

2009 - News ~ Medical Marijuana and Glaucoma.

2010 - NewsAre There Any Herbal Supplements to Reduce Intraocular Pressure?

2011 - Study ~ Alternative therapy in glaucoma management: Is there any role?

2011 - Study ~ Ocular Hypotensive Effect of Oral Palmitoyl-ethanolamide: A Clinical Trial.

2011 - Study ~ Cannabinoid applications in glaucoma.

2011 - Study ~ A cannabinoid ligand, anandamide, exacerbates endotoxin-induced uveitis in rabbits.

2011 - Study ~ Effect of ion pairing on in vitro transcorneal permeability of a Δ(9) -tetrahydrocannabinol prodrug: Potential in glaucoma therapy.

2011 - Study ~ Comparison Of Rat And Human Eyes For The Presence And Distribution Of Cb1 And Cb2 Receptors.

2011 - Study ~ Nonpsychotropic Cannabinoids, Abnormal Cannabidiol and Canabigerol-Dimethyl Heptyl, Act at Novel Cannabinoid Receptors to Reduce Intraocular Pressure.

2011 - Study ~ Indirect Sympatholytic Actions at β-Adrenoceptors Account for the Ocular Hypotensive Actions of Cannabinoid Receptor Agonists.

2011 - News ~ January is Glaucoma Awareness Month: Can Marijuana save eyesight?

2011 - News ~ Medical Reasons for Marijuana.

2011 - News ~ In decades-old program, Uncle Sam provides pot.

2012 - Study ~ Effect of ion pairing on in vitro transcorneal permeability of a Δ(9) -tetrahydrocannabinol prodrug: potential in glaucoma therapy.

2012 - Study ~ Effects of Palmitoylethanolamide on Aqueous Humor Outflow.

 

 


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Dronabinol and retinal hemodynamics in humans

Source

Department of Ophthalmology, RWTH Aachen University, Pauwelstrasse 30, 52057 Aachen, Germany. [email protected]

Abstract

PURPOSE:

To investigate the effects of oral cannabinoids on retinal hemodynamics assessed by video fluorescein angiography in healthy subjects.

DESIGN:

Interventional study.

METHODS:

In a self-experiment, the cannabinoid dronabinol (delta-9-tetrahydrocannabinol [THC]) was administered orally to eight healthy medical doctors (7.5 mg Marinol; Unimed Pharmaceuticals, Chicago, Illinois, USA). At baseline and two hours after dronabinol intake, intraocular pressure (IOP) was measured and retinal hemodynamics were assessed by fluorescein angiography. The retinal arteriovenous passage time was determined on the basis of dye dilution curves by means of digital image analysis in a masked fashion.

RESULTS:

Dronabinol resulted in a significant IOP reduction from 13.2 +/- 1.9 mm Hg to 11.8 +/- 2.0 mm Hg (P = .038). The retinal arteriovenous passage time decreased from 1.77 +/- 0.35 seconds to 1.57 +/- 0.31 seconds (P = .028). Systemic blood pressure and heart rate were not statistically significantly altered.

CONCLUSIONS:

Cannabinoids, already known for their ability to reduce IOP, may result in increased retinal hemodynamics. This may be beneficial in ocular circulatory disorders, including glaucoma.

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Effect of Sublingual Application of Cannabinoids on Intraocular Pressure

TitleEffect of Sublingual Application of Cannabinoids on Intraocular Pressure: A Pilot Study.
Author(s)Tomida I, Azuara-Blanco A, House H, Flint M, Pertwee RG, Robson PJ.
Journal, Volume, IssueJ Glaucoma 2006 15(5):349-353.
Major outcome(s)Significant reduction of intraocular pressure
 
IndicationGlaucomaAbstract
MedicationDelta-9-THC;Cannabidiol

PURPOSE: The purpose of this study was to assess the effect on intraocular pressure (IOP) and the safety and tolerability of oromucosal administration of a low dose of delta-9-tetrahydrocannabinol (Delta-9-THC) and cannabidiol (CBD).

PATIENTS AND METHODS: A randomized, double-masked, placebo-controlled, 4 way crossover study was conducted at a single center, using cannabis-based medicinal extract of Delta-9-THC and CBD. Six patients with ocular hypertension or early primary open angle glaucoma received a single sublingual dose at 8 AM of 5 mg Delta-9-THC, 20 mg CBD, 40 mg CBD, or placebo. Main outcome measure was IOP.

Secondary outcomes included visual acuity, vital signs, and psychotropic effects.

RESULTS: Two hours after sublingual administration of 5 mg Delta-9-THC, the IOP was significantly lower than after placebo (23.5 mm Hg vs. 27.3 mm Hg, P=0.026). The IOP returned to baseline level after the 4-hour IOP measurement. CBD administration did not reduce the IOP at any time.

However, the higher dose of CBD (40 mg) produced a transient elevation of IOP at 4 hours after administration, from 23.2 to 25.9 mm Hg (P=0.028).

Vital signs and visual acuity were not significantly changed. One patient experienced a transient and mild paniclike reaction after Delta-9-THC administration.

CONCLUSIONS: A single 5 mg sublingual dose of Delta-9-THC reduced the IOP temporarily and was well tolerated by most patients.

Sublingual administration of 20 mg CBD did not reduce IOP, whereas 40 mg CBD produced a transient increase IOP rise.

 

Route(s)Sublingual
Dose(s)5 mg
Duration (days)1
Participants6 patients with increased intraocular pressure
DesignControlled study
Type of publicationMedical journal
Address of author(s)Department of Ophthalmology, Aberdeen Royal Infirmary, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, UK, Cannabinoid Research Institute, Magdalen Centre, Oxford Science Park, Oxford OX4 4GA
Full text

Delta 9-tetrahydrocannabinol in cancer chemotherapy. Ophthalmologic implications

TitlePhysiologic observations in a controlled clinical trial of the antiemetic effectiveness of 5, 10, and 15 mg of delta 9-tetrahydrocannabinol in cancer chemotherapy. Ophthalmologic implications.
Author(s)Levitt M, Wilson A, Bowman D, Kemel S, Krepart G, Marks V, Schipper H, Thomson G, Weinerman B, Weinerman R
Journal, Volume, IssueJ Clin Pharmacol 1981;21(8-9 Suppl):103S-109S
Major outcome(s)Patients were remarkably free of adverse physiologic effects.
 
IndicationCancer chemotherapy;GlaucomaAbstract
MedicationDelta-9-THC

One hundred twenty patients about to receive their first treatment with potentially nauseant cancer chemotherapy were randomized to one of si xantiemetic treatments:

(1) no treatment;

(2) placebo;

(3) prochlorperazine (PCPZ), 10 mg; (4) delta 9-tetrahydrocannabinol (THC), 5 mg; (5) THC, 10 mg; (6) THC, 15 mg.

Four doses of each medication were given orally at 4-hour intervals starting 2 hours before chemotherapy.

A study nurse was responsible for both objective (nurse) and subjective (patient) symptom questionnaires.

Serum levels were obtained at intervals for cross-reacting cannabinoids.

Physiologic measurements including intraocular pressure (IOP), blood pressure, and pulmonary function were also recorded.

In summary, the patients were remarkably free of adverse physiologic effects.

All intraocular pressures before and after treatment were within the normal range, although a surprising statistically significant increase in IOP occurred in the group receiving 5 mg THC.


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Route(s) 
Dose(s) 
Duration (days) 
Participants120
DesignControlled study
Type of publicationMedical journal
Address of author(s) 
Full text

Effect of marihuana on intraocular and blood pressure in glaucoma

TitleEffect of marihuana on intraocular and blood pressure in glaucoma.
Author(s)Merritt JC, Crawford WJ, Alexander PC, Anduze AL, Gelbart SS
Journal, Volume, IssueOphthalmology 1980;87(3):222-8
Major outcome(s)Marihuana inhalation decreased intraocular and blood pressure.
 
IndicationGlaucomaAbstract
MedicationCannabis

Marihuana inhalation was accompanied by increased heart rate and decreased intraocular and blood pressure in 18 subjects with heterogenous glaucomas.

The hypotensive effects appeared in 60 to 90 minutes as the decrease in intraocular pressure (IOP) appeared to follow the decrease in blood pressure.

In addition to any local effect, the mechanism of lowered to any local effect, the mechanism of lowered IOP may also involve the decreased pressure perfusing the ciliary body vasculature as a result of the peripheral vasodilatory properties of marihuana.

Postural hypotension, tachycardia, palpitations, and alterations in mental status occurred with such frequency as to mitigate against the routine used in the general glaucoma population.

