The hallucinogens are divided into three groups: adrenaline-related, tryptamine-related, and miscellaneous, and their chemistry is reviewed. The author points out the limitations of the biochemical and classical pharmacological approaches to understanding the varieties of psychological responses to the drugs. He urges that we view the function of the central nervous system in terms of structure, chemistry, and information so that we can better comprehend and predict psychological reactions to the drugs.

A VARIETY of names have been proposed for the group of drugs most popularly called "hallucinogens." Names such as psychotomimetic, psycholytic, psychedelic, schizophrenogenic, cataleptogenic, phantastica, or mysticomimetic have been suggested at one time or another to emphasize a particular aspect of the reactions(8, 24). But, as we shall see later, the type of reaction depends more on the personality and momentary mental set of the subject and on the setting of the experiment than of, the drug itself, so that the noncommittal designation psychodysleptic (meaning distortion of mental functioning), proposed by Delay, seems to be the name of choice (10). The name hallucinogenic, however, is so extensively used that we shall use the two terms interchangeably.

The literature is replete with vivid descriptions of the striking and varied symptoms produced by these drugs(l, 2, 6, 13, 14, 18, 20, 24). These include marked disturbances in sensory perception, lability of emotional experiences, and feelings of depersonalization and derealization. Various characteristics of the primary process thinking, including a dream-like quality of thought, are brought on by these drugs; this aspect of the effect is so prevalent that these drugs are often called "primitivizing agents."

Many of the drugs have their origin in concoctions prepared by primitive natives and used in their religious ceremonies, but quite a few hallucinogens were synthetically prepared and were discovered either by accident or as a result of systematic research.

Chemistry and Dosage

From a chemical point of view, we can classify the hallucinogens roughly into three groups(7,13).

1. The phenylethylamine group might also be called an adrenaline-related group since many of its members show a clear chemical relationship to the sympathomimetic catechols. (See Figure 1.)
   
   Mescaline is clearly the major hallucinogen in this group. It is the active ingredient of peyote, the dried tops of the cactus of the Lophophora williamsii used by some Indian tribes in the U. S. and Mexico. The active dose of mescaline is in the 300-500 mg. range.
   
   The other members of this group are either active, like TMA (trimethoxy-amphetamine) or MDA (methylenedioxy-amphetamine), in the same dose range as mescaline, or the activity is shown in animals only (N.N.-dimethylmescaline and 3, 4-dimethoxyphenylethylamine).
   
   
2. The tryptamine group contains most of the known hallucinogens and some of the most active ones. (See Figure 2.)
   
   Among the simple derivatives of trvptamine we have a score of compounds with proven hallucinogenic activity. DMT (N.N.-dimethyltryptamine), DET (N.N.-diethyl- tryptamine), DPT (N.N.-dipropyltryptamine), a -MT (dl-a -methyltryptamine), psilocybin, psilocin, and the dimethyl homolog of psilocin have been reported to be active in the 10-50 mg. dose range. The psychodysleptic action of serotonin and bufotenin is not definitely established. DMT and bufotenin are present in the snuff called "cohoba," prepared by Haitian natives from Piptadenia peregrina seeds, while psilocybin is the active substance in the sacred Mexican mushrooms called "teonanacatl" and has been shown to belong to the Psilocybe species.
   
   There are quite a few compounds with proven or suspected hallucinogenic activity which contain the tryptamine structure concealed in a more complex ring structure. (See Figure 3.)
   
   LSD-25 is of course the best known hallucinogen. it is a synthetic product prepared from lysergic acid, the common nucleus of the ergot alkaloids. Its activity bad been discovered in a laboratory accident by A. Hofmann; it proved to be not only the most active hallucinogen (30-100 ug. range) but one of the most active drugs ever known.
   
   The other two representatives of the complex tryptamine class shown in the figure are harmine and ibogain. Both of them are of plant origin. Harmine and its hydrogenated derivative, tetrahydroharmine, were found in Banisteria Caapi and Prestonia amazonicum, used by South American Indians in their concoction called "yage," while ibogain seems to be the active ingredient of the African shrub Tabernanthe iboga, taken by some inhabitants of West Africa and the Congo. The psychodysleptic dosage range for synthetic harmine is between 150-400 mg., while the dosage for ibogain in man has not yet been esablished.
   
   
3. The third group is a chemically heterogeneous group and its psychological effect in man is distinctly different from that of mescaline or LSD. Among the many pi-peridyl glycollates, the one called "ditran"
   
   in doses of 10-20 mg. produces a pattern of somatic and psychological symptoms which is distinctly different from the pattern produced by the typical hallucinogens. The most striking difference is a complete loss of contact with the environment and a considerable amnesia for the hallucinatory period. In contrast, during the effect of LSD or mescaline, the consciousness is mostly clear, and a large portion of the experience is recalled after the effect wears off. (See Figure 4.)
   
   The pattern of psychological reaction to marihuana, in which tetrahydrocannabinol, was shown to be the active ingredient, is also distinguishable from, that of LSD or mescaline. The effective dosage range for the synthetic drug is variously put at 5 mg. to as high as 200 mg.
   
   The effects of the morphine antagonist, N-allylmorphine (nalorphine), are comparable to those of marihuana, and the hallucinogenic dose is 30-75 mg.,
   
   The mental symptoms produced by phenycyclidine (sernyl) are body image changes, anaesthesia, and delirium; these are distinctly different from the effects of any other hallucinogen(l, 7, 13). The effective intravenous dose was found to be about 0.1 mg./kg., and the effective oral dose was found to be 10 mg.
   
