The Psychotomimetic Drugs: An Overview

    Jonathan O. Cole, M.D. & Martin M. Katz, PH.D.*

        from: Journal of the American Medical Association, Vol 187, No. 10, March 7, 1964

note: The criticisms expressed in the following paper, relatively typical of those workers whose establishment opinions helped to bring on the current era of Prohibition, are answered by Humphrey Osmond and Abram Hoffer in their 1967 book, The Hallucinogens. An excerpt from that book dealing with the Cole And Katz criticisms can be found in this library.

    For many years several pharmacologically similar drugs—lysergic acid diethylamide (LSD-25), psilocybin, and mescaline, among others—have been of special scientific interest. In volunteer subjects, they have been known to produce a variety of intense and unusual psychic effects. These include bizarre visual phenomena, ranging from heightening of the apparent brightness or beauty of colored objects in the environment, through distortions in the perceived nature or meaning of real objects (illusions) to true visual hallucinations of colors, shapes, or even of complex scenes or events. These visual phenomena are usually accompanied by intense and often rapidly shifting emotional experiences (ranging from mild apprehension to panic, severe depression or mystical elation) or by concurrent emotions (such as depression and joy) which are not experienced simultaneously under ordinary conditions. Subjects describe changes in body image, the body or its parts appearing larger or smaller, intense feelings of depersonalization, including states in which the subject believes he is outside his own body viewing it from afar, or even sensations of death and rebirth.
    Occasionally there may be loss of insight into the drug-induced nature of these sensations, with paranoid delusions about other people in the environment who are believed to be trying to harm or kill the subject. Intense self-loathing with suicidal impulses or great feelings of mystical revelation can also occur. Distortions in experiencing passage of time and, more rarely, disorientation as to time and place can occur. The exact quality, nature, and content of these experiences appear to depend in a complex manner on the personality and expectations of the subject, the dose of the drug, and the setting in which the drug is administered (1, 2).
    Particularly since the synthesis of LSD-25 in 1943, there has been intense scientific interest in the possibility that these agents reproduce naturally occurring schizophrenic states. After twenty years of research, it seems most reasonable to state that these drugs can produce a state which is similar but not identical to naturally occurring schizophrenia, and which may also resemble the toxic deliria caused by other agents such as atropine or scopolamine. Since subjects acquire tolerance to LSD, psilocybin, and mescaline after repeated administration (3-6), the possibility that such compounds are of etiological significance in naturally occurring schizophrenia seems remote.
    Because of the assumed similarities of the state produced by these agents to schizophrenia, they have been termed "psychotomimetics" or mimickers of psychosis. Even less accurately, because of the visual effects, they have been termed, "hallucinogenics." These names reflect a careful scientific concern with potentially dangerous, though unique drugs. More recently Osmond (7) has coined a term, "psychedelic," meaning "mind manifesting," which has begun to be used widely. Its implications are certainly more vague than those of the other terms. In the contexts in which it is used, it seems to imply that these drugs bring to the fore aspects of the subject's mind previously hidden or at least less manifest, and suggests that these effects may be "good." Assuredly, many investigators believe that the effects of these drugs result in an intensity of personal experience and emotion more meaningful than the terms "psychotomimetic" or "hallucinogenic" imply.
    Therein lies the present problem in the use or abuse of these agents. Rather than being the subject of careful scientific inquiry, these agents have become invested with an aura of magic, offering creativity to the uninspired, "kicks" to the jaded, emotional warmth to the cold and inhibited, and total personality reconstruction to the alcoholic or the psychotherapy-resistant chronic neurotic. On the West Coast, the effects are judged by some to be related to the insights of Zen Buddhism; on the East Coast, they are judged by others to lead the way to a new and free social order. Like the broom in "The Sorcerer's Apprentice," the drugs seem to have walked out of the laboratory into the outside world on their own feet and to have turned on the unsuspecting apprentice.
    To be sure, the therapeutic uses of these agents have been pioneered by psychiatrists in many instances, including Abramson (8), Frederking (9), Osmond (7), Savage (10, 11), and Sandison (12, 13). With much of the published work, however, there is an implicit or explicit attitude that the self-knowledge of the leverage for self-change allegedly effected by these drugs may be of value or benefit to individuals who do not ordinarily consider themselves psychiatrically ill. At the extreme of this attitude-dimension is the International Foundation for Inner Freedom, formed by two psychologists, Doctors Leary and Alpert, who claim that these agents (14) should not be considered drugs at all but should be classed with poetry, music, literature, and art, and should be available to all men wishing to improve their minds and "expand their consciousness." There is, apparently, an active black market in these drugs in major urban centers, where these drugs may have more snob appeal than diacetyl morphine (heroin), marihuana, or dextroamphetamine.
    Major attention has been focused on these drugs, their effects, and the personal eccentricities and misadventures of the more notorious people advocating their use by a series of articles in national popular magazines—Look (14), The Reporter (15), Cosmopolitan (16), Time (17), the Saturday Evening Post (18), and the Ladies' Home Journal (19). As with other forms of illicit drug abuse, it is hard to tell the real extent or seriousness of the psychotomimetic problem, despite this rather florid publicity.
    The present article has two purposes: first, to underline the real and important dangers inherent in the self-administration of these agents or in their administration by uncritical enthusiasts and inadequately trained individuals; second, to stress that some of the therapeutic claims made for these drugs are of sufficient potential importance to warrant serious, unprejudiced study.

