No drug group has been the subject of more controversy and confusion in this century than the class of drugs referred to as “hallucinogens” or “psychedelics.” Each of these terms implies a different orientation to the effects, actions and significances of these drugs on the part of those who have used them and written about them. Different factions have named them for what they see as their defining traits: for causing a temporary and artificial psychosis (psychomimetics), for producing an analog of a transformative mystical experience in which the divine is recognized directly (entheogens), or for provoking an interruption of habitual psychological functioning which allows self-generated modification of patterns of behavior, and reorganization of feelings and thoughts (psycholytics) (Calabrese 1994; Strassman 1995; Clark 1985; Walsh 1982; Silverman 1976; Zinberg 1976; Zaehner 1972; Kurland et al. 1971, 1967; Louria 1966; Cohen 1964, 1960). The medical literature most frequently refers to them as hallucinogens, and the lay press as psychedelics (a term coined by Humphrey Osmond indicating “manifesting the mind”).

For three decades, these substance have been marginalized by mainstream medicine and psychiatry and trivialized by the media and conventional opinion. Once the cutting edge of brain/mind research, the laboratory study of hallucinogens during the 1950s and 1960s had made strong contributions to the foundation for much of what became modern neurotransmitter theory. In clinical settings, investigators had begun to identify an inherent capacity for healing and transformation that was catalyzed by hallucinogens under certain conditions, and that appeared to alleviate many disabling symptoms in patients who had been unresponsive to conventional treatments. Cultural upheaval, however, disrupted the natural progression to formal and rigorous investigations of the myriad properties of hallucinogenic drugs and plants. During a time of radical political and social polarization, in large part catalyzed by an unpopular and divisive war in Southeast Asia, hallucinogens had become identified with a highly visible and controversial counter-culture. The properties and effects of these very unusual chemical compounds (known popularly as psychedelics) were exaggerated and distorted by the press. Psychiatrists and educators expressed fears that an entire generation of unsupervised psychedelic experimenters would drop out of their social responsibilities (thus threatening the fabric of society) or become permanently impaired (Louria 1968). Concerned social and behavioral scientists had to decide whether to unleash the unknown power of these substances, or to retreat from this line of research and ignore their potential value in exploring the nature of the mind, understanding mental illness and developing new treatment modalities. Finally support for research was withdrawn, and the force of law was used to restrain use of these substances.

For many years the rigorous study of hallucinogens was neglected. Research was either stopped or placed on interminable hold. The notion that hallucinogens could be used to facilitate healing was banished from psychiatric and medical discourse, while increased attention was given to the dangers of unsupervised use. In contrast to aboriginal societies, where elders ensured safeguards and facilitated young initiates’ entry into shamanic realms of nonordinary consciousness, young people in contemporary Euro-American culture often took hallucinogens within the context of high risk, unstructured and unsupervised settings and combined them with alcohol and other drugs (Dobkin de Rios & Grob 1994; Grob & Dobkin de Rios 1992).A lack of objective information about hallucinogens and their use deprived them of knowledge of how to safely structure use and minimize risk. Enthusiasm over the potential of hallucinogens to induce positive states of change had been replaced by apprehension that they were instead serious hazards to public health.

After more than twenty-five years of stasis and restricted vision, however, the study of hallucinogen has recently started to show signs of revival. By the mid-1990s federal regulatory agencies had approved several studies designed to examine basic physiological and central nervous system effects in human subjects, ending a decadeslong hiatus in this program of research (Mash et al. 1998; Grob et al 1996b; Strassman, Qualls & Uhlenhuth 1994). Quietly and with little fanfare, investigators and scholars in Europe and the United States have begun to consider the possible salutary effects of these long-forgotten plants and synthetic compounds, and the need for careful, sanctioned evaluation. The old clinical research records are now being subjected to renewed scrutiny, and their methods and conclusions, as well as their unexplored potentials, are being openly discussed. Greater respect is also being accorded to the technologies and ancient wisdom of indigenous peoples with long traditions of experience with hallucinogenic plants. As the century draws to a close, the long-repudiated and taboo area of hallucinogen studies is once again being opened to critical examination. For the potential of the hallucinogens to help us learn about human consciousness, psychopathology and the development of new treatment paradigms to be realized, however, it is essential that contemporary investigators learn from the problems of the past (Grob 1994). Only in this way will the clinical and political difficulties be overcome, allowing us to fully explore the innate potentialities of these substances to aid us in the challenges we and our descendants will face in the new century and beyond.

The establishment of a comprehensive multidisciplinary knowledge base on these substances is an essential step to furthering understanding of both their potential and their risks. This issue of the Journal of Psychoactive Drugs brings together a collection of articles addressing key questions concerning the nature and potential uses of hallucinogens. The relevance of shamanistic belief systems and technologies to our own evolving understanding of this unique phenomenon is explored, along with explanations of how modern neurobiological science conceptualizes their mechanism of action. The extensive research on the use of hallucinogens to treat alcoholism, accumulated during an early era of sanctioned investigation, is critiqued in order to assess the relative value of knowledge accrued during that period, and to suggest future investigations utilizing contemporary research methodologies which will address the as-yet unanswered questions. It is time for a renewal of the long-suppressed interest in the extraordinary range of effects this class of biochemical compounds may induce, and the establishment of a new program of scientific research dedicated to exploring this rich and largely untapped area of investigation. The articles presented in this issue of the Journal of Psychoactive Drugs are a contribution to that effort.

