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.