Psychotomimetic Agents as Therapy

    We take the second issue first, since the first issue has already been outlined above. There have been an increasing series of studies reporting LSD-25 and/or mescaline to be effective in the treatment of chronic alcoholism, with remission rates of approximately 50 percent being usually described (20-25).
    Similar results have been observed in the treatment of chronic neuroses (9, 10-13, 26, 27). The claims for the utility of these drugs in the treatment of chronic neuroses range from dramatic improvement to modest descriptions of improved communication with the therapist, emotional release, and ability to talk about difficult personal topics. There have also been informal claims that these drugs are useful in producing valuable personality changes in juvenile delinquents and other individuals with serious personality disorders.
    In brief, it is claimed that these agents are of striking value in some groups of patients who are highly resistant to more conventional forms of psychotherapy or pharmacotherapy. Many of these claims stress, further, the occurrence of basic changes in attitudes or personality, not mere symptom reduction. If these claims are confirmed, this new therapeutic approach could add substantially to the psychiatrist's tools. We must stress that none of these claims are based on detailed, carefully controlled studies designed to be free from possible distortions due to bias or enthusiasm. Further, the terms in which the effects are often explained are not formulations common either to medicine in general or to psychiatry in particular. "Our own conception is that people live an inauthentic existential modality (i.e., alienation), and that illness arises from an inability to see meaning in life. LSD provides an encounter which brings a sudden liberation from ignorance and illusion, enlarges the spiritual horizon and gives a new meaning to life" (11).Such explanations may have a mystical or philosophical sound which appeals to the enthusiast, but they are likely to produce doubt or even violent disbelief and concern in physicians used to a more pragmatic approach and in scientists used to a more communicative language. The present authors occupy a skeptical middle position, favoring the Scotch verdict of "not proven." We feel strongly that this approach to therapy should neither be rejected out of hand as "crazy," nor accepted and applied in an uncritical manner, but should be subjected to careful study under closely controlled conditions.
    It is important also to note that the "treatment" discussed above is not a drug therapy in the conventional sense. It is, rather, a complex mixture of drug therapy and brief psychotherapy, with one or more prolonged sessions, lasting eight to ten hours, during which the patient experiences the drug effect and discusses his experiences and the light they throw on his problems, needs, and past experiences in a prolonged and intensive manner. The drug session is usually preceded by several interviews in which the patient's problems and the changes he desires from treatment are explored, a relationship with the therapist is established, and strong positive expectations concerning the drug session are developed. The treatment, as administered by many, seems to include strong suggestion, aspects of dynamic insight-oriented psychotherapy, mystico-religious exhortation, catharsis, and pressure on the patient to confront his problems head on. It is possible that with all these components the intense and bizarre drug experience may indeed permit an impact on the subject not obtainable by any other means. It is difficult to break down the therapeutic process into its component parts. The proportions of the components may vary from therapist to therapist or from patient to patient, especially with regard to the amount of therapist interpretation and the extent of his active participation in the solution of the patient's problems.
    When this treatment is given in a hospital setting, there is also considerable personal interaction between the individual patient and other patients who have already undergone this experience or are about to undergo it. The whole milieu has an aura of intense conviction that change will occur and that the experience will be highly meaningful and highly therapeutic. Intensive group therapy sessions may occur before and after the actual LSD experience. The entire therapeutic process, including preparation for the psychotomimetic experience and subsequent reinterpretation of it, may resemble the group interaction common to successful experience with Alcoholics Anonymous. It may resemble also the intense personalinteraction used at the National Training Laboratory, at Bethel, Maine (16), where revelations and emotional experiences are created by intensive interpersonal and group interaction alone, without the aid of any drug.

