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US: Medical Marijuana: Doing the Science
November 20, 1997
Source: Synapsehttp://itsa.ucsf.edu/~synapse/
In late October, postdoc Ian Meng presented a paper at the Society for
Neuroscience meeting in New Orleans, summarized thus in a UCSF press
release and newspapers across the world: "a synthetic marijuana-like
drug called WIN 55212 enhances the brain's ability to suppress pain in
rats, and probably in humans as well."
This debriefing was conducted in early November, back in the crowded
lab on the 7th floor of Medical Sciences that Meng shares with
co-investigators Barton Manning, PhD, and Howard Fields, MD, professor
of neurology, and nine others. Meng is 28; he did his undergraduate
work at Brown, and got his PhD there.
Synapse: Who decided to name a cannabinoid WIN 55212-2?
IM: The company that distributes it is called RBI. [Research Biology
International. The compound was synthesized by Sterling Winthrop in
1990.] Right now there are three good synthetic cannabinoid agonists
that act specifically on the CB-1 receptor. There's been a big
breakthrough in the last year, because they now have a specific
antagonist, which lets you be sure that the compound is having its
effect on that specific receptor.
Synapse: In your study, who took the initiative: you or RBI?
IM: I did. Actually, the antagonist is now free from National
Institutes of Drug Abuse (NIDA). I just gave them a call and did the
paperwork.
Synapse: Why is NIDA making the antagonist available? In case somebody
accidentally ingests some marijuana?
IM: Well, marijuana is not lethal, so that's not a big concern.
Recently it's been made available because they want more studies done
on cannabinoids. They're actually getting on the bandwagon and
starting to support this kind of research. It's been a big switch.
Until recently the government was only willing to fund research that
asked questions about the possible negative side effects of marijuana.
But there have been so many anecdotal reports of marijuana helping
people with a variety of diseases that people in California and
Arizona voted to legalize marijuana for medical purposes. The voters
said, "We're going to use it anyway," so all of a sudden the
government is saying, "We'd better start funding research to really
see what's happening."
Synapse: That is news... Could you define a cannabinoid?
IM: The most active ingredient in cannabis is the delta-9 THC
molecule, which binds with a certain affinity to a specific receptor
in the brain known as the CB-1 receptor. There have now been two
proposed endogenous ligands for this receptor. So cannabinoids are
drugs that bind to the CB-1 receptor... There are less active
ingredients in marijuana which may have some role in its effects.
That's why we need to do studies where we compare the effects of
smoking marijuana to the effects of specific agonists. You do want to
know whether there are other components in the actual marijuana
influencing the effect.
Synapse: Have all the different cannabinoids been isolated? Wouldn't
you want to know what's in the plant first before you start working
with synthetics?
IM: I think most of that work was done in the 1970s. For the kinds of
studies I do I want to know that a particular drug is acting at a
specific receptor. That's why I use synthetic compounds... (Takes a 20
ml vial of clear fluid from a desk drawer) It comes in a powdered
form, I mix it in an oil-based solution and give it intravenously, and
I look at the activity of single cells in this particular brain region
which can modulate pain. That's the basic paper I presented at the
neuroscience meeting. I found that when I give the cannabinoids
intravenously, it will affect a group of cells in one of the brain's
pain areas. It's thought that these cells, when activated, reduce the
amount of pain allowed to be transmitted up through the spinal cord to
the brain, where sensation occurs. So when the cells in this area are
activated, they inhibit pain. Morphine activates these cells to
inhibit pain; and so -we found looking at single cells- do
cannabinoids. I wanted to show that the activity of these cells was
related to the analgesia being produced. So the second step was to
give the drug to awake rats systemically and then do a microinjection
into this brain region to inhibit all cell activity. Under those
circumstances, the animals do not show an analgesic effect after the
systemic cannabinoid. The activity of cells in this brain region is
necessary for the cannabinoid to have its analgesic effect.
Synapse: So you're trying to figure out how cannabinoids work -you're
not trying to prove that they do work. You recognize the existing
evidence.
IM: Yes. People know that they're analgesic. But until fairly recently
it hadn't been proven in animal studies that cannabinoids affect
sensation. When you do pain research it's important to differentiate
between the motor effects a drug might have versus the sensory
effects. If you give a drug that has a motor effect -that decreases
the rat's activity, for example-then some observers might say, "That
explains the apparent decrease in pain..." You can't ask an animal,
"Do you feel less pain?" You have to look at certain behaviors.. What
I do is called the tail flick.[Meng has a testing device in which the
heat source is a light bulb inside a gray metal box. The anesthetized
rat is placed on the box with its tail in a groove above a hole, so
that the radiant heat from the bulb will reach the tail, which the
animal then flicks out of the groove. More time before flick feeling
less pain.] If you give an analgesic drug, a cannabinoid, or morphine,
then the animal will leave its tail on the heat source much longer.
