21
Interview
Professor Dr. Raphael Mechoulam, the discoverer of THC
Although research into the
psychoactive components of Cannabis began before the start of this century, it
was not until 1964 that Dr. Raphael Mechoulam, of the Hebrew University of Jerusalem,
identified delta-9-tetrahydrocannabinol (THC) as the most active compound.
Mechoulam's discovery led to a lot of research into other natural and synthetic
cannabinoids. In recent years many exciting discoveries were made. In 1990 the
cannabinoid receptor, the "lock" into which cannabinoids fit, activating the
specific biochemical events, was discovered. This of course intensified the search
for the cannabinoid-like brain molecule that binds to the cannabinoid receptor. In
1992 William Devane and Raphael Mechoulam identified a natural brain molecule that binds
to the cannabinoid receptor. They called it anandamide, from the Sanskrit word for
"eternal bliss". While the substance mimics the action of THC,
interestingly, it doesn't look anything like it. Additional natural anandamides have
since been found and it is specula ted that a family of receptors may exist.
One thing is certain: the pace of cannabinoid
research has picked up and the field is entering a new and exciting era! An
exclusive interview (June 17 1994) with the man who has been in the forefront of Cannabis
research for the last thirty years: Professor Raphael Mechoulam.
Professor Dr. Raphael Mechoulam (Photo R.C. Clarke)
David Pate: Can
you describe anandamide, its possible function in the brain and where its discovery leads
us?
Raphael Mechoulam: It has been
known since 1988 that THC acts on a specific receptor in the brain. This specific
receptor obviously was not built by the brain just for the sake of tetrahydrocannabinol -
a compound present in a plant - which is of course foreign to the receptor.
Presumably the receptor is present because it has a function, which has nothing to do with
a plant constituent. We considered that possibly this particular receptor is
activated by a compound found in the brain itself. We succeeded 2 years ago to
identify such a compound in pig brain. We called it anandamide. It binds to
this cannabinoid receptor. Anandamide differs completely from THC in its structure.
THC is an aromatic compound, while anandamide is a fatty acid derivative. It
also has a nitrogen atom in it, which is rather unusual for fatty acid derivatives.
DP: Any speculation as to why it
is there, what it actually does, both the receptor and its ligand?
RM: We know that the cannabinoid
receptor system is involved in sedation; at high doses THC can even cause catalepsy in
animals. In humans we know that Cannabis has a lot of effects which
together cause the well known "high". These also include memory effects
and some effects on movement. Most of the effects caused by THC are also seen with
anandamide in animals. Anandamide has not yet been given to humans but judging from
the animal effects these two compounds seem to parallel each other in activity.
Whatever THC does, anandamide does as well.
DP: What is the role of anandamides in
the brain?
RM: Anandamides and the receptor are
found in areas of the brain which have to do with the coordination of movement, with
memory and with emotions. We assume that the brain has anandamides and the receptors
to participate in the regulation of movement and to participate in memory and emotions.
But there is no proof that this is indeed the case, it is a circumstantial
evidence.
DP: Since three natural
anandamides have been found, how broad do you think the family is? Are there
multiple types of receptors?
RM: The three anandamides which
are known bind to the same receptor. They are actually a family of closely related
compounds. This is well known with other fatty acid derivatives in the body which
also appear in large families of closely related substances, such as prostaglandins and
the leukotriens. The three anandamides so far known seem to have the same biological
activity, but once we know more about how and what they do we may find small differences.
DP: Are there families of
receptors as well?
RM: This is another point.
In the brain, so far, just one receptor has been found. However, a second
receptor has been found in the spleen, it is related chemically to the brain receptor and
anandamide binds to both the central receptor (in the brain) and to the peripheral
receptor (in the spleen). Anandamide has not been found so far in the periphery, so
chances are that the fact that it binds to the receptor in the spleen is just because the
structures of the two receptors are somewhat close. Maybe the brain transmits the
brain mediator. The peripheral receptor seems to have its own endogenous ligands.
As a matter of fact we have found an endogenous compound in the gut which binds to
both the central and peripheral receptors. We are working on it at the moment and
have not published its structure or function. I think that the peripheral receptor
has to do with the immune system as it is well known that THC affects this system.
At present however this is just a speculation.
DP: Can you further speculate on
what triggers production of anandamides naturally and whether they are degraded by an
enzyme system like the cannabinoids?