   

The Use and Misuse of Psychodysleptics

At the beginning of the scientific inquiry into the nature of the drug-produced so-called "model psychosis," the biochemical and pharmacological approach offered exciting perspectives. Reviewing critically the work done in the previous 19 years, Giarman and Freedman came to the disappointing conclusion that the biochemical approach had shed little light on the mode of action of the hallucinogenic drugs (12). Apparently the gap between the molecular and the behavioral or subjective level proved to be more than what biochemistry or classical pharmacology could successfully handle.

The brain is clearly a very complex nervous control system in which chemical interaction is only part of the story(3, 11, 25, 26, 27). The physical structure of the intricate feedback loops between various areas are equally important in determining the functional characteristics of the CNS. Finally, the individual's reaction to a particular situation will depend on the information received from the environment and stored in his memory files.

Unless we understand the function of the CNS in these three terms, namely structure, chemistry, and information, we cannot hope to understand and predict the psychological reaction to the psychodysleptic drugs.

I will try to illustrate what I mean, first, at the general level, and then by a concrete example show how results of the basic science level can be applied on the practical clinical level even before the complete picture of the relationships is clarified.

We have already mentioned that the effect of psychodysleptic drugs depends to a large extent on the mental set of the subject and on the environment or the setting of the experiment. In other words, the effect of a chemical depends on the information available to a particular individual with an individual personality.

Without the drug, we have three broad categories of personality characteristics as they are presented to other people. A person may have a well-adjusted, a psychotic, or a borderline personality. If a psychodysleptic drug is given, there are two variations for each category depending upon the information provided. (See Figure 5.)

If, for example, the drug is administered to a psychotic subject, we can observe an exaggeration of existing psychotic symptomatology(2, 5, 22). Here the information input has little significance since these patients have already lost contact with reality.

If the drug is taken by a borderline psychotic person or by a subject with personality defects in a medically unsupervised or socially unsanctioned setting, the results can he read in the criminal columns of the newspapers and in the nationwide magazines. The subjects are likely to end up in jail or become psychotic and require hospitalization(4, 17).

A third variation of the same theme would be an instance when the drugs are given to well adjusted normal or normally functioning persons, as we did in two sets of experiments in a medically supervised atmosphere; the subjects were kept "blind" as to the nature of the drug. It is then most likely that a temporary "model psychosis" will develop, as it actually did in our experiments, justifying the "psychotomimetic label for these compounds(5,22).

The next variation, the most important one, is when the drug is given to a well adjusted person who is well informed about the possible effects of the drug. In this case the kind of setting will determine what will happen. If the setting is religious, it is likely that a mystical, or mystic-like, experience will ensue. This is the most controversial area at this moment(9, 16. 18, 24).

If the setting is a therapeutic one, the legal considerations are superseded by safety considerations. Here I should emphasizethat these drugs, given under proper medical supervision, are relatively safe(4, 5, 17). In this therapeutic setting, depending on the orientation of the therapist we could elicit any of three different types of experiences. Followers of the psychedelic school would strive for an overwhelming transcendental experience (single large dose[19] ); the psychoanalytically oriented therapist would try to bring to the surface repressed, emotionally-loaded childhood memories (moderate doses, several sessions[6]); while others' versed in the technique of hypnosis, would induce hypnosis while the patient could still concentrate and then explore the major problem areas, using posthypnotic suggestions to work on a particular problem area (moderately high dose, several sessions[15]).

I am of course aware of the vagueness of the categories and that the idea of structure is being used very loosely, tacitly assuming that the structure of personality is somehow related to the physical and functional structure of the CNS. I am also cognizant of the fact that the information classes are actually end points of a continuum. I have only been trying to show that the contradictory results obtained with these drugs, as reported in the literature, are the results of certain basic relationships of which we were perhaps not fully aware.

The Question of Scientific Control

A concrete example of how basic science results can be applied to clinical studies is cited from our own work. Briefly, it is based on the recognition that the metabolism of hallucinogenic tryptamine derivatives proceeds via hydroxylation in the 6 position. If we make a slight change in the structure of DET, for example, by substituting a fluoro-atom in the 6 position, the resulting drug (6-FDET) can no longer be hydroxylated and has a very curious property. In two pilot studies (one single blind, the other double blind), with a total of 18 patients, the drug proved to be nonhallucinogenic while retaining much of the autonomic activity. We gave it the name of "active placebo," meaning that it does produce bodily changes somewhat similar to those seen after DET but without being hallucinogenic itself (21, 23).

Such an "active placebo" might play an important methodological role in well-controlled clinical trials in which the effect of the hallucinogenic property of a drug is to be tested.

The Question of Public Control

Finally, there is a situation I feel compelled to comment upon. I am referring to the gray area of the nonmedical use or abuse of hallucinogenic drugs(5, 15). There is an obvious need for regulating the use of these powerful and potentially dangerous agents. However, we should not throw the baby out with the bath water. The recent run of unfavorable publicity in newspapers and national magazines has forced the Sandoz Company to stop manufacturing LSD in the United States, and the company has turned over its LSD supply to the NIMH as of April 15, 1966(16).

This publicity pressure threatens serious scientific research not only with LSD but with the entire class of hallucinogenic drugs. We cannot put blame on the drugs; we can only put blame on the manner and the ways they are being used. It is my belief that it would be most unfortunate if we were to permit undue hysteria to destroy a valuable tool of science and evaporate an eventual hope for the many hopeless.

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Get the facts or the facts will get you. -JUSTICE LOUIS BRANDEIS