Our data indicate that further research should be directed to local means of delivering the ocular hypotensive cannabinoid to the glaucomatous eye.

 

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Route(s)Inhalation
Dose(s)Smoked THC (2%)
Duration (days) 
Participants18 patients with glaucoma
DesignControlled study
Type of publicationMedical journal
Address of author(s) 
Full text

Effect of delta-9-tetrahydrocannabinol on intraocular pressure in humans

TitleEffect of delta-9-tetrahydrocannabinol on intraocular pressure in humans.
Author(s)Cooler P, Gregg JM
Journal, Volume, IssueSouthern Medical Journal 1977;70(8):951-954
Major outcome(s)reduction in intraocular pressure
 
IndicationGlaucomaAbstract
MedicationDelta-9-THC

As early as 1971, it was noted that smoking marijuana lowered intraocular pressure. In this study one of the active components of marijuana, delta-9-tetrahydrocannabinol, was given intravenously to ten subjects with normal intraocular pressures.

Two strengths were used--0.022 mg/kg of body weight and 0.044 mg/kg of body weight. Intraocular pressure was found to decrease as much as 51% of baseline normal with an average decrease of 37%.

Heart rate increased in a range of 22% and 65% of the resting pulse. Respiratory rate was not affected.

No analgesic properties were demonstrated by either cutaneous or periosteal stimulation.

Anxiety levels were increased by delta-9-tetrahydrocannabinol over placebo and diazepam (Valium).

The mechanism of action is still uncertain but it is believed by some workers to be similar to that of a beta-adrenergic stimulator.


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Route(s) 
Dose(s)1.5-3.0 mg THC
Duration (days)1
Participants10 healthy subjects
DesignControlled study
Type of publication 
Address of author(s) 
Full text

Marihuana smoking and intraocular pressure

TitleMarihuana smoking and intraocular pressure.
Author(s)Hepler RS, Frank IR
Journal, Volume, IssueJournal of the American Medical Association 1971;217(10):1392
Major outcome(s)9 of 11 had drop in intraocular pressure of 16-45%
 
IndicationGlaucomaAbstract
MedicationCannabis

To the Editor
It is accepted widely that physiologic effects of smoking marihuana are not well known, despite an acknowledged high incidence of usage.

Even the President of the United States has called for a major effort to study drug effects in a scientific manner.

In an attempt to investigate the effects of marihuana smoking upon the human visual system, complete ocular examinations were performed in a group of youthful subjects, before and one hour after smoking.

Selection of subjects, medical an other safeguards utilized, and details of the protocol will be presented in a later publication.

The purpose of this letter is to present preliminary data concerning the most impressive change observed so far, namely, a substantial decrease in intraocular pressure observed in a large percentage of subjects.

Applanation tonometry was performed by the same experienced examiner, using the same tonometer for each pair of observations.

Marihuana was provided by the National Institute for Mental Health, and assays proved the concentration of tetrahydrocannabinol to be high (0.9%).

Two grams were smoked by each subject using an ice cooled water pipe.
It is our hope that further investigations by clinicians and basic scientists will be stimulated by the observations recorded in the Table.

The possible implications, including the mechanisms of action, and even possible therapeutic action in the treatment of glaucoma, are obvious.


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Neuroprotective and Intraocular Pressure-Lowering Effects of Delta 9 -Tetrahydrocannabinol

Crandall J, Matragoon S, Khalifa YM, Borlongan C, Tsai NT, Caldwell RB, Liou GI


Neuroprotective and intraocular pressure-lowering effects of (-)Delta9-tetrahydrocannabinol in a rat model of glaucoma. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't]
Ophthalmic Res 2007; 39(2):69-75.

In glaucoma, retinal ganglion cell (RGC) death is induced by many risk factors, including ocular hypertension. It has been proposed that glutamate-mediated oxidative stress may also contribute to this RGC death.

Cannabinoids are known to possess therapeutic properties including ocular hypotension and antioxidation. In this study, we test the hypothesis that (-)Delta(9)-tetrahydrocannabinol (THC) lowers intraocular pressure (IOP) and prevents RGC death in a rat model of glaucoma. Arat model of experimental glaucoma with chronic, moderately elevated IOP was produced unilaterally by cauterization of episcleral vessels.

Rats received weekly injections of THC at a level of 5 mg/kg or vehicle for 20 weeks. IOP of both eyes was measured weekly on anesthetized animals immediately before THC treatment.

RGCs were labeled in a retrograde fashion and counted in whole-mounted retinas. IOP was elevated in all operated eyes 1 day after the operation and remained elevated in the vehicle-treated rats throughout 20 weeks.

In THC-treated rats, IOP elevation in operated eyes was diminished 2 weeks after operation and remained reduced. IOP in the contralateral control eyes was not affected by THC. In the operated eyes of vehicle-treated animals, there was a loss of approximately 50 and 40% of the RGCs in the peripheral and central retina, respectively.

The RGC loss in the operated eyes of the THC-treated animals was reduced to 10-20%. These results demonstrate that THC is a neuroprotectant that preserves RGCs in an experimental model of glaucoma, possibly through a reduction in IOP.

 

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Neuroprotective effect of Delta9 tetrahydrocannabinol and cannabidiol

El-Remessy AB, Khalil IE, Matragoon S, Abou-Mohamed G, Tsai NJ, Roon P, Caldwell RB, Caldwell RW, Green K, Liou GI

 Neuroprotective effect of (-)Delta9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite. [Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.]

Am J Pathol 2003 Nov; 163(5):1997-2008.

 In glaucoma, the increased release of glutamate is the major cause of retinal ganglion cell death.

Cannabinoids have been demonstrated to protect neuron cultures from glutamate-induced death. In this study, we test the hypothesis that glutamate causes apoptosis of retinal neurons via the excessive formation of peroxynitrite, and that the neuroprotective effect of the psychotropic Delta9-tetrahydroxycannabinol (THC) or nonpsychotropic cannabidiol (CBD) is via the attenuation of this formation.

Excitotoxicity of the retina was induced by intravitreal injection of N-methyl-D-aspartate (NMDA) in rats, which also received 4-hydroxy-2,2,6,6-tetramethylpiperidine-n-oxyl (TEMPOL,a superoxide dismutase-mimetic), N-omega-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor), THC, or CBD.

Retinal neuron loss was determined by TDT-mediated dUTP nick-end labeling assay, inner retinal thickness, and quantification of the mRNAs of ganglion cell markers. NMDA induced a dose- and time-dependent accumulation of nitrite/nitrate, lipid peroxidation, and nitrotyrosine (foot print of peroxynitrite), and a dose-dependent apoptosis and loss of inner retinal neurons.

Treatment with L-NAME or TEMPOL protected retinal neurons and confirmed the involvement of peroxynitrite in retinal neurotoxicity. The neuroprotection by THC and CBD was because of attenuation of peroxynitrite. The effect of THC was in part mediated by the cannabinoid receptor CB1. These results suggest the potential use of CBD as a novel topical therapy for the treatment of glaucoma.


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Effects of tetrahydrocannabinol on arterial and intraocular hypertension

Int J Clin Pharmacol Biopharm.  1979; 17(5):191-6 (ISSN: 0340-0026)

Crawford WJ; Merritt JC

Clinical studies were conducted to determine the relationship between simultaneous changes in heart rate, blood pressure, and intraocular pressure in systemic normotensive (N=8) and hypertensive (N=8) open-angle glaucoma patients (N=16) after inhalation of tetrahydrocannabinol (THC).

Insignificant changes occurred in arterial and ocular pressures after placebo pertubations. The functional responses after 2.8% THC inhalation in sitting normotensive and hypertensive patients included invariable increases in heart rate (range 20-62 beats/min greater than control) followed by substantial decreases in systolic pressure (range 12-52 mmHg less than control), diastolic pressure (range 6-28 mmHg less than control), and intraocular pressure (range 6-21 mmHg less than control).

The intensity and duration (3-4 hours) of the arterial and ocular pressure responses to THC were greater in hypertensives than in normotensive patients. The salient observation after THC inhalation was that the changes in ocular pressure paralleled the changes in blood pressure in each glaucoma patient.

These findings suggest that the positive chronotropic response to THC tends to maintain cardiac output which limits further decreases in blood pressure and the capillary filtration of aqueous humor decreases or the reabsorption of aqueous humor increases because of the systemic hypotensive effect attending THC inhalation.

