MEDICAL MARIJUANA: DOING THE SCIENCE

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.