24

Interview

Dr. Mahmoud A. ElSohly

    In the United States, the University of Mississippi, and specifically its Research Institute of Pharmaceutical Sciences (RIPS), is famous for hosting the NIDA Marijuana Project, wbich grows the Cannabis it supplies to researchers.  The head of this project is currently Mahmoud A. ElSohly, a Research Professor at the institute, as well as its former Assistant Director of Physical Sciences from 1976 to 1988.  He is also the Director of his own private laboratory, where he continues to work with Cannabis and the cannabinoids.  Our interview, conducted by Dave Pate on December 19, 1995, appears below.

    JIHA:  Dr. ElSohly, what is your academic background and how do you find yourself in this position?

    MAE:  I have a bachelor's and master's degree in Pharmacy and Pharmaceutical Sciences from the University of Cairo and I have a Ph.D. degree in Pharmacognosy, natural products chemistry, from the University of Pittsburgh.  My major professor was Dr. Paul Schiff, who was a student of Professor Jack Beal at Ohio State.  As soon as I had finished all my practical work for the Ph.D., we had twin daughters and my major professor said "Well, you better go and find yourself a job somewhere".  He knew Carlton Turner at the University of Mississippi and said that he had a good graduating student and I was offered a post-doctoral position.  I moved there in August of 1975, before I had actually defended my doctoral dissertation in November.  Things worked out with Cartlon and I started out on a poison ivy project and then a research associate position opened up with the marijuana project, which paid a littte more money, in November, just a few months after I moved there.

    JIHA:  Sounds like you lucked into dropping through all the right slots.

    MAE:  Right, and then things just kept happening to me here and I began to move very quickly in the ranks, in 1978 coming into an assistant professor position, and by 1982 advancing to associate professor.  When I first arrived at RIPS, all you could be was a "post-doc" or a research associate of some sort, but in the early '80s, one of the vice-chancellors, Peter Wagner, believed in rewarding those that have accomplishments, so in 1984, I applied for and received a full-professorship.  To achieve that position in only 6 years is a record for the university.  I guess I was in the right place at the right time, but I had also been turning in 7, 8, 10 publications every year, so I had a lot of good productivity at that time.

    JIHA:  When did you first become interested in Cannabis?

    MAE:  In 1976, when I was a "post-doc" working on Cannabis.

    JIHA:  You had no particular interest in the subject before then?

    MAE:  Not really.  I knew about Cannabis from my undergraduate work in pharmacy and I knew hashish, but I didn't know what "marijuana" was, as a name, because in the middle-east where I come from, it's just not-known as that.

    JIHA:  You were exposed culturally to hashish?

    MAE:  I don't believe that I ever saw it myself, but in the culture people always talked about hashish and smoking it.  My father never did, but there were a lot of people in my town that smoked hashish all the time.

    JIHA:  Is that seen as clandestine or just as accepted tradition?

    MAE:  It's seen as clandestine, because, at least when I was growing up, it's distribution was a major crime.  It was 25 years in prison if you were caught with hashish as a distributor, which didn't mean necessarily tons.  Even just a few grams and if you are selling it, you were considered a distributor.  It was a terrible punishment, so it certainly was clandestine, but the use was culturally allowed, a lot of people were using it.  But in the culture, it was known who was using it.  As a child, I knew who in my hometown were the people that used hashish and if you wanted hashish, where to go to get it.  So it was a very well-known thing, hut nevertheless it was not known to the authorities.

    JIHA:  It was not broadly practiced, but did occur sporadically.

    MAE:  That's right.  So, when I came to Ole Miss, I didn't know about "marijuana", hut I did know about hashish, the botany of the plant, etc., so when that position became available, I was ready.  We isolated a lot of new cannabinoids and other phenols, alkaloids and other new compounds.  That period, the late 70s and early 80's was the surge of new compounds found in Cannabis.

    JIHA:  Over 60 at last count.

    MAE:  Yes, and in 1980 we did our review article which showed 412 compounds belonging to 18 different classes.

    JIHA:  Has that vein of research been pretty-well exhausted?

    MAE:  Well, we have just finished another review, submitted for publication, in which we have mentioned another few compounds which were not previously reported.

    JIHA:  These compounds are present to minuscule amounts aren't they?

    MAE:  That's true.

    JIHA:  What is the scope of your research activities?