RM: Incidentally, also in answer to
your previous question, the peripheral receptor is found in the spleen, but there is also
a receptor in the testis, we do not know whether it is the peripheral or the central
receptor and we know that THC and anandamides act on the sperm. There is a paper in
publication in the proceedings of the National Academy of Sciences showing that both THC
and anandamides act on activation of the sperm before it fertilizes the egg. So it
is involved, whether that is relevant or not, I don't know.
We do not know what triggers the production of
anandamides. Incidentally, Bill Devane and J. Axelrod at NIH have now found an
enzyme which synthesizes anandamide in the brain from arachidonic acid and ethanolamine.
The anandamides are labile compounds and they are degraded by an enzyme - an
amidase.
DP: Are there interactions
between the cannabinoid receptor and other receptors or receptor systems?
RM: Most definitely. The
cannabinoids (and presumably the anandamides) like most mediators in the body interact
with other systems: the dopaminergic, the adrenergic, the opiate systems etc. For
example we have found that when anandamides are injected into the brain the concentration
of cortical steroids goes up. There are indications that the cortical steroids
themselves may act on the cannabinoid receptor, presumably bringing down its activity.
DP: Were you surprised that
anandamide was the structure it was and not a protein?
RM: No, there is no reason why
it should be a protein. As a matter of fact, we thought originally that anandamide
should be a lipid-soluble compound, because the cannabinoids are lipid-soluble, and
therefore chances were that the compound in the body will be lipid-soluble and it turned
out to be a fatty acid.
DP: How do cannabinoids and
anandamides happen to fit into the same receptor, considering their structures are quite
different?
RM: We assume that in space and
in distribution of electronic charges the anandamides and the cannabinoids take up the
same kind of structure. A few groups are using models to calculate the electronic
densities and the structures of both types of compounds in space and to compare them.
However, as yet no definite answer has been provided.
DP: Are the relative affinities
of cannabinoids and anandamides and their receptors about the same?
RM: Anandamides and THC have
more or less the same affinity for the receptor. There are synthetic cannabinoids
which are a hundred and maybe a thousand times more active than THC. But that is
irrelevant, THC and anandamide are not very potent, but then the body does not want very
potent compounds. It wants compounds with intermediate potency, because if the
potency is very high and there is a chance increase of the compound the body will go into
stress. Changes in the body are usually gradual so one does not need very active
compounds in the body. This is of course a generalization which does not aply to all
body constituents as there are some compounds present in the body which act at extremely
low concentrations.
DP: Do you think there is
sufficient research into cannabinoids and will cannabinoids play a significant role in the
future of therapeutic medicine? If so, for what indications?
RM: After the identification of delta-9-THC
as the active component of Cannabis there was a huge wave of research in
chemistry, pharmacology and clinical aspects dealing with this plant constituent.
Many thousands of papers were published on it. By the late 1970s research started
slowing down as the mode of action was not clear at all. With the discovery of
receptors and of endogenous ligands interest has very much increased and numerous new
laboratories are working on various aspects. We can expect in the future
clarification of many of the problems associated with cannabinoid activity and possibly
advances in the field of therapeutics. So far the only cannabinoid which has been
legalized is THC for use in cases of vomiting due to cancer chemotherapy. THC has
also been used for a few other things like appetite stimulation (in cases of AIDS) as well
as in glaucoma. There is also illegal use in some neurological diseases such as
spasticity in multiple sclerosis and even in asthma. In the past several companies
worked on synthetic cannabinoids as analgetics or in reduction of blood pressure but these
projects were terminated. The synthetic compounds produced still caused psychotropic
effects which were unacceptable. In the last few years we have synthesized and
widely tested a cannabinoid, HU-211, which causes none of the typical psychotropic
cannabinoid effects but is a blocker of the action of the stimulatory transmitter glutamic
acid, in particular on one of its subreceptors named NMDA. This receptor is involved
in stimulatory activity. However, during trauma it causes excessive opening of ion
channels in many cells in the vicinity of the trauma. This introduces large amounts
of calcium ions into the cells and they may die. Blocking this activity is of
considerable potential importance in cases of trauma and possibly stroke, and a company
with which we are associated is developing HU-211 as an anti-trauma agent. We expect
to start human testing within a few months.
The discovery of anandamide has apparently
stimulated interest in several pharmaceutical companies. I am aware of a Japanese
company which is working in the field as well as a French one. Apparently the French
company has discovered an antagonist to anandamide - the first ever described antagonist
in the cannabinoid series. They are about to present it at a forthcoming meeting.
