Psychotomimetics

In 1943 H. Hofmann, a Swiss chemist, described some unusual experiences while working in his laboratory. He had difficulty concentrating on his work and noted that the shape and size of his co-workers and laboratory equipment appeared to change. Later, on closing his eyes, he experienced fantastic visual hallucinations in many colors. These experiences lasted for several hours. Hofmann had been working on the synthesis of ergot derivatives; and the substance that was found to be responsible for these unusual experiences was identified as lysergic acid diethylamide (LSD). Hofmann's report of his experience renewed interest in a class of drugs generally termed psychotomimetics, or hallucinogens, which bring about changes in psychologic functioning which resemble those of "functional" psychoses such as schizophrenia.

Actually, drugs which induce profound perceptual and behavioral alterations have been known for a long time. These substances have probably played an important role in the development of religion, philosophy, art, science, and civilization as a whole throughout the ages. The necromancers and priests of some South American Indian tribes have used cohoba snuff in their religious rites for many centuries. This substance, obtained from the seeds of the plant, Piptadenia peregrina, has been identified as the psychotomimetic, bufotenine, mentioned previously (66). There is some evidence that the use of this substance by some of the Norse invaders of the eight and ninth centuries accounted for their savagery and fierceness in battle. They were called Berserkers, from which the English word denoting frenzied, enraged behavior comes.

Similar to this is the ololiuqui drug, a psychotomimetic used by the Aztecs, and mescaline, obtained by American Indians in the Southwest by chewing peyote cactus and used by them in religious rites. References to substances producing similar effects are found in the writings, records, and folklore of most ancient civilizations about which much is known. Most of the substances are unidentified as yet. It appears, however, that the search for such drugs has a long history.

The term, psychotomimetic, is properly applied to substances producing transient but marked alterations in experience and behavior in normal subjects, which resemble those characteristics of the major psychoses. They may include visual and auditory hallucinations; distortions in visual and auditory perceptions; feelings of unreality, depersonalization, or estrangement; marked changes in affect such as euphoria, depression, or apprehension; and tendencies toward paranoid or autistic thinking. However, gross disturbances in memory, orientation, or the level of consciousness, such as dullness and stupor, are not characteristically present. It is the relative freedom from these other changes that differentiates the psychotomimetics from drugs such as atropine and bromides which, in overdosage, produce a so called toxic psychosis. However, by no means are the changes in mental state induced by psychotomimetics identical with those seen in naturally occurring psychosis. For example, visual hallucinations are rare in functional psychoses and a general disruption of integrated personality functioning is characteristically present. The discussion here will be limited to several of these drugs which have been studied intensively and which offer some clues as to normal and abnormal mental functioning. These are LSD, mescaline, bufotenine, adrenochrome, and adrenolutin.

Lysergic Acid Diethylamide (LSD). When taken by mouth in minute quantities (100 to 200 pg), LSD causes marked changes in behavior and experience in most subjects. It contains the familiar indole nucleus (Fig. 3). Its relationship to serotonin has already been mentioned. The substance is rapidly metabolized but its behavioral effects persist for many hours after its apparent disappearance from the body, an observation not yet explained.

Mescaline. Mescaline was one of the first psychotomimetics used experimentally, the pure alkaloid being isolated in 1894. It produces effects similar to LSD but higher dosages are required (0.5 to 1 gm.). Also it produces more autonomic disturbances such as tachycardia, mydriasis, and temperature rise. Mescaline bears some structural similarity to norepinephrine (Fig. 3), another suggestion that a disturbance in epinephrine metabolism may be involved in some functional psychoses by the production of a toxic catechol amine.

Bufotenine, Adrenochrome, and Adrenolutin. The psychotomimetic properties of bufotenine have been described by Fabing and Hawkins (18). Those of adrenochrome and adrenolutin, and their possible relation to epinephrine metabolism, have been described by Hoffer and his associates (39).

Probably the greatest source of interest in psychotomimetics derives from the possibility of learning something of the etiology or pathogenesis of naturally occurring psychoses by studying the biochemical, neurophysiologic, and behavioral changes induced by these drugs. Of course, implicit in this search is the assumption that the biologic mechanisms by which these substances bring about their behavioral effects are related to those operating in psychoses. This aspect of psychotomimetics will be developed in the next section.

Other uses of psychotomimetics have been recommended and explored to some extent. Efforts have been made to develop new methods of treating naturally occurring psychosis by first studying their effects on the more labile symptoms induced by psychotomimetics. They have been used also as an adjunct to the psychotherapeutic treatment of patients with schizophrenia and other disorders. In some cases they appear to facilitate the recall of emotionally important memories (62).

Psychotomimetics have been recommended also for the exploration of experience in general, without any specific medical interest. This use of psychotomimetics, with its implications for philosophy, religion, and aesthetic experience, has been written about by men of letters such as Aldous Huxley (40, 41).