Problems in Evaluation

    This form of treatment is, therefore, highly intense and highly complex, necessitating strong convictions and great sensitivity on the part of the therapist, and requiring the creation of a social milieu in which all patients not only share in a strong conviction that change will occur but also hold a personal commitment to make certain that change does occur. Dramatic short-term effects under such conditions have been described. The durability on prolonged follow-up study of acute changes in behavior, induced by therapy or perhaps even changes in personality, is yet to be determined.
    Several problems face investigators who wish to make careful studies of such a complex treatment. It seems likely that people who administer the treatment effectively must be convinced of its efficacy. Further, they must be highly biased in favor of it for the treatment to have the described effect. The physician may be so involved in the treatment that he can not evaluate its effects objectively. Independent evaluation of outcome is, therefore, essential to any good research design in this area. This independent procedure should make it easier to evaluate the efficacy of treatment in a condition like chronic alcoholism where an objective index of success or failure, namely, excessive drinking, exists.
    A much more complex problem must be faced in evaluating the effects of these drugs on individuals with personality disorders, severe or mild. Here a value judgment must be made concerning the goodness or badness of the changes which occur, if any. For example, how should one evaluate outcome if an individual were to divorce his wife and take a job which paid him less but which he said he enjoyed more than his previous job? If a person becomes more relaxed and happy go lucky, more sensitive to poetry or music, but less concerned with success or competition, is this good? There are suggestions that individuals who take drugs like LSD either illicitly or as therapy may become more detached from reality or less concerned with the real world, more "transcendental." A few of the reports concerning this treatment, both published and unpublished, mix a variety of poetic metaphors and occasionally bizarre-sounding elaborations with serious descriptions of the details of treatment and the valuable changes to be expected. For example, certain kinds of artistic experience, certain types of music, etc., are said to be particularly valuable in inducing the desired effects. Specific components of the therapeutic process described may often have a bizarre—almost schizophrenic—component, which tends to make serious investigators discount this whole area as a delusional belief shared by a group of unstable clinicians and lay enthusiasts. Whether or not this criticism is justified can be judged only by future studies designed to be immune to such criticism. Future studies must decide whether these treatments do indeed have promise for specific clinical conditions which are now highly resistant to conventional psychiatric approaches.

The Current Situation

    At present a small number of facts are strikingly clear. None of these drugs has been proved to be effective or safe therapies for any psychiatric condition. Because of the apparent potential of these agents for producing bizarre behavior, suicidal impulses, or undesirable personality change in some subjects or patients receiving them (28, 29), there is some question as to whether they should be administered outside a hospital. They are not available for general prescription use, and there is some question whether they should ever be so available. Because neither their safety nor their efficacy has been adequately demonstrated, two of these agents, LSD-25 and psilocybin, are being controlled as investigational drugs in conformity with the existing Food and Drug Administration regulations under the sponsorship of the drug company which holds the patent rights for both substances. It is our understanding that this company is at present providing these agents for scientific study only to investigators functioning within federal or state agencies with formal approval of the agency, or to investigators doing research under ,rants from these agencies. This policy decision has been made presumably to insure that these drugs will not be misused by unqualified or unscientific investigators without adequate checks and balances necessary for safe and careful research. The other agent, mescaline, is not to our knowledge being sponsored currently by any pharmaceutical company, although it can be obtained for animal or biochemical research from certain biochemical supply houses.
    Legally none of these agents can be used, even on an investigational basis, except by investigators who have filed a formal research plan with the FDA through a sponsoring pharmaceutical company, or by investigators who have themselves assumed sponsorship and satisfied the FDA concerning the safety of the agents and their proposed research use in man. Any reported use of these agents outside of these approved channels should be reported to the FDA. Since there have been a number of reports of suicide attempts or prolonged psychotic reactions requiring psychiatric hospitalization in persons obtaining these drugs outside of approved medical channels, their indiscriminate unsupervised use is clearly dangerous. In addition, there have been reports of insidious personality changes occurring in individuals who have indulged in repeated self-administration of these agents. It is, of course, difficult to determine whether or not some of the bizarre behaviors of such individuals are a product of the drug itself or are a product of the underlying personality aberrations which lead the individuals to seek out these agents. In any case, there is no evidence that uncontrolled self-administration of these drugs is either safe or desirable. There has also been concern over the possibility that investigators who have embarked on serious scientific work in this area may have been subject to the deleterious and seductive effects of these agents.
    Thesee statements are made in hope that warranted concern over illicit abuse of these agents will not prevent systematic study of their possible potential in the treatment of psychiatric conditions which are otherwise severely treatment resistant.

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    * Dr. Cole is chief and Dr. Katz is research psychologist of the Psychopharmacology Service Center, National Institute of Mental Health, National Institutes of Health.