  • PreMedline Identifier: 468444

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Cannabis improves night vision

Journal of Ethnopharmacology


Volume 93, Issue 1, July 2004, Pages 99-104

doi:10.1016/j.jep.2004.03.029 | How to Cite or Link Using DOI
Copyright © 2004 Elsevier Ireland Ltd. All rights reserved.

 

E. B. RussoCorresponding Author Contact Information, E-mail The Corresponding Author, , A. Merzouki, J. Molero Mesa, K. A. Freydand P. J. Bach

2235 Wylie Avenue, Missoula, MT 59802, USA

Department of Botany, Faculty of Pharmacy, University of Granada, Granada 18071, Spain

Laboratory of Ethnobotany, Faculty of Sciences, University Abdelmalek Essaadi, Tétouan, Morocco

Montana State University School of Nursing, 236 Corbin Hall, University of Montana, Missoula, MT 59812, USA

Montana Neurobehavioral Specialists, 900 North Orange St., Missoula, MT 59802, USA

Received 1 January 2003; 
Revised 1 March 2004; 
accepted 18 March 2004. 
Available online 13 May 2004.

Abstract

Previous reports have documented an improvement in night vision among Jamaican fishermen after ingestion of a crude tincture of herbal cannabis, while two members of this group noted that Moroccan fishermen and mountain dwellers observe an analogous improvement after smoking kif, sifted Cannabis sativa mixed with tobacco (Nicotiana rustica).

Field-testing of night vision has become possible with a portable device, the LKC Technologies Scotopic Sensitivity Tester-1 (SST-1).

This study examines the results of double-blinded graduated THC administration 0–20 mg (as Marinol®) versus placebo in one subject on measures of dark adaptometry and scotopic sensitivity. Analogous field studies were performed in Morocco with the SST-1 in three subjects before and after smoking kif. In both test situations, improvements in night vision measures were noted after THC or cannabis.

It is believed that this effect is dose-dependent and cannabinoid-mediated at the retinal level. Further testing may assess possible clinical application of these results in retinitis pigmentosa or other conditions.

Author Keywords: Cannabis; Medical marijuana; Ethnobotany; Night vision; Ophthalmology; Visual testing

Article Outline

Therapeutic Aspects of Cannabis and Cannabinoids

 
The British Journal of Psychiatry
Volume 178             February 2001             pp 107-115

© 2001 The Royal College of Psychiatrists

ROBSON, PHILIP


PHILIP ROBSON, FRCPsych, Consultant Psychiatrist and Senior Clinical Lecturer, Warneford Hospital, Oxford OX3 7JX

(First received 22 July 1999, final revision 14 March 2000, accepted 15 March 2000)

 Abstract

Background: Review commissioned in 1996 by the Department of Health (DOH).

Aims: Assess therapeutic profile of cannabis and cannabinoids.

Method: Medline search, references supplied by DOH and others, and personal communications.

Results and Conclusions: Cannabis and some cannabinoids are effective antiemetics and analgesics and reduce intraocular pressure. There is evidence of symptom relief and improved well-being in selected neurological conditions,

AIDS and certain cancers. Cannabinoids may reduce anxiety and improve sleep. Anticonvulsant activity requires clarification. Other properties identified by basic research await evaluation. Standard treatments for many relevant disorders are unsatisfactory.

Cannabis is safe in overdose but often produces unwanted effects, typically sedation, intoxication, clumsiness, dizziness, dry mouth, lowered blood pressure or increased heart rate. The discovery of specific receptors and natural ligands may lead to drug developments. Research is needed to optimise dose and route of administration, quantify therapeutic and adverse effects, and examine interactions.

Declaration of interest: Funding from DOH. Between writing this paper and its acceptance for publication, P.R. was appointed Medical Director of GW Pharmaceuticals.

 


In 1996 I was commissioned by the Department of Health (DOH) to review the scientific literature regarding the potential therapeutic utility of cannabis and its derivatives.

The review was based upon primary sources (identified from a Medline literature search, reference lists supplied by the DOH and the Institute for the Study of Drug Dependence, and personal communications with relevant academics and clinicians). This paper is a greatly shortened version of the review.

The 4 years which have elapsed have seen little in the way of new clinical results but considerable advances in cannabinoid basic science (Institute of Medicine, 1999).

Government licences have recently been granted for several controlled trials of both synthetic and plant-derived cannabinoids in multiple sclerosis and chronic pain. In January 2000, I was appointed Medical Director of GW Pharmaceuticals, a company established to derive medicinal extracts from standardised cannabis plants.

HISTORY OF THERAPEUTIC USE


The first formal report of cannabis as a medicine appeared in China nearly 5000 years ago when it was recommended for malaria, constipation, rheumatic pains and childbirth and, mixed with wine, as a surgical analgesic (Mechoulam, 1986). There are subsequent records of its use throughout Asia, the Middle East, Southern Africa and South America. Accounts by Pliny, Dioscorides and Galen remained influential in European medicine for 16 centuries.

It was not until the 19th century that cannabis became a mainstream medicine in Britain. W. B. O'Shaughnessy, an Irish scientist and physician, observed its use in India as an analgesic, anticonvulsant, antispasmodic, anti-emetic and hypnotic. After toxicity experiments on goats and dogs, he gave it to patients and was impressed with its muscle-relaxant, anticonvulsant and analgesic properties, and recorded its usefulness as an anti-emetic.

After these observations were published in 1842, medicinal use of cannabis expanded rapidly. It soon became available 'over the counter' in pharmacies and by 1854 it had found its way into the United States Dispensatory. The American market became flooded with dozens of cannabis-containing home remedies.

Queen Victoria's personal physician wrote (Reynolds, 1890), on the basis of more than 30 years' experience, that "Indian hemp, when pure and administered carefully, is one of the most valuable medicines we possess". He found it incomparable for "senile insomnia", "night restlessness" and "temper disease" in both children and adults, but not helpful in melancholia, "very uncertain" in alcoholic delirium, and "worse than useless" in mania. It was very effective in neuralgia, period pains, migraine, "lightning pain of the ataxic patient" and gout, but useless in sciatica and "hysteric pains".

He found it impressive in clonic spasms and certain epileptiform convulsions related to brain damage, but no good at all in petit mal or "chronic epilepsy", tetanus, chorea or paralysis agitans. It effectively relieved nocturnal cramps, asthma and dysmenorrhoea.

Reynolds was writing at a time when the zenith of cannabis as prescribed medicine and home remedy was already past. Although Sir William Osler was still recommending it for migraine sufferers in 1913, it was by then in steep decline because of variable potency of herbal preparations, poor storage stability, unpredictable response to oral administration, increasing enthusiasm for parenteral medicines and availability of potent synthetic alternatives, commercial pressures and American concern about recreational use.

Cannabis was outlawed in 1928 by ratification of the 1925 Geneva Convention on the manufacture, sale and movement of dangerous drugs. Prescription remained possible until final prohibition under the 1971 Misuse of Drugs Act, against the advice of the Advisory Committee on Drug Dependence.

In the USA, medical use was effectively ruled out by the Marijuana Tax Act 1937. This ruling has been under almost constant legal challenge and many special dispensations were made between 1976 and 1992 for individuals to receive 'compassionate reefers'.

Although this loophole has been closed, a 1996 California state law permits cultivation or consumption of cannabis for medical purposes, if a doctor provides a written endorsement. Similar arrangements apply in Italy and Canberra, Australia.

CANNABINOID PHARMACOLOGY RELEVANT TO THERAPEUTICS
Cannabinol was isolated in 1895 and cannabidiol in 1934, but the most significant discovery was that of [DELTA]9-tetrahydrocannabinol (THC) in 1964. Chromatographic and spectroscopic methods subsequently uncovered many closely related compounds.

Capsules of synthetic THC (dronabinol) have been available for restricted medical use in the USA since 1985. Nabilone, a synthetic THC analogue, was marketed in 1983 and is the only cannabinoid licensed for prescription in the UK, restricted to treatment of nausea and vomiting caused by cytotoxic chemotherapy unresponsive to conventional anti-emetics. Use in other indications is only possible on a 'named patient' basis if the drug is supplied by a hospital pharmacy.

In 1988, a specific protein receptor (known as CB1) for THC was discovered in mouse nerve cells. This mediates most of the central nervous system (CNS) responses to cannabinoids, and is abundant in basal ganglia, hippocampus and cerebellum, globus pallidus, substantia nigra and cerebral cortex. An endogenous ligand was identified in 1992 and labelled anandamide (ananda: 'bliss' in Sanskrit). Anandamide has analgesic and tranquillising effects in animals, is involved in muscle coordination and affects the secretion and function of certain hormones. Other endogenous agonists almost certainly exist.