The possibility that some psychotomimetic drugs, like LSD, exert their effects by the competitive inhibition of neurohormones like serotonin and norepinephrine has been mentioned previously. This hypothesis gains support by the observation that LSD readily crosses the blood-brain barrier, has some structural similarity to serotonin, and is a powerful inhibitor of serotonin in in vitro studies. It should be pointed out, however, that there are compounds structurally similar to LSD and inhibitors of serotonin in vitro which do not produce mental aberrations (16). Another clue is provided by the observation that chlorpromazine and reserpine, both potent tranquilizer drugs used in the treatment of schizophrenia and related disorders, as well as serotonin, are in vitro inhibitors of the metabolism of LSD (5).

In vitro studies with LSD have also provided clues as to its biochemical mode of action. Illustrative of these methods is that of Mayer-Gross, McAdam, and Walker (47). They report that LSD causes an increase in blood hexose monophosphate, presumably an antienzymatic property of LSD which prevents the complete metabolism of this sugar. They suggest that related changes in carbohydrate metabolism may bring about a mental aberration with LSD administration and may point to a similar mechanism in schizophrenia. Alterations in carbohydrate metabolism have been implicated by other investigators as playing a role in the pathogenesis of schizophrenia.

The structural similarity of serotonin and bufotenine is striking (Figs. 2 and 3). Further evidence for the importance of a bufotenine-like compound in the biochemistry of psychosis is provided in a recent report by Fischer and his associates (22), who recovered bufotenine from the urine of 14 out of 15 chronic schizophrenics, none being recovered in 10 nonpsychotic control subjects. Further, an enzyme has recently been reported by Axelrod (4) in rabbit lung which N-methylates serotonin to bufotenine.

Mescaline has an indole-like structure but is more closely related to norepinephrine (Figs. 3 and 4). Psilocybin, a potent psychotomimetic, is closely related to serotonin and bufotenine (Fig. 3).

Another approach to the problem of the behavioral effects of psychotomimetics is their effect on cerebral electrophysiology. Thus, Marazzi and Hart (45) report that LSD and mescaline, as well as epinephrine, have an inhibiting effect on synaptic transmission. They report also that some tranquilizing drugs, such as chlorpromazine and reserpine, protect against this inhibitory effect. Serotonin also has an inhibiting influence. ACh would have a contrary action as a possible chemical mediator of nervous impulses at the synapse. They hypothesize that mental aberration may be related to imbalance between inhibitory and excitatory neurohumors in the brain. The action of psychotomimetics such as LSD and mescaline and of such tranquilizers as chlorpromazine and reserpine might have their effect by their action on these systems.

BRAIN METABOLISM, SERUM PROTEINS, ANDABNORMAL MENTAL FUNCTIONING An approach to the biochemical bases of behavior which has immediate relevance to clinical medicine and psychiatry is the search for metabolic abnormalities in mental illnesses. Specific biochemical lesions have not been identified in the most common psychiatric disorders such as schizophrenia. However, specific etiologic abnormalities have been identified in a few instances, as in phenylpyruvic oligophrenia.

The role of genetic factors in this form of mental deficiency was mentioned in Chapter 1. It is now known that the genetically determined defect in this disorder is the absence of an enzyme to metabolize the amino acid, phenylalanine, to tyrosine (Fig. 6). As a result, phenylalanine levels of the blood rise. In addition, phenylpyruvic acid is formed and appears in the blood and urine where it is not normally found. Associated with these biochemical abnormalities is the development of mental deficiency, seizures, and skin lesions. A causal inference is supported by the observation that elimination of phenylalanine from the diet of individuals afflicted with this disease sometimes arrests the usual progression of the mental changes and reverses other symptoms such as the rash. In addition, experimental animals fed diets high in phenylpyruvic acid develop severe, diffuse brain damage (68).

Although such clear-cut metabolic abnormalities have not been demonstrated in most mental disorders, biochemical alterations have been identified in various psychiatric conditions. These alterations suggest that chemical factors may play an etiologic or pathogenetic role in these conditions and provide clues to their nature. Exemplary of these relationships are reports of Gottlieb, Frohman, and their colleagues of alterations of glucose metabolism in schizophrenia (24, 25, 30, 31). They report a factor in the plasma of schizophrenics, probably a globulin, which interferes with energy production from glucose. The differences are sufficient to enable these investigators to separate plasma specimens of schizophrenics from normal control subjects on a blind basis (25). These findings are especially provocative since the brain depends very heavily on the metabolism of glucose for its energy supply. Differences have been reported also in other aspects of energy transfer in schizophrenics, as, for example, the rate of turnover of phosphorus in ADP and ATP in red blood cells (11).

Another approach has been the distribution of serum proteins in mental disturbances. By ultracentrifugation technics, Fessel and Grunbaum (21) found elevated macroglobulin in acutely disturbed patients. Related to this, perhaps, is the frequently reported elevation of plasma globulins in schizophrenia and other disorders as determined by electrophoresis (20). These reports suggest that plasma protein factors occur somewhere in the pathogenetic chain of events in some mental illnesses. However, the specificity of these changes and their significance must yet be elucidated since similar biochemical alterations have been reported in a wide variety of physical illnesses.