    MAE:  We do potency monitoring of roughly 3-4 thousand seizures of marijuana every year, and we get samples of hash and hash oil. We have done a lot of work, not part of the funded project, but on the side, looking at the biology of the plant material: some smoke studies with Dr. Sue Watson looking at the immune system, new formulations for THC, and so on.  I would say our most significant contribution in the ares of Cannabis research was the isolation and characterization of a good number of the new components that were discovered in the 80s.  There really haven't been many compounds discovered after we stopped working. We also have monitored the incidence and levels of paraquat, sprayed by the Mexican government, in confiscated marijuana, which would he a good representation of the marijuana on the streets, to see if it represented a terrible health hazard or not.

    JIHA:  What was your opinion on that?

    MAE:  Based on our results over the last few years, there is only about 5% of the material we examined that had any level of paraquat, but the levels aren't as high as people think it might be.  Most sample have less than 100 parts per million, on the average 20-30 parts per million, which is not enough to cause any lung damage.  In addition, this figure is based on material seized at the Mexican border and doesn't account for material coming into the country from other areas, which we don't monitor, so the percent of contaminated material is probably less.

    JIHA:  I found intriguing the RIPS discovery that there are varieties of Cannabis without any CBD whatsoever (some of the South African varieties) considering some of the proposed cannabinoid biogenetic theories.

    MAE:  Right, CBC and CBD weren't separable until relatively recently and their reliable separation was a critical discovery done by Carlton Turner, before I actually started working on the project.  Plant material with CBC predominant is felt to be a drug type.  Either CBD is not present or only in small amounts.

    JIHA:  So you would say that temperate fiber varieties would be characterized and identifiable by the predominance of CBD and a lack of, or small amount of CBC.  And the tropical drug varieties would have the reverse ratio.

    MAE:  That's correct.

    JIHA:  Have you examined any tropical varieties that were grown for hemp purposes?

    MAE:  No.

    JIHA:  What would you do if you were given a blank check and told to do something that you've always wanted to do, but had up to now, lacked a priority.

    MAE:  I've been fortunate enough to have really had the opportunity to do a lot of things, so there's not something out there in particular that I would say "if only".  But the one thing that I started years ago, and for which the funding was discontinued, was the fingerprinting project.  We did a good bit of work and actually brought it to a conclusion, but it was just a matter of taking it one step further to confirm the conclusions.  I would also like to do breeding with analytical feedback.  That was my next step, to take the chemical fingerprinting and kind-of marry that with the genetic fingerprinting and see if they agree.

    JIHA:  Are these results proprietary?

    MAE:  At this time they are proprietary, but I think I'm going to go ahead and publish, since these conclusions are three years old.  Unfortunately, because of the funding cuts, it was never put to a comprehensive field test with blind samples.  Even though our work was reasonably large in scope, it was not large enough to make it foolproof.  But it was giving us at least 90% confidence.  I could tell you where it was not from, and where it was very probably from, but some samples were so similar that it was hard to tell for absolutely sure, but at worst, you could narrow it down to between two countries.

    JIHA:  But if someone imported seeds from one geographic area and grew them in another, what would happen?

    MAE:  If you got Colombian seeds and grew them in the US, that material would be different than if it would have been grown in Colombia.  There would be much similarity, obviously, but there would be enough difference between them to say they are also different.

    JIHA:  So, there are both environmental and hereditary inputs.

    MAE:  Yes.

    JIHA:  How many varieties of Cannabis do you have?

    MAE:  We have a number of the usual varieties, Colombian, Jamaican, Mexican, Thai.  We used to have Turkish material, but haven't used it in recent years.  But we can get just about any material that we want from a country through the DEA offices there.  The bulk of our production material is Mexican.

    JIHA:  Do you have any interest in industrial hemp?

    MAE:  It's a new interest since I have received many, many phone calls from interested individuals, entrepreneurs, and state legislators from Kentucky and other states.

    JIHA:  What would you say is the potential for industrial hemp in the US?

    MAE:  There's a tremendous interest in the US for industrial hemp.  Now obviously there is, from the law-enforcement standpoint, opposition, simply because it makes their life harder and they really don't know how to control it.  People might want to grow other varieties of Cannabis and it is hard to tell which is which, just from looking at it, and it might be used as a cover up. There's also the issue about what to do with the leaves.  They're afraid people will try to make hashish or hash oil.  Where all of this is going to end up is anybody's guess.  But there is movement in other countries and we are having to import these fiber materials and yet have the capability to produce that here, so there is the question of "Why can't we also do that as well?".  I think that Canada is currently doing stuff, so that's putting a lot of pressure on our government to move on this issue.

