Drug Abuse

SUMMARY

1. This review of the pharmacology of marihuana is centered around the chemical and pharmacological identification of the active principles of hemp. Coordination of chemical and pharmacological investigations as a prerequisite to success in the search for unknown principles and of the analysis of the structure-activity relationship of these compounds is discussed.

2. In a survey of the sources of preparations with marihuana activity, hemp seeds are disclosed as a heretofore unknown source of active substances.

3. Varieties of hemp can be distinguished according to genotypic differences of the content of active principles which persist over generations independently of soil and climate.

4. The pharmacological actions of marihuana are analyzed with regard to their specificity and their usefulness as indicators of specific components.

5. Sixty-five substances from the new class of cannabinols and related classes are reviewed, among which are the essential components of the marihuana-active hemp oils. The discovery of this class, the synthesis of these representatives, and their structural elucidation led the way to the discovery of the active substances.

6. Quantitative assay procedures are described for the most importent marihuana effects that are observed in the animal experiment. The assay of the ataxia effect in the dog and of the synergistic hypnotic effect in the mouse with refined procedures are shown to be reliable expedients for measuring these two marihuana actions, whereas the areflexia effect in rabbits failed to show the reproducibility required for quantitative purposes.

7. With the aid of these methods the natural tetrahydrocannabinols are shown to be active principles responsible for ataxia in dogs and psychic action in man. They are intermediate products between the two ineffective substances which compose the bulk of hemp oil: a labile excretion product of the plant, cannabidiol, and a stable end-product, cannabinol, The conversion of cannabidol into active tetrahydrocannabinol by a natural environmental influence has been paralleled by ultraviolet irradiation in vitro.

8. Numerous isomers, homologs and analogs of tetra- and hexahydrocannabinol are shown to possess the specific marihuana action. The potency varies enormously and is highesi in natural, optically active—laevogyrous—tetrahydrocanna binols.

9. The significance of many of the structural details of th( tetrahydrocannabinol molecule for marihuana activity is elu. cidated by quantitative determinations of relative potency Special attention was devoted to a study of the importanct of variations in the length of the 3-alkyl side chain of tetra hydrocannabinols. In studying methyl to nonyl homologs the original amyl derivative occurring in nature, it was founc that the maximum potency is not at the amyl, but at the hexy homolog, and in two out of four homologous series at th( representatives with still longer side chains.

10. In addition to the ataxia and the psychic action, othei pharmacological attributes of the tetrahydrocannabinols an a decrease in the respiratory and an increase in the pulse rate in the non-narcotized dog.

11. The synergistic hypnotic action of marihuana in till mouse is to be attributed to the otherwise inert cannabidiol

12. The corneal areflexia action in the rabbit was mudl stronger in impure distillate oils than in pure tetrahydrocanbinols, which leads to the conclusion that this action is her poorly reproducible or must be attributed to a different, yet unknown, principle.
13. Only one among the numerous cannabinol derivatives, nethyltetrahydrocannabinol, was found to produce a motor mutant—convulsant—action concomitant with ataxia action. cannabidiol derivative, tetrahydrocannabidiol, was found to ve specific convulsant action in the dog.

14. A central stimulant (benzedrine) considerably increased !. ataxia action of marihuana, whereas a hypnotic (amytal) d no influence.

 

1 From the Department of Pharmacology, Cornell University Medical College.

2 Part of the experimental work here reported was conducted in collaboration with W. Modell.

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