In 1993, a second receptor (CB2) was identified in rat spleen macrophages, and this occurs only outside the CNS. There is scope for chemical manipulation of cannabinoids to maximise selectivity for CB2 and so avoid psychoactive effects. It is thought this receptor has relevance for anti-inflammatory and immunosuppressive activity.

Pertwee (1995) has suggested that the anandamide system might be concerned with mood, memory and cognition, perception, movement, coordination, posture and skeletal muscle tone, sleep, thermoregulation, appetite and immune response.

CLINICAL APPLICATIONS
Nausea and vomiting
Many cytotoxic drugs are powerful emetics, and this is the major limiting factor in patients' acceptance of cancer chemotherapy (see Table 1 and Appendix).


Graphic


Table 1 Human randomised controlled trials (RCTs): anti-emetic effects


Many recreational smokers receiving cancer chemotherapy have told their doctors that cannabis relieved their nausea (Grinspoon & Bakalar, 1993). Sallan et al's (1975) randomised control trial (RCT) compared oral THC and placebo in 22 cancer patients who had proved resistant to conventional anti-emetics.

 

Comparisons using patients' self-reports of nausea and vomiting demonstrated that THC was statistically superior to placebo. THC (10 mg/m2) produced euphoria in the majority of patients, and one-third experienced sedation.

Subsequent RCTs (listed in Table 1) confirmed that natural and synthetic THC is invariably superior to placebo. Comparisons with anti-emetics available in the 1970s and 1980s suggest that THC is either equivalent in effect or better.

A combination of prochlorperazine and THC was superior to either drug alone, and nabilone combined with prochlorperazine was better than dexamethazone plus metoclopramide. Although THC and nabilone produced more unwanted effects than comparison drugs, patients generally preferred them.

Children seem to respond well to nabilone and are tolerant of side-effects, but larger studies are required. [DELTA]8-THC performed well in a pilot study (Abrahamov et al, 1995) involving eight children aged 3-13 years with various blood cancers receiving chemotherapy, 60% of whom had experienced distressing vomiting despite treatment with metoclopramide. [DELTA]8-THC was given orally 2 hours before cytotoxics and repeated 6-hourly. No vomiting was recorded during this treatment and over the following 2 days.

Two children were "slightly irritable" and one also showed "slight euphoria".

In a review of 12 studies involving 600 patients (Penta et al, 1981), THC was "effective" in 8/9 and nabilone in 3/3. The most common side-effects were somnolence (33%), dry mouth (9%), ataxia (8%), dizziness (6%), dysphoria (6%), and orthostatic hypotension (4%). A further review (Levitt, 1986) incorporating 55 studies, of which 32 were RCTs, showed that low-dose preventive treatment gives better results than targeting established vomiting. Younger patients may respond better than older ones.

Meta-analysis (Plasse et al, 1991) suggested that an optimal balance of efficacy and unwanted effects was achieved with relatively modest doses (7 mg/m2 or less).

Sedation and psychotropic symptoms are commonly reported, but are usually mild to moderate in intensity and resolve rapidly on discontinuation. No "persistent or fatal" adverse effects have been reported. Many American oncologists encourage nauseous patients to try cannabis and would prescribe it if it were legal (Doblin & Kleiman, 1991). Mode of action remains uncertain.

Multiple sclerosis and other neurological conditions


Drug therapy of muscle spasticity is generally only moderately effective and is limited by adverse effects (see Appendix). Spasticity is a central feature of multiple sclerosis (MS), cerebral palsy and spinal cord injury. Tremor, ataxia and incontinence also contribute to the high incidence of anxiety and depression in these conditions.

Cannabis was often used to treat pain, muscle spasm, cramps and ataxia in the 19th century, and many modern sufferers have reported benefits (Grinspoon & Bakalar, 1993).

Most respondents to a questionnaire sent to British and American MS patients reported problems with symptom control (Consroe et al, 1997). Those who smoked cannabis claimed improvements in night-time spasticity and muscle pain (91-98%); night leg pain, depression, tremor, anxiety, spasms on walking, paraesthesiae (80-89%); leg weakness, trunk numbness, facial pain (71-74%); impaired balance (57%); constipation (33%); memory loss (31%).

In a small single-blind comparison with placebo (Clifford, 1983), THC improved tremor and ataxia in most patients. All experienced a 'high' at the top dose (15 mg), and two reported dysphoria. Dose-related improvements in dystonia were noted in five patients given cannabidiol 100-600 mg daily for 6 weeks. Hypotension, dry mouth, sedation and light-headedness occurred but were described as mild. Parkinsonian symptoms were aggravated in two subjects.

An RCT by Petro & Ellenberger (1981) compared the effects of placebo and THC in doses of 5 or 10 mg on muscle tone, reflexes and muscle power in nine MS patients. Both doses of THC reduced spasticity (P < 0.005). One patient receiving THC 10 mg and one patient receiving placebo felt 'high' but no other side-effects were recorded. In a small RCT (Ungerleider et al, 1987) with 5-day treatment periods, THC 7.5 mg significantly improved spasticity in comparison with placebo.

Nabilone 1 mg on alternate days was compared with placebo in a double-blind randomised crossover trial with 4-week treatment periods in a single MS patient. Nocturia, muscle spasm and general well-being showed striking improvement during each active treatment period. Mild sedation was noted on active medication.

Cannabidiol had no beneficial effects in 15 patients with Huntington's disease (Consroe et al, 1991). Posture and balance were impaired by a single dose of smoked THC in 10 MS patients and 10 non-MS volunteers (Greenberg et al, 1994), but there was no active control to determine the effects of standard anti-spastic medication in this model.

Possible sites of action of cannabinoids in dystonia include basal ganglia, cerebellum, spinal motor neurons, somatic nerves and neuromuscular junction.

Loss of appetite and weight in cancer and AIDS
Several studies have investigated effect on appetite and weight (Table 2). The appetite-stimulating effect of cannabis was confirmed in fasting and non-fasting volunteers in an RCT of oral THC with alcohol, amphetamine and placebo (Hollister, 1971). A standardised THC smoking regime over 25 days in a residential laboratory was associated with significant increases in calorie intake and frequency of eating occasions in comparison with placebo.


Graphic


Table 2 Human randomised controlled trials (RCTs): appetite and weight


Open studies in cancer patients also showed appetite improvements and slowing of weight loss. Regelson et al's (1976) RCT explored the effect on appetite (and mood) of oral THC in 54 cancer patients over a 2-week period. There were nine with-drawals due to side-effects (six in THC period - dizziness, disassociation, confused thinking, panic, "feelings of disturbance"; three in the placebo period - anxiety, fits, dizziness, lethargy, weakness).

 

Patients receiving THC in the first period gained weight (P<0.05), and those receiving placebo first showed reduced weight loss on transfer to THC (P<0.05). Depression, tranquillity and "forthrightness" scores all improved on THC. In a quarter of the patients, somnolence, dizziness and disassociation were severe enough to negate these effects.

Many people with AIDS have claimed that smoking marijuana inhibits nausea, improves appetite, reduces anxiety, relieves aches and pains, improves sleep and inhibits oral candidiasis. A small pilot study supported the hypothesis that dronabinol might reduce weight loss or even promote weight gain (Plasse et al, 1991).

Beal et al (1995) conducted an RCT over 42 days of treatment with dronabinol 5 mg daily in 139 AIDS patients who had lost at least 2.3 kg. Six receiving dronabinol and three receiving placebo withdrew because of "perceived drug toxicity".

Dronabinol boosted appetite in comparison to placebo (P<0.015) and nausea was reduced (P=0.05). Improvement in mood was a strong trend (P=0.06) and there was a tendency toward weight gain (P=0.1). Dronabinol produced more adverse effects than placebo (P<0.001), but 75% of these were mild or moderate. Most frequent were euphoria (9), dizziness (5), thinking abnormalities (5) and sedation (4).

Further investigation is amply justified. Careful monitoring of possible effects upon the immune system is needed, although a prospective multi-centre study (Kaslow et al, 1989), which followed nearly 5000 HIV-positive men for 18 months, showed no link between use of psychoactive substances and mean T-cell counts or progression to AIDS.

Pain
Cannabinoids are effective analgesics in animal models with non-opiate mechanisms predominating. There are many anecdotal reports (Grinspoon & Bakalar, 1993) of benefits in bone and joint pain, migraine, cancer pain, menstrual cramps and labour.

