NARCOTIC SUBSTANCES

Mode of Action
The substances whose effects I have in a general manner just described may be divided into several groups which, though not absolutely distinct, exhibit differences in the nature and manifestations of their energy. It will easily be understood that if an influence is exercised on the brain, its different parts may react differently although the effective agents seem to produce the same result. Even if we confess that the identity of the effects is not real, but that owing to the unsatisfactory means of investigation there is an apparent identity, there still remain enough experimentally proved toxicological facts to indicate that the chemical constitution of the various parts of the brain cannot be considered as identical. There must be quantitative and qualitative chemical differences in both the gray and the white matter of the brain. Chemical investigations up to the present have told us very little as to this. They inform us that the quantity of neuralgia and albumen represents more than half the organic matter of the gray substance and only a quarter of that of the white substance, that the quantity of cholesterol and fatty matter is only one-third of the gray substance, and that the proportion of cerebrin, approximately one-twentieth, is the same as in the white substance, etc. Even if the substances mentioned were really integral constituents of the cerebral tissues and not the result of chemical analysis, then we are enlightened only as to the chemical constitution of the dead brain and not in the least as to the function on which the activity of the brain is based. If, as I think, there are differences, it can be understood why substances which exert an influence on the brain evoke diverse effects in quality and quantity in its different departments. Cholesterol, phoshatide, cephaline, cerebroside are only names which we apply to substances whose active part in the functional process of the normal or morbid brain we cannot understand.
Several toxic processes have brought me to the conclusion that there are differences also in the vital requirements of the various parts of the brain. It has been impossible to understand, even approximately, why in the case of carbon monoxide poisoning it is the ganglions of the base which are most affected, especially the corpus striatum and also the thalamus and copora quadrigemina. The simplest explanation would be to suppose that these parts of the brain have a greater need of blood that is rich in oxygen and undeteriorated, and cannot be satisfied with blood containing carbon monoxide. At the same time perhaps we may assume an increased chemical reactivity towards substances which are produced by disintegration of the aforementioned parts through malnutrition.
The functional response of the spinal bulb, for instance, towards narcotics, is an example of the differences which can be ascertained with regard to the reactive capacity towards certain chemical substances of single parts or points of the brain. Whereas the centres of the cerebral cortex react by a rapid cessation of certain of their functions, more time and a greater mass of the effective agent is necessary in order to bring about a functional modification of the respiratory centre. These various results should not be attributed solely to the size of the dose administered, for if the law of mass action can undoubtedly be applied to a certain extent to the medicinal and toxic action of drugs, its importance cannot be compared with the part it plays in chemistry.
A primary excitation should be included among the constant reactions of the brain to narcotics. I regard it as a general law of biology that a diminution of the functions of any organ of the body is preceded by an increase of functional energy, the expression of the primary excitation. The force and duration of this excitation depends upon the state of the individual brain and the nature of the exciting agent. It is always there, even if it cannot by ordinary means be perceived, and may be so considerable as to represent for some time the only determinable reaction.
Besides the direct effects on the central nervous system brought about by the substances in question, there are, as I have already stated, effects which extend to the other organic functions, and may be called secondary effects.
If we consider the great and permanent influence exercised by the brain and spinal cord on the life of the organism, on the heart and respiration, the glands, the muscles, the sense-organs, etc., and if it is true, as I believe, that even the processes of nutrition and assimilation are dependent on the nervous centres, it will be evident without further explanation that the action of narcotic substances will also be felt in the organs which are under the influence of the nervous system. The symptoms which result from this dependence, combined with the manifestations of direct action on the brain and spinal cord, form the clinical record of the effects of these substances.
The final explanation of the mode of action on the brain is far from having as yet been found. It has even been found impossible to theorize on the phenomena of artificial sleep or the anaesthesia of pain. None of the numerous attempts at explanation deserve to be quoted. They are nothing else than the circumscription of the process itself and merely provoke ridicule. Is it a chemical process which takes place in the nervous substance of the cerebral cortex? This is my view, although it is urged against this opinion that the minute quantities of the active substance introduced into the organism which bring about such evident effects would not be sufficient to cause a chemical reaction to take place. I regard this objection as not having sufficient support to refute my point of view. For even if half a milligramme of scopolamine is a very small quantity compared with the mass of the brain to bring about a cerebral action in the form of somnolence, we must not forget the action probably affects certain definite centres which are no more than points in the brain. The narcotic may have on these limited points a catalytic action, i.e. without producing any chemical change it may cause paralysis or excitation so long as it remains in contact with the centre capable of being influenced. We may easily conclude that scopolamine or morphia may arrest or accelerate normal functions which would, in this case, lead to sleep.
The chemical action of one group of these substances, the anesthetics that are inhaled, is more accessible, because they possess the recognizable property of dissolving the fatty matter of the brain, a property which can be regarded as also capable of promoting a functional modification. This explanation of the mode of action of these substances, which I gave many years ago,' and which has been adopted by others and put forward as their own, has a high degree of probability. The rapidity of the re-establishment of the normal state after the cessation of the toxic action, which remains unexplained, cannot be understood. But if we admit that a catalytic action by contact exists, as is possible with other substances of the same group, there will be no difficulty in understanding the re-establishment of the normal state.

Classifications of Narcotic and Stimulating Drugs
I classify the agents capable of effecting a modification of the cerebral functions, and used to obtain at will agreeable sensations of excitement or peace of mind, as follows:

First group: Euphorica; sedatives of mental activity. These substances diminish or even suspend the functions of emotion and perception in their widest sense, sometimes reducing or suppressing, sometimes conserving consciousness, inducing in the person concerned a state of physical and mental comfort. To this group belong opium and its components, morphia, codeine, etc., and cocaine.

Second group: Phantastica; hallucinating substances. This series comprises a number of substances of vegetable origin, varying greatly in their chemical constitution, and to these belongs in its proper sense the name Phantastica, or Drugs of Illusion. The representatives of this group, such as mescal buttons (anhalonium lewinii), Indian hemp (cannabis indica), and the plants which contain tropines, bring about evident cerebral excitation in the form of hallucinations, illusions, and visions. These phenomena may be accompanied or followed by unconsciousness or other symptoms of altered cerebral functioning.

Third group: Inebriantia. These bodies can be produced by chemical synthesis (e.g. alcohol, chloroform, ether, benzine). A primary phase of cerebral excitation is followed by a state of depression which may eventually extend to complete temporary suppression of the functions.

Fourth group: Hyponitca; sleep-producing agents, such as chloral, veronal, sulphonal, etc.

Fifth group: Excitantia; mental stimulants. Substances of vegetable origin which produce without alteration of consciousness a generally more or less apparent excitation of the brain. To this series belong the plants containing caffeine, tobacco, betel, etc.