There is archeological evidence of thousands of years of plant hallucinogen use. Shamanic societies throughout prehistory have utilized a variety of technologies, including ethnobotanical, to induce altered states (Schultes & Hofmann 1992); but with the inexorable encroachment of dominant Euro-American culture, the numbers of native peoples still able to practice the ways of their ancestors have dwindled. Anthropological investigation of the botanical preparations, rituals and belief systems of those remaining practitioners of the ancient arts are invaluable in grasping the full breadth of experience encountered in these shamanic realms. Glenn Shepard’s study of hallucinogenic plants used by the Matsigenka tribe of the southeastern Peruvian rainforest provides new evidence of the centrality of these botanically inspired visionary compounds to the aboriginal world view. The primary role of these psychoactive plants is to facilitate harmonious relationships within the social community and with the world of the spirits. Examination of Matsigenka ethnopsychiatry provides an illustrative example of the use of psychoactive plants for healing and for optimizing collective and individual function.

Since the discovery of synthetic hallucinogens and the rediscovery of their plant sources in the middle of this century, efforts have been made to apply their properties within psychotherapeutic models. Ralph Metzner has been one of the pioneers in this field. Trained at Harvard by the iconoclastic Professors Leary and Alpert, Metzner over the past thirty-five years has become one of the most prolific and articulate investigators and scholars of hallucinogenic experiences. Exploring models of both hallucinogencatalyzed psychotherapy and shamanism, Metzner has identified profound differences between their underlying world views and assumptions about the nature of reality. The realization that the fundamental mystical experience induced by these compounds transcends the materialistic ego-bound consciousness of contemporary EuroAmerican culture makes the importance of the metaphysical world view of the shaman to understanding and navigating these states clear. An understanding of the role of ritual structure, setting and intention in plant shamanism provides a time-tested model that optimizes safety and efficacy; such knowledge may be useful in designing future hallucinogen-facilitated psychotherapy.

During the 1950s and until the mid-1960s, research investigations of hallucinogenic drugs were viewed with considerable enthusiasm and support by some members of the psychiatric profession. Seen as windows into the mind, these drugs were increasingly credited with providing valuable clues to the evolving understanding of brain function and mental disturbance. Working in Czechoslovakia, psychiatrist Stanislav Grof was one prominent researcher of that era who supervised thousands of experimental hallucinogen sessions. Invited to work in the United States by the Chairman of Psychiatry at Johns Hopkins Hospital, Grof relocated his hallucinogen research program to Spring Grove State Hospital in Maryland, where he continued to administer experimental treatments into the 1970s to diverse patient groups that included alcoholics, narcotic addicts and individuals with terminal medical illness (Grof 1980; Grof & Halifax 1977). Following termination of his hallucinogen research program, Grof shifted his focus to nondrug techniques for inducing altered states of consciousness. From his forty years of experience as a respected consciousness researcher, Grof has evolved an important and novel theory challenging not only the fundamental belief systems of mainstream psychiatry, but the very philosophical assumptions of materialistic science as well. Identifying the capacity of integrative holotropic states to induce intrinsic healing forces within the organism, Grof has called for open dialogue on the meaning and heuristic value of the transpersonal, holotropic perspective. The implications of this challenge to current psychiatric and psychological theories are considerable and point to the need for a committed program of objective, well-controlled investigations into the nature of holotropic, nonordinary states of consciousness and the technologies which induce them.

An additional challenge to psychiatry comes from the field of neuroscience investigation. Although quietly acknowledged for having provided valuable clues in the development of basic neurotransmitter theory (Freedman 1986), particularly that involving serotonin systems, hallucinogens were ultimately repudiated as therapeutic agents in humans following the dissolution of research programs three decades ago. One of the few types of anecdotal accounts to have persisted in penetrating the medicalpsychiatric literature has been case histories of individuals with refractory obsessive-compulsive disorder who had successfully treated themselves with serotonergically active hallucinogens. Pedro Delgado and Francisco Moreno have proposed a psychobiological mechanism of action involving the effects of hallucinogens on serotonin subsystems which ameliorate symptoms by altering the underlying neural substrate of obsessive-compulsive disorder. Given the severity of the disorder and its accustomed resistance to conventional treatments, a formal, methodologically controlled clinical investigation of hallucinogen administration as treatment for obsessive-compulsive disorder would appear warranted. Delgado and Moreno express understandable concern, however, over the potential risks of hallucinogens causing serious adverse effects. Since the onset of widespread unstructured use of hallucinogens in the 1960s, clinical medicine and psychiatry have been replete with reports of individuals sustaining significant psychological injury as a result of unwise self-administration. Comprehensive retrospective reviews of closely monitored research investigations have suggested, however, that when proper attention is given to ensuring optimal safety parameters, the risk of long-term damage to human subjects is significantly limited (Strassman 1984; Cohen 1960). The treatment of obsessive-compulsive disorder with serotonergically active hallucinogens provides a model for the impartial and dispassionate risk/benefit analysis in which modern medicine and psychiatry must engage to reinvest themselves of this long-neglected field of study.