Five small RCTs (Table 3) show that THC is significantly superior to placebo and produces dose-related analgesia peaking at around 5 hours, comparable to but out-lasting that of codeine. Side-effects were also dose-related, and consisted of slurred speech, sedation and mental clouding, blurred vision, dizziness and ataxia. Levonantradol was also superior to placebo and notably long-acting, but almost half the patients reported sedation. Cannabinoids may have considerable potential in neuropathic pain (Institute of Medicine, 1999).


Graphic

Table 3 Human randomised controlled trials (RCTs): pain

Raised intra-ocular pressure
Glaucoma due to obstructed outflow of aqueous humour or anatomical eye defects is the most common cause of blindness in the Western world. Some RCTs investigating this area are given in Table 4.


Graphic

Table 4 Human randomised controlled trials (RCTs): raised intra-ocular pressure (IOP)

There have been many anecdotal reports that street marijuana can relieve glaucoma symptoms and individuals have successfully argued in the USA for legal access to the drug (Grinspoon & Bakalar, 1993). A pilot study of smoked marijuana and oral THC (15 mg) in 11 glaucoma patients found an average intra-ocular pressure (IOP) reduction of 30% in seven subjects and no response in four (Hepler et al, 1976).

Randomised controlled trials in volunteers confirmed that oral, injected or smoked cannabinoids produce dose-related reductions of IOP (Hepler et al, 1976; Perez-Reyes et al, 1976). Conjunctival engorgement and tear reduction were often noted. THC, [DELTA]8-THC and 11-hydroxy-THC are more effective than cannabinol, while cannabidiol was without effect. Tolerance may develop on multiple dosing.

An RCT in patients showed IOP reductions of similar magnitude following smoked THC along with "alterations in mental status" and tachycardia (Merritt et al, 1980). THC eyedrops produced dose-related IOP reduction with minimal side-effects though parallel reductions in the untreated eye (also seen in animal models) suggested a systemic rather than local mode of action.

Insomnia, anxiety and depression
Randomised controlled trials investigating insomnia, anxiety and depression are given in Table 5.


Graphic


Table 5 Human randomised controled trials (RCTs): insomnia, anxiety, depression


Nabilone (1 mg three times daily) produced "dramatic improvements" on the Hamilton Anxiety Scale in 20 anxious patients in comparison to placebo (P<0.001), which were mirrored by other measures (Fabre & McLendon, 1981). Seven days into the study, nabilone patients' anxiety scores were halved, and this persisted unchanged throughout treatment.

 

Side-effects included dry mouth, dry eyes and drowsiness. The authors concluded that nabilone is a "very effective anxiolytic deserving of further study". In a cross-over comparison of nabilone (1-2.5 mg twice daily) and placebo in 11 anxious patients (Ilaria et al, 1981), significant improvements in anxiety scores (P<0.05) were again noted.

The only clinically significant adverse effect was postural hypotension with related dizziness, light-headedness or weakness. This was dose-related, experienced by most patients, and tended to tolerate out over time.

Preliminary data suggest that cannabidiol (160 mg) may be an effective hypnotic, and that THC (0.1 mg/kg) may have antidepressant properties in cancer patients and others (Grinspoon & Bakalar, 1993).

Epilepsy
Epilepsy afflicts 1% of the world's population. Conventional anticonvulsants provide unsatisfactory control for up to 30% of patients, and all can produce disabling or even life-threatening adverse effects.

The effect of cannabinoids on seizure activity in laboratory animals is complicated. Cannabidiol is a powerful anti-convulsant free of tolerance, but its profile varies between species. THC can produce seizures in big doses or when genetically seizure-sensitive animals are used, yet it is also robustly anticonvulsant in certain seizure models.

A lack of stereospecificity suggests that the mechanism may not be related to a single receptor interaction. Serotonin, [gamma]-aminobutyric acid, acetylcholine or prostaglandin systems may be involved.

There are many anecdotal reports of beneficial effects in humans with epilepsy (Grinspoon & Bakalar, 1993) but research data are virtually non-existent. Two single-case reports (Keeler & Reifler, 1967; Consroe et al, 1975) give confounding information.

A young man suffered seizures on his regular medication and began smoking several cannabis cigarettes nightly alongside this. No further seizures occurred while this combination was maintained. In contrast, a man with grand mal epilepsy stopped taking anticonvulsants and suffered no fits for 6 months.

He then smoked cannabis on seven occasions over a 3-week period and suffered three fits during this time, although not coincident with actual intoxication.

Only one RCT (Cunha et al, 1980) exists. Fifteen poorly controlled patients with secondary generalised epilepsy continued with their regular therapy but were also given either cannabidiol or placebo daily for up to 4.5 months while undergoing regular clinical and electroencephalogram evaluation. Half the patients on cannabidiol remained "almost free" of fits throughout the experiment, and all but one of the others showed "partial improvement". All but one of the placebo patients remained entirely unchanged. Somnolence occurred in four patients receiving cannabidiol.

Asthma
Small-scale controlled studies in volunteers with asthma show that oral, smoked and aerosolised THC has comparable bronchodilatory activity to salbutamol, although onset is quicker with the latter. Dose-related tachycardia occurred in some individuals, and subjective intoxication with higher doses.

A THC aerosol was free of systemic unwanted effects, but was irritant to the lungs (Tashkin et al, 1977). Nabilone does not produce bronchodilation. Since THC-induced bronchodilation is not mediated through the sympathetic nervous system, synergistic combinations with [beta]2-adrenoceptor stimulants might be possible.

Other possible therapeutic applications
Basic research indicates that THC and analogues inhibit opioid withdrawal (Chesher & Jackson, 1985). Anecdotal reports from patients also point to beneficial effects beyond those which could be accounted for by sedative or hypnotic activity.

Cannabinoids inhibit primary tumour growth and increase survival in animal tumour models (Harris et al, 1976) by an unknown mechanism. They also show antipyretic and anti-inflammatory activity (Formukong et al, 1989). Mechoulam (1986) has drawn attention to the lack of modern research directed at possible antihelmintic, antimigraine and oxytocic applications.

DISCUSSION
Therapeutic profile on existing evidence
Tetrahydrocannabinol and nabilone are effective anti-emetics but there are no comparisons with 5-HT3 antagonists, so a role in modern anti-emetic regimes remains to be determined. Currently, only nabilone is licensed in the UK and available for prescription and research.

THC (as dronabinol) has recently been rescheduled to permit prescription but remains unlicensed and must be specially imported on a named-patient basis.

Delta-8-THC looks worthy of further investigation, particularly in children, and is much simpler to synthesise than THC.

Many individuals with MS have claimed a benefit from cannabis and small controlled trials support this, although effect upon posture and balance requires clarification. THC is an effective analgesic at the expense of sedation with larger doses and may have special merit in neuropathic pain.

No conclusions are possible as yet about anticonvulsant potential. Some cannabinoids reduce IOP, though side-effects of products currently available limit application and effects of tolerance are uncertain. The mechanism for bronchodilation probably differs from that of [beta]2-stimulants, so synergistic combinations may be possible.

Cannabis and THC are effective appetitc stimulants. Alongside anti-emetic, analgesic, anxiolytic, hypnotic and antipyretic properties this suggests a unique role in alleviating symptoms in selected patients with cancer or AIDS.

This is a compelling area for future research, although possible effects upon immune function require careful monitoring.

Optimal doses and routes of delivery have not been established. Absorption by the oral route is unreliable. Smoking the drug is generally not a viable option since advantages such as rapid onset, accurate titration of effects and reliability in patients who are vomiting have to be set against the likelihood of lung irritation or damage, and it would in any case be unacceptable to most patients. However, pending availability of more satisfactory preparations,

I believe that the existing profile of efficacy and toxicity justifies the provision of a legal supply of standardised herbal material ('compassionate reefers') to patients with terminal conditions who currently obtain relief with street cannabis. Sublingual sprays or tablets, nebulisers and aerosols look promising for the future, and THC is effective by the rectal route. Many potentially active cannabinoids have yet to be investigated and the recent identification of a peripheral receptor may lead to new drugs devoid of central nervous system effects.

Cannabis arouses passion in those who support or condemn it, and few people approach the clinical literature with dispassionate objectivity.

Poorly controlled research produces ambiguous results which are then interpreted according to the prejudices of the reader. Anecdotes seem to be more readily accepted when they point to adverse rather than positive effects (Hall et al, 1994).

Yet the known adverse effects of oral cannabinoids are rarely intolerable or life-threatening, in contrast to those associated with some standard therapies. A British Medical Association survey indicated that many UK doctors believe that cannabis should once again be available on prescription (Meek, 1994).

