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DR. MATCHETT: The problem is clarified a little bit by recognizing that there are two distinct phases involved, the first of which must be pretty well finished before the second can begin.
First of all, there is the separation of the active principle from other material, and second, the characterization of it. Before a competent separation can be undertaken, we must be in possession of suitable assay methods.
We, of course, are interested in those manifestations of Marihuana that lead to the effects, which have led in turn, to the passage of the Act We are not sure, I take it, whether the substance produces ataxia in the dog, or sleep in the mouse, or corneal(?) anesthesia in the rabbit is the
same as the one in which we are interested.

Nevertheless, something must be adopted, and by common consent, a dog assay, with all its faults, has been the method of choice. It seems obvious that these various principles, if more than one exists, will be each characterized on its own merits.
In considering this phase of it, also, it must not be forgotten that any one of the effects may be combinations, and any of the effects that we are able to measure may possibly be combined effects, of which the bad effect of the drug itself may be only one.
With that so disposed of, it is possible to recognize that certain characteristics of the so-called resin are fairly well defined already, although I think we must recognize that the resin itself is variable, and to what extent, we are not yet able to say very definitely. As Dr. Blatt said, there have been certain individuals isolated in pure form, of which the most important are Cannabinol and the hydrocarbon nonacosame.
There is also present definitely in the resin a substance that responds to the alkaline Beam test.
There are still other substances among all those responsible for the psychological and physiological activity; of such there may be one or more.

And finally, there are those volatile oils, in which there is no tremendous interest other than to dispose of them before being able to isolate the drug.
Now, little or nothing is known of the nature of the active substance. All attacks on the problem have, thus far, broadly speaking, produced negative results. The thing, in any event, is not an alkaloid, because we are not able to extract it into acid solutions from solvents, nor does it contain any nitrogen. It is not an acid, since it does not extract into alkaline solution. And it has not been shown to contain any carbonyl groups because it does not form any derivatives with the common reagents for such.

There is evidence on the other hand that it forms esters and that it is an aromatic substance, the latter from the refractive index of the most active fraction. From that it would appear to be a phenolic compound. The substance is thermostable under rather rigorous conditions, but it is
quickly destroyed in the presence of oxygen. It is also quite likely that it is unsaturated since reduction by hydrogen is possible.
But all those, unfortunately, are properties of the active mixtures that Dr. Blatt referred to, rather than of any chemical individual. They are all of some assistance though, in considering methods by which the problem may be attacked.
Now, only distillation in a rather high vacuum has been of any assistance thus far in fractionating the mixture, known as Cannabis resin. The volatile oils are so separated with relative ease. The substance responsible for the acid Beam test, whatever it may be, is removed, the acid test no longer appearing in the distillate. The hydrocarbon which does appear in the distillate can be removed by crystallization from alcohol or some other solvent, and pure Cannabinol can
be removed as a crystalline acetate or paranitry benzoate. As Dr. Blatt pointed out, this point is where the trail ends at present, with the exception of a brief note indicating that it is definitely possible to find physiological effects in the material remaining after Cannabinol has been removed.
It is at that point that we purpose ultimately to actually begin. The former distillation has been carried out at pressures anywhere from atmospheric down to a reported pressure of about five-one thousandths of a millimeter.
From the character of the work in which this was reported it would appear that the reported pressures must be taken with a grain of salt. No essential difference however has appeared
in the products of fractionation. The material, as you may be aware, is an exceedingly difficult material to work with, a heavy tar-like oil, and it does not lend itself readily to distillation by any means. We have considered that at this point it might be preferable to resort to molecular distillation in an effort to obtain a more competent separation. If this hope be realized, a number of avenues of attack are opened or re-opened. That is, among other things the action of solvents may be reinvestigated, and of particular interest will be the action of solvents at low temperatures. Then there are possibilities of preferential adsorption, and also it may be possible to prepare crystalline derivatives. They fail to appear from treatment of the present mixtures.
Now, the molecular distillation outfit that we have chosen for this work is of the static type, rather than the cyclic still with which you are probably more familiar, because the higher boiling fractions of this material are so viscous that they probably would not cycle with in that
still without special precautions to maintain a high temperature.

The original material has been distilled before passing it into the molecular still in a flash apparatus that operates under a good vacuum. This is necessary since the crude oil is particularly prone to spit in the molecular still and ruin the distillation. More specifically, the process that we are following is extraction from the plant material with cold alcohol, alcohol being chosen as a solvent rather than petroleum ether, on account of fire hazard. This process is
followed by a liquid extraction from the alcohol by pentane, which does away with a lot of water soluble material, and tarry material of a nondescript character.
We have not yet thoroughly satisfied ourselves that all of the active material is extracted by pentane, but we believe we have every reason to think it is.
Then the pentane, which incidentally, extracts quite a little alcohol, is removed, and the alcohol is also removed. The material is then passed through the flash process that I referred to a moment ago, and the distillate from here is placed in the molecular still. That is the point which the investigation has reached at this particular moment.

Now, it is expected to divide the oil into about ten fractions in the stills, then to remove Cannabinol as the acetate and the hydrocarbon by precipitation from a suitable solvent, and then to refractions, to the remaining material. The work from that point, of course, all depend upon the results of the fractionations, and can not be very definitely foreseen, other than that
those processes, to which I referred a moment ago, will be applied. Now, it would have been possible to have attacked certain phases of the problem along a number of other lines, a few of which I will suggest in conclusion. The first would be a characterization of those volatile oils,
which have been referred to, and which would be of interest from a purely chemical point of view. They are separated with relative ease, by steam distillation, for example. No one, of course, has been very much interested in them, and that line of attack has not been followed.
Again, someone might become interested in the substance which responds to the acid Beam test. It can be removed from a solution in petroleum either by means of alkali, and presumably would be isolated with relatively little difficulty, but experience shows that resins so prepared
are not physiologically active, hence little interest is attached to that substance.

A third possible line of attack would have been in connection with the Beam test itself. The development of the color is due to a product resulting from oxidation of some substance which is present In the resin. This substance is soluble in aqueous alkali, and is precipitated by acid. It can be readily extracted from acid solution. It, of course, is not actually the substance which responds to the alkaline Beam test, but it would be of great interest from the purely scientific point of view.

MR. WOLLNER: I would like to make a couple of announcements. Those of you who are not particularly interested in the chemical attack here may find this part of the program a little arduous, and I want you to understand that you are at liberty to leave and interrupt if you want
to, as I think this part of the program might be a little obtuse at certain points.
Dr. Blatt has just indicated that there are some errors in the material which he distributed on the critical review. Do you want to indicate those?

DR. BLATT: There is one error in the literature, for example on page 469 in the middle of the page are three formulas, just one the paragraph beginning in the middle of those formulas.
There is a carbon atom, a "C", a single line to an oxygen "0", and that should be a double line to make it conform to the other two. Then, on that flow sheet, on the left-hand half of the page, the second of those errors reads "dihydrogenation with sulphur," and that should be "dehydrogenation", and not "dihydrogenation".

MR. WOLLNER: As you gathered, Dr. Matchett's attack there is directed at the heart of the problem; that is to say, the isolation and characterization of the extreme number of active principles. I indicated at the beginning that there is another phase of the problem, and that was identification. We at this time do not know whether the chemical attack is destined to determine the active principle in one year or sixty years.

The Treasury has issued a little manual of identification, consisting largely of photographs, and it is being distributed. In this country we are mostly dealing with the drug in its plant form, and in this manual they are showing the separate parts of plants, and so on, and it is helpful in that
direction. I am going to ask Mr. Levine to give us a picture of the Beam test.


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