Bridging the gulf between the worlds of modern medical psychiatry and prehistoric plant shamanism has been the Hoasca Project, a series of pilot research investigations exploring the physiological, central nervous system and psychological effects of the prototype tropical rain forest hallucinogen concoction, ayahuasca (Callaway et al.1998; McKenna, Callaway & Grob 1998; Callaway et al 1996; Grob et al. 1996; Callaway et al. 1994). Conducted in the Brazilian Amazon city of Manaus, standard Phase 1 evaluations of the short and long-term effects of ayahuasca on experienced users were conducted by an international team of investigators. Significant findings of these pilot investigations have included evidence of healthy psychological and physical function in the ayahuasca-using subjects, as well as the identification of upregulated serotonin systems which may be the neurobiologic substrate responsible for the positive clinical changes in ayahuasca users observed by these researchers. Use of ayahuasca has rapidly increased during the final decade of the 20th Century; in large part it is attributable to the success of the syncretic ayahuasca churches of Brazil. Since 1987, the use of ayahuasca in Brazil has been legal when utilized within the context of religious ceremony. Although considerable enthusiasm exists for ayahuasca’s potential to induce profound salutary effects when used appropriately, sufficient formal study has not as yet been undertaken to establish clear safety parameters. The article by James Callaway and Charles Grob presented in this issue identifies one potential risk, the interaction between ayahuasca and the selective serotonin reuptake inhibitor (SSRI) class of antidepressants. Given the vast numbers of individuals taking SSRIs around the world, knowledge of the mechanism of the serotonin syndrome induced by an ayahuasca/SSRI interaction, a serious and on occasion life threatening condition, should be understood by religious practitioners as well as those planning to conduct investigations in the field. A comprehensive understanding of potential risks of ayahuasca and other hallucinogens will facilitate the development of effective models for safe and efficacious research investigation and clinical use.

Questions of safety also achieve levels of critical importance in the case of the phenethylamine MDMA (3,4-Methylenedioxymethampetamine). Touted in the 1980s as a promising psychotherapeutic tool with clear advantages over classical hallucinogens, MDMA’s putative clinical applications were never subjected to rigorous methodologically controlled trials because of concerns raised over possible neurotoxic brain damage (Grob & Poland 1997). Although the overall evidence for human neurotoxicity of MDMA has remained tentative, the controversy has inhibited the institution of formal research programs designed to test its clinical utility. Recent progress has been made, however, with the completion of standard Phase 1 testing in normal volunteers (Grob et al. 1996b). In anticipation of the eventual clearance for treatment studies, further examination of MDMA’s unique range of action and the structures designed to optimize safety and efficacy of therapeutic use is necessary. George Greer and Requa Tolbert, veteran MDMA therapists from that period prior to the drug’s scheduling, provide valuable insight into the process of developing a safe and effective model for treatment.

For hallucinogenic drug researchers of today, poised on the threshold of what may possibly be a revived era of sanctioned clinical research investigations into the potential therapeutic effects of hallucinogens, it will be essential not to neglect the lessons of past research. From 1950 to the mid-1960s, over 1,000 professional papers were published in the clinical psychiatric literature in Europe and the United States describing the treatment of an estimated 40,000 patients with hallucinogens (Grinspoon & Bakalar 1979). Although methodologies employed were primitive by modern standards, and studies were often encumbered by investigators with preestablished beliefs concerning treatment outcome, much can be learned by scrutinizing the written record. Maria Mangini has undertaken the task of examining the history of the program of clinical research of alcoholism treatment with hallucinogens. In an article that is a model for conducting meticulous review and critique of prior investigations into the putative applications of hallucinogens, Mangini has concluded that in spite of ardent outspoken advocacy on both sides of the issue, neither efficacy nor failure of the experimental treatment had been proven.

In an article that corroborates Mangini’s assessment of the general lack of rigor in much of the early psychedelic research, Rick Doblin reviews the Concord Prison Experiment conducted by Timothy Leary, Richard Alpert and Ralph Metzner during the 1960s. Ralph Metzner’s thoughtful reply to Doblin’s critique provides a personal insight into the methods of these early researchers, and into the way that what he describes as a “halo effect” shaped the interpretation of their findings.

As efforts begin to reopen psychedelic research in an environment somewhat less fraught with media sensationalism and professional vacillation, there is hope that the application of state-of-the-art research methodologies to this neglected area of investigation will allow the question of the hallucinogens’ capacity to facilitate healing to be reexamined in an atmosphere of objectivity by contemporary researchers.