The way forward
A Select Committee of the House of Lords recently examined the scientific information concerning medical cannabis and took verbal and written evidence from a wide range of witnesses.

Their conclusion (House of Lords, 1998) published in November 1998, was that, although cannabis should remain a controlled drug, the law should be changed to allow doctors to prescribe "an appropriate preparation of cannabis if they saw fit". The government rejected this recommendation on the day of publication.

Under the auspices of the Royal Pharmaceutical Society, large-scale multi-centre trials are under way to explore further the efficacy of cannabinoids in relieving spasticity and postoperative pain.

A pharmaceutical company has obtained a licence to cultivate medicinal cannabis on a large scale in the UK.

By selecting a specific genotype then carefully controlling all other relevant variables such as soil conditions, temperature and humidity, it is possible to obtain levels of purity in plant extracts equal or superior to those of 'pure' synthetic cannabinoids.

Most of the 60 or so naturally occurring cannabinoids are present in tiny amounts, and synthetic cannabinoids such as nabilone themselves contain up to 5% impurities, some of which are of unknown identity.

Whether obtained by synthetic means or by plant extraction, it is essential that cannabinoids for prescription and research in the future should demonstrate excellent purity, stability and bioavailability.

The medicinal properties of cannabis are still mainly delineated by the anecdotal reports of those who believe their symptoms are relieved by its use, and these accounts are often dismissed as wishful thinking or even mischievous.

Since the conventional treatments for many of these disorders are both toxic and relatively ineffectual, a more constructive response would be to expose such claims to careful scientific examination and, in the meantime, search for a way to avoid criminalising those who seek only to assuage their own suffering.

CLINICAL IMPLICATIONS
* Cannabis and its derivatives show promise of beneficial effects in a number of medical conditions for which standard treatment is less than satisfactory, and further controlled research is fully justified.
* Cannabis is very safe in overdose, but often produces unwanted effects which are better tolerated by patients with some conditions (e.g. multiple sclerosis, chronic pain, AIDS, cancer) than others (e.g. glaucoma).
* Optimal for mutations, doses and routes of delivery have not yet been established.

LIMITATIONS
* Because of imposed time constraints, the review is not fully comprehensive, although all accessed sources were incorporated.
* Much of the evidence is anecdotal, and many of the research studies cited have serious methodological shortcomings.
* Few researchers (or reviewers) approach the subject of cannabinoid therapeutics in a spirit of dispassionate objectivity.

ACKNOWLEDGEMENT
This review was originally commissioned and funded by the Department of Health. The author thanks Dr Anthony Thorley for his support and encouragement. The views expressed in the paper are those of the author and not necessarily of the Department of Health.

APPENDIX
Existing anti-emetics
Phenothiazzines and butyrophenones can cause sedation, movement disorders which may be irreversible, neuroleptic malignant syndrome, dry mouth, blurred vision, urinary retention, hypotension, allergic reactions, jaundice, hypothermia, hormonal disturbances, irreversible eye damage and, rarely, life-threatening anaemias. Domperidone has a more benign profile but is not recommended for long-term use. Metoclopramide produces movement disorders (1% of patients), dizziness and drowsiness. Selective 5-HT3 antagonists (ondansetron, granisetron) are newer and more expensive. Side-effects include constipation, headache, flushing, liver enzyme changes, allergic reactions, visual disturbances, chest pain and dysrhythmias.

Existing neurological treatments
Baclofen alleviates spasticity, but may accentuate muscle weakness. It produces dose-related nausea and vomiting, drowsiness, vertigo, confusion, fatigue and hypotonia. Less commonly, fits, psychiatric disorder and hypotension occur. Sudden withdrawal can cause hallucinations.

Diazepam is useful but can worsen weakness or incoordination and cause drowsiness; ataxia, depression, disinhibition and dependence. Dantrolene may cause weakness, hypotonia, drowsiness, dizziness, vertigo and anxiety. Rarely, it damages the liver, and is not recommended in those with co-existing heart or lung disease.

Existing glaucoma treatments
Eye-drops. Miotics can produce blurring of vision, headache, and parasympathetic effects including sweating, bradycardia, colic and bronchospasm. Adrenaline often causes local discomfort. Dipivefrine and guanethicline may cause conjunctival fibrosis on chronic use. Beta-blockers may cause bradycardia, heart block or bronchoconstriction.

Systemic drugs (acctazolamide, dichlorphenamide) can cause hypokalaemia, appetite suppression, paraesthesiae, drowsiness, depression, rashes and, rarely, bone marrow suppression. [Context Link]

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Pomeroy, M., Fennelly, J. J. & Towers, M. (1986) Prospective randomized double-blind trial of nabilone versus domperidone in the treatment of cytotoxic-induced emesis. Cancer Chemotherapy and Pharmacology, 17, 285-288.

Regelson, W., Butler, J. R., Schuiz, J., et al (1976) Delta-9-THC as an effective antidepressant and appetite-stimulating agent in advanced cancer patients. In The Pharmacology of Marihuana (eds M. C. Braude & S. Szara), pp. 763-775. New York: Raven Press. [Context Link]

Reynolds, J. R. (1890) Therapeutic uses and toxic effects of cannabis indica. Lancet, i, 637-638. [Context Link]

Sallan, S. E., Zinberg, N. E. & Frei, E. 3rd (1975) Antiemetic effect of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy. New England Journal of Medicine, 293, 795-797. [Context Link]

Tashkin, D. P., Reiss, S., Shapiro, B. J., et al (1977) Bronchial effects of aerosolized delta-9-THC in healthy and asthmatic subjects. American Review of Respiratory Disease, 115, 57-65. [Context Link]

Ungerleider, J. T., Andrysiak, T., Fairbanks, L., et al (1982) Cannabis and cancer chemotherapy: a comparison of oral delta-9-THC and prochlorperazine. Cancer, 50, 636-645.

Ungerleider, J. T., Andrysiak, T., Fairbanks, L., et al (1987) Delta-9-THC in the treatment of spasticity associated with multiple sclerosis. Advances in Alcoholism and Substance Abuse, 7, 39-50. [Context Link]

 


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US Patent 4189491 - Tetrahydrocannabinol in a method of treating glaucoma

Patent References

3668224

3728360

3734930

3799946

3920809

Tri-cyclic compounds derived from thiaphloroglucinol ethers

 

Abstract

Significant success in alleviating the symptoms of glaucoma is achieved by orally administering to a glaucoma sufferer a therapeutically effective, but sub-psychotropic dose of tetrahydrocannabinol (THC), which is the most active ingredient in marijuana.


 The most significant results are achieved when this form of treatment is combined with conventional types of anti-glaucoma treatment, although in a limited number of cases, THC therapy alone proved successful.

Also disclosed is a dosage unit form for THC comprising a suitable dose of THC in combination with an innocuous diluent such as fructose.

Other References

  • The Merck Index, 8th ed. pp. 830, 831 and 833 (1968) Merck & Co
  • Ophthalmologica 168 366-369 (1974)--D. Shapiro--The Ocular Manifestations of the Cannabinols, Newsweek, 11/8/76, Pot and Glaucoma
  • Chem. Abst. 83 158,044(r) (1975)--Purnell et al. "A9 -Tetrahydrocannabinol . . . in Man"
  • Chem. Abst. 84 130,270(h) (1976)--Green et al. Interaction of . . . Tetrahydrocannabinol in the Eye"

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Reduction of Congenital Nystagmus in a Patient after Smoking Cannabis

Pradeep A, Thomas S, Roberts EO, Proudlock FA, Gottlob I

Strabismus 2008 Mar; 16(1):29-32.

Introduction: Smoking cannabis has been described to reduce acquired pendular nystagmus in MS, but its effect on congenital nystagmus is not known.
Purpose: To report the effect of smoking cannabis in a case of congenital nystagmus.


Methods: A 19-year-old male with congenital horizontal nystagmus presented to the clinic after smoking 10 mg of cannabis. He claimed that the main reason for smoking cannabis was to improve his vision.

At the next clinic appointment, he had not smoked cannabis for 3weeks. Full ophthalmologic examination and eye movement recordings were performed at each visit.
Results: Visual acuity improved by 3 logMar lines in the left eye and by 2 logMar lines in the right eye after smoking cannabis. The nystagmus intensities were reduced by 30% in primary position and 44%, 11%, 10% and 40% at 20-degree eccentricity to the right, left, elevation and depression, respectively, after smoking cannabis.


Conclusion: Cannabis may be beneficial in the treatment of congenital idiopathic nystagmus (CIN). Further research to clarify the safety and efficacy of cannabis in patients with CIN, administered for example by capsules or spray, would be important.