    JIHA:  What directions should the hemp movement take, as far as you're concerned?

    MAE:  Certainly one area that if it is resolved, would have a tremendous economic impact is if you can produce a Cannabis variety that does not have THC.

    JIHA:  Zero?

    MAE:  Zero THC or close to zero THC.  Something not enough to make hashish or anything out of it.

    JIHA:  What would you say is that target level that would be universally acceptable?

    MAE:  Less than 0.1%

    JIHA:  You would think the DEA would have no problem with that?

    MAE:  I can't, obviously, speak for the DEA, But I would say that if you say the THC content is less than 0.0-something, they might be able to listen, but what they really want is zero, there's no THC in it, so that it becomes like the stalks, like the roots, like the seeds.  Although seeds have a little THC.

    JIHA:  Adherent?

    MAE: Well I don't know, adherent or otherwise.  I haven't examined it closely enough to tell.  Cannabis seed oil has THC and it's legal.  They're not worried too much about it because the amount is just so small.  And so that's the kind of level you would need to get in the leaves of a variety, and you guys ought to make this a priority item for you.  That can be a tremendous plus.

    JIHA:  For the expansion of Cannabis?

    MAE:  Yes, as hemp! If you didn't have THC, you wouldn't have to worry about it!

    JIHA:  But what about the fact that technically CBD, CBC and all these other compounds are also forbidden substances in the US?

    MAE:  Yeah, but I think that right now, it's just because they are associated with THC.  But I think that problem could be overcome.  Right now, there is THC, so there's no reason to look beyond that.  Now obviously CBD could serve as a starting material for manufacturing THC, and that's why CBD might also be a problem, but for now, probably more than 90% of the problem is with THC.

    JIHA:  What about the medical potential for Cannabis, either as whole drug or isolated products?

    MAE:  There is no question about the use of Cannabis for certain conditions.  It does have a history.  It does have the utility and so on.  However, Cannabis as a smoked product, in my judgment, would not be a useful product simply because of the lack of standardization, the fact that it's a smoked material: you can't determine the dose, people smoke in different ways, plus the interaction of the many different components and degradation products, and the tars associated with smoked materials.  So smoking is not a good delivery system. However, Cannabis as a plant that is rich in chemical components, would have potential for producing useful drugs, for example, THC.  Now THC in the oral preparation, it doesn't seem to be doing the good job it should or was expected to.  My personal view on the reason for this is the "first-pass effect".  The material taken orally goes through the liver and is converted to the 11-hydroxy metabolite, which is 4-5 times more potent in terms of psychoactivity, before getting into the bloodstream, and the profile of these two drugs is quite different.  Smoked material dosn't cause much of the 11-hydroxy metabolite to appear in the blood at all.  You really only see THC and its inactive carboxy metabolite.  Therefore, the pharmaco-logical profile of smoked material is the result of free THC in the blood. Suppositories were tried with THC and it didn't get absorbed at all, zero.  So I took THC and converted it to a pro-drug that would be bioavailable from a suppository.  Then, once it hits the bloodstream, it gets immediately converted to THC, which then mimics the smoked material.  This had a number of advantages: number one, it avoids the "first pass effect" through the liver; number two, it never gives such a high level of THC all of a sudden, which gives a "rush" high that is normally associated with "abuse" and also paranoia for those people who are not used to the effect of THC, the overwhelming effect.  Our dosage form gives a very subtle effect.  If anything it's a more calming and sedating effoct that does not make the individual "lose touch with reality", and that blood level remains for quite a long time, it has a long plateau.  Plus, it has a very quick onset of action, as compared to the oral.  In 15 minutes, you see good measurable blood levels of THC, reaching a maximum at an hour, stays up there for 2, 3, 4 hours and then comes down again slowly.  So it appears to me that what we ended up with is a preparation that you give as a suppository, but that doesn't have to be kept in the body for a long time, only 15-20 minutes.  If you can retain it for 15-20 minutes, that's sufficient.  The reason I say that, is that there was the concern about AIDS patients who might be suffering from diarrhea.  There is diarrhea associated with that condition and if the person can keep the suppository in for 15 minutes, that's all you need to do.  What happens is this drug almost gets sucked into the mucosa, maybe the fatty tissues of the intestine, and then it's a slow release into the bloodstream from that point on.

    JIHA:  Has any work been done on the anti-nausea, appetite stimulating properties or other potential medical uses of the 11-hydroxy compound?