You can also do this tail-flick in another set-up through a glass
bottom with freely moving, unanesthetized rats.
I also look at the actual transmission of pain signals through the
central nervous system. I do single cell recording -looking at the
activity of single neurons that are related to pain. I can actually
look at the electrical impulses that travel down neurons to tell me
how active a cell is. By doing that we've been able to show, it's not
just motor effects; this cannabinoid has very specific sensory
effects. It affects the neurons in the pain pathway.
Synapse: So where is this research heading? What happens next?
IM: One thing I'm very interested in is, why is there this endogenous
cannabinoid system in the body? It's got to be there for some reason.
And it has to be activated under certain types of conditions. It's
been known for a long time that certain types of stress will activate
the endogenous opioid system so the endorphins and those kinds of
things can kick in. Say if somebody gets their arm blown off in a war,
they won't feel any pain because this pain-modulating brain center
that I record in is activated, and it shuts off pain before it can
reach the part of the brain that coordinates sensation. And that's
important for survival because you don't want to be distracted by your
pain, you want to get out of there.
So certain kinds of stress involve opioids. The cannabinoid system is
a very separate system but it activates the same kind of neurons. One
hypothesis is that there are different kinds of stress that activate
the cannabinoid system.
Synapse: Why do plants contain cannabinoids? And why do poppies
contain opium? Do you find yourself pondering the big evolutionary
questions?
IM: And the bark of the willow tree for aspirin... Yeah, there are a
lot of natural substances which have specific actions that reduce
pain. I'm not sure why plants have evolved to make these compounds,
but it has really helped scientists gain insights into the way the
brain works. It also makes me believe that the Western scientific and
medical community could learn something from people in other parts of
the world who use all kinds of herbal and other natural remedies.
Synapse: Why did the company want to develop a synthetic cannabinoid
in the first place? Why not study the naturally occurring ones first?
Were they trying to create a patentable molecule? Or a legal molecule?
IM: The real reason is, when you make a synthetic compound it can
actually be more potent and more effective.
Synapse: Why is that?
IM: It can bind to the receptor molecule better. You can target that
receptor. It can also have a longer duration of action.
Synapse: Is that what the makers of WIN 55212-2 did?
IM: Actually, I think the WIN compound was discovered by accident.
They were looking for something completely different.
Synapse: They weren't tweaking naturally occurring cannabinoids?
IM: Not at all.
Synapse: And this drug you're working with is a cannabinoid because it
binds to the cannbinoid receptor.
IM: Yes. And now they have other synthetic compounds that have been
screened for activity at the cannabinoid receptor.
Synapse: What makes a molecule want to bond with the cannabinoid
receptor? Is there some chemical group offering a special handshake?
IM: Basically it's got to do with the make-up of the receptor. You
have certain amino acids and certain positive and negative charges
which have to match both the shape and the charges on the drug. So you
can do computer models to try to figure out what would be a good
synthetic compound. But those usually aren't that good at predicting
what's going to bind. Normally, it's just making a lot of compounds
and screening them [for function by biological assay] and seeing what
works.
Synapse: Do you talk to people back at the company? Are they following
your work? Could your work translate into big bucks for this company?
IM: I really don't know. I've come to this purely through scientific
interest and I never even think about that kind of thing. I probably
should.
Synapse: When I read the story out of New Orleans, I thought about
those chemists in Basel 30 years ago, tweaking the amphetamine
molecule to come up with Ritalin.
IM: No, we really rely on what the chemists give us. They give us the
tools, and then we can kind of figure out what's happening...
Synapse: I have a vested interest in seeing that the appropriate
research is done on any drug that offers hope in the treatment of
epilepsy.
IM: Of course there have been anecdotal reports of people using
marijuana to help their epilepsy. I'm sure it's just a matter of time
before scientists start looking at the actual mechanisms by which
cannabinoids can control seizures. It's through this type of research
that new and better treatments could result.
Synapse: Has your life changed since your paper was published?
IM: (laughs) A little bit. One part is people calling up wanting to
know how they can get this drug to help them, because there are a lot
of people with really severe chronic pain for whom nothing to this
point has worked. So we've gotten some calls like that. Then you've
got reporters calling, wanting to know how it affects the whole
political debate.
Synapse: And what's your line on that?
IM: My line is that it should be legal. It definitely should be legal
for people who need it to help with an illness or a disease like
chronic pain or epilepsy. And cannabis can really help. Basically the
science is just showing that there are very specific mechanisms by
which the cannabis can help. People are taking this as a medicine, and
for very specific reasons. It's hard to get that point through.
Synapse: We've all had a lifetime of prejudice and propaganda.
IM: Absolutely... It's satisfying to really do the science.
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