 

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Cannabinoids and glaucoma

 
Br J Ophthalmol. 2004 May; 88(5): 708–713.
PMCID: PMC1772142

CONJUGATE DEVIATION OF THE EYES AFTER Cannabis indica INTOXICATION

 
Br J Ophthalmol. 1964 March; 48(3): 160–161.
PMCID: PMC505931

Endocannabinoids in the retina: From marijuana to neuroprotection

Yazulla SProg Retin Eye Res 2008 Aug 3.

The active component of the marijuana plant Cannabis sativa, Delta(9)-tetrahydrocannabinol (THC), produces numerous beneficial effects, including analgesia, appetite stimulation and nausea reduction, in addition to its psychotropic effects. THC mimics the action of endogenous fatty acid derivatives, referred to as endocannabinoids.

The effects of THC and the endocannabinoids are mediated largely by metabotropic receptors that are distributed throughout the nervous and peripheral organ systems.

There is great interest in endocannabinoids for their role in neuroplasticity as well as for therapeutic use in numerous conditions, including pain, stroke, cancer, obesity, osteoporosis, fertility, neurodegenerative diseases, multiple sclerosis, glaucoma and inflammatory diseases, among others. However, there has been relatively far less research on this topic in the eye and retina compared with the brain and other organ systems.

The purpose of this review is to introduce the "cannabinergic" field to the retinal community. All of the fundamental works on cannabinoids have been performed in non-retinal preparations, necessitating extensive dependence on this literature for background.

Happily, the retinal cannabinoid system has much in common with other regions of the central nervous system.

For example, there is general agreement that cannabinoids suppress dopamine release and presynaptically reduce transmitter release from cones and bipolar cells. How these effects relate to light and dark adaptations, receptive field formation, temporal properties of ganglion cells or visual perception are unknown.

The presence of multiple endocannabinoids, degradative enzymes with their bioactive metabolites, and receptors provides a broad spectrum of opportunities for basic research and to identify targets for therapeutic application to retinal diseases.

 

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The role of endocannabinoid system in physiological and pathological processes in the eye

Nadolska K, Goś R

Klin Oczna 2008; 110(10-12):392-6.

Plant of Cannabis sativa/ marihuana except for its psychotropic effects possesses a range of pharmacological properties, that has been utilized for medical purposes over a period of millenia. Investigations concerning biochemical mechanism of action of the main and most active pharmacological compound of Cannabis sativa, cannabinoid 9-THC, contributed to the discovery of cannabinoid receptors both in the central nervous system (CNS) and peripheral tissues, that mediated actions of this substance.

The discovery made possible identification of a new, endogenous signaling system reffered to as the endocannabinoid system. Besides cannabinoid receptors CB1 and CB2, the system includes it's endogenic ligands (endocannabinoids) and compounds that participate in their biosynthesis and inactivation.

Structure and functioning of the endocannabinoid system is conservative in all vertebrates. It's activation with plant, synthetic and endogenous cannabinoids has an influence on multiple physiological and pathological processes within the eye.

 

 

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Marijuana Smoking vs Cannabinoids for Glaucoma Therapy


Keith Green, PhD, DSc

Arch Ophthalmol. 1998;116:1433-1437.

ABSTRACT



Objective  To discuss the clinical effects, including toxicological data, of marijuana and its many constituent compounds on the eye and the remainder of the body. A perspective is given on the use of marijuana and the cannabinoids in the treatment of glaucoma.

Results  Although it is undisputed that smoking of marijuana plant material causes a fall in intraocular pressure (IOP) in 60% to 65% of users, continued use at a rate needed to control glaucomatous IOP would lead to substantial systemic toxic effects revealed as pathological changes.

Conclusions  Development of drugs based on the cannabinoid molecule or its agonists for use as topical or oral antiglaucoma medications seems to be worthy of further pursuit. Among the latter chemicals, some have no known adverse psychoactive side effects. Smoking of marijuana plant material for the reduction of elevated IOP in glaucoma is ill-advised, given its toxicological profile.



INTRODUCTION


 


PREVIOUS REVIEWS of the ocular and toxic effects of marijuana have provided considerable background on general human responses. Use of marijuana for medicinal purposes decreased markedly in Western civilizations during the 1930s and 1940s, due to the variable potency of these herbal preparations and the parallel development of specific medications that were more potent and targeted toward specific symptoms.

This philosophical alteration in medical therapy reflected changes that occurred in all branches of medicine. Only in the latter part of this century has marijuana been used as a pleasure-inducing substance during liberalization of ethics and social behavior in many cultures. After tobacco, alcohol, and caffeine, it is probably the most widely used drug in society.

More recently, legislation has been passed by certain states (with subsequent revocation in 1 state) that has led to a resurgence of interest in the evaluation of possible medical uses of marijuana. Extensive evaluations have resulted in 1 report to the director of the National Institutes of Health, and will result in another from the Institute of Medicine of the National Academy of Sciences. Furthermore, a meeting on this topic held in March 1998 at New York University School of Medicine, New York, will result in publication of a book in the spring of 1999. In many areas of interest, there is little but anecdotal material on which to rely, but in the area of glaucoma, there exists a substantial literature.


MEDICAL EFFECTS


 


A number of health hazards of marijuana have been identified, but some are difficult to document completely. Acute effects are increased pulse rate, orthostatic hypotension, euphoria, and conjunctival hyperemia.

Long-term clinical effects in humans include respiratory, hormonal, and pulmonary toxic effects, although effects on many other organ systems, including the brain, have been noted. Marijuana smoking leads to emphysemalike lung changes that are caused by the products of marijuana burning (ie, cannabinoids) or through the release of tars, carcinogens, and other volatile materials, as occurs with tobacco smoke.

The latter products, however, occur in greater concentration than in tobacco smoke. The cognitive effects induced by marijuana are of equal concern; these assume greater relevance with chronic, repetitive exposure, especially in the age group in which glaucoma is most prevalent. These factors must be considered when potential chronic use of cannabis is considered as a treatment.

This is especially true of glaucoma, where continuous use would be necessary to control this 24-hour-a-day disease, requiring as many as 2920 to 3650 marijuana cigarettes per year.

The widespread effects of the cannabinoids and marijuana on many biological systems have been attributed to direct effects on certain biochemical processes, perturbations in cell membranes, or attachment to 1 of the 2 identified cannabinoid receptors, CB1 and CB2. The CB1 receptor is located in the central nervous system, whereas CB2 receptors occur in immune system tissues, such as spleen.

Through use of cannabinoid agonists such as WIN5512-2 and methanandamide, identification of cannabinoid receptors, and evaluation of their role in reflecting the biological activity of the cannabinoids, a better and more complete picture has arisen of the effects of these compounds.


OCULAR EFFECTS


 


Inhalation of marijuana smoke or smoke of cigarettes laced with {Delta}9-tetrahydrocannabinol ({Delta}9-THC), intravenous injection of cannabinoids, or ingestion of {Delta}9-THC or marijuana ("brownies") causes conjunctival hyperemia and decreased lacrimation. Ocular side effects include diplopia, impairment of accommodation, photophobia, nystagmus, and blepharospasm.

The ocular effects of long-term marijuana inhalation seem to be similar. Pupillary effects appear to differ depending somewhat on the circumstances of marijuana intake.

Different cannabinoids reduce intraocular pressure (IOP) in about 60% to 65% of humans, and marijuana and {Delta}9-THC (inhaled or taken orally) also decrease IOP in the same percentage of nonglaucomatous volunteers and of volunteer patients with glaucoma. Orthostatic hypotension and 50% decreased lacrimation occur quickly after inhalation of 2% {Delta}9-THC cigarettes, as noted with a synthetic THC homolog.

An apparent dose-response relationship occurred between cannabinoids or marijuana and IOP when groups were evaluated. Although the peak fall in IOP was dose related, the time of maximal change was unchanged. The IOP fell, on average, by about 25% (range, -45% to +5%) after smoking 2% marijuana through a water-cooled pipe. Duration of the reduction of IOP is about 3 to 4 hours, by which time the IOP approaches the presmoking level.

The major difficulty with marijuana smoking was to separate the reduction in IOP and the euphoric effect. These findings confirmed the physiological and pharmacological effects found in experimental animals after intravenous drug administration.

Studies in patients with primary open-angle glaucoma (POAG) indicated a reduction of IOP in 60% to 65% of the population after marijuana smoking or {Delta}9-THC ingestion. Seven of 11 patients in 1 study showed a reduction in IOP of about 30% after smoking 2% marijuana cigarettes.