    MAE:  No, not as much, no.  The notion some people have that the action of smoked Cannabis is due to the 11-hydroxy metabolite, I honestly don't believe that, because in the blood stream you don't see much 11-hydroxy at all.  When we developed our THC suppository, we did it with the idea of imitating smoking, without actually smoking.  One option is to give it by injection.  If you do, then you get the same profile as the smoked material, but people don't want to get a "shot".  So the next choice is intradermal, a skin patch.  But it doesn't work, THC just does not get absorbed through the skin.

    JIHA:  Have you ever considered anything like a bronchial inhaler?

    MAE:  Somebody made bronchial inhalers, but they couldn't get those particles to be small enough.  There were some technical problems.  Technical problems with the inhalers and technical problems with the skin patches, which leaves really two available ways: suppository or injectable.  And certainly injectables would work and would work fine if someone would want a shot, every now and then.  But especially in chronic use, the suppository would be the second, and better, alternative.

    JIHA:  THC is an accepted drug in the pharmacopoeia at ant point.  Can you tell us about some of the other ones, perhaps in the order of their likelihood to become commercial products?

    MAE:  I certainly think that CBD will be one of those.  CBD is being looked at as an analgesic.  I read in a newspaper article that Professor Evans and his group in England are looking at CBD as a possible component that is responsible for analgesic activity and so they were going to do trials with different types of Cannabis and with CBD itself.

    JIHA:  Have you heard of the anti-psychotic effect of CBD that the Brazilian groups of Zuardi and Guimaraes are investigating?

    MAE:  No, the main activity that I know CBD is famous for is the anti-convulsant activity.  Now the anti-convulsant activity of CBD would be worthwhile pursuing.

    JIHA:  So it may have some use in epilepsy?

    MAE:  Yes, in epilepsy.  This use and this activity has been around for many, many years.  And then CBC obviously has good anti-inflammatory activity.  Now whether this would be something that could be commercialized or not, there are so many non-steroidal anti-inflammatory agents, that CBC might take a "back seat" to those compounds.  But certainly there is the folkloric use and every day you look at the cannabinoids and activities in the light of today's science and today's pharmacology and so on, and you can really go back and scientifically and legitimately explain the usc of Cannabis over the years for so many things.

    JIHA:  Cannabis may contain particular useful compounds, but in an unpredictable fashion in the whole natural product.  That's been probably the main drawback of Cannabis in history.  Some people would find it would work and for others it didn't, probably because they would be using different strains of plant.

    MAE:  Different strains and even with the same strain collected at different times, you might have different chemical compositions and that's really one of the reasons why Cannabis as Cannabis would suffer from problems in terms of its use as a drug.  Unless you can really specify every component in there, how can you say that the variety that you use today it going to have the same effect as the variety you use tomorrow?  Unless you go with the kinds of material that HortaPharm is going with right now.

    JIHA:  So you would say that defining chemical profile, overcoming pyrolytic products in the lungs and perhaps microbiological contamination are probably the three major objections of the medical community for using crude Cannabis as a medicine?

    MAE:  That's true, yes.

    JIHA:  Do you think the lack of other cannabinoids on the market, besides THC, has more to do with pharmacological or commercial considerations?

    MAE:  Number one, the pharmacology of most cannabinoids is not overwhelming.  They have some activity, but their activity is often not as high as some already existing products.  Number two: the stigma of being associated with marijuana.  Pharmaceutical companies just don't want to deal with that.  Number three: the fact that they have already been known for so long and therefore there's no exclusivity, you can't patent it anymore and therefore pharmaceutical companies are not interested.  It's already well known, so what are you going to do?  The only reason we were able to do this suppository patent is because we have a new formulation, a new prodrug that you could prescribe for these indications, but you couldn't patent THC itself for these indications, since it's already known.

    JIHA:  What about anandamide?  Do you have any interest in that?

    MAE:  No, I really haven't had much to do with this particular area.  Obviously the discovery of this compound and the receptor have made people believe more in cannabinoids and the possibility of developing real drugs.  That discovery in itself has "legitimized" cannabinoid research and made it on par with research on other potential pharmaceuticals.

    JIHA:  There are illegal, but unofficially tolerated, Cannabis "buyers' clubs" which have sprung up, some of which cater to thousands of patients.  To implement the same thing on a more legitimate basis would require an expansion of the extiting federal "compassionate-use" program, which is now down to, I believe, 8 patients.  Do you think that is feasible, if politically mandated?

