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Cannabis Science: Cannabinoid Derivative Protects Neurons

The Lancet
Vol 348 (No. 9039) Nov 23 1996
by Rachelle H B Fishman


A cannabinoid derivative, dexanabinol (HU-211), could be the first neuroprotective agent to be approved for human use. If it is successful it might become a "standard inclusion in the kit bag of every medic and ambulance", says neurosurgeon Nachshon Knoller (Tel Hashomer,Israel).

Dexanabinol is a non-psychotropic derivative of a synthetic family of tetrahydrocannabinoid analogues. The drug has three independent mechanisms of action: it blocks glutamate-induced neurotoxicity; it scavenges both peroxy and hydroxy free-radicals; and it inhibits the action of the inflammatory cytokine alpha-tumour necrosis factor. "The triple action stops the spread of the primary neuronal damage from the core of injury to the surrounding brain tissue, even after a single intravenous injection, up to 6 hours after the initial insult", says Raphael Mechoulam, professor of pharmacology, Hadassah Medical School, Jerusalem, Israel.

The results of a UK phase I clinical trial showing lack of adverse reactions to dexanabinol and results from earlier animal studies were presented on Nov 15 in Washington, DC, USA, at the annual meeting of the Society of Neurotrauma. A phase II clinical study of dexanabinol started in Israel on Nov 9, under the auspices of the American Brain Injury Consortium, in patients with severe head injury exhibiting abnormal computed tomography scans and requiring intracranial pressure monitoring.

Cannabinoids Neuroprotective? - by Earth Erowid
Research has begun to accumulate over the past few years showing that
cannabinoids are neuroprotective against brain injury resulting from toxins, hypoxia, and head trauma. Cannabinoids are, loosely, chemicals that are similar in structure to the psychoactive components in cannabis and/or chemicals that activate the cannabinoid receptor system in the
body. Researchers have found protective effects not only from the plant-derived cannabinoids such as THC, but also from endogenous cannabinoids (those occurring naturally in the body, such as anandamide) and some synthetic pharmaceutical cannabinoids.
The research with the cannabissource cannabinoids, conducted in mice,
rats, and in vitro, has shown remarkable effectiveness in reducing brain damage from injected toxins, hypoxia, and head trauma.
1 Other research has found that anandamide levels in the brains of rats
naturally rise after brain injury or death and the cannabinoid system may play a primary role in limiting brain damage.
2 Because psychoactivity is considered an unwanted side effect, much of the current research is being done with synthetic cannabinoid system agonists. One synthetic cannabinoid, Dexanabinol HU-211), is already in phase 3 trials medium scale, involving humans) headed towards governmental approval as a neuroprotective pharmaceutical.
Research conducted in Israel that gave 67 patients with serious head trauma either Dexanabinol or placebo confi rms similar research in rats showing reduced damage and faster recovery among those receiving the cannabinoids.
3 Although other promising head trauma treatments have failed in the demanding and complex phase 3 research trials, many interested in
the fi eld of neuroinjury are excited about the fi ndings to date.
The mechanisms by which the cannabinoids reduce damage from both
toxic and traumatic injury to the brain are not yet fully understood. Although some researchers have suggested that the cannabinoids may offer protection through a strong antioxidant effect, this is now considered unlikely to account for much of the protection, since cannabinoidreceptor
antagonists block the benefi cialeffects and the doses of the cannabinoids
given are very low. Perhaps the current best guess for how
these chemicals provide their protective effects is that their general dampening of neural activity reduces excitotoxicity (damage caused by overly excited neurons). One of the specifi c ways this happens is
through the inhibition of the glutamate system in the brain. The glutamatergic neurons are part of the excitatory system in the brain; inhibiting glutamate reduces the activity of other neurons. At least in
some parts of the brain, activation of the CB1 cannabinoid receptor (a specifi c type of cannabinoid receptor) has been shown to block pre-synaptic release of glutamate. CB1 receptor activation is also known to inhibit certain calcium channels, directly reducing the production of nitric oxide and other potentially damaging reactive oxygen species.1,4
For more information and a more complete list of references, see erowid.org/extracts/n5/cannabinoids.shtml and read the summary article ?Cannabinoids and brain injury: therapeutic implications? by Mechoulam et al. 2002.5 ? References 1. van der Stelt M, Veldhuis WB, Bar PR,Veldink GA, et al. ?Neuroprotection by Delta9-tetrahydrocannabinol, the main
active compound in marijuana, against ouabain-induced in vivo excitotoxicity.?J Neurosci. 2001; 21(17):6475-6479.2. Marsicano G, oodenough S, MonoryK, Hermann H, et al. ?CB1 cannabinoid
receptors and on-demand defense against excitotoxicity.? Science. Oct 3, 2003;302(5642):84-88.3. Knoller N, Levi L, Shoshan I, Reichenthal E,et al. ?Dexanabinol (HU-211) in the treatmentof severe closed head injury: a randomized,placebo-controlled, phase II clinical trial.?Crit Care Med. Mar 2002; 30(3):548-554.4. Shen M, Piser TM, Seybold VS, ThayerSA. ?Cannabinoid receptor agonists inhibitglutamatergic synaptic transmission in rathippocampal cultures.? J Neurosci. Jul 15,1996; 16(14):4322-4334.
5. Mechoulam R, Panikashvili D, Shohami E.?Cannabinoids and brain injury: therapeuticimplications.? Trends Mol Med. Feb 2002;8(2):58-61.

Marijuana Is Neuroprotective

... Utrecht, The Netherlands: Compounds in marijuana dramatically protect brain cells during acute head trauma, according to research findings published in this week's Journal of Neuroscience. Researchers reported that THC injected intracerebrally in rats significantly "reduce[d] neuronal injury ... compared with control animals."

Scientists concluded, "These results provide evidence that the cannabinoid system can serve to protect the brain against neurodegeneration." NORML Foundation Executive Director Allen St. Pierre said that the findings should dispel myths that marijuana is toxic to the brain. "This research indicates that just the opposite is true" he said.

Former NORML Foundation Chairman Dr. Lester Grinspoon, author of Marijuana: The Forbidden Medicine, said the study confirms earlier research performed in Israel and the US showing cannabinoids to be potent anti-oxidants. He added that smoked marijuana likely also possesses the same neuroprotective properties. In their 1999 report Marijuana as Medicine: Assessing the Science Base, authors at the Institute of Medicine noted, "One of the most prominent new applications for cannabinoids is for 'neuroprotection,' the rescue of neurons from cell death associated with trauma ... and neurological diseases."

(For more information, please contact Paul Armentano or Allen St. Pierre of The NORML Foundation at (202) 483-8751, NORML Newsletter, 07.09.01)

- London, United Kingdom: Cannabinoids and the cannabinoid receptor system offer neuroprotection against allergic encephalo myelitis (EAE), an animal model of Multiple Sclerosis (MS), according to findings published in the July 22, 2003 issue of the journal Brain.

Scientists at London's Institute of Neurology determined that mice deficient in the cannabinoid receptor CB1 developed "substantial neurodegeneration" as a result of EAE Researchers also noted that "exogenous CB1 agonists (agents that bind to the receptor, such as THC) can provide significant neuroprotection from the consequences of inflammatory CNS disease in an experimental ... model."

Authors concluded: "Therefore, in addition to symptom management, cannabis may also slow down the neurodegenerative processes that ultimately lead to chronic disability in multiple sclerosis and probably other diseases."

....A previous study published in the May 6, 2003 issue of the journal NeuroReport similarly noted that "cannabinoids could provide neuroprotection" and "modify neurodegeneration in Huntington's disease."

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