A Brief Review

Jay R. Cavanaugh, Ph.D.

Late on Saturday afternoon just before the 2002 Portland National Clinical Conference on Cannabis Therapeutics was adjourned, a quiet and highly technical presentation was made by David W. Pate, PhD, MSc of HortaPharm B.V.

Dr. Pate who was kind enough to provide AAMC with his doctoral dissertation on anandamide (the bodies natural THC) and glaucoma, proceeded to describe a model of glaucoma that raised many new questions. What if the painful intra-ocular pressures present in glaucoma were not the cause of the disease but the symptom of underlying neuroinflammation? Presenting elegant experimental data, Dr. Pate demonstrated that indeed key nerves involved in the "gating" of fluids within the eye were inflamed in glaucoma and that such inflammation could be countered by anandamide.

It shouldn’t be surprising that CB1 receptors were identified by Dr. Pate within the eye. Binding to these sites reduced inflammation and reduced painful pressure. Cannabinoids are seen by Dr. Pate as providing an "ocular stabilizing" effect helping to prevent the inflammation of nerves within the eye. A significant volume of work supports Dr. Pate’s findings including that of Dr. R. Ritch from the Department of Ophthalmology, New York Eye and Ear Infirmary. In a recently published article Dr. Ritch answers the question:

"Neuroprotection: is it already applicable to glaucoma therapy? Many categories of both natural and synthetic compounds have been reported to have neuroprotective activity. These include not only antioxidants, N-methyl-D-aspartate receptor antagonists, inhibitors of glutamate release, calcium channel blockers, polyamine antagonists, and nitric oxide synthase inhibitors, but cannabinoids, aspirin, melatonin, and vitamin B-12. The lack of availability of specific neuroprotectant compounds in the United States and the lack of clinical trials examining the benefits of neuroprotective agents for glaucoma currently limit the use of these agents. This article provides a short overview of the concept of neuroprotection as it applies to glaucoma and suggests the possibility of neuroprotective activity that might be provided by compounds that are presently easily available."

Earlier in the conference Juan Sanchez-Ramos, PhD, MD, of the University of South Florida, had detailed neuroprotective effects in movement disorders including Parkinson’s disease and Tourette’s syndrome. Is it possible that a new general theme of cannabinoid action was emerging? Dr. Sanchez-Ramos indicated that the therapeutic neuroprotective effects seen with cannabis in Parkinson’s and Tourette’s were probably due to the stabilization of neurotransmitters levels which are unbalanced in these disorders and can be further unbalanced by the very drugs used to treat these illnesses. This mechanism might be described as a neuromodulatory effect as opposed to anti-inflammation.

Inflammation (usually autoimmune related) is also involved in arthritis, MS, diabetic and AIDS related neuropathy, spinal cord injury and acute brain injury. Can the Cannabinoids have an impact on these processes? In Portland, I was able to speak with Dr. Ester Fried who works in Dr. Mechoulam’s pioneering laboratory in Jerusalem. In the summer of 2001, Dr. Mechoulam published an excellent review article describing the utility of the Cannabinoids in many of these conditions. In part he stated,

"Clinical work in multiple sclerosis, which may lead to the approval of tetrahydrocannabinol as a drug for this condition, is presented. Preclinical and clinical investigations with cannabidiol, a non-psychotropic cannabis constituent, are also described. Recent work with cannabidiol in animal models of rheumatoid arthritis may lead to clinical investigations. A synthetic cannabinoid, HU-211 (Dexanabinol), is in advanced clinical stages of investigation as a neuroprotectant in head trauma. The above clinical approaches may ultimately lead to the realization that cannabinoids are valuable clinical drugs in numerous fields."

Dr. Mechoulam followed this fine review article in the spring of 2002 with an excellent peer reviewed Journal article entitled "Endocannabinoids and Neuroprotection". In part Dr. Mechoulam stated that,

"Traumatic brain injury (TBI) releases harmful mediators that lead to secondary damage. On the other hand, neuroprotective mediators are also released, and the balance between these classes of mediators determines the final outcome after injury. Recently, it was shown that the endogenous brain cannabinoids anandamide and 2-Arachidonoyl glycerol (2-AG) are also formed after TBI in rat and mouse respectively, and when administered after TBI, they reduce brain damage. In the case of 2-AG, better results are seen when it is administered together with related fatty acid glycerol esters. Significant reduction of brain edema, better clinical recovery, and reduced infarct volume and hippocampal cell death are noted. This new neuroprotective mechanism may involve inhibition of transmitter release and of inflammatory response. 2-AG is also a potent modulator of vascular tone, and counteracts the endothelin (ET-1)-induced vasoconstriction that aggravates brain damage; it may thus help to restore blood supply to the injured brain."