    MAE:  First, let me comment on that program, which provides 300 cigarettes per month to a patient.  In my judgment, that's way too much material for an individual to use for whatever condition.  It's too much THC.  I don't know how this was picked as the dose.  But coming back to your question, if there is the political will to make it happen, it just means that NIDA will provide material for these clinical trials, because these are nothing but clinical trials.

    JIHA:  Even the current "compassionate-use" program is considered a clinical trial?

    MAE:  Absolutely, under an IND (Investigational New Drug protocol).  And that's the reason most of this has been stopped.  You've started doing research to see if it will work, yet you're continuing to do it, so you're beyond the scope of a clinical trial.  So you can do one of two things.  Either you can continue to give it to them whether it works or not.  Or you have decided that maybe the stuff works, so you continue to give it.  Then you're talking about giving it to them as an approved drug for that indication.

    JIHA:  As an investigative drug or as a more accepted pharmaceutical?  Can it stay in that limbo, practically speaking?

    MAE:  I guess its up to the FDA.

    JIHA:  The program would have to be expanded on a case by casc basis with multiple clinical trials or could one huge clinical trial he opened up?

    MAE:  There's not just one clinical trial.  Each of those patients is on a different clinical trial.  You can have one IND that includes 15 or 20 or 100 patients, but you've got to have a physician monitoring all these patients.

    JIHA:  And the normal site protocol for monitoring these patients has to be followed?

    MAE:  Absolutely, yes.

    JIHA:  In San Francisco alone, there are several thousand patients and if you add in that, the demand across the country, that's a rather large load.

    MAE:  It would be, there is no question that it would be.  Then our program here would have to expand tremendously to keep up with that.  But those INDs don't get approved all at once, they take time.  And all those thousands of patients are not going to he under one IND.  They will not, because no one physician can monitor and deal with all those people.  So this would be a slow process, but I would say that if the number of people is going to be in the hundreds, we could probably deal with it under existing circumstances.  We could produce in excess of 5000 kilograms, so we could produce about 5 million cigarettes.

    JIHA:  Do you think that you could produce reliable material, consistent in quality, in those quantities?  You certainly have the analytical capability, but do you think that, horticulturally speaking or otherwise, you would have significant practical problems with giving everybody the same thing?

    MAE:  Not really, no.  We can do a lot.  We've done an experiment this last season with cuttings and things like that.  We have done one part of the garden, just all cuttings.  And it works.  We did cuttings of different plants and each group of cuttings came out exactly the same.  I don't think it's unreasonable to do that.  We would have to have a facility and a whole program to do it that way.  But I don't think in an initial clinical trial, that everyone has to be given the exact same thing, so long as you blend things together to get the required THC level.

    JIHA:  Do you put any credence in the lore that certain types of Cannabis are good for one thing or not so good for another?  Do you see that as just subjective impression or do you think that there is a chemical and pharmacological basis for variation of patient reaction?

    MAE:  Well, that depends on what you say it is good for or not good for.  Now I don't want to understate the importance of the chemical profile of the plant material, because it's very important what you have in there.  After all, when it gets smoked, you're getting the effect of everything that's going in.  But for small differences between varieties and so on, I don't think they are going to have a really significant effect on the pharmacology simply because THC is by far of the highest concentration in whatever it is that's being consumed.  The overwhelming effect is going to be that of THC in my judgment.

    JIHA:  Do you see subtle effects by CBD, CBC, CBG?

    MAE:  There are effects, but whether these will have a pharmacological impact or not, I'm not really sure.  But in terms of approving that as a drug, in the final analysis, you would have to show what impact those changes are going to have on the final activity, or get a variety that's similar to whatever you did your clinical trials with.

    JIHA:  Any final comments on the future of Cannabis?

    MAE:  In terms of the cannabinoids, I think that THC is going to have a much wider use in the pharmaceutical area, for other indications.  We've already gotten a patent on the use of suppositories for the treatment of different conditions, glaucoma, nausea and vomiting, appetite stimulation, as an analgesic, as an anxiolytic, and also as an anti-spastic for MS, spinal injuries and so on.  These are conditions that we have actually applied for in the patent and these are good legitimate areas where THC could be a very helpful drug.  So I would say in the future we'll see much more acceptable use of THC as a drug.

    JIHA:  More broadly prescribed.

    MAE:  More broadly prescribed, yes.

    JIHA:  Thank you.