http://www.maps.org/pipermail/maps_forum/1998-October/001231.html
Science / Marit Slavin
How hash became a smash in brain trauma research
The story behind a major Israeli medical breakthrough - the marijuana
derivative that promises to help treat head injuries=20
In the mid-1960s, when researchers Rafael Meshulam and Yehiel Ga'oni
isolated the active component in cannabis sativa - marijuana - and
identified it chemically, they never for a moment imagined that 35 years
later this knowledge would be able to help save people with serious head
injuries."It was recognized then that cannabis had useful medical
properties beyond its influence on the sensations and emotions," says
Professor Meshulam, who researches natural substances at the Hebrew
University medical school. "So I decided to try separate these properties
from its ability to alter perception."=20
Accordingly, Meshulam and his students synthesized several hundred
substances similar in structure to the active ingredient in cannabis but
each with minute chemical differences. One of the families of substances
tested included one that looked liked the mirror image of cannabis,
something like the resemblance between the right and left hands.=20
When this family was tested, it did not affect perception - but did have
several other effects on the brain, which surprised the researchers. One
member of the family got the code name 211HU/UH112, now commercially known
as Dexanabinol.=20
Meshulam turned to biochemists Yoel Klug and Mordechai Sokolovsky at the
Tel Aviv University Neurobiology Department to continue testing the action
of the substances they had isolated. It emerged that dexanabinol was
involved in the action of the neurotransmitter glutamate, which
participates in the transmission of neural signals in the brain. Glutamate
is secreted in the brain synapses, and after it has been secreted it
connects with special receptors located in the nerve cells. When connected,
a channel opens in the cell wall, enabling calcium ions to enter.=20
Normal neural communication is a controlled procedure denoted by the
limited entry of calcium ions into the nerve cells. However, when the brain
is injured or suffering from impaired blood or oxygen supply, excess
quantities of glutamate are secreted and large quantities of calcium ions
penetrate the nerve cells, causing them to die off.
Research over the last 10 years showed that excess secretion of glutamate
from damaged cells to neighboring cells and from them to connecting cells
in a steadily-increasing pattern leads to brain damage that spreads from an
injured area to much wider areas of the brain. This prompted the theory
that a substance capable of blocking the entrance of calcium ions to nerve
cells might prevent the death of injured brain cells. The surprising
property found in dexanabinol was its ability to block the calcium channels
linked to the glutamate receptor. The finding opened the way for wide
medical use, and the Israeli biotech company Pharmos purchased the rights
to the "mirrorsubstance and financed continued study. Led by Dr. Anat
Bi'agon, vice president of research and development at Pharmos, research
focused on the possibilities of using the substance to treat all kinds of
brain injuries. In addition to glutamate secretion, there are other
biochemical processes that contribute to brain damage. An increased number
of damaging free radicals (substances with strong chemical action) is
created in the injured area and an infectious process is triggered in the
brain, for example. It emerged that dexanabinol neutralizes the free
radicals and also halts the infectious process.
"A unique picture emerged of a substance that works on three different
mechanisms, all involved in the pathological processes occurring in the
injured brain," says Bi'agon. After that success, research was extended to
yet another team, which studied whether the material could help treat
general head injuries. Professor Esther Shohami of the pharmacology
department at Hebrew University Medical School conducted this part of the
research. Shohami tested the material on rats. As a result of head injury,
rats, like humans, are susceptible to brain processes that cause short and
long-term clinical symptoms like temporary or continuing loss of
consciousness, paralysis, and death. In addition to brain cell damage,
which spreads from cell to cell, an edema can develop in the brain 24 to 48
hours after an injury. The edema in itself could cause death or long-term
neural damage. In addition, the patient's blood pressure often drops,
preventing optimal blood supply to the brain cells, undermining
rehabilitation. Both the edema and lowered blood pressure increase the
damage to the injured brain. The rats were given a single injection of
dexanabinol up to six hours after the injury. A control group received no
treatment after the injury. It was found that dexanabinol prevented neural
damage from spreading in the treated rats, while the control group
exhibited classic head injury symptoms like paralysis and disturbances in
perception. When the researchers examined what had happened in the rats'
brains, they saw that the brain edema that develops in head injuries was
prevented in the experimental group. Dexanabinol also prevented long-term
nerve damage.
Until this breakthrough there had been no effective treatment for head
injuries. The usual treatment is supportive and attempts to minimize brain
damage by reducing the edema. There is still no medication available to
prevent brain cells from dying. But the encouraging results with animals
led to a series of experiments with humans. In the first stage of
experiments using humans, the safety of the medication was tested; in other
words, the extent, if any, of its toxicity to humans. This experiment was
conducted about two years ago in England on a group of healthy volunteers
who received varying quantities of the substance. It provided researchers
with information on what doses of the medication could be used effectively
without side effects. The results were good: The substance was not toxic
and could be given to patients in quantities required for therapeutic=
action.
The success of the first phase of the experiment allowed the second phase
to commence in October 1996 in Israel. In this stage the efficacy of the
medication was tested on a relatively small number of people. The
experiment was conducted at six Israeli centers under the direction of Dr.
Nahshon Kanolar, senior doctor in the neurosurgery department of the Sheba
Medical Center at Tel Hashomer Hospital. Sixty-seven patients aged 16 to 65
participated in the experiment. All were unconscious, with serious head
injuries and evidence of brain damage. The medication was injected within
six hours of injury.The patients were divided into two groups. The
experimental group received the medication and the control group received a
placebo. The experiment was blind - none of the participants, neither
doctors nor patients, knew who was in the experimental group and who in the
control group. Participants in the two groups were randomly chosen. The 67
patients represented all that is known about people with head injuries:
Most are men, the average age is 30 and the primary reason for head injury
is road accidents. During the experiment the patients were under close
observation for up to six months after the injury. Special emphasis was
laid on the safety of the medication. Research was thoroughly checked by an
outside safety committee from the United States that received data on each
patient while the experiment was underway.
No safety problems were discovered and no side effects of the medication
were seen. Kanolar and Bi'agon are currently reporting on the results at a
major medical conference in Seattle. Their findings: a comparison between
the experimental and control groups shows that the treated group had a
significant advantage. The medication clearly lowered the extent of the
edema developing in the brain, a fact observed by checking the
inter-cranial pressure in the two groups of patients. The medication also
prevented the drop in blood pressure common to head injuries. "These two
findings indicate that the medication improves the patients' condition, and
definitely improves their chances of recovery," says Kanolar. When the rate
of recovery of the patients was examined, a definite difference emerged in
favor of those who received the medication, both in terms of the number of
patients who achieved full recovery and the speed of recovery. The
difference in the mortality rate was not notable. There was a 10 percent
mortality rate for those receiving the medication while for the control
group it was 13 percent. "In serious head injuries it is common to
concentrate on improving the situation, because the mortality rate is low.
No one is seeking a medication to reduce mortality, because that has no
significance. What is important here is the extent of reduced disability
and return to normal functioning," says Bi'agon. In the next stage, phase
three, the experiment goes international and will be conducted on hundreds
of patients. If it proves itself the medication will be given the go-ahead
for marketing.
copyright 1998 Ha'aretz. All Rights Reserved
The question arises: Is this compound even naturally occuring in marijuana,
in significant amounts? And if it is not, what is responsible for the
reported anti-stroke effect of cannabis? Ibogaine has been patented as a
superior (i.e., less toxic) anti-stroke medication by Olney. Nowhere does
Ha'aretz explain that the receptor in question is the NMDA receptor, famous
from Ibogaine research.
Dana
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