These finding are confirmed by the Laboratory of Cellular and Molecular Regulation, part of the National Institutes of Mental Health in Bethesda, Maryland. As early as 1998, Dr.’s Hampson, Gimaldi, Axelrod, and Wink, published key work in the Proceedings of the National Academy of Science. This important government laboratory found in part that:

"The neuroprotection observed with cannabidiol and THC was unaffected by cannabinoid receptor antagonist, indicating it to be cannabinoid receptor independent. Previous studies have shown that glutamate toxicity may be prevented by antioxidants. Cannabidiol, THC and several synthetic cannabinoids all were demonstrated to be antioxidants by cyclic voltametry. Cannabidiol and THC also were shown to prevent hydroperoxide-induced oxidative damage as well as or better than other antioxidants in a chemical (Fenton reaction) system and neuronal cultures. Cannabidiol was more protective against glutamate neurotoxicity than either ascorbate or alpha-tocopherol, indicating it to be a potent antioxidant. These data also suggest that the naturally occurring, nonpsychotropic cannabinoid, cannabidiol, may be a potentially useful therapeutic agent for the treatment of oxidative neurological disorders such as cerebral ischemia."

To demonstrate that research verifying the importance of cannabis in neuroprotection is far from isolated, attention is called to a recent peer reviewed article (September, 2001) in the Journal of Neuroscience where a Dutch team details protection from neurodegeneration by THC. Dr.’s Van der Stelt, Veldhuis and others from Utrecht University found in part that,

"Excitotoxicity is a paradigm used to explain the biochemical events in both acute neuronal damage and in slowly progressive, neurodegenerative diseases. Here, we show in a longitudinal magnetic resonance imaging study that Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the main active compound in marijuana, reduces neuronal injury in neonatal rats injected intracerebrally with the Na(+)/K(+)-ATPase inhibitor ouabain to elicit excitotoxicity. In the acute phase Delta(9)-THC reduced the volume of cytotoxic edema by 22%. After 7 d, 36% less neuronal damage was observed in treated rats compared with control animals. Coadministration of the CB(1) cannabinoid receptor antagonist SR141716 prevented the neuroprotective actions of Delta(9)-THC, indicating that Delta(9)-THC afforded protection to neurons via the CB(1) receptor. In Delta(9)-THC-treated rats the volume of astrogliotic tissue was 36% smaller. The CB(1) receptor antagonist did not block this effect. These results provide evidence that the cannabinoid system can serve to protect the brain against neurodegeneration."

Inflammation and neurotoxicity are basic elements of many common disorders that don’t respond well to current medications. A significant volume of research both in animal and human models suggests the efficacy of cannabis in treating such disorders like RA, MS, Acute Brain Injury, excitotoxicity generated from drug treatment in Parkinson’s and Tourette’s Syndromes, neuropathies, glaucoma, and spinal cord injury, to name a few. The powerful anti-oxidant effect of the Cannabinoids seen in these disorders also provides hope that cannabis will be demonstrated clinically efficacious in disorders like liver inflammation from Hepatitis C, lupus, irritable bowel syndrome, and many other serious medical conditions that all involve inflammation and oxidative damage.

Some references:

Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA 1998 Jul 7;95(14):8268-73

Van der Stelt M, Veldhuis WB, Bar PR, Veldink GA, Vliegentharet JF, Nicolay K. Neuroprotection by Delta9-tetrahydrocannabinol, the main active compound in marijuana, against ouabain-induced in vivo excitotoxicity. J Neurosci 2001 Sep 1;21(17): 6475-

Mechoulam R, Hanu L. The cannabinoids: an overview. Therapeutic implications in vomiting and nausea after cancer chemotherapy, in appetite promotion, in multiple sclerosis and in neuroprotection. Pain Res Manag 2001 Summer;6(2): 67-73.

Mechoulam R, Spatz M, Shohami E. Endocannabinoids and neuroprotection. Sci STKE Apr 23;2002(129):RE5

Ritch R. Neuroprotection: is it already applicable to glaucoma therapy? Curr Opin Opthalmol 2000 Apr;11(2): 78-