DP: Do you see the very limited
use of cannabinoids in medicine as the result of their intrinsic medicinal value or as the
result of the restrictions surrounding them?
RM: In the past most companies
refrained from working on cannabinoids mostly because of the legal restrictions. It
seems reasonable to expect that as at the moment there are no such legal restrictions
concerning anandamides it will be easier for companies to start projects in this field.
I expect that such research projects will be mostly in the neurological area and
possibly in inflammation research and immunology. This assumption is based on the
high concentrations of the cannabinoid receptor in the basal ganglia - an area involved in
coordination of movement and the peripheral receptor being in the spleen - an organ of
immune importance.
DP: Do you think new delivery
systems would help cannabinoid therapeutics gain more acceptance?
RM: Definitely. One delivery
system which has not been investigated is the aerosol system. People smoke
cannabinoids, this is the best way of getting them into the body, and getting them to act
fast. And in asthma for example, THC is known to be a bronchodilator. So if
people want to use a compound against asthma, obviously they will prefer inhalation rather
than any other way and very little work has been done in this area.
DP: Was THC patentable at the
time of your discovery? Why didn't you patent its synthesis?
RM: We didn't patent THC as it
was of no apparent medical use. One cannot patent compounds which have no practical
use.
DP: I'm thinking now of the
Unimed use of this as a pharmaceutical.
RM: We didn't patent the
synthesis either. I had asked my university authorities about this and they decided
against it. There was no apparent practical use of THC or its synthesis. On
the other hand we should have patented the major cannabinoid metabolite - THC-11-oic-acid
which we identified and synthesized in 1972. This acid stays in the body for a very
long time and most tests of cannabinoid use look for the presence of this acid rather than
for THC itself. Numerous radio immuno assays are based on this acid and we realize
now that it was foolish not to patent it.
DP: Is this approach basically a
reflection of your background, which is academic rather than industrial?
RM: Yes, now we patent quite a few
things, we patented HU-211 and that's why a company was willing to take it over. We
now patent quite a few more compounds, but at that time we didn't and it is a pity, and
the university lost a lot of money.
DP: Is there any relatively
unknown or unusual Cannabis research, past or present, that deserves a wider
mention?
RM: Well, if you look at what is
going on now, there is a huge amount of research going in all kind of directions.
For example, groups working on the immune system may be using the receptor in the
spleen. Research goes into subjects like emotions, asking why does Cannabis
do what it does? People are looking into schizofrenia and finding some unusual
things, some relationship between cannabinoids and schizofrenia, I think it has to do with
the receptor. Even though all these things are not well defined, I am under the
impression that there is a burst of research in many directions. Where that will
lead I don't know. I think that the most promising approach is to look into neurological
problems, coordination of movement and things of that sort.
DP: So the cannabinoids serve
less as prototypes for drugs per se, but rather as probes of the systems, which other
drugs may be later able to affect.
RM: Many if not most drugs used
today are really structural modifications of natural products, be they plant products of
known therapeutic value, or hormones, or transmitters. In most cases the new drugs
have less side effects than the natural product. I expect that this is going to
happen with the cannabinoids and anandamides. Academic and industrial research
groups will probably try to modify these molecules in order to minimize the side effects
as well as to make the compounds more specific. This is what we did with HU-211 and
this is probably going to be done with these compounds in other fields as well.
DP: Is there anything else you
may want to add to any of the previous questions?
RM: Research in the last 20
years has shown that Cannabis differs from most other illicit drugs - it is not a
major addictive agent and it seems to act through mechanisms which are quite different
from those of the opiates and cocaine.
Hence investigations in this field may lead us
into understanding of very basic problems in biology such as memory and emotions.
There are few tools for work in these areas and any additional one may be of great
importance. The National Institute of Drug Abuse of the USA which is the major
granting agency in the field of drug abuse is looking into cannabinoids with great
interest now and this will be of considerable help. I would like to mention that the
United Nations which has a huge budget devoted to drug abuse prevention does not support
research at all. This is a strange situation and probably reflects the background of
the officials dealing with drug abuse at the UN level. They view drug abuse as a
social problem with little value of research for the solution of this problem. Too
bad.
DP: Would you say that the
perceptions are changing as cannabinoids are seen less as a source of problems and more as
a source of opportunity for exploration?
RM: Right, you just put it down
very well.
DP: Sorry, I didn't want to put
words in your mouth.
RM: No, no, you just said it.