More quantities of oral drug or marijuana were needed compared with inhaled drug, presumably due to the poorer absorption by the former route.

About 300 volunteers (nonglaucomatous subjects or patients with POAG) overall have participated in studies to examine the acute effects of marijuana smoking or cannabinoid use (topical, oral, or intravenous).

Since the largest individual group was about 40 persons, this constitutes a large number of groups and a range of conditions under which marijuana or 1 of its constituents reduced IOP.

Topical {Delta}9-THC was examined in rabbits, dogs, and primates for pharmacological activity and toxic effects before being tested in humans.

The best vehicle identified for delivery of the lipophilic agent in the early 1980s has been superseded by vehicles that permit internalization of lipid-soluble compounds into other materials that are themselves water soluble. This provides an excellent delivery mode of a lipophilic drug through the aqueous tear environment to the lipid corneal epithelium.

Other approaches have entailed water-soluble esters of a maleate salt of a {Delta}9-THC–related compound. This prodrug approach offers a new modality for encouraging greater drug penetration to the site of action.

The development of nonpsychoactive, cannabinoid-related drugs also has resulted in separation of IOP reduction from euphoric effects, at least in experimental animal tests, and holds promise for more future developments. In humans, {Delta}9-THC drops were ineffective in reducing IOP in single- or multiple-drop studies, due to the induction of ocular irritation. This effect was revealed only in humans.


MARIJUANA SMOKING AS TREATMENT FOR GLAUCOMA


 


Use of marijuana smoking as a treatment for glaucoma is not desirable for several reasons. Although drug absorption is maximum with smoking, and the user or patient can titrate the drug to a level of euphoria indicative of a pharmacological response, this approach is poor.

The pathological effects on the lung already described, exposure to carcinogens, and the other pulmonary and respiratory changes at the organ and cellular levels all make smoking a nonviable mechanism. The systemic toxic effects that result in pathological changes alone seem sufficient to discourage smoking marijuana.

Primary open-angle glaucoma is a 365-day-a-year disease, and since the marijuana-induced fall in IOP lasts only 3 hours, the drug consumption conceivably needed to reduce and keep IOP at a safe level would be very high.

The IOP is the only readily measurable parameter that one can use as an index of POAG and is still the major indicator of what is essentially a neuropathogenic disease.

No indication has been obtained or reported that those highly limited number of persons who consume marijuana cigarettes as a compassionate investigational new drug have shown any maintenance of visual function or visual fields or stabilization of optic disappearance.

Since marijuana reduces IOP for 3 to 4 hours, after which the IOP returns to baseline, control of IOP at a significantly lowered value, including maintenance of IOP at a 2-hour minimal low value, requires a marijuana cigarette to be smoked 8 or l0 times a day (by those persons in whom IOP actually decreases).

This use corresponds to at least 2920 and as many as 3650 marijuana cigarettes consumed per year. It is difficult to imagine anyone consuming that much marijuana and being a productive individual who is incorporated into society and perhaps operating machinery or driving on the highways.

Similarly, the systemic end-organ effects at this level of consumption have the potential of being quite high. On the other hand, the availability of once- or twice-a-day eye drops ({beta}-blockers such as timolol maleate, or the prostaglandin agonist latanoprost) makes IOP control a reality for many patients and provides round-the-clock IOP reduction.

Glaucoma treatment requires a round-the-clock reduction in IOP, and treatments are evaluated as successful if this level of activity is achieved without progression of visual field loss or optic disc changes.

There has been considerable press coverage of the use of marijuana as an antiemetic or as treatment for glaucoma.

Dangers arise from 2 considerations of the latter. First, intermittent use would lead to a lack of IOP reduction on a continued basis, thereby permitting visual function loss to proceed. Second, full use of enough smoked marijuana leads to the need, as described above, of an average of at least 3300 cigarettes per year.

Advocates of the latter approach often cite using marijuana for the relief of symptoms, whereas POAG has no symptoms until too late, when vision is irreversibly lost.

The advocates of marijuana smoking for glaucoma treatment also must contend with the lack of standardization of the plant material.

The 480 chemicals, including 66 cannabinoids, in marijuana vary depending on the site and circumstances of growth and certainly vary in content depending on which plant part is smoked.

This variability goes counter to the requirements of the Food and Drug Administration, Washington, DC, concerning the chemical identity and performance characteristics of specific drugs. Indeed, dronabinol (Marinol), an oral form of {Delta}9-THC, is approved by the Food and Drug Administration for the treatment of chemotherapy-induced nausea and acquired immunodeficiency syndrome wasting syndrome.

Further, despite attempts by individual states to change their laws, marijuana remains a schedule 1 controlled substance, and federal law prevails.

Lastly, there is an increasing movement at the federal and state levels to confine tobacco smoking to highly restricted areas to reduce smoking and the exposure of nonsmokers to second-hand smoke.

In the face of this societal change, it is difficult to advocate increased smoking, particularly of marijuana, in settings where smoking is normally banned.


CANNABINOIDS FOR GLAUCOMA TREATMENT


 


Oral or topical cannabinoids show promise for future use in glaucoma treatment. Newer topical delivery technologies are available for these lipophilic drugs, including the formation of microemulsions and use of cyclodextrins to increase the solubility in aqueous-based solutions.

This is a marked improvement over the lipid-based vehicles that were the only ones available during earlier basic and clinical studies of topical cannabinoids.

The development of compounds related to {Delta}9-THC, such as HU211 (dexanabinol), that show a complete absence of euphoric effects while retaining IOP-reducing activity is a major advance. Increasing knowledge concerning the topical cannabinoid receptors and ligands that reduce IOP in rabbit or monkey eyes will allow exploration of different structural analogs that may identify compounds efficacious as potential glaucoma medications.

Topical administration also has the advantage of permitting the use of a low mass of drug per delivery volume. Even at 5% concentration, a 30-µL drop would contain only 1.5 mg.

Oral administration of cannabinoids that lack psychoactive effects but will reduce IOP could be a significant addition to the ophthalmic armamentarium against glaucoma. The cannabinoids that exist in the plant material or as metabolites do not appear to be viable candidates for oral use because of the inability to separate their euphoric and IOP-reducing effects.

Because they are readily characterized from a chemical perspective, the cannabinoids and related substances represent an area of focus for future studies. Such attention would allow the development of appropriate vehicles for these chemicals into the predominantly aqueous environment of the tears.

Compounds would be identified that have no euphoric effects or at least a very high ratio of IOP reduction to euphoric effects.

Such chemicals would eliminate any potential abuse problems while providing drugs that would reduce IOP by unique interaction with receptors or other membrane components that could be additive to other currently available glaucoma medications. In experiments where the action of cannabinoids in causing an IOP reduction has been sought, evidence points to an influence on increasing outflow of fluid from the eye as the major component.

This is true for {Delta}9-THC and HU211, although the binding of each of these compounds to the cannabinoid receptor differs widely. The rapidity of onset of the responses strongly suggests that an effect is occurring that can undergo rapid adjustment rather than be related to slow alterations in trabecular meshwork glycoproteins.

The perspective presented herein differs in several ways from the conclusions reached by the National Institutes of Health–assembled panel to provide a written report on medicinal use of marijuana.

The primary difference is the focus of research efforts, which the panel concluded should have marijuana smoking as its delivery mode, whereas my review recommends cannabinoids. The reasons for this divergence of opinion are given and, I believe, are compelling for glaucoma studies to focus on individual chemicals rather than a nonstandardized plant material.

The latter has no possibility, due to the inherent variability and the plant versatility, of reaching the standards required by the Food and Drug Administration in terms of chemical identity, purity, or characterization.

A contemporary review of medicinal applications that evaluated the effect of {Delta}9-THC and marijuana on a broad spectrum of medical problems indicated that THC may have a role in treating nausea associated with cancer chemotherapy and in appetite stimulation. Other uses of either material were not supported.


AUTHOR INFORMATION


 

 

Accepted for publication July 21, 1998.

This study was supported in part by an unrestricted departmental award and a Senior Scientific Investigator award from Research to Prevent Blindness Inc, New York, NY.

I thank Brenda Sheppard for her valuable secretarial assistance.

Reprints: Keith Green, PhD, DSc, Department of Ophthalmology, Medical College of Georgia, 1120 15th St, Augusta, GA 30912-3400 (e-mail: [email protected]).

From the Departments of Ophthalmology, and Physiology and Endocrinology, Medical College of Georgia, Augusta. The author has no commercial or proprietary interest in any drug